WO2010046780A2 - Anti viral compounds - Google Patents

Anti viral compounds Download PDF

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Publication number
WO2010046780A2
WO2010046780A2 PCT/IB2009/007420 IB2009007420W WO2010046780A2 WO 2010046780 A2 WO2010046780 A2 WO 2010046780A2 IB 2009007420 W IB2009007420 W IB 2009007420W WO 2010046780 A2 WO2010046780 A2 WO 2010046780A2
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WO
WIPO (PCT)
Prior art keywords
nmr
mhz
oxo
ethyl
carboxylate
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PCT/IB2009/007420
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French (fr)
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WO2010046780A3 (en
Inventor
Junwon Kim
Jonathan Cechetto
Zaesung No
Thierry Christophe
Taehee Kim
Ji Youn Nam
Wonyoung So
Mina Jo
Taedong Ok
Changmin Park
Min Jung Seo
Jeong-Hun Sohn
Peter Sommer
Annette Sophia Boese
Sung-Jun Han
Young Sam Park
Hwa Pyung Kim
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Institut Pasteur Korea
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Publication of WO2010046780A2 publication Critical patent/WO2010046780A2/en
Publication of WO2010046780A3 publication Critical patent/WO2010046780A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • anti-HIV small molecule anti-human immunodeficiency virus
  • HTS high throughput screening
  • HIV continues to be a serious worldwide health problem.
  • people continue to be infected with HIV and die due to AIDS.
  • 2007 alone 2.5 million people were infected with HIV and 2.1 million people died.
  • HIV remains a serious public health problem as there were 33.2 million people living with HIV in 2007 [2].
  • it is not all bad news as global rates of HIV infection have leveled off, and the number of deaths due to AIDS has decreased over the past few years [2]. This decrease coincides with the greater availability of antiretro viral therapy, particularly in sub-Saharan Africa where the highest rates of HIV infection and AIDS is found [2].
  • HIV belongs to the retrovirus family, which contain genetic information in the form of RNA.
  • HIV-I HIV-I is much more prevalent and is thought to have arisen from cross-species transmission of a chimpanzee virus to humans [3-5].
  • gpl20, gp41 viral envelope glycoprotein
  • CD4 and coreceptors such as CXCR4 or CCR5
  • the viral DNA enters the nucleus, where it is integrated to the genetic material of the cell by the viral enzyme, integrase.
  • the provirus creates the mRNA through the transcription and then it is translated into viral proteins.
  • the viral enzyme, protease is required to cut a viral polyprotein precursor into individual mature proteins.
  • the HIV proteins and HIVs RNA genetic material assemble at the cell surface into new virions, which then bud from the cell and are released to infect another cell [6,7].
  • HAART highly active antiretroviral therapy
  • HAART requires a strict adherence to the treatment protocol and can have severe side-effects [2].
  • Current anti-HIV drugs are active on only a few targets and stages of the HIV life cycle. Many current drugs act at the stages of viral fusion, reverse transcription and viral maturation. Novel anti-viral compounds that affect other stages of the viral life cycle would be a valuable addition to the anti-HIV armamentarium.
  • HIV targets eg. reverse transcriptase, protease
  • HIV targets eg. reverse transcriptase, protease
  • the cell based assay has the advantage of opening up every step of the HIV-I life cycle, and allows for identification of compounds that may inhibit viral and host cell proteins involved in HIV-I infection and replication.
  • a number of compounds that inhibit HIV-I infection of host cells were identified. These compounds belong to two structural classes, and their anti -HIV-I activity was confirmed and/or determined by dose response and p24 secondary assay.
  • A is selected from the group consisting of;
  • n 1, 2, or 3;
  • X is selected from the group consisting of NR 4 , O, or S;
  • Y and Z are independently selected from the group consisting of NR 4 , C, O, or S;
  • R 1 is selected from the group consisting of hydrogen, halogen, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 2 -C 10 alkenyl, C 3 -C 10 cycloalkenyl, C 2 -Ci 0 alkynyl, C 1 -C 10 haloalkyl, -OH, -OR 5 , C 1 -C 10 alkoxy, C 3 -Ci 0 cycloalkoxy, C 3 -Ci 5 cycloalkylalkoxy, C 3 -Ci 5 cycloalkylalkyl, -CN, -NO 2 , - NH 2 , -N(R 5 ) 2 , -C(O)R 5 , -C(O)OR 5 , -C(O)N(R 5 ) 2 , -SR 5
  • R 2 is each independently selected from the group consisting of hydrogen, halogen, C 1 -C 10 alkyl, C 3 -C 0 cycloalkyl, hydroxyl, -OR 5 , -CN, -NO 2 , -NH 2 , -N(R 5 )C(O)R 5 , -C(O)R 5 , - C(O)OR 5 , -C(O)N(R 5 ) 2> -S(O)R 5 , -S(O) 2 R 5 , -S(O) 2 N(R 5 ) 2 , aryl, benzyl, heteroaryl, heterocyclyl or two groups of R 2 are connected each other to make five or six membered cyclic and heterocyclic rings; each R 3 is independently selected from the group consisting of hydrogen, halogen, Ci-C 10 alkyl, C 3 -Ci 0 cycloalkyl, hydroxyl, -OR 5 , -CN,
  • R 4 is independently selected from the group consisting from hydrogen, Ci-C 10 alkyl, C 3 -C 10 cycloalkyl, C 2 -C 10 alkenyl, C 3 -C 10 cycloalkenyl, C 2 -C 10 alkynyl, C 1 -Ci 0 haloalkyl, -C(O)R 5 , - C(O)OR 5 , -C(O)N(R 5 ) 2, -S(O)R 5 , -S(O) 2 R 5 , -S(O) 2 N(R 5 ) 2 , aryl, benzyl, heteroaryl, or heterocyclyl;
  • R 5 is independently selected from the group consisting from hydrogen, Ci-Ci 0 alkyl, C 3 -Ci 0 cycloalkyl, C 2 -Ci 0 alkenyl, C 3 -Cj 0 cycloalkenyl, C 2 -Ci 0 alkynyl, Ci-Ci 0 haloalkyl, aryl, benzyl, heteroaryl, or heterocyclyl.
  • halogen including fluorine, Ci-Ci 0 alkyl, Ci-C 3 haloalkyl, C 3 -C 7 cycloalkyl, oxo, -OH, -OR 7 , -
  • R 7 is each independently selected from the group consisting of hydrogen, aryl, benzyl, heterocyclyl, Ci-C 8 alkyl, or C 3 -C 7 cycloalkyl;
  • R 8 , R 9 , R 10 and R 11 are each independently selected from the group consisting of hydrogen, halogen, C 1 -Ci 0 alkyl, C 1 -C 3 haloalkyl, C 3 -C 7 cycloalkyl, hydroxyl, oxo, -OR 12 , -C(O)OR 12 , -
  • R 12 is each independently selected from the group consisting of hydrogen, Ci-C 8 alkyl optionally substituted with at least one hydroxyl or halogen; C 3 -C 7 cycloalkyl, aryl; phenyl, benzyl, or heterocyclyl;
  • alkyl refers to a monovalent straight or branched chain, saturated aliphatic hydrocarbon radical having a number of carbon atoms in the specified range.
  • Ci-C 6 alkyl refers to any of the hexyl alkyl and pentyl alkyl isomers as well as n-, iso-, sec-, and t-butyl, n- and isopropyl, ethyl and methyl.
  • alkoxy means a group having the formula -O-alkyl, in which an alkyl group, as defined above, is attached to the parent molecule via an oxygen atom.
  • the alkyl portion of an alkoxy group can have 1 to 20 carbon atoms (i.e., C 1 -C 20 alkoxy), 1 to 12 carbon atoms (i.e.,
  • C 1 -C 12 alkoxy or 1 to 6 carbon atoms (i.e., C 1 -C 6 alkoxy).
  • suitable alkoxy groups include, but are not limited to, methoxy (-0-CH 3 or OMe), ethoxy (-OCH 2 CH 3 or -
  • alkenyl refers to a monovalent straight or branched chain aliphatic hydrocarbon radical containing one carbon-carbon double bond and having a number of carbon atoms in the specified range.
  • C 2 -C 6 alkenyl refers to all of the hexenyl and pentenyl isomers as well as 1-butenyl, 2-butenyl, 3-butenyl, isobutenyl, 1-propenyl, 2- propenyl, and ethenyl (or vinyl).
  • alkynyl refers to a monovalent straight or branched chain aliphatic hydrocarbon radical containing one carbon-carbon triple bond and having a number of carbon atoms in the specified range.
  • C 2 -C 6 alkynyl refers to all of the hexynyl and pentynyl isomers as well as 1-butynyl, 2-butynyl, 3-bytynyl, 1-propynyl, 2-propynyl, and ethynyl.
  • Alkylene refers to a saturated, branched or straight chain or cyclic hydrocarbon radical having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms.
  • Typical alkylene radicals include, but are not limited to, methylene (-CH 2 -), 1,1 -ethyl (- CH(CH 3 )-), 1,2-ethyl (-CH 2 CH 2 -), 1,1 -propyl (-CH(CH 2 CH 3 )-), 1,2-propyl (-CH 2 CH(CH 3 )-), 1,3-propyl (-CH 2 CH 2 CH 2 -), 1,4-butyl (-CH 2 CH 2 CH 2 CH 2 -), and the like.
  • alkenylene refers to an unsaturated, branched or straight chain or cyclic hydrocarbon radical having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of parent alkene.
  • an alkenylene group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms.
  • Alkynylene refers to an unsaturated, branched or straight chain or cyclic hydrocarbon radical having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of parent alkyne.
  • an alkynylene group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms or 1 to 6 carbon atoms.
  • cycloalkyl refers to a group, such as optionally substituted or non-substituted cyclic hydrocarbon, having from three to eight carbon atoms, unless otherwise defined.
  • C 3 -C 8 cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • haloalkyl refers to an alkyl group, as defined herein that is substituted with at least one halogen.
  • straight or branched chained “haloalkyl” groups useful in the present invention include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, and t-butyl substituted independently with one or more halogens.
  • haloalkyl should be interpreted to include such substituents such as -CHF 2 , -CF 3 , -CH 2 -CH 2 -F, -CH 2 -CF 3 , and the like.
  • heteroalkyl refers to an alkyl group where one or more carbon atoms have been replaced with a heteroatom, such as, O, N, or S.
  • a heteroatom e.g., O, N, or S
  • the resulting heteroalkyl groups are, respectively, an alkoxy group (e.g., -OCH 3 , etc.), an amine (e.g., -NHCH 3 , -N(CH 3 ) 2 , etc.), or thioalkyl group (e.g., -SCH 3 , etc.).
  • a non-terminal carbon atom of the alkyl group which is not attached to the parent molecule is replaced with a heteroatom (e.g., O, N, or S) and the resulting heteroalkyl groups are, respectively, an alkyl ether (e.g., -CH 2 CH 2 -O-CH 3 , etc.), alkyl amine (e.g., -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 , etc.), or thioalkyl ether (e.g., -CH 2 -S-CH 3 ).
  • an alkyl ether e.g., -CH 2 CH 2 -O-CH 3 , etc.
  • alkyl amine e.g., -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 , etc.
  • thioalkyl ether e.g., -CH 2 -S-CH 3
  • halogen refers to fluorine, chlorine, bromine, or iodine.
  • aryl refers to (i) optionally substituted phenyl, (ii) optionally substituted 9- or 10 membered bicyclic, fused carbocyclic ring systems in which at least one ring is aromatic, and (iii) optionally substituted 11- to 14-membered tricyclic, fused carbocyclic ring systems in which at least one ring is aromatic.
  • Suitable aryls include, for example, phenyl, biphenyl, naphthyl, tetrahydronaphthyl (tetralinyl), indenyl, anthracenyl, and fluorenyl.
  • phenyl as used herein is meant to indicate that optionally substituted or non- substituted phenyl group.
  • benzyl as used herein is meant to indicate that optionally substituted or non- substituted benzyl group.
  • heteroaryl refers to (i) optionally substituted 5- and 6-membered heteroaromatic rings and (ii) optionally substituted 9- and 10-membered bicyclic, fused ring systems in which at least one ring is aromatic, wherein the heteroaromatic ring or the bicyclic, fused ring system contains from 1 to 4 heteroatoms independently selected from N, O, and S, where each N is optionally in the form of an oxide and each S in a ring which is not aromatic is optionally S(O) or S(O) 2 .
  • Suitable 5- and 6-membered heteroaromatic rings include, for example, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thienyl, furanyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isooxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, and thiadiazolyl.
  • Suitable 9-and 10-membered heterobicyclic, fused ring systems include, for example, benzofuranyl, indolyl, indazolyl, naphthyridinyl, isobenzofuranyl, benzopiperidinyl, benzisoxazolyl, benzoxazolyl, chromenyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, isoindolyl, benzodioxolyl, benzofuranyl, imidazo[l,2-a]pyridinyl, benzotriazolyl, dihydroindolyl, dihydroisoindolyl, indazolyl, indolinyl, isoindolinyl, quinoxalinyl, quinazolinyl, 2,3-dihydrobenz
  • heterocyclyl refers to (i) optionally substituted 4- to 8-membered, saturated and unsaturated but non-aromatic monocyclic rings containing at least one carbon atom and from 1 to 4 heteroatoms, (ii) optionally substituted bicyclic ring systems containing from 1 to 6 heteroatoms, and (iii) optionally substituted tricyclic ring systems, wherein each ring in (ii) or (iii) is independent of fused to, or bridged with the other ring or rings and each ring is saturated or unsaturated but nonaromatic, and wherein each heteroatom in (i), (ii), and (iii) is independently selected from N, O, and S, wherein each N is optionally in the form of an oxide and each S is optionally oxidized to S(O) or S(O) 2 .
  • Suitable 4- to 8-membered saturated heterocyclyls include, for example, azetidinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, pyrrolidinyl, imidazolidinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl, hexahydropyrimidinyl, thiazinanyl, thiazepanyl, azepanyl, diazepanyl, tetrahydropyranyl, tetrahydrothiopyranyl, dioxanyl, and azacyclooctyl.
  • Suitable unsaturated heterocyclic rings include those corresponding to the saturated heterocyclic rings listed in the above sentence in which a single bond is replaced with a double bond. It is understood that the specific rings and ring systems suitable for use in the present invention are not limited to those listed in this and the preceding paragraphs. These rings and ring systems are merely representative.
  • n 1, 2, or 3
  • o 1, 2, or 3
  • A is C 5 -C 12 aryl or C 5 -Ci 2 heteroaryl
  • B, C, D and E are each independently selected from the group consisting of C(R 2 ), C(O), C(S),
  • each R 1 is independently selected from the group consisting of hydrogen, halogen, -CN, C 1 -C 5 alkyl, Cj-C 3 haloalkyl, , C 2 -C 5 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, hydroxyl, C 1 -C 8 alkoxy, -C(O)OR 3 , -C(O)N(R 3 ) 2 , aryl, oxo, -OH, -OR 3 , -OCH 2 R 3 , -R 4 CN, -NO 2 , -
  • each R 2 is independently selected from the group consisting of hydrogen, halogen, C 1 -C 5 alkyl,
  • each R 3 is independently selected from the group consisting of hydrogen, C 1 -C 8 alkyl, C 1 -C 3 haloalkyl, C 3 -C 7 cycloalkyl, C 1 -C 3 alkylaryl, aryl, benzyl, or; heteroaryl; each R 4 is independently selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 8 alkylene,
  • X and Y are each independently selected from the group consisting of -C(R 5 R 6 )-, -N(R 5 )-, -
  • R 5 and R 6 are each independently selected from the group consisting of hydrogen, halogen,
  • Z is selected from the group consisting of:
  • Aryl is C 4 -C 12 aryl and is optionally substituted; HetA and heteroaryl are C 3 -C 10 heteroaryl and are optionally substituted,
  • R 7 , R 8 , R 9 and R 10 are each independently selected from the group consisting of hydrogen, halogen, Ci-C 10 alkyl, Cj-C 3 haloalkyl, C 3 -C 7 cycloalkyl, hydroxyl, oxo, -OR 11 , -C(O)OR 11 , -
  • R 11 is each independently selected from the group consisting of hydrogen, Ci-C 8 alkyl optionally substituted with at least one hydroxyl or halogen; C 3 -C 7 cycloalkyl, aryl; benzyl, or heterocyclyl.
  • alkyl has the same meaning as defined above.
  • alkoxy has the same meaning as defined above.
  • alkenyl has the same meaning as defined above.
  • alkynyl has the same meaning as defined above.
  • Alkylene has the same meaning as defined above.
  • Alkenylene has the same meaning as defined above.
  • Alkynylene has the same meaning as defined above.
  • cycloalkyl alone or in combination with any other term, has the same meaning as defined above.
  • haloalkyl has the same meaning as defined above.
  • heteroalkyl has the same meaning as defined above.
  • halogen has the same meaning as defined above.
  • phenyl has the same meaning as defined above.
  • heteroaryl has the same meaning as defined above.
  • heterocyclyl has the same meaning as defined above.
  • the stereochemistry of general formula of I and II includes independently R or S as enantiomerically pure form or racemic mixtures.
  • Another embodiment of the present invention is compounds of general formula I and II, or pharmaceutically acceptable salts thereof. According to one aspect, there is provided a compound having one of the general formulas I to II, as defined above, as well as derivatives thereof for the treatment of viral infections.
  • HIV human immunodeficiency virus
  • said virus is selected from HIV.
  • said host cells are T cells or B cells or a hybrid thereof.
  • HIV human immunodeficiency virus
  • a compound listed in Figure 8A-F or Table 1 for the manufacture of a medicament for the treatment of viral infections.
  • a compound listed in Figure 8A-F or Table 1 for the manufacture of a medicament for the treatment of human immunodeficiency virus (HIV).
  • HIV human immunodeficiency virus
  • a pharmaceutical composition or combined preparation having synergistic effects against a viral infection and containing: (a) at least one compound listed in Figure 8 A-F or Table 1 , (b) (a) otionally one or more anti-viral agents, and (c) optionally one or more pharmaceutical excipients or pharmaceutically acceptable carriers,for simultaneous, separate or sequential use in the treatment or prevention of a viral infection.
  • Suitable anti-viral agents for inclusion into the synergistic antiviral compositions or combined preparations of this invention include, for instance, retroviral enzyme inhibitors belonging to categories well known in the art, such as HIV-I IN inhibitors, nucleoside reverse transcriptase inhibitors (e.g. zidovudine, lamivudine, didanosine, stavudine, zalcitabine and the like), non- nucleoside reverse transcriptase inhibitors (e.g. nevirapine, delavirdine and the like), other reverse transcriptase inhibitors (e.g. foscamet sodium and the like), and HIV-I protease inhibitors (e.g.
  • retroviral enzyme inhibitors belonging to categories well known in the art, such as HIV-I IN inhibitors, nucleoside reverse transcriptase inhibitors (e.g. zidovudine, lamivudine, didanosine, stavudine, zalcitabine and the like), non-
  • Suitable antiviral agents include for instance acemannan, acyclovir, adefovir, alovudine, alvircept, amantadine, aranotin, arildone, atevirdine, pyridine, cidofovir, cipamfylline, cytarabine, desciclovir, disoxaril, edoxudine, enviradene, enviroxime, famciclovir, famotine, fiacitabine, fialuridine, floxuridine, fosarilate, fosfonet, ganciclovir, idoxuridine, kethoxal, lobucavir, memotine, methisazone, penciclovir, pirodavir, somantadine, sorivudine, tilorone, trifluridine, val
  • Especially relevant to this aspect is the inhibition of the replication of HIV, in particular in human beings and other mammals such as primates.
  • nucleoside reverse transcriptase inhibitors e.g, tenofovir, didanosine and the like
  • non-nucleoside reverse transcriptase inhibitors e.g, efavirenz, delavirdine and the like
  • HIV-I protease inhibitors e.g. saquinavir, ritonavir, indinavir, nelfinavir and the like
  • HIV-I integrase inhibitors e.g, raltegravir and the like
  • HIV-I entry inhibitors e.g, maraviroc and the like
  • Synergistic activity of the pharmaceutical compositions or combined preparations of this invention against viral infection may be readily determined by means of one or more tests such as, but not limited to, the isobologram method, as previously described by Elion et al. in J. Biol. Chem. (1954) 208:477-488 and by Baba et al. in Antimicrob. Agents Chemother. (1984) 25:515-517, using EC 50 for calculating the fractional inhibitory concentration (hereinafter referred as FIC).
  • FIC fractional inhibitory concentration
  • the combination When the minimum FIC index corresponding to the FIC of combined compounds (e.g., FlC x +FIC y ) is equal to 1.0, the combination is said to be additive; when it is between 1.0 and 0.5, the combination is defined as sub-synergistic, and when it is lower than 0.5, the combination is by defined as synergistic. When the minimum FIC index is between 1.0 and 2.0, the combination is defined as subantagonistic and, when it is higher than 2.0, the combination is defined as antagonistic.
  • the pharmaceutical composition or combined preparation with synergistic activity against viral infection, especially HIV may contain at least one compound listed in Figure 8A-F or Table 1 over a broad content range depending on the contemplated use and the expected effect of the preparation.
  • the contents of the at least one compound listed in Figure 8 A-F or Table 1 in the pharamaceutical preparation is within the range of from 0.1 to 99.9% by weight, preferably from 1 to 99% by weight, more preferably from about 5 to 95% by weight.
  • compositions and combined preparations may be administered orally or in any other suitable fashion. Oral administration is preferred and the pharmaceutical composition or preparation may have the form of a tablet, aqueous dispersion, dispersable powder or granule, emulsion, hard or soft capsule, syrup, elixir or gel.
  • the dosing forms may be prepared using any method known in the art for manufacturing these pharmaceutical compositions and may comprise as additives sweeteners, flavoring agents, coloring agents, preservatives and the like.
  • Carrier materials and excipients are detailed hereinbelow and may include, inter alia, calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, binding agents and the like.
  • compositions or combined preparation of this invention may be included in a gelatin capsule mixed with any inert solid diluent or carrier material, or has the form of a soft gelatin capsule, in which the ingredient is mixed with a water or oil medium.
  • Aqueous dispersions may comprise the biologically active composition or combined preparation in combination with a suspending agent, dispersing agent or wetting agent.
  • Oil dispersions may comprise suspending agents such as a vegetable oil.
  • Rectal administration is also applicable, for instance in the form of suppositories or gels.
  • Injection e.g. intramuscularly or intraperiteneously
  • mode of administration for instance in the form of injectable solutions or dispersions, depending upon the disorder to be treated and the condition of the patient.
  • pharmaceutically acceptable carrier or excipient as used herein in relation to pharmaceutical compositions and combined preparations means any material or substance with which the active acomponent, , and optionally the additional antiviral agent, may be formulated in order to facilitate its application or dissemination to the locus to be treated, for instance by dissolving, dispersing or diffusing the said composition, and/or to facilitate its storage, transport or handling without impairing its effectiveness.
  • the pharmaceutically acceptable carrier may be a solid or a liquid or a gas which has been compressed to form a liquid, i.e. the compositions or preparations of the present invention can suitably be used as concentrates, emulsions, solutions, granulates, dusts, sprays, aerosols, pellets or powders.
  • Suitable pharmaceutical carriers for use in the said pharmaceutical compositions and their formulation are well known to those skilled in the art.
  • Suitable pharmaceutical carriers include additives such as wetting agents, dispersing agents, stickers, adhesives, emulsifying or surface-active agents, thickening agents, complexing agents, gelling agents, solvents, coatings, antibacterial and antifungal agents (for example phenol, sorbic acid, chlorobutanol), isotonic agents (such as sugars or sodium chloride) and the like, provided the same are consistent with pharmaceutical practice, i.e. carriers and additives which do not create permanent damage to mammals.
  • compositions may be prepared in any known manner, for instance by homogeneously mixing, dissolving, spray-drying, coating and/or grinding the active ingredients, in a one-step or a multi-steps procedure, with the selected carrier material and, where appropriate, the other additives such as surface-active agents. They may also be prepared by micronisation, for instance in view to obtain them in the form of microspheres usually having a diameter of about 1 to 10 ⁇ m, namely for the manufacture of microcapsules for controlled or sustained release of the biologically active ingredient(s).
  • Suitable surface-active agents to be used in the pharmaceutical compositions of the present invention are non-ionic, cationic and/or anionic surfactants having good emulsifying, dispersing and/or wetting properties.
  • Suitable anionic surfactants include both water-soluble soaps and water-soluble synthetic surface-active agents.
  • Suitable soaps are alkaline or alkaline-earth metal salts, unsubstituted or substituted ammonium salts of higher fatty acids (C 10-22 ), e.g. the sodium or potassium salts of oleic or stearic acid, or of natural fatty acid mixtures obtainable form coconut oil or tallow oil.
  • Synthetic surfactants include sodium or calcium salts of polyacrylic acids; fatty sulphonates and sulphates; sulphonated benzimidazole derivatives and alkylarylsulphonates.
  • Fatty sulphonates or sulphates are usually in the form of alkaline or alkaline-earth metal salts, unsubstituted ammonium salts or ammonium salts substituted with an alkyl or acyl radical having from 8 to 22 carbon atoms, e.g.
  • Suitable sulphonated benzimidazole derivatives preferably contain 8 to 22 carbon atoms.
  • alkylarylsulphonates include, but are not limited to, the sodium, calcium or alcanolamine salts of dodecylbenzene sulphonic acid or dibutyl- naphthalenesulphonic acid or a naphthalene-sulphonic acid/formaldehyde condensation product.
  • corresponding phosphates e.g. salts of phosphoric acid ester and an adduct of p-nonylphenol with ethylene and/or propylene oxide, or phospholipids.
  • Suitable phospholipids for this purpose are the natural (originating from animal or plant cells) or synthetic phospholipids of the cephalin or lecithin type such as e.g.
  • phosphatidylethanolamine phosphatidylserine, phosphatidylglycerine, lysolecithin, cardiolipin, dioctanylphosphatidylcholine, dipalmitoylphoshatidyl-choline and their mixtures.
  • Suitable non-ionic surfactants include, but are not limited to, polyethoxylated and polypropoxylated derivatives of alkylphenols, fatty alcohols, fatty acids, aliphatic amines or amides containing at least 12 carbon atoms in the molecule, alkylarenesulphonates and dialkylsulphosuccinates, such as polyglycol ether derivatives of aliphatic and cycloaliphatic alcohols, saturated and unsaturated fatty acids and alkylphenols, said derivatives preferably containing 3 to 10 glycol ether groups and 8 to 20 carbon atoms in the (aliphatic) hydrocarbon moiety and 6 to 18 carbon atoms in the alkyl moiety of the alkylphenol.
  • non- ionic surfactants include, but are not limited to, water-soluble adducts of polyethylene oxide with poylypropylene glycol, ethylenediamino-polypropylene glycol containing 1 to 10 carbon atoms in the alkyl chain, which adducts preferably contain 20 to 250 ethyleneglycol ether groups and/or 10 to 100 propyleneglycol ether groups. Such compounds usually contain from 1 to 5 ethyleneglycol units per propyleneglycol unit.
  • non-ionic surfactants include, but are not limited to, nonylphenol-polyethoxyethanol, castor oil polyglycolic ethers, polypropylene/polyethylene oxide adducts, tributylphenoxypolyethoxyethanol, polyethyleneglycol and octylphenoxy-polyethoxyethanol.
  • Fatty acid esters of polyethylene sorbitan such as polyoxyethylene sorbitan trioleate
  • glycerol glycerol
  • sorbitan sucrose and pentaerythritol are also suitable non-ionic surfactants.
  • Suitable cationic surfactants include, but are not limited to, quaternary ammonium salts, preferably halides, having four hydrocarbon radicals optionally substituted with halo, phenyl, substituted phenyl or hydroxy; for instance quaternary ammonium salts containing as N- substituent at least one C 8-22 alkyl radical (e.g. cetyl, lauryl, palmityl, myristyl, oleyl and the like) and, as further substituents, unsubstituted or halogenated lower alkyl, benzyl and/or hydroxy-C 1-4 alkyl radicals.
  • quaternary ammonium salts preferably halides, having four hydrocarbon radicals optionally substituted with halo, phenyl, substituted phenyl or hydroxy
  • quaternary ammonium salts containing as N- substituent at least one C 8-22 alkyl radical (e.g. cetyl, lauryl, palmityl
  • Structure-forming, thickening or gel-forming agents may be included into the pharmaceutical compositions and combined preparations of the invention.
  • Suitable such agents are in particular highly dispersed silicic acid, such as the product commercially available under the trade name Aerosil; bentonites; tetraalkyl ammonium salts of montmorillonites (e.g., products commercially available under the trade name Bentone), wherein each of the alkyl groups may contain from 1 to 20 carbon atoms; cetostearyl alcohol and modified castor oil products (e.g. the product commercially available under the trade name Antisettle).
  • Gelling agents which may be included into the pharmaceutical compositions and combined preparations of the present invention include, but are not limited to, cellulose derivatives such as carboxymethylcellulose, cellulose acetate and the like; natural gums such as arabic gum, xanthum gum, tragacanth gum, guar gum and the like; gelatin; silicon dioxide; synthetic polymers such as carbomers, and mixtures thereof.
  • Gelatin and modified celluloses represent a preferred class of gelling agents.
  • additives such as magnesium oxide; azo dyes; organic and inorganic pigments such as titanium dioxide; UV-absorbers; stabilisers; odor masking agents; viscosity enhancers; antioxidants such as, for example, ascorbyl palmitate, sodium bisulfite, sodium metabisulfite and the like, and mixtures thereof; preservatives such as, for example, potassium sorbate, sodium benzoate, sorbic acid, propyl gallate, benzylalcohol, methyl paraben, propyl paraben and the like; sequestering agents such as ethylene-diamine tetraacetic acid; flavoring agents such as natural vanillin; buffers such as citric acid and acetic acid; extenders or bulking agents such as silicates, diatomaceous earth, magnesium oxide or aluminum oxide; densif ⁇ cation agents such as magnesium salts; and mixtures thereof.
  • additives such as magnesium oxide; azo dyes; organic and inorganic pigments such as titanium dioxide; UV-
  • Control release compositions may thus be achieved by selecting appropriate pharmaceutically acceptable polymer carriers such as for example polyesters, polyamino-acids, polyvinylpyrrolidone, ethylene-vinyl acetate copolymers, methylcellulose, carboxy-methylcellulose, protamine sulfate and the like.
  • the rate of drug release and duration of action may also be controlled by incorporating the active ingredient into particles, e.g. microcapsules, of a polymeric substance such as hydrogels, polylactic acid, hydroxymethyl-cellulose, polymethyl methacrylate and the other above-described polymers.
  • Such methods include colloid drug delivery systems like liposomes, microspheres, microemulsions, nanoparticles, nanocapsules and so on.
  • the pharmaceutical composition or combined preparation of the invention may also require protective coatings.
  • compositions suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation thereof.
  • Typical carriers for this purpose therefore include biocompatible aqueous buffers, ethanol, glycerol, propylene glycol, polyethylene glycol, complexing agents such as cyclodextrins and the like, and mixtures thereof.
  • the selected active agent may be administered topically, in an ointment, gel or the like, or transdermally, using a conventional transdermal drug delivery system.
  • the said combined preparation may be in the form of a medical kit or package containing the two ingredients in separate but adjacent form.
  • each ingredient may therefore be formulated in a way suitable for an administration route different from that of the other ingredient, e.g. one of them may be in the form of an oral or parenteral formulation whereas the other is in the form of an ampoule for intravenous injection or an aerosol.
  • a method of treatment of human immunodeficiency virus comprising the application of an effective amount of a compound listed in Figure 8A-F or Table 1 to a person in need thereof.
  • the patient may be a mammal such as a primate, more preferably a human being.
  • the method consists of administering to the patient in need thereof a therapeutically effective amount of at least one compound listed in Figure 8A-F or Table 1, optionally together with an effective amount of another antiviral agent, or a pharmaceutical composition comprising the same, such as disclosed above in extensive details.
  • the therapeutically effective amount is usually in the range of about 0.01 mg to 20 mg, preferably about 0.1 mg to 5 mg, per day per kg bodyweight for humans.
  • the said therapeutically effective amount may be divided into several sub-units per day or may be administered at more than one day intervals.
  • the patient to be treated may be any warm-blooded animal, preferably a mammal, more preferably a human being, suffering from said viral infection or associated pathologic condition.
  • a screening method comprising the steps of
  • the screening method provided is a phenotypic cell-based assay enabling the search for drugs that interfere with the infection or replication of HIV within host T or B cells or a hybrid thereof.
  • the assay makes use of viral infection induced fluorescent protein expressing living cells infected with HIV-I (Bru) virus and uses automated confocal fluorescence microscopy and fluorescence intensity to measure infection.
  • the assay has been set-up for the high throughput screening (HTS) of large scale chemical libraries.
  • Figure 1 A plot of positive and negative controls from the primary screen of the Timtec compound library. The inhibition of HIV-I infection (%) is plotted. The T value of 0.54 indicates the separation between the Nevirapine (black) and DMSO (gray) controls and is indicative of a screen of high quality.
  • Figure 2 A plot of the compound data from the primary screen of the Timtec compound library. Each circle represents one compound with 26,500 compounds tested in total. Activity is expressed as a percentage inhibition of infection and was calculated on a per plate basis using the Nevirapine and DMSO controls from each plate. The compounds indicated in dark gray are those considered active against HIV infection in the assay (1891 compounds), based upon a statistical cut off of 70% inhibition of activity (black line).
  • Figure 3 Quality control of the Timtec compound library primary screen. The location of active compounds was assessed based on the well location of the compound. Pie charts were constructed in order to identify any column (A) or row (B) bias in the assay. A trellis plot (C) indicates that the active compounds are distributed across different plates.
  • Figure 4 Identification of active compounds for further characterization. Compounds identified as active in the primary screen were re-tested in duplicate, at 3 different compound concentrations, 10 ⁇ M (A), 1 ⁇ M (B) and 0.1 ⁇ M (C). Compounds indicated in black are those exhibiting 50% inhibition of infection at 1 ⁇ M. These compounds were selected for dose-response analysis.
  • Figure 5 Schematic of the process used to identify compounds active against HIV infection of CEMxI 74 cells. From a primary screen of 26,500 compounds, 1,891 compounds were identified as active from the primary screen (in singlet). Of these, 170 exhibited 50% inhibition of infection at a compound concentration of 1 uM. Of the 170 compounds, 7 were identified that showed activity against HIV infection while also exhibiting low toxicity against CEMxI 74 cells. These 7 compounds can be classified into 3 structural classes or scaffolds.
  • Figure 6 A plot of positive and negative controls from the primary screen of the ChemBridge and Cerep compound libraries. The inhibition of HIV-I infection (%) is plotted. The ⁇ value of 0.56 indicates the separation between the Nevirapine (black) and DMSO (gray) controls and is indicative of a screen of high quality.
  • Figure 7 Plots of the compound data from the primary screen of the ChemBridge (A) and Cerep (B) compound libraries. Each circle represents one compound with 30,480 compounds tested in total (20,000 ChemBridge compounds and 10,480 Cerep compounds). Activity is expressed as a percentage inhibition of infection and was calculated on a per plate basis using the Nevirapine and DMSO controls from each plate. The compounds indicated in light gray in the upper right corner of each plot are those considered active against HIV infection in the assay (496 compounds from ChemBridge and 286 compounds from Cerep), based upon a statistical cut off of activity of greater than 6 standard deviations from the mean of the average percentage inhibition of infection (bracket indicates bin of active compounds).
  • Figure 8 Identification of 6 compounds from the compounds libraries that are active against HIV-I infection of CEMx 174 cells while exhibiting low cellular toxicity. Activity of the compounds based on a decrease in fluorescence (RFU) is indicated in the dose-response curves on the left of each pair and the potency of each compound is indicated as a calculated EC 50 value. Curves on the right side of each pair indicate the effect of the compound on cell number ( ⁇ ) and cell viability, in the presence (A) and absence (•) of HIV-I infection.
  • REU fluorescence
  • the 6 compounds can be identified as belonging to 2 distinct structural scaffolds, cyclic-urea containing (A-D; Scaffold I; Timtec compound library) and amino biphenyl containing (E-F; Scaffold II; ChemBridge compound library). Data for known anti-HIV agents is included (G; Nevirapine, AZT and Saquinavir).
  • Table 1 Summary of derivative activity data for Scaffolds I and II which exhibited anti-HIV- 1 activity.
  • Derivatives 1 to 323 are based on Scaffold I and derivative compounds 324 to 650 are based on Scaffold II. The number allocated to each compound and its corresponding activity value(s) are indicated to the right of the compound.
  • the HIV infection screening assay is based on the GFP expression under HIV infection using a LTR-GFP fusion stably expressed in CEM cells.
  • the viral DNA is integrated and expressed, the viral protein TAT is expressed and promotes the expression of the gene controlled by LTR (i.e. GFP).
  • CEMxI 74 cells were cultured in RPMIl 640-Glutamax with 10% heat-inactivated fetal calf serum (Gibco), 100units/ml penicillin and streptomycin, 2mM sodium pyruvate, 2mM L-Glutamine at 37°C in 5% CO2.
  • Bru virus To produce Bru virus, one million CEMxI 74 cells were infected with Bru virus (M.O.I, of 20) for 2 hr. After 24 hr incubation, the virus was transferred to a T-75 flask. After two weeks, ten million fresh cells were added to the flask. After a further two weeks 600 ml of virus- containing supernatant was collected, filtered and assayed for virus levels by a p24 assay. The virus is stocked and the cells are cultured in the same medium.
  • M.O.I Bru virus
  • the small synthetic molecules from the screening libraries were resuspended in pure DMSO at an initial concentration of 1OmM (master plates) in 96 well polypropylene plates.
  • master plates of 96 well plates were reformatted to mother plates of the 384 well polypropylene plates (Greiner) and diluted to a final concentration of 2mM in pure DMSO.
  • the compounds were kept frozen until use.
  • the compound plates were thawed at room temperature.
  • the compounds were directly added to the assay plates from the DMSO stock using an EVObird liquid handler (Evotec Technologies) which transfers 250nl of compound to achieve a dilution step of 1 :200. A fast mixing is performed to ensure complete diffusion of the small volume in the assay well.
  • Cells (4,000/well) were dispensed using a Wellmate (Matrix) into 384 well Evotec glass plates pre-dispensed with lOul of compound diluted in PBS and incubated for 1 hr at 37 degrees, 5% CO2. Cells were then infected with Bru virus at multiplicity of infection (MOI) 3.7 and incubated for 5 days at 37 degrees, 5% CO2. The plates were read for fluorescence detection using Victor3. Cells were then stained with Syto ⁇ O (Invitrogen) for Ih for imaging by an automated fluorescent confocal microscope OperaTM (Evotec Technologies).
  • MOI multiplicity of infection
  • Example 1 Development and validation of a visual, high-throughput HIV-I full replication
  • reporter cell lines harbouring an integrated HIV mini-genome encoding only the EGFP gene under the transcriptional control of the genuine HIV LTR promoter were constructed. Briefly, CEMx 174 [10] cells were stably transfected with TRIP-LTR-EGFP vector particles [11] and cloned. Cell lines were selected that expressed minimal levels of basal EGFP in an uninfected state, but responded to HIV-I infection with high levels of EGFP fluorescence.
  • CEMx 174 #CG8 the cell line with the most desirable phenotype
  • Timtec - ActiProbe-25K a diverse 20,000 compounds set
  • ChemBridge - NOVACore a diverse 10,480 compound set
  • Talep - Odyssey II a 1,000 compound kinase focused library
  • Timtec - ActiTarg-K a 1,000 compound kinase focused library
  • Timtec - ActiTarg-P a 500 compound protease focused library
  • 1,891 compounds were identified as being active against HIV infection in CEMx 174 cells (Figure 2), an active rate of 7%.
  • the plate and well locations of the active compounds were examined in order to identify any plate and/or well bias in the screen.
  • the actives were found to be evenly distributed across the plates tested, except in the cases of structurally similar compounds that are grouped together on the plate ( Figure 3).
  • a 3 step process was used to identify the most active and structurally interesting compounds. The overall process is shown in Figure 5.
  • the active compounds were cherry picked from the compound library and re-screened at 3 concentrations (10, 1 and 0.1 uM) in order to filter out false positives and gain a first measure of active potency and toxicity. Image analysis was used to assess compound toxicity. Fluorescence intensity was also used to quantify compound activity, and a resazurin-based cell viability assay was used to complement the image based cell toxicity data. This active confirmation screen was performed in duplicate with both cell lines. Of the 1,891 compounds tested, 1,237 were active at the primary screening concentration of 10 uM, an active confirmation rate of 65% (Figure 4A). Compounds were selected for further characterization based on their ability to inhibit HIV infection by 50% at the intermediate concentration of 1 uM ( Figure 4B).
  • Compound activity was measured by FI and compound toxicity was assessed by image analysis and resazurin-based cell viability in the presence and absence of HIV. As with the 3 concentration experiment, the compounds were tested in duplicate. A total of 7 compounds from the Timtec compound library were determined to be active with cell protection. These 7 compounds were grouped into three scaffolds, one of which, Scaffold I (4 compounds; 8A-D) is disclosed herein. These four compounds, Timtec I, II, III and IV were purchased as required or Timtec II was also synthesized in-house and is also referred to as Compound 1 (Table 1) herein.
  • ChemBridge and Cerep compound libraries were determined to be active with cell protection. Two of these compounds were grouped as Scaffold II (ChemBridge compound library; 8E-F) which is disclosed herein. These two compounds, ChemBridge I and II were purchased from ChemBridge but were also synthesized in-house and are also referred to as Compound 278 and 280 respectively (Table 1) herein.
  • the activity of the compounds was assessed in a p24 activity assay. All 6 compounds showed a dose-dependent effect on the amount of p24 core antigen (not shown), confirming the results of the GFP-based assay, and indicating that the 6 compounds are hits against HIV infection.
  • Scaffolds I and II underwent derivatization according to the methods outlined below. Scaffold I derivatives correspond to compounds 1 to 323 and Scaffold II derivatives correspond to compounds 324 to 650. Resulting derivatives were examined for inhibitory activity using the assay(s) described above and the results are summarized in Table 1.
  • the salt above (80 mg) was resuspended in water (4 mL) and acidified with IN HCl (500 ⁇ L, pH ⁇ 2). The resulting suspension was sonicated for 10 min and then centrifuged to remove the upper layer.
  • the resulting white suspension was stirred for 7 h, and then quenched with a mixture of saturated aqueous NaHCO 3 (50 mL) and H 2 O (30 mL). The mixture was extracted with Et 2 O (3 x 100 mL) and dried over Na 2 SO 4 .
  • the resulting solution was stirred at -78 °C for 50 min, and then warmed to 25 °C and stirred for an additional 30 min.
  • the mixture was quenched at 25 °C with saturated aqueous NH 4 Cl (150 mL).
  • the organic layer was washed with brine (100 mL) and dried over Na 2 SO 4 .
  • Acetyl protected Biginelli product (9.8 ⁇ mol, 1.0 equiv) was suspended in MeOH (1 mL) and was added potassium carbonate (6.8 mg, 49 ⁇ mol, 5.0 equiv) and water (200 ⁇ L). The reaction was stirred at 25 °C for 30 min. The reaction was quenched with aqueous 2 N HCl and the mixture was extracted with CH 2 Cl 2 (3 x 5 mL) and dried over MgSO 4 . After filtration and concentration in vacuo, the crude residue was purified via flash column chromatography on silica gel.
  • Enantiomeric pure forms were obtained from 209a/209b by hydrolysis using K 2 CO 3 in

Abstract

There is provided small molecule anti-human immunodeficiency virus (anti-HIV) compounds as well as a phenotypic cell-based high throughput screening (HTS) assay for their identification.

Description

Anti Viral Compounds
This application claims benefit of patent application Nos. 61/107,448 filed October 22, 2008, 61/109,028 filed October 28, 2008, and 61/228,837 filed July 27, 2009, contents of which are incorporated by reference in their entirety.
There is provided small molecule anti-human immunodeficiency virus (anti-HIV) compounds as well as a phenotypic cell-based high throughput screening (HTS) assay for their identification.
Background of the Invention
Almost 30 years after it was first identified [1], HIV continues to be a serious worldwide health problem. Despite many years and billions of dollars invested in research and development aimed at finding a cure for HIV, people continue to be infected with HIV and die due to AIDS. In 2007 alone 2.5 million people were infected with HIV and 2.1 million people died. HIV remains a serious public health problem as there were 33.2 million people living with HIV in 2007 [2]. However, it is not all bad news as global rates of HIV infection have leveled off, and the number of deaths due to AIDS has decreased over the past few years [2]. This decrease coincides with the greater availability of antiretro viral therapy, particularly in sub-Saharan Africa where the highest rates of HIV infection and AIDS is found [2]. HIV belongs to the retrovirus family, which contain genetic information in the form of RNA. There are two types of HIV, HIV-I and HIV-2. HIV-I is much more prevalent and is thought to have arisen from cross-species transmission of a chimpanzee virus to humans [3-5]. HIV infects T cells that express CD4 on their surface. HIV infection requires a fusion of viral and cellular membranes. This process is accomplished by viral envelope glycoprotein (gpl20, gp41) and receptors (CD4 and coreceptors, such as CXCR4 or CCR5) on the target cell. After the virus enters the cell, its RNA is reverse - transcribed to the DNA by a viral enzyme, reverse transcriptase (RT). The viral DNA enters the nucleus, where it is integrated to the genetic material of the cell by the viral enzyme, integrase. When the cell receives a signal to become active, the provirus creates the mRNA through the transcription and then it is translated into viral proteins. The viral enzyme, protease is required to cut a viral polyprotein precursor into individual mature proteins. The HIV proteins and HIVs RNA genetic material assemble at the cell surface into new virions, which then bud from the cell and are released to infect another cell [6,7].
Current antiretroviral therapy is suppressive and cannot cure an individual of HIV infection. Furthermore, shortly after introduction of the first anti-HIV drug, azidothymidine (AZT), HIV-I demonstrated its ability to rapidly generate drug-resistant mutants. In order to overcome the problem of resistance when using one anti-viral agent, combination HAART (highly active antiretroviral therapy) is now widely used [2,8]. While effective, HAART requires a strict adherence to the treatment protocol and can have severe side-effects [2]. Current anti-HIV drugs are active on only a few targets and stages of the HIV life cycle. Many current drugs act at the stages of viral fusion, reverse transcription and viral maturation. Novel anti-viral compounds that affect other stages of the viral life cycle would be a valuable addition to the anti-HIV armamentarium.
Most the anti-HIV drug discovery performed to date has been focused on identifying inhibitors of known HIV targets (eg. reverse transcriptase, protease) [9]. In this manner, only a few of a potentially large number of targets can be interrogated for their effect on HIV infection. It was an object of the present invention to develop a phenotypic cell-based assay suitable for high throughput screening that allows for the search of compounds that would prevent HIV infection and replication regardless of the target.
There is provided a high throughput, fully infectious HIV-I cell based assay used to screen a diverse small molecule library. The cell based assay has the advantage of opening up every step of the HIV-I life cycle, and allows for identification of compounds that may inhibit viral and host cell proteins involved in HIV-I infection and replication.
It was another object of the present invention to identify compounds that would prevent HIV infection and replication.
A number of compounds that inhibit HIV-I infection of host cells were identified. These compounds belong to two structural classes, and their anti -HIV-I activity was confirmed and/or determined by dose response and p24 secondary assay.
Detailed Description
According to one aspect, there is provided compounds having the general formula I:
Figure imgf000005_0001
wherein
A is selected from the group consisting of;
Figure imgf000006_0001
n is 1, 2, or 3;
X is selected from the group consisting of NR4, O, or S;
Y and Z are independently selected from the group consisting of NR4, C, O, or S; R1 is selected from the group consisting of hydrogen, halogen, C1-C10 alkyl, C3-C10 cycloalkyl, C2-C10 alkenyl, C3-C10 cycloalkenyl, C2-Ci0 alkynyl, C1-C10 haloalkyl, -OH, -OR5, C1-C10 alkoxy, C3-Ci0 cycloalkoxy, C3-Ci5 cycloalkylalkoxy, C3-Ci5 cycloalkylalkyl, -CN, -NO2, - NH2, -N(R5)2, -C(O)R5, -C(O)OR5, -C(O)N(R5)2, -SR5, -S(O)R5, -S(O)2R5, -S(O)2N(R5),, aryl, benzyl, heteroaryl, or heterocyclyl;
R2 is each independently selected from the group consisting of hydrogen, halogen, C1-C10 alkyl, C3-C0 cycloalkyl, hydroxyl, -OR5, -CN, -NO2, -NH2, -N(R5)C(O)R5, -C(O)R5, - C(O)OR5, -C(O)N(R5)2> -S(O)R5, -S(O)2R5, -S(O)2N(R5)2, aryl, benzyl, heteroaryl, heterocyclyl or two groups of R2 are connected each other to make five or six membered cyclic and heterocyclic rings; each R3 is independently selected from the group consisting of hydrogen, halogen, Ci-C10 alkyl, C3-Ci0 cycloalkyl, hydroxyl, -OR5, -CN, -NO2, -NH2, -N(R5)C(O)R5, -C(O)R5, - C(O)OR5, ^C(O)N(R5)2, S(O)R5, -S(O)2R5, -S(O)2N(R5)2, aryl, benzyl, heteroaryl, heterocyclyl, or two groups of R3 are connected each other to make five or six membered cyclic and heterocyclic rings;
R4 is independently selected from the group consisting from hydrogen, Ci-C10 alkyl, C3-C10 cycloalkyl, C2-C10 alkenyl, C3-C10 cycloalkenyl, C2-C10 alkynyl, C1-Ci0 haloalkyl, -C(O)R5, - C(O)OR5, -C(O)N(R5)2, -S(O)R5, -S(O)2R5, -S(O)2N(R5)2, aryl, benzyl, heteroaryl, or heterocyclyl;
R5 is independently selected from the group consisting from hydrogen, Ci-Ci0 alkyl, C3-Ci0 cycloalkyl, C2-Ci0 alkenyl, C3-Cj0 cycloalkenyl, C2-Ci0 alkynyl, Ci-Ci0 haloalkyl, aryl, benzyl, heteroaryl, or heterocyclyl. The term "optionally substituted" as used herein is meant to indicates that a hydrogen atom attached to a member atom within a group is possibly replaced by group, such as halogen including fluorine, Ci-Ci0 alkyl, Ci-C3 haloalkyl, C3-C7 cycloalkyl, oxo, -OH, -OR7, -
OC(O)R7 , -CN, -NO2, -N(R7)2, -N(R7)C(O)R7, -C(O)R7, -C(O)OR7, -C(O)N(R7)2, -S(O)R7, -
S(O)2R7, -S(O)2N(R7)2, phenyl, benzyl, or heterocyclyl;
R7 is each independently selected from the group consisting of hydrogen, aryl, benzyl, heterocyclyl, Ci-C8 alkyl, or C3-C7 cycloalkyl;
R8, R9, R10 and R11 are each independently selected from the group consisting of hydrogen, halogen, C1-Ci0 alkyl, C1-C3 haloalkyl, C3-C7 cycloalkyl, hydroxyl, oxo, -OR12, -C(O)OR12, -
C(O)R12, -C(O)N(RI2)2, -CN, -NO2, -NH2, -N(R12)2, -OR4HetA, -OR4N(R12)2, -
C(O)N(R12)HetA, -C(O)HetA, -C(O)N(R12)R4S(O)2R12; -S(O)2N(R12)2, -S(O)2R12, -
N(R12)C(O)R4SR12, -N(R12)R4S(O)2R12, or -N(R12)S(O)2R12, aryl, benzyl, or heterocyclyl;
R12 is each independently selected from the group consisting of hydrogen, Ci-C8 alkyl optionally substituted with at least one hydroxyl or halogen; C3-C7 cycloalkyl, aryl; phenyl, benzyl, or heterocyclyl;
The term "alkyl" refers to a monovalent straight or branched chain, saturated aliphatic hydrocarbon radical having a number of carbon atoms in the specified range. Thus, for example, "Ci-C6 alkyl" refers to any of the hexyl alkyl and pentyl alkyl isomers as well as n-, iso-, sec-, and t-butyl, n- and isopropyl, ethyl and methyl.
The term "alkoxy" means a group having the formula -O-alkyl, in which an alkyl group, as defined above, is attached to the parent molecule via an oxygen atom. The alkyl portion of an alkoxy group can have 1 to 20 carbon atoms (i.e., C1-C20 alkoxy), 1 to 12 carbon atoms (i.e.,
C1-C12 alkoxy), or 1 to 6 carbon atoms (i.e., C1-C6 alkoxy). Examples of suitable alkoxy groups include, but are not limited to, methoxy (-0-CH3 or OMe), ethoxy (-OCH2CH3 or -
OEt), t-butoxy (-O-C(CH3)3 or -OtBu) and the like.
The term "alkenyl" refers to a monovalent straight or branched chain aliphatic hydrocarbon radical containing one carbon-carbon double bond and having a number of carbon atoms in the specified range. Thus, for example, "C2-C6 alkenyl" refers to all of the hexenyl and pentenyl isomers as well as 1-butenyl, 2-butenyl, 3-butenyl, isobutenyl, 1-propenyl, 2- propenyl, and ethenyl (or vinyl).
The term "alkynyl" refers to a monovalent straight or branched chain aliphatic hydrocarbon radical containing one carbon-carbon triple bond and having a number of carbon atoms in the specified range. Thus, for example, "C2-C6 alkynyl" refers to all of the hexynyl and pentynyl isomers as well as 1-butynyl, 2-butynyl, 3-bytynyl, 1-propynyl, 2-propynyl, and ethynyl. The term "Alkylene" refers to a saturated, branched or straight chain or cyclic hydrocarbon radical having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Typical alkylene radicals include, but are not limited to, methylene (-CH2-), 1,1 -ethyl (- CH(CH3)-), 1,2-ethyl (-CH2CH2-), 1,1 -propyl (-CH(CH2CH3)-), 1,2-propyl (-CH2CH(CH3)-), 1,3-propyl (-CH2CH2CH2-), 1,4-butyl (-CH2CH2CH2CH2-), and the like. The term "Alkenylene" refers to an unsaturated, branched or straight chain or cyclic hydrocarbon radical having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of parent alkene. For example, an alkenylene group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Typical alkenylene radicals include, but are not limited to, 1,2-ethenyl (-CH=CH-). The term "Alkynylene" refers to an unsaturated, branched or straight chain or cyclic hydrocarbon radical having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of parent alkyne. For example, an alkynylene group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms or 1 to 6 carbon atoms. Typical alkynylene radicals include, but are not limited to, acetylene (-C≡C-), propargyl (-CH2C≡C-), and 4-pentynyl (-CH2CH2CH2C=CH-).
The term "cycloalkyl", alone or in combination with any other term, refers to a group, such as optionally substituted or non-substituted cyclic hydrocarbon, having from three to eight carbon atoms, unless otherwise defined. Thus, for example, "C3-C8 cycloalkyl" refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
The term "haloalkyl" refers to an alkyl group, as defined herein that is substituted with at least one halogen. Examples of straight or branched chained "haloalkyl" groups useful in the present invention include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, and t-butyl substituted independently with one or more halogens. The term "haloalkyl" should be interpreted to include such substituents such as -CHF2, -CF3, -CH2-CH2-F, -CH2-CF3, and the like.
The term "heteroalkyl" refers to an alkyl group where one or more carbon atoms have been replaced with a heteroatom, such as, O, N, or S. For example, if the carbon atom of alkyl group which is attached to the parent molecule is replaced with a heteroatom (e.g., O, N, or S) the resulting heteroalkyl groups are, respectively, an alkoxy group (e.g., -OCH3, etc.), an amine (e.g., -NHCH3, -N(CH3)2, etc.), or thioalkyl group (e.g., -SCH3, etc.). If a non-terminal carbon atom of the alkyl group which is not attached to the parent molecule is replaced with a heteroatom (e.g., O, N, or S) and the resulting heteroalkyl groups are, respectively, an alkyl ether (e.g., -CH2CH2-O-CH3, etc.), alkyl amine (e.g., -CH2NHCH3, -CH2N(CH3)2, etc.), or thioalkyl ether (e.g., -CH2-S-CH3).
The term "halogen" refers to fluorine, chlorine, bromine, or iodine.
The term "aryl" refers to (i) optionally substituted phenyl, (ii) optionally substituted 9- or 10 membered bicyclic, fused carbocyclic ring systems in which at least one ring is aromatic, and (iii) optionally substituted 11- to 14-membered tricyclic, fused carbocyclic ring systems in which at least one ring is aromatic. Suitable aryls include, for example, phenyl, biphenyl, naphthyl, tetrahydronaphthyl (tetralinyl), indenyl, anthracenyl, and fluorenyl. The term "phenyl" as used herein is meant to indicate that optionally substituted or non- substituted phenyl group.
The term "benzyl" as used herein is meant to indicate that optionally substituted or non- substituted benzyl group.
The term "heteroaryl" refers to (i) optionally substituted 5- and 6-membered heteroaromatic rings and (ii) optionally substituted 9- and 10-membered bicyclic, fused ring systems in which at least one ring is aromatic, wherein the heteroaromatic ring or the bicyclic, fused ring system contains from 1 to 4 heteroatoms independently selected from N, O, and S, where each N is optionally in the form of an oxide and each S in a ring which is not aromatic is optionally S(O) or S(O)2. Suitable 5- and 6-membered heteroaromatic rings include, for example, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thienyl, furanyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isooxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, and thiadiazolyl. Suitable 9-and 10-membered heterobicyclic, fused ring systems include, for example, benzofuranyl, indolyl, indazolyl, naphthyridinyl, isobenzofuranyl, benzopiperidinyl, benzisoxazolyl, benzoxazolyl, chromenyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, isoindolyl, benzodioxolyl, benzofuranyl, imidazo[l,2-a]pyridinyl, benzotriazolyl, dihydroindolyl, dihydroisoindolyl, indazolyl, indolinyl, isoindolinyl, quinoxalinyl, quinazolinyl, 2,3-dihydrobenzofuranyl, and 2,3- dihydrobenzo- 1 ,4-dioxinyl.
The term "heterocyclyl" refers to (i) optionally substituted 4- to 8-membered, saturated and unsaturated but non-aromatic monocyclic rings containing at least one carbon atom and from 1 to 4 heteroatoms, (ii) optionally substituted bicyclic ring systems containing from 1 to 6 heteroatoms, and (iii) optionally substituted tricyclic ring systems, wherein each ring in (ii) or (iii) is independent of fused to, or bridged with the other ring or rings and each ring is saturated or unsaturated but nonaromatic, and wherein each heteroatom in (i), (ii), and (iii) is independently selected from N, O, and S, wherein each N is optionally in the form of an oxide and each S is optionally oxidized to S(O) or S(O)2. Suitable 4- to 8-membered saturated heterocyclyls include, for example, azetidinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, pyrrolidinyl, imidazolidinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl, hexahydropyrimidinyl, thiazinanyl, thiazepanyl, azepanyl, diazepanyl, tetrahydropyranyl, tetrahydrothiopyranyl, dioxanyl, and azacyclooctyl. Suitable unsaturated heterocyclic rings include those corresponding to the saturated heterocyclic rings listed in the above sentence in which a single bond is replaced with a double bond. It is understood that the specific rings and ring systems suitable for use in the present invention are not limited to those listed in this and the preceding paragraphs. These rings and ring systems are merely representative.
According to another aspect, there is provided compounds having the general formula II:
Figure imgf000010_0001
wherein, m is 1, 2, 3, or 4; n is 1, 2, or 3; o is 1, 2, or 3;
A is C5-C12 aryl or C5-Ci2 heteroaryl;
B, C, D and E are each independently selected from the group consisting of C(R2), C(O), C(S),
N, or N oxide; each R1 is independently selected from the group consisting of hydrogen, halogen, -CN, C1-C5 alkyl, Cj-C3 haloalkyl, , C2-C5 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, hydroxyl, C1-C8 alkoxy, -C(O)OR3, -C(O)N(R3)2, aryl, oxo, -OH, -OR3, -OCH2R3, -R4CN, -NO2, -
N(R3)C(O)R3, -N(R3)2, aryl, benzyl, or heteroaryl; each R2 is independently selected from the group consisting of hydrogen, halogen, C1-C5 alkyl,
C1-C3 haloalkyl, C3-C7 cycloalkyl, -OH, -OR3, -CN, -NO2, -N(R3)2, aryl, benzyl, or heteroaryl; each R3 is independently selected from the group consisting of hydrogen, C1-C8 alkyl, C1-C3 haloalkyl, C3-C7 cycloalkyl, C1-C3 alkylaryl, aryl, benzyl, or; heteroaryl; each R4 is independently selected from the group consisting of C1-C6 alkyl, C1-C8 alkylene,
C1-C8 alkenylene, C1-C8 alkynylene, each optionally substituted with at least one hydroxyl or hydrogen;
X and Y are each independently selected from the group consisting of -C(R5R6)-, -N(R5)-, -
0-, -S-, -S(O)2-, or -C(O)-;
R5 and R6 are each independently selected from the group consisting of hydrogen, halogen,
Ci-C8 alkyl, 8TyI5 Or C(O)R1;
Z is selected from the group consisting of:
Figure imgf000011_0001
Figure imgf000012_0001
Aryl is C4-C12 aryl and is optionally substituted; HetA and heteroaryl are C3-C10 heteroaryl and are optionally substituted,
R7, R8, R9 and R10 are each independently selected from the group consisting of hydrogen, halogen, Ci-C10 alkyl, Cj-C3 haloalkyl, C3-C7 cycloalkyl, hydroxyl, oxo, -OR11, -C(O)OR11, -
C(O)R11, -C(O)N(R1 %, -CN, -NO2, -NH2, -N(R1 ')2, -OR4HetA, -OR4N(R11^, -
C(O)N(R1 ')HetA, -C(O)HetA, -C(O)N(R1^R4S(O)2R11; -S(O)2N(R11^, -S(O)2R11, -
N(R1 ^C(O)R4SR11, -N(R1^R4S(O)2R11, or -N(Rn)S(O)2Rn, aryl, benzyl, or heterocyclyl;
R11 is each independently selected from the group consisting of hydrogen, Ci-C8 alkyl optionally substituted with at least one hydroxyl or halogen; C3-C7 cycloalkyl, aryl; benzyl, or heterocyclyl.
The term "optionally substituted" has the same meaning as defined above.
The term "alkyl" has the same meaning as defined above.
The term "alkoxy" has the same meaning as defined above.
The term "alkenyl" has the same meaning as defined above.
The term "alkynyl" has the same meaning as defined above.
The term "Alkylene" has the same meaning as defined above.
The term "Alkenylene" has the same meaning as defined above.
The term "Alkynylene" has the same meaning as defined above.
The term "cycloalkyl", alone or in combination with any other term, has the same meaning as defined above.
The term "haloalkyl" has the same meaning as defined above.
The term "heteroalkyl" has the same meaning as defined above.
The term "halogen" has the same meaning as defined above.
The term "aryl" has the same meaning as defined above.
The term "phenyl" has the same meaning as defined above.
The term "benzyl" has the same meaning as defined above.
The term "heteroaryl" has the same meaning as defined above.
The term "heterocyclyl" has the same meaning as defined above.
The stereochemistry of general formula of I and II includes independently R or S as enantiomerically pure form or racemic mixtures.
Another embodiment of the present invention is compounds of general formula I and II, or pharmaceutically acceptable salts thereof. According to one aspect, there is provided a compound having one of the general formulas I to II, as defined above, as well as derivatives thereof for the treatment of viral infections.
According to one aspect, there is provided the use of a compound having one of the general formulas I to II, as defined above, as well as derivatives thereof for the treatment of human immunodeficiency virus (HIV).
According to another aspect, there is provided the use of a compound having one of the general formulas I to II, as defined above, as well as derivatives thereof for the manufacture of a medicament for the treatment of viral infections.
According to another aspect, there is provided the use of a compound having one of the general formulas I to II, as defined above, as well as derivatives thereof for the manufacture of a medicament for the treatment of human immunodeficiency virus (HIV).
According to one aspect, there is provided a compound listed in Figure 8 A-F or Table 1.
According to another aspect, there is provided the use of a compound listed in Figure 8A-F or Table 1 for the inhibition of virus replication within and virus infection of host cells.
In one embodiment said virus is selected from HIV.
In one embodiment said host cells are T cells or B cells or a hybrid thereof.
According to one aspect, there is provided the use of a compound listed in Figure 8A-F or Table 1 for the treatment of viral infections.
According to one aspect, there is provided the use of a compound listed in Figure 8A-F or Table 1 for the treatment of human immunodeficiency virus (HIV).
According to another aspect, there is provided the use of a compound listed in Figure 8A-F or Table 1 for the manufacture of a medicament for the treatment of viral infections. According to another aspect, there is provided the use of a compound listed in Figure 8A-F or Table 1 for the manufacture of a medicament for the treatment of human immunodeficiency virus (HIV).
According to an aspect, a pharmaceutical composition or combined preparation having synergistic effects against a viral infection and containing: (a) at least one compound listed in Figure 8 A-F or Table 1 , (b) (a) otionally one or more anti-viral agents, and (c) optionally one or more pharmaceutical excipients or pharmaceutically acceptable carriers,for simultaneous, separate or sequential use in the treatment or prevention of a viral infection.
Suitable anti-viral agents for inclusion into the synergistic antiviral compositions or combined preparations of this invention include, for instance, retroviral enzyme inhibitors belonging to categories well known in the art, such as HIV-I IN inhibitors, nucleoside reverse transcriptase inhibitors (e.g. zidovudine, lamivudine, didanosine, stavudine, zalcitabine and the like), non- nucleoside reverse transcriptase inhibitors (e.g. nevirapine, delavirdine and the like), other reverse transcriptase inhibitors (e.g. foscamet sodium and the like), and HIV-I protease inhibitors (e.g. saquinavir, ritonavir, indinavir, nelfinavir and the like). Other suitable antiviral agents include for instance acemannan, acyclovir, adefovir, alovudine, alvircept, amantadine, aranotin, arildone, atevirdine, pyridine, cidofovir, cipamfylline, cytarabine, desciclovir, disoxaril, edoxudine, enviradene, enviroxime, famciclovir, famotine, fiacitabine, fialuridine, floxuridine, fosarilate, fosfonet, ganciclovir, idoxuridine, kethoxal, lobucavir, memotine, methisazone, penciclovir, pirodavir, somantadine, sorivudine, tilorone, trifluridine, valaciclovir, vidarabine, viroxime, zinviroxime, moroxydine, podophyllotoxin, ribavirine, rimantadine, stallimycine, statolon, tromantadine and xenazoic acid, and their pharmaceutically acceptable salts.
Especially relevant to this aspect is the inhibition of the replication of HIV, in particular in human beings and other mammals such as primates.
Therefore, of particular relevance in the context of HIV prevention or treatment is coadministration with one or more other agents aiming at HIV inhibition well known in the art, such as but not limited to, nucleoside reverse transcriptase inhibitors (e.g, tenofovir, didanosine and the like), non-nucleoside reverse transcriptase inhibitors (e.g, efavirenz, delavirdine and the like), HIV-I protease inhibitors (e.g. saquinavir, ritonavir, indinavir, nelfinavir and the like), HIV-I integrase inhibitors (e.g, raltegravir and the like) and HIV-I entry inhibitors (e.g, maraviroc and the like). Synergistic activity of the pharmaceutical compositions or combined preparations of this invention against viral infection may be readily determined by means of one or more tests such as, but not limited to, the isobologram method, as previously described by Elion et al. in J. Biol. Chem. (1954) 208:477-488 and by Baba et al. in Antimicrob. Agents Chemother. (1984) 25:515-517, using EC50 for calculating the fractional inhibitory concentration (hereinafter referred as FIC). When the minimum FIC index corresponding to the FIC of combined compounds (e.g., FlCx+FICy) is equal to 1.0, the combination is said to be additive; when it is between 1.0 and 0.5, the combination is defined as sub-synergistic, and when it is lower than 0.5, the combination is by defined as synergistic. When the minimum FIC index is between 1.0 and 2.0, the combination is defined as subantagonistic and, when it is higher than 2.0, the combination is defined as antagonistic. The pharmaceutical composition or combined preparation with synergistic activity against viral infection, especially HIV may contain at least one compound listed in Figure 8A-F or Table 1 over a broad content range depending on the contemplated use and the expected effect of the preparation. Generally, the contents of the at least one compound listed in Figure 8 A-F or Table 1 in the pharamaceutical preparation is within the range of from 0.1 to 99.9% by weight, preferably from 1 to 99% by weight, more preferably from about 5 to 95% by weight.
The pharmaceutical compositions and combined preparations may be administered orally or in any other suitable fashion. Oral administration is preferred and the pharmaceutical composition or preparation may have the form of a tablet, aqueous dispersion, dispersable powder or granule, emulsion, hard or soft capsule, syrup, elixir or gel. The dosing forms may be prepared using any method known in the art for manufacturing these pharmaceutical compositions and may comprise as additives sweeteners, flavoring agents, coloring agents, preservatives and the like. Carrier materials and excipients are detailed hereinbelow and may include, inter alia, calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, binding agents and the like. The pharmaceutical composition or combined preparation of this invention may be included in a gelatin capsule mixed with any inert solid diluent or carrier material, or has the form of a soft gelatin capsule, in which the ingredient is mixed with a water or oil medium. Aqueous dispersions may comprise the biologically active composition or combined preparation in combination with a suspending agent, dispersing agent or wetting agent. Oil dispersions may comprise suspending agents such as a vegetable oil. Rectal administration is also applicable, for instance in the form of suppositories or gels. Injection (e.g. intramuscularly or intraperiteneously) is also applicable as a mode of administration, for instance in the form of injectable solutions or dispersions, depending upon the disorder to be treated and the condition of the patient.
The term "pharmaceutically acceptable carrier or excipient" as used herein in relation to pharmaceutical compositions and combined preparations means any material or substance with which the active acomponent, , and optionally the additional antiviral agent, may be formulated in order to facilitate its application or dissemination to the locus to be treated, for instance by dissolving, dispersing or diffusing the said composition, and/or to facilitate its storage, transport or handling without impairing its effectiveness. The pharmaceutically acceptable carrier may be a solid or a liquid or a gas which has been compressed to form a liquid, i.e. the compositions or preparations of the present invention can suitably be used as concentrates, emulsions, solutions, granulates, dusts, sprays, aerosols, pellets or powders.
Suitable pharmaceutical carriers for use in the said pharmaceutical compositions and their formulation are well known to those skilled in the art. Suitable pharmaceutical carriers include additives such as wetting agents, dispersing agents, stickers, adhesives, emulsifying or surface-active agents, thickening agents, complexing agents, gelling agents, solvents, coatings, antibacterial and antifungal agents (for example phenol, sorbic acid, chlorobutanol), isotonic agents (such as sugars or sodium chloride) and the like, provided the same are consistent with pharmaceutical practice, i.e. carriers and additives which do not create permanent damage to mammals.
The pharmaceutical compositions may be prepared in any known manner, for instance by homogeneously mixing, dissolving, spray-drying, coating and/or grinding the active ingredients, in a one-step or a multi-steps procedure, with the selected carrier material and, where appropriate, the other additives such as surface-active agents. They may also be prepared by micronisation, for instance in view to obtain them in the form of microspheres usually having a diameter of about 1 to 10 μm, namely for the manufacture of microcapsules for controlled or sustained release of the biologically active ingredient(s).
Suitable surface-active agents to be used in the pharmaceutical compositions of the present invention are non-ionic, cationic and/or anionic surfactants having good emulsifying, dispersing and/or wetting properties. Suitable anionic surfactants include both water-soluble soaps and water-soluble synthetic surface-active agents. Suitable soaps are alkaline or alkaline-earth metal salts, unsubstituted or substituted ammonium salts of higher fatty acids (C10-22), e.g. the sodium or potassium salts of oleic or stearic acid, or of natural fatty acid mixtures obtainable form coconut oil or tallow oil. Synthetic surfactants include sodium or calcium salts of polyacrylic acids; fatty sulphonates and sulphates; sulphonated benzimidazole derivatives and alkylarylsulphonates. Fatty sulphonates or sulphates are usually in the form of alkaline or alkaline-earth metal salts, unsubstituted ammonium salts or ammonium salts substituted with an alkyl or acyl radical having from 8 to 22 carbon atoms, e.g. the sodium or calcium salt of lignosulphonic acid or dodecylsulphonic acid or a mixture of fatty alcohol sulphates obtained from natural fatty acids, alkaline or alkaline-earth metal salts of sulphuric or sulphonic acid esters (such as sodium lauryl sulphate) and sulphonic acids of fatty alcohol/ethylene oxide adducts. Suitable sulphonated benzimidazole derivatives preferably contain 8 to 22 carbon atoms. Examples of alkylarylsulphonates include, but are not limited to, the sodium, calcium or alcanolamine salts of dodecylbenzene sulphonic acid or dibutyl- naphthalenesulphonic acid or a naphthalene-sulphonic acid/formaldehyde condensation product. Also suitable are the corresponding phosphates, e.g. salts of phosphoric acid ester and an adduct of p-nonylphenol with ethylene and/or propylene oxide, or phospholipids. Suitable phospholipids for this purpose are the natural (originating from animal or plant cells) or synthetic phospholipids of the cephalin or lecithin type such as e.g. phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerine, lysolecithin, cardiolipin, dioctanylphosphatidylcholine, dipalmitoylphoshatidyl-choline and their mixtures.
Suitable non-ionic surfactants include, but are not limited to, polyethoxylated and polypropoxylated derivatives of alkylphenols, fatty alcohols, fatty acids, aliphatic amines or amides containing at least 12 carbon atoms in the molecule, alkylarenesulphonates and dialkylsulphosuccinates, such as polyglycol ether derivatives of aliphatic and cycloaliphatic alcohols, saturated and unsaturated fatty acids and alkylphenols, said derivatives preferably containing 3 to 10 glycol ether groups and 8 to 20 carbon atoms in the (aliphatic) hydrocarbon moiety and 6 to 18 carbon atoms in the alkyl moiety of the alkylphenol. Further suitable non- ionic surfactants include, but are not limited to, water-soluble adducts of polyethylene oxide with poylypropylene glycol, ethylenediamino-polypropylene glycol containing 1 to 10 carbon atoms in the alkyl chain, which adducts preferably contain 20 to 250 ethyleneglycol ether groups and/or 10 to 100 propyleneglycol ether groups. Such compounds usually contain from 1 to 5 ethyleneglycol units per propyleneglycol unit. Representative examples of non-ionic surfactants include, but are not limited to, nonylphenol-polyethoxyethanol, castor oil polyglycolic ethers, polypropylene/polyethylene oxide adducts, tributylphenoxypolyethoxyethanol, polyethyleneglycol and octylphenoxy-polyethoxyethanol. Fatty acid esters of polyethylene sorbitan (such as polyoxyethylene sorbitan trioleate), glycerol, sorbitan, sucrose and pentaerythritol are also suitable non-ionic surfactants.
Suitable cationic surfactants include, but are not limited to, quaternary ammonium salts, preferably halides, having four hydrocarbon radicals optionally substituted with halo, phenyl, substituted phenyl or hydroxy; for instance quaternary ammonium salts containing as N- substituent at least one C8-22 alkyl radical (e.g. cetyl, lauryl, palmityl, myristyl, oleyl and the like) and, as further substituents, unsubstituted or halogenated lower alkyl, benzyl and/or hydroxy-C1-4 alkyl radicals.
Structure-forming, thickening or gel-forming agents may be included into the pharmaceutical compositions and combined preparations of the invention. Suitable such agents are in particular highly dispersed silicic acid, such as the product commercially available under the trade name Aerosil; bentonites; tetraalkyl ammonium salts of montmorillonites (e.g., products commercially available under the trade name Bentone), wherein each of the alkyl groups may contain from 1 to 20 carbon atoms; cetostearyl alcohol and modified castor oil products (e.g. the product commercially available under the trade name Antisettle).
Gelling agents which may be included into the pharmaceutical compositions and combined preparations of the present invention include, but are not limited to, cellulose derivatives such as carboxymethylcellulose, cellulose acetate and the like; natural gums such as arabic gum, xanthum gum, tragacanth gum, guar gum and the like; gelatin; silicon dioxide; synthetic polymers such as carbomers, and mixtures thereof. Gelatin and modified celluloses represent a preferred class of gelling agents.
Other optional excipients which may be included in the pharmaceutical compositions and combined preparations of the present invention include additives such as magnesium oxide; azo dyes; organic and inorganic pigments such as titanium dioxide; UV-absorbers; stabilisers; odor masking agents; viscosity enhancers; antioxidants such as, for example, ascorbyl palmitate, sodium bisulfite, sodium metabisulfite and the like, and mixtures thereof; preservatives such as, for example, potassium sorbate, sodium benzoate, sorbic acid, propyl gallate, benzylalcohol, methyl paraben, propyl paraben and the like; sequestering agents such as ethylene-diamine tetraacetic acid; flavoring agents such as natural vanillin; buffers such as citric acid and acetic acid; extenders or bulking agents such as silicates, diatomaceous earth, magnesium oxide or aluminum oxide; densifϊcation agents such as magnesium salts; and mixtures thereof.
Additional ingredients may be included in order to control the duration of action of the biologically-active ingredient in the compositions and combined preparations of the invention. Control release compositions may thus be achieved by selecting appropriate pharmaceutically acceptable polymer carriers such as for example polyesters, polyamino-acids, polyvinylpyrrolidone, ethylene-vinyl acetate copolymers, methylcellulose, carboxy-methylcellulose, protamine sulfate and the like. The rate of drug release and duration of action may also be controlled by incorporating the active ingredient into particles, e.g. microcapsules, of a polymeric substance such as hydrogels, polylactic acid, hydroxymethyl-cellulose, polymethyl methacrylate and the other above-described polymers. Such methods include colloid drug delivery systems like liposomes, microspheres, microemulsions, nanoparticles, nanocapsules and so on. Depending on the route of administration, the pharmaceutical composition or combined preparation of the invention may also require protective coatings.
Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation thereof. Typical carriers for this purpose therefore include biocompatible aqueous buffers, ethanol, glycerol, propylene glycol, polyethylene glycol, complexing agents such as cyclodextrins and the like, and mixtures thereof.
Other modes of local drug administration can also be used. For example, the selected active agent may be administered topically, in an ointment, gel or the like, or transdermally, using a conventional transdermal drug delivery system.
Since, in the case of combined preparations including at least at least one compound listed in Figure 8A-F or Table 1, and an additional antiviral agent, both active ingredients do not necessarily bring out their synergistic therapeutic effect directly at the same time in the patient to be treated, the said combined preparation may be in the form of a medical kit or package containing the two ingredients in separate but adjacent form. In the latter context, each ingredient may therefore be formulated in a way suitable for an administration route different from that of the other ingredient, e.g. one of them may be in the form of an oral or parenteral formulation whereas the other is in the form of an ampoule for intravenous injection or an aerosol.
According to one aspect, there is provided a method of treatment of human immunodeficiency virus (HIV), comprising the application of an effective amount of a compound listed in Figure 8A-F or Table 1 to a person in need thereof.
According to the method for preventing or treating a viral infection or a pathologic condition associated therewith, including HIV in a patient, the patient may be a mammal such as a primate, more preferably a human being. The method consists of administering to the patient in need thereof a therapeutically effective amount of at least one compound listed in Figure 8A-F or Table 1, optionally together with an effective amount of another antiviral agent, or a pharmaceutical composition comprising the same, such as disclosed above in extensive details. The therapeutically effective amount is usually in the range of about 0.01 mg to 20 mg, preferably about 0.1 mg to 5 mg, per day per kg bodyweight for humans. Depending upon the pathologic condition to be treated, the severity of infection, and the patient's condition, the said therapeutically effective amount may be divided into several sub-units per day or may be administered at more than one day intervals. The patient to be treated may be any warm-blooded animal, preferably a mammal, more preferably a human being, suffering from said viral infection or associated pathologic condition.
According to another aspect, there is provided a screening method comprising the steps of
(a) adding compounds that are to be tested to a multi-well plate;
(b) seeding of host cells that express GFP upon infection by HIV-I;
(c) infection of said host cells with HIV-I virus into said multi-well plate containing said compounds;
(d) incubating said multi-well plate containing GFP expressing host cells infected with HIV-I virus and said compounds;
(e) analyzing said multi-well plate using automated confocal microscopy and fluorescent microplate readers.
The screening method provided is a phenotypic cell-based assay enabling the search for drugs that interfere with the infection or replication of HIV within host T or B cells or a hybrid thereof. The assay makes use of viral infection induced fluorescent protein expressing living cells infected with HIV-I (Bru) virus and uses automated confocal fluorescence microscopy and fluorescence intensity to measure infection. The assay has been set-up for the high throughput screening (HTS) of large scale chemical libraries.
Figures and Tables
Reference is now made to the figures and tables, wherein
Figure 1: A plot of positive and negative controls from the primary screen of the Timtec compound library. The inhibition of HIV-I infection (%) is plotted. The T value of 0.54 indicates the separation between the Nevirapine (black) and DMSO (gray) controls and is indicative of a screen of high quality.
Figure 2: A plot of the compound data from the primary screen of the Timtec compound library. Each circle represents one compound with 26,500 compounds tested in total. Activity is expressed as a percentage inhibition of infection and was calculated on a per plate basis using the Nevirapine and DMSO controls from each plate. The compounds indicated in dark gray are those considered active against HIV infection in the assay (1891 compounds), based upon a statistical cut off of 70% inhibition of activity (black line).
Figure 3: Quality control of the Timtec compound library primary screen. The location of active compounds was assessed based on the well location of the compound. Pie charts were constructed in order to identify any column (A) or row (B) bias in the assay. A trellis plot (C) indicates that the active compounds are distributed across different plates.
Figure 4: Identification of active compounds for further characterization. Compounds identified as active in the primary screen were re-tested in duplicate, at 3 different compound concentrations, 10 μM (A), 1 μM (B) and 0.1 μM (C). Compounds indicated in black are those exhibiting 50% inhibition of infection at 1 μM. These compounds were selected for dose-response analysis.
Figure 5: Schematic of the process used to identify compounds active against HIV infection of CEMxI 74 cells. From a primary screen of 26,500 compounds, 1,891 compounds were identified as active from the primary screen (in singlet). Of these, 170 exhibited 50% inhibition of infection at a compound concentration of 1 uM. Of the 170 compounds, 7 were identified that showed activity against HIV infection while also exhibiting low toxicity against CEMxI 74 cells. These 7 compounds can be classified into 3 structural classes or scaffolds.
Figure 6: A plot of positive and negative controls from the primary screen of the ChemBridge and Cerep compound libraries. The inhibition of HIV-I infection (%) is plotted. The Ε value of 0.56 indicates the separation between the Nevirapine (black) and DMSO (gray) controls and is indicative of a screen of high quality.
Figure 7: Plots of the compound data from the primary screen of the ChemBridge (A) and Cerep (B) compound libraries. Each circle represents one compound with 30,480 compounds tested in total (20,000 ChemBridge compounds and 10,480 Cerep compounds). Activity is expressed as a percentage inhibition of infection and was calculated on a per plate basis using the Nevirapine and DMSO controls from each plate. The compounds indicated in light gray in the upper right corner of each plot are those considered active against HIV infection in the assay (496 compounds from ChemBridge and 286 compounds from Cerep), based upon a statistical cut off of activity of greater than 6 standard deviations from the mean of the average percentage inhibition of infection (bracket indicates bin of active compounds). Figure 8: Identification of 6 compounds from the compounds libraries that are active against HIV-I infection of CEMx 174 cells while exhibiting low cellular toxicity. Activity of the compounds based on a decrease in fluorescence (RFU) is indicated in the dose-response curves on the left of each pair and the potency of each compound is indicated as a calculated EC50 value. Curves on the right side of each pair indicate the effect of the compound on cell number (■) and cell viability, in the presence (A) and absence (•) of HIV-I infection. The 6 compounds can be identified as belonging to 2 distinct structural scaffolds, cyclic-urea containing (A-D; Scaffold I; Timtec compound library) and amino biphenyl containing (E-F; Scaffold II; ChemBridge compound library). Data for known anti-HIV agents is included (G; Nevirapine, AZT and Saquinavir).
Table 1: Summary of derivative activity data for Scaffolds I and II which exhibited anti-HIV- 1 activity. Derivatives 1 to 323 are based on Scaffold I and derivative compounds 324 to 650 are based on Scaffold II. The number allocated to each compound and its corresponding activity value(s) are indicated to the right of the compound.
Examples
The invention is now further described by reference to the following examples which are intended to illustrate, not to limit the scope of the invention.
Materials and Methods
Host cells
The HIV infection screening assay is based on the GFP expression under HIV infection using a LTR-GFP fusion stably expressed in CEM cells. Upon infection by HIV (Bru strain), the viral DNA is integrated and expressed, the viral protein TAT is expressed and promotes the expression of the gene controlled by LTR (i.e. GFP). CEMxI 74 cells were cultured in RPMIl 640-Glutamax with 10% heat-inactivated fetal calf serum (Gibco), 100units/ml penicillin and streptomycin, 2mM sodium pyruvate, 2mM L-Glutamine at 37°C in 5% CO2.
To produce Bru virus, one million CEMxI 74 cells were infected with Bru virus (M.O.I, of 20) for 2 hr. After 24 hr incubation, the virus was transferred to a T-75 flask. After two weeks, ten million fresh cells were added to the flask. After a further two weeks 600 ml of virus- containing supernatant was collected, filtered and assayed for virus levels by a p24 assay. The virus is stocked and the cells are cultured in the same medium.
Chemical compounds
The small synthetic molecules from the screening libraries were resuspended in pure DMSO at an initial concentration of 1OmM (master plates) in 96 well polypropylene plates. To perform the primary screening, master plates of 96 well plates were reformatted to mother plates of the 384 well polypropylene plates (Greiner) and diluted to a final concentration of 2mM in pure DMSO. The compounds were kept frozen until use. For screening, the compound plates were thawed at room temperature. The compounds were directly added to the assay plates from the DMSO stock using an EVObird liquid handler (Evotec Technologies) which transfers 250nl of compound to achieve a dilution step of 1 :200. A fast mixing is performed to ensure complete diffusion of the small volume in the assay well.
Positive controls AZT, Nevirapine, and Saquinavir as well as negative control (DMSO) were added manually to each plate in columns 1-2 and 23-24.
During this study, a total of 56,980 compounds were tested. These compounds were sourced from Timtec (25,000 from the ActiProbe diverse library, 1,000 from the Kinase inhibitors ActiTargK library and 500 from the Protease inhibitors ActitargP library), ChemBridge (20,000 from the NOVACore library) and Cerep (10,480 from the Odyssey II library). They were initially screened at one concentration (primary screen, concentration = lOuM). The "positives" identified from the primary screen were then confirmed either with a first step at 3 concentrations (10, 1 and 0.IuM) to identify the most active and/or by 10 concentration serial dilutions (from lOuM to 0.25nM).
Virus infection assay scale-up
Cells (4,000/well) were dispensed using a Wellmate (Matrix) into 384 well Evotec glass plates pre-dispensed with lOul of compound diluted in PBS and incubated for 1 hr at 37 degrees, 5% CO2. Cells were then infected with Bru virus at multiplicity of infection (MOI) 3.7 and incubated for 5 days at 37 degrees, 5% CO2. The plates were read for fluorescence detection using Victor3. Cells were then stained with SytoόO (Invitrogen) for Ih for imaging by an automated fluorescent confocal microscope OperaTM (Evotec Technologies).
Image acquisition and data analysis
Confocal images were recorded on an automated fluorescent confocal microscope OperaTM (Evotec Technologies) using 20X-water objective (NA 0.70), 488nm, 635nm lasers and 488/635 primary dichroic mirror. Each image was then processed using Accapella software (Evotec technologies). ActivityBase (IDBS) and DecisionSite (Tibco Spotfire) were used to store and analyze the screening data. IC50 values were calculated in Prism (GraphPad software) from assay data using non-linear regression analysis and curve fitting to a sigmoidal dose-response (variable slope) model.
Example 1 : Development and validation of a visual, high-throughput HIV-I full replication In order to develop a high-throughput HIV-I full replication assay, reporter cell lines harbouring an integrated HIV mini-genome encoding only the EGFP gene under the transcriptional control of the genuine HIV LTR promoter were constructed. Briefly, CEMx 174 [10] cells were stably transfected with TRIP-LTR-EGFP vector particles [11] and cloned. Cell lines were selected that expressed minimal levels of basal EGFP in an uninfected state, but responded to HIV-I infection with high levels of EGFP fluorescence. Individual clones were screened for high susceptibility to HIV-I infection and the cell line with the most desirable phenotype (named CEMx 174 #CG8) was chosen for further characterization. To facilitate effective screening under high-throughput conditions, optimized conditions for cell density (4,000 cells/well), the amount of virus used for infection (10 ng p24/well, M.O.I, of 3.7) and the incubation time (5 days) in 384-well plates were determined.
Example 2: High Throughput Screening
A 56,980 member small molecule library from Timtec, ChemBridge and Cerep was screened using CEMxl74 cells. This library is composed of a diverse 25,000 compound set (Timtec - ActiProbe-25K), a diverse 20,000 compounds set (ChemBridge - NOVACore), a diverse 10,480 compound set (Cerep - Odyssey II), a 1,000 compound kinase focused library (Timtec - ActiTarg-K) and a 500 compound protease focused library (Timtec - ActiTarg-P). The primary screen of the Timtec compounds was performed in singlet and was of high quality, with a Ε of 0.45 for the entire screen (Figure 1). Based on a statistical cut off of 70% inhibition of infection, 1,891 compounds were identified as being active against HIV infection in CEMx 174 cells (Figure 2), an active rate of 7%. The plate and well locations of the active compounds were examined in order to identify any plate and/or well bias in the screen. The actives were found to be evenly distributed across the plates tested, except in the cases of structurally similar compounds that are grouped together on the plate (Figure 3). As the active rate is high, and only the most active compounds will be selected for further characterization, a 3 step process was used to identify the most active and structurally interesting compounds. The overall process is shown in Figure 5. The active compounds were cherry picked from the compound library and re-screened at 3 concentrations (10, 1 and 0.1 uM) in order to filter out false positives and gain a first measure of active potency and toxicity. Image analysis was used to assess compound toxicity. Fluorescence intensity was also used to quantify compound activity, and a resazurin-based cell viability assay was used to complement the image based cell toxicity data. This active confirmation screen was performed in duplicate with both cell lines. Of the 1,891 compounds tested, 1,237 were active at the primary screening concentration of 10 uM, an active confirmation rate of 65% (Figure 4A). Compounds were selected for further characterization based on their ability to inhibit HIV infection by 50% at the intermediate concentration of 1 uM (Figure 4B). Although a number of these compounds exhibited some toxicity based on cell number quantification and resazurin-based cell viability, they were included for further analysis. Thus, 170 compounds were selected for a third round of characterization. Among the compounds identified were a number of known anti-HIV compounds. These included colchicine, an inhibitor of microtubule polymerization and weak inhibitor of HIV replication [12], and floxuridine and 5-fluorouridine, inhibitors of thymidylate synthase that suppress replication of multidrug-resistant HIV type 1 when used in combination with zidovudine or stavudine [13]. In the third round of active compound selection, compounds were tested in 10 point dose-response experiments, using CEMx 174 cells. Compound activity was measured by FI and compound toxicity was assessed by image analysis and resazurin-based cell viability in the presence and absence of HIV. As with the 3 concentration experiment, the compounds were tested in duplicate. A total of 7 compounds from the Timtec compound library were determined to be active with cell protection. These 7 compounds were grouped into three scaffolds, one of which, Scaffold I (4 compounds; 8A-D) is disclosed herein. These four compounds, Timtec I, II, III and IV were purchased as required or Timtec II was also synthesized in-house and is also referred to as Compound 1 (Table 1) herein.
The primary screen of the ChemBridge and Cerep compounds was performed in duplicate and was of high quality, with a T of 0.56 for both replicates (Figure 6). Based on a statistical cut off of activity of greater than 6 standard deviations from the mean of the average percentage inhibition of infection, 782 compounds were identified as being active against HIV infection in CEMx 174 cells (Figure 7), an active rate of 3%. This lower hit rate as compared to the Timtec library is likely a result of screening in duplicate versus singlet, and the different chemical compositions of the libraries. Active compounds were tested in 10 point dose- response experiments using CEMx 174 cells. Compound activity was measured by FI and compound toxicity was assessed by image analysis and resazurin-based cell viability in the absence of HIV. Testing was performed in duplicate. A total of 7 compounds from the ChemBridge and Cerep compound libraries were determined to be active with cell protection. Two of these compounds were grouped as Scaffold II (ChemBridge compound library; 8E-F) which is disclosed herein. These two compounds, ChemBridge I and II were purchased from ChemBridge but were also synthesized in-house and are also referred to as Compound 278 and 280 respectively (Table 1) herein.
Based on the screening of the compound libraries mentioned herein, 4 Timtec (Scaffold I) and 2 ChemBridge (Scaffold II) compounds were identified that exhibited potent activity against HIV infection of CEMx 174 while also showing a cell protective effect, similar to that seen with HIV reference compounds (Figure 8G) and have additional structure activity relationship data disclosed herein.
To confirm that the 6 compounds are active against HIV infection and are not interfering with the fluorescence-based assay and are false positives, the activity of the compounds was assessed in a p24 activity assay. All 6 compounds showed a dose-dependent effect on the amount of p24 core antigen (not shown), confirming the results of the GFP-based assay, and indicating that the 6 compounds are hits against HIV infection.
Example 3: Derivatization of anti -HIV-I Scaffolds I and II
Scaffolds I and II underwent derivatization according to the methods outlined below. Scaffold I derivatives correspond to compounds 1 to 323 and Scaffold II derivatives correspond to compounds 324 to 650. Resulting derivatives were examined for inhibitory activity using the assay(s) described above and the results are summarized in Table 1.
General procedure for Biginelli Reaction
Figure imgf000030_0001
A mixture Of Yb(OTf)3 (0.05 mmol, 0.1 equiv), β-ketoester (0.5 mmol, 1.0 equiv), benzaldehyde (0.5 mmol, 1.0 equiv) and urea (0.5 mmol, 1.0 equiv) in THF (2 mL) was refluxed 20-30 h under Ar. After adding H2O (5 mL), the mixture was extracted with EtOAc (3 x 5 mL). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, n- Hexanes/EtOAc/AcOH, 50:50:0.5) to afford the desired pyrimidinone compound.
General procedure for transesterification
Figure imgf000030_0002
To a solution of β-keto ester (12.1 mmol, 1.0 equiv) and alcohol (14.5 mmol, 1.0 equiv) in toluene (24 mL) was added iodine (0.36 mmol, 0.03 equiv) at 25 0C. The reaction was heated to reflux for 12 h at 120 °C. After the starting material disappeared on TLC, the mixture was cooled to 25 0C and quenched by the addition of water (10 mL), sodium thiosulfate (20 mL) and extracted with CH2Cl2 (3 x 50 mL). The combined organic layers were washed with brine (50 mL) and dried over Na2SO4. After filtration and concentration in vacuo, the residue was purified via flash column chromatography on silica gel.
General procedure for EDC coupling for the synthesis of β-keto ester
Figure imgf000031_0001
To a solution of β-keto ester (69.4 mmol, 1.0 equiv) in water (70 mL) was added NaOH (138.7 mmol, 2.0 equiv) at 25 °C and stirred for 12 h. After 12 h at 25 °C, the reaction mixture was acidified with 6 N HCl to set pH < 2 at 0 °C. The resulting solution was concentrated in vacuo at a temperature below 30-35 °C. The residue was rinsed with EtOAc and filtered. The filtrate was dried over Na2SO4. After filtration and concentration in vacuo, the crude β-keto acid was subjected to the following step without further purification.
To a 0 °C solution of β-keto acid (52.9 mmol, 1.2 equiv) and alcohol (44.1 mmol, 1.0 equiv) in CH2Cl2 (88 mL) was added EDC (66.2 mmol, 1.5 equiv) and DMAP (66.2 mmol, 1.5 equiv) successively. The reaction mixture was warmed to 25 °C and stirred overnight. The reaction was quenched by the addition of saturated aqueous NH4Cl (50 mL). The phases were separated and the organic layer was washed with brine (100 mL), and then dried over Na2SO4. After filtration and concentration in vacuo, the residue was purified via flash column chromatography on silica gel.
Experimental procedure for Fractional Crystallization
Figure imgf000031_0002
The β-keto ester (1.0 g, .4.84 mmol), 3-hydroxybenzaldehyde (590 mg, 4.84 mmol), urea (290 mg, 4.84 mmol), and Yb(OTf)3 (30 mg, 0.484 mmol) were dissolved in THF (9.6 mL) and stirred under Argon for 24 h at 90 °C. After cooling to room temperature, the reaction was quenched by the addition of saturated aqueous NaHCO3 (10 mL) and extracted with CH2Cl2 (4 x 20 mL). The combined organic layers were dried over Na2SO4. After filtration and concentration in vacuo, the residue was purified via flash column chromatography (SiO2, n- Hexanes/EtOAc/AcOH = 5:1 :0.5) to give Biginelli adduct (1.31 g, 77%) as a pale yellow solid.
To a solution of Biginelli adduct (1.30 g, 3.69 mmol) in DMF (19 mL) was added TBSCl (834 mg, 5.53 mmol) and imidazole (377 mg, 5.53 mmol) at 25 °C. After stirring for overnight at 25 °C, the reaction mixture was quenched by the addition of H2O (30 mL), extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (30 mL) and dried over Na2SO4. After filtration and concentration in vacuo, the residue was purified via flash column chromatography (SiO2, «-Hexanes/Et2O = 5:1 → n-Hexanes/EtOAc = 2: 1 to 1 : 1 → CH2Cl2MeOH = 20: 1) to give a TBS protected product with a quantitative yield as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.81 (s, IH), 7.14-7.12 (m, 3H), 7.01- 6.98 (m, 3H), 6.70 (d, J= 7.2 Hz, IH), 6.61 (bs, IH), 6.60 (d, J= 8.4 Hz, IH), 5.48 (bs, IH), 5.21 (s, IH), 4.91 (s, 2H), 2.67-2.57 (m, 2H), 1.09-1.05 (m, 3H), 0.81 (s, 9H), 0.00 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 164.9, 156.1, 153.2, 152.5, 144.9, 136.0, 129.8, 128.4, 128.0, 127.9, 119.7, 119., 118.1, 99.9, 65.9, 55.4, 25.7, 25.3, 18.2, 12.5, -4.4; TLC R1 (CH2Cl2MeOH 10:1) = 0.51.
To a solution of TBS protected product (721 mg, 1.545 mmol) in MeOH (16 mL) was added 10% Pd on carbon (72 mg) and Et3N (215 μL, 1.545 mmol) at room temperature. The reaction mixture was hydrogenated with H2 gas (3 bar) for 3 h at 25 °C. The mixture was filtered through a pad of Celite and concentrated in vacuo. The residue was resuspended in water (20 mL) and acidified with IN HCl (~3 mL, pH < 2). The resulting suspension was sonicated for 10 min and then filtered and washed with H2O. After freeze drying in vacuo, the resulting acid (white solid, 529 mg, 91%) was used in the following step without further purification. To a suspension of acid (1.00 g, 2.655 mmol) in MeOH (20 mL) was added cinchonine (782 mg, 2.655 mmol) at 76 ° C. The resulting suspension was treated with the slow addition of MeOH (10 mL) at 76 °C. The resulting clear solution was slowly cooled to room temperature followed by overnight storage at -20 °C. The next day, the salt was filtered and rinsed with EtOH to give an acid/cinchonine salt (614 mg, 69%) as a white solid. The filtrate was concentrated in vacuo and the residue was resubjected to fractional crystallization in MeOH (10 mL) to give an additional acid/cinchonine salt (125 mg, 14%).
The salt above (80 mg) was resuspended in water (4 mL) and acidified with IN HCl (500 μL, pH < 2). The resulting suspension was sonicated for 10 min and then centrifuged to remove the upper layer. After repeating the same procedure one more time, the resulting solid was washed with H2O (3 x 4 mL) and freeze dried to give a salt-free acid (43 mg, 97%) as a white solid: 1H NMR (400 MHz, DMSO-J6) δ 8.90 (s, IH), 7.47 (s, IH), 7.03 (t, J= 8.0 Hz, IH), 6.70 (d, J= 7.6 Hz, IH), 6.58 (s, IH), 6.55 (d, J= 8.0 Hz, IH), 4.90 (d, J= 3.6 Hz, IH), 2.50- 2.47 (m, 2H), 0.94 (t, J= 7.2 Hz, 3H), 0.77 (s, 9H), 0.00 (s, 6H); 13C NMR (100 MHz, OMSO-d6) δ 167.5, 155.8, 153.4, 147.1, 130.1, 120.1, 119.2, 118.1, 54.2, 26.2, 24.6, 18.6,
13.8, -3.8; TLC Rf (CH2Cl2: MeOH 10:1) = 0.31.
To a solution of acid (20 mg, 0.053 mmol) and alcohol (18 mg, 0.159 mmol) in DMF (5 mL) was added EDC (31 mg, 0.159 mmol) and DMAP (32 mg, 0.266 mmol) at room temperature. The resulting mixture was heated at 50°C overnight under Argon. The reaction was quenched by the addition of saturated aqueous NH4Cl (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with H2O (2 x 5 mL) and brine (5 mL) successively, and then dried over Na2SO4. After filtration and concentration in vacuo, the residue was purified via preparative TLC (SiO2, 0.5 mm, CH2Cl2/Me0H = 10:1) to give an ester with a quantitative yield as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.75 (s, IH), 7.14 (t, J= 8.0 Hz, IH), 6.86 (d, J= 7.6 Hz, IH), 6.75-6.72 (m, IH), 6.71 (dd, J= 6.4, 1.6 Hz, IH), 5.59 (s, IH), 5.31 (d, J= 2.8 Hz, IH), 3.85-3.76 (m, 2H), 2.81-2.68 (m, 2H), 1.65-0.78 (m, 1 IH), 1.22 (t, J= 7.2 Hz, 3H), 0.94 (s, 9H), 0.14 (s, 6H); 13C NMR (100 MHz, CDCl3) δ D 157.9, 148.7, 145.8, 144.5, 137.6, 122.4, 112.3, 112.0, 110.7, 92.9, 62.0, 48.1, 29.8, 22.3,
18.9, 18.5, 18.3, 17.9, 10.8, 5.1; TLC Rf (CH2Cl2MeOH 10:1) = 0.47.
To a 0 0C solution of the above ester (0.053 mmol) in CH2Cl2 (2 mL) was added dropwise TBAF (IM in THF, 64 μL, 0.064 mmol). After 10 min at 0 °C, the reaction was quenched by the addition of saturated aqueous NaHCO3 (2 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10 mL) and dried over Na2SO4. After filtration and concentration in vacuo, the residue was purified via preparative TLC (SiO2, 0.5 mm, CH2Cl2MeOH = 10:1) to give a desilylated product 2a (17 mg, 86% over 2 steps) as a white solid. The enantiomeric excess was determined to be 98% ee by chiral HPLC (Daicel Chiralcel AD column, 0.85 mL/min, rc-Hexanes/z-PrOH = 75:25).
Figure imgf000034_0001
Cyclohexylmethyl 4-(3-hydroxyphenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5- carboxylate (1)
1H NMR (400 MHz, CD3OD) δ 7.08 (t, J= 7.6 Hz, IH), 6.73 (d, J- 7.2 Hz, IH), 6.70 (s, IH), 6.63 (d, J= 6.8 Hz, IH), 5.19 (s, IH), 3.88 (dd, J= 10.4, 5.6 Hz5IH), 3.70 (dd, J= 10.4, 5.6 Hz, IH), 2.32 (s, 3H), 1.59-1.42 (m, 6H), 1.11-1.06 (m, 3H), 0.84-0.76 (m, 2H). Enantiomerically pure forms were obtained by chiral HPLC (OD-H column, 25% /-PrOH in rø-Hexanes, 0.85 mL/min): Ia (R — 15.0 min, Ib tβ = 20.0 min.
Figure imgf000034_0002
Cyclohexylmethyl 6-ethyl-4-(3-hydroxyphenyl)-2-oxo-l,2,3»4-tetrahydropyrimidine-5- carboxylate (2)
1U NMR (400 MHz, OMSO-d6) δ 9.36 (s, IH), 9.15 (s, IH), 7.63 (s, IH), 7.09 (t, J= 8.0 Hz,
IH), 6.66-6.61 (m, 3H), 5.04 (d, J= 3.2 Hz, IH), 3.83 (dd, J= 10.8, 6.0 Hz, IH), 3.72 (dd, J=
10.8, 6.0 Hz, IH), 2.76-2.68 (m, IH), 2.66-2.57 (m, IH), 1.61-1.41 (m, 6H), 1.40-1.00 (m,
6H), 0.87-0.75 (m, 2H);
13C NMR (100 MHz, DMSO-^) δ 165.7, 158.1, 154.7, 152.9, 146.7, 129.9, 117.6, 114.8,
113.8, 98.8, 68.8, 54.6, 37.4, 29.72, 29.65, 26.4, 24.7, 13.7.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H column, 25% /-PrOH in rø-Hexanes, 0.85 mL/min): 2a fø = 8.0 min, 2b fø= 15.0 min.
Figure imgf000035_0001
Cyclohexylmethyl 6-cyclopropyl-4-(3-hydroxyphenyl)-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (3)
1H NMR (400 MHz, CDCl3) δ 7.10 (t, J= 8.0 Hz, IH), 6.77-6.69 (m, 2H), 6.61 (s, IH), 6.17 (s, IH), 5.28 (d, J= 2.4 Hz, IH), 3.87 (dd, J= 10.8, 6.4 Hz, IH), 3.80 (dd, J= 10.8 , 6.4 Hz, IH), 2.99-2.94 (m, IH), 1.64-1.47 (m, 6H), 1.12-1.04 (m, 3H), 0.95-0.74 (m, 6H); 13C NMR (100 MHz, DMSO-^) δ 171.1, 162.8, 158.2, 157.7, 151.4, 134.7, 122.3, 119.6, 118.5, 105.6, 73.6, 59.2, 42.2, 34.5, 34.4, 31.2, 30.7, 16.4, 12.7, 11.8.
Figure imgf000035_0002
Cyclohexylmethyl 4-(3-hydroxyphenyI)-2-oxo-6-((trimethylsilyl)ethynyl)-l,2,3)4- tetrahydropyrimidine-5-carboxylate (4)
1H NMR (400 MHz, CDCl3) δ 7.30 (s, IH), 7.07 (t, J= 8.0 Hz, IH), 6.77 (d, J= 6.8 Hz, 2H), 6.69 (d, J= 7.6 Hz, IH), 6.37 (s, IH), 5.28 (d, J= 2.4 Hz, IH), 3.95 (dd, J= 10.8, 6.8 Hz, IH), 3.84 (dd, J= 10.8, 6.8 Hz, IH), 1.65-1.54 (m, 5H), 1.24-1.07 (m, 4H), 0.88-0.79 (m, 2H), 0.22 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 165.0, 157.2, 153.9, 144.2, 130.6, 128.0, 118.9, 116.2, 114.2, 110.2, 106.6, 97.1, 70.8, 55.8, 37.6, 30.3, 27.0, 26.3, 0.1, 0.0.
Figure imgf000035_0003
Cyclohexylmethyl 6-ethynyl-4-(3-hydroxyphenyl)-2-oxo-l,2,3,4-tetrahydropyrimidine-5- carboxylate (5) 4 (100 mg, 0.23 mmol), K2CO3 (32 mg, 0.23 mmol) and anhydrous methanol (2 mL) was added to a 25 mL round-bottom flask. After stirring for 10 min at room temperature, the reaction mixture was diluted with ethyl acetate (10 mL), washed with aqueous 1 N HCl (2 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (SiO2, «-Hexanes/EtOAc/AcOH = 50:50: 0.5) to give 60 (62 mg, 74%): 1H NMR (400 MHz, CDCl3) δ 7.75 (s, IH), 7.12 (t, J= 7.8 Hz, IH), 6.84-6.72 (m, 3H), 6.00 (s, IH), 5.34 (s, IH), 3.95 (dd, J= 10.2, 6.2 Hz, IH), 3.83 (dd, J= 10.2, 6.2 Hz, IH), 3.42 (s, IH), 1.65-1.52 (m, 5H), 1.16-1.05 (m, 4H), 0.86-0.83 (m, 2H).
Figure imgf000036_0001
6
CyclohexylmethyI 6-cyclopropyl-4-(4-nitrophenyl)-2-oxo-l,2,3,4-tetrahydropyrimidine- 5-carboxylate (6)
1H NMR (400 MHz, CDCl3) δ 8.15 (d, J- 8.4 Hz, 2H), 7.45 (d, J= 8.4 Hz, 2H), 6.78 (s, IH), 6.17 (s, IH), 5.48 (d, J= 3.2 Hz, IH), 3.89-3.81 (m, 2H), 3.10-3.03 (m, IH), 1.65-1.44 (m, 6H), 1.28-0.77 (m, 9H); 13C NMR (IOO MHz, CDCl3) δ 165.7, 152.9, 151.4, 150.6, 147.7, 127.7, 124.4, 101.3, 69.8, 55.4, 37.4, 31.8, 29.90, 29.88, 26.4, 25.79, 25.76, 22.9, 14.3, 12.0, 7.6, 7.0.
Figure imgf000036_0002
7
CyclohexylmethyI 4-(4-aminophenyl)-6-cyclopropyl-2-oxo-l,2,3,4-tetrahydropyrimidine- 5-carboxylate (7)
1H NMR (400 MHz, DMOS-J6) δ 8.05 (s, IH), 7.53 (s, IH), 6.86 (d, J= 8.4 Hz, 2H), 6.47 (d, J= 8.4 Hz, 2H), 4.99 (s, IH), 4.98 (s, 2H), 3.81 (dd, J= 10.6, 6.2 Hz, IH), 3.74 (dd, J= 10.6, 6.2 Hz, IH), 3.13-3.06 (m, IH), 1.63-1.46 (m, 6H), 1.15-1.04 (m, 4H), 0.85-0.81 (m, 2H); 13C NMR (100 MHz, DMSO-^) δ 166.5, 153.1, 152.7, 148.6, 132.6, 127.6, 114.2, 101.6, 68.8, 54.2, 37.4, 29.78, 29.71, 26.5, 25.92, 25.91, 11.6, 7.8, 6.9.
Figure imgf000037_0001
Cyclohexylmethyl 6-cyclopropyl-4-(3-nitrophenyl)-2-oxo-l,2,3,4-tetrahydropyrimidine- 5-carboxylate (8)
1H NMR (400 MHz, CDCl3) δ 8.10 (m, 2H), 7.61 (d, J= 8.0 Hz, IH), 7.47 (t, J= 7.8 Hz, IH), 6.92 (s, IH), 6.36 (s, IH), 5.48 (d, J= 2.8 Hz, IH), 3.87 (dd, J= 10.8, 6.0 Hz, IH), 3.81 (dd, J = 10.8, 6.0 Hz, IH), 3.12-3.05 (m, IH), 1.73-1.43 (m, 6H), 1.28-0.76 (m, 9H); 13C NMR (IOO MHz, CDCl3) δ 165.7, 153.0, 151.7, 148.6, 146.0, 132.8, 130.1, 123.1, 122.0, 101.2, 69.8, 55.4, 37.3, 30.0, 26.4, 25.78, 25.77, 12.0, 7.6, 7.0.
Figure imgf000037_0002
Cyclohexylmethyl 4-(3-aminophenyl)-6-cyclopropyl-2-oxo-l,2,3,4-tetrahydropyrimidine- 5-carboxylate (9)
1U NMR (400 MHz, OMSO-d6) δ 8.07 (s, IH), 7.59 (s, IH), 6.92 (t, J= 7.8 Hz, IH), 6.42- 6.67 (m, 3H), 5.02-5.00 (m, 3H), 3.82 (dd, J= 10.4, 6.0 Hz, IH), 3.75 (dd, J= 10.4, 6.0 Hz, IH), 3.13-3.06 (m, IH), 1.61-1.47 (m, 6H), 1.54-1.04 (m, 4H), 0.85-0.79 (m, 5H).
Figure imgf000037_0003
10 Cyclohexylmethyl 4-(3-nitrophenyI)-2-oxo-6-((trimethylsilyl)ethynyl)-l,2,3»4- tetrahydropy rimidine-5-carboxylate (10)
1H NMR (400 MHz, CDCl3) δ 8.16 (s, IH), 8.11 (d, J= 8.0 Hz, IH), 7.66 (d, J= 7.6 Hz, IH), 7.48 (t, J= 8.0 Hz, IH), 7.21 (s, IH), 5.52 (d, J= 3.2 Hz, IH), 3.94 (dd, J= 10.6, 6.2 Hz, IH), 3.85 (dd, J= 10.6, 6.2 Hz, IH), 1.70-1.56 (m, 5H), 1.23-1.06 (m, 4H), 0.88-0.80 (m, 2H), 0.24 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 164.5, 152.9, 149.1, 145.2, 133.5, 130.6, 129.1, 123.9, 122.5, 108.9, 107.6, 96.7, 71.0, 55.7, 37.6, 30.4, 26.9, 26.2, 0.1, 0.0.
Figure imgf000038_0001
(£)-Cyclohexylmethyl 4-(3-hydroxyphenyl)-2-oxo-6-(prop-l-enyl)-l,2,354- tetrahydropy rimidine-5-carboxylate (11)
Figure imgf000038_0002
To a mixture of ethylcyanoacetate (5.17 g, 45.7 mmol) in water (5.00 mL) was added HNO3 (0.50 mL), and the resulting mixture was heated to 95-100 °C with stirring for 4 h. After cooling to room temperature, the mixture was concentrated under reduced pressure to give 2- cyanoacetic acid 11-a as a white solid (2.80 g, 72%): 1H NMR (400 MHz, CD3OD) δ 3.68 (s, 2H).
To a mixture of cyclohexane methanol (1.34 g, 11.76 mmol) in CH2Cl2 (20 mL) was added 11-a (1.00 g, 11.76 mmol), EDC (3.38 g, 17.6 mmol), and DMAP (0.72 g, 5.88 mmol) at 0 0C. After stirring at 25 °C for 12 h, the mixture was diluted with CH2Cl2 (30 mL), washed with water (20 mL), saturated aqueous NH4Cl (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography to afford the desired product 11-b (1.94 g, 91%): 1H NMR (400 MHz, CDCl3) δ 4.00 (s, 2H), 3.43 (s, 2H), 1.68-1.73 (m, 6H), 1.12-1.29 (m, 3H), 0.92-0.98 (m, 2H).
To a mixture of zinc powder (430 mg, 6.64 mmol), cyclohexylmethyl 2-cyanoacetate (300 mg, 1.66 mmol) and allyl bromide (210 μL, 2.49 mmol) in dry THF (8.3 mL) was added AlCl3 (88.5 mg, 0.66 mmol) at 0 0C. The mixture was allowed to warm to room temperature and stir for 2 h. The resulting mixture was cooled to 0 0C and aqueous 2 N HCl solution (20 mL) was added dropwise. The mixture was allowed to warm to room temperature and stirred for 24 h at room temperature. All organic volatiles were removed in vacuo and the remaining mixture was extracted with EtOAc. The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography to give β-keto ester 11-c (223 m, 60%): 1H NMR (400 MHz, CDCl3) δ 5.84-5.91 (m, IH), 5.13 (dd, J= 13.4, 7.8 Hz, 2H), 3.89 (d, J= 7.8 Hz, 2H), 3.27 (s, 2H), 3.26 (s, 2H), 1.59-1.71 (m, 6H), 0.94-1.23 (m, 3H), 0.88-1.13 (m, 2H).
A mixture of Yb(OTf)3 (76.0 mg, 0.12 mmol), β-keto ester 11-c (184 mg, 0.82 mmol), 3- hydroxybenzaldehyde (100 mg, 0.82 mmol) and urea (49.0 mg, 0.82 mmol) in THF (1.5 mL) was refluxed for 30 h under Argon. After adding H2O (5 mL), the mixture was extracted with EtOAc (3 x 5 mL). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, n-Hexanes/EtOAc/AcOH, 50:50:0.5) to afford Biginelli adduct 11 (179 mg, 59%): 1H NMR (400 MHz, CD3OD) δ 7.27 (d, J= 16.4 Hz, IH), 7.12 (t, J= 8.0 Hz, IH), 6.66-6.79 (m, 3H), 6.40-6.46 (m, IH), 5.28 (s, IH), 3.94 (dd, J= 10.8, 5.6 Hz, IH), 3.78 (dd, J= 10.6, 5.4 Hz, IH), 1.93 (d, J= 6.8 Hz, 3H), 1.06-1.78 (m, 12H), 0.80-0.89 (m, 2H); 13C NMR (100 MHz, CD3OD) δ 167.3, 159.0, 155.3, 146.7, 145.9, 134.5, 130.8, 124.8, 118.9, 115.7, 114.5, 102.1, 70.5, 56.2, 38.7, 30.8, 30.7, 27.1, 27.0, 19.0.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H column, 25% /-PrOH in π-Hexanes, 0.8 mL/min): 11a ΪR = 11.0 min, lib ΪR = 21.5 min.
Figure imgf000040_0001
12
Cyclohexylmethyl 4-(3-hydroxyphenyl)-6-isopropyl-2-oxo-l,2,3?4-tetrahydropyrimidine- 5-carboxylate (12)
1H NMR (400 MHz, DMSO-J6) δ 9.36 (s, IH), 8.82 (s, IH), 7.63 (s, IH), 7.09 (t, J= 8.0 Hz, IH), 6.66-6.61 (m, 3H), 5.04 (d, J= 3.2 Hz, IH), 4.21-4.14 (m, IH), 3.80 (dd, J= 10.8, 6.0 Hz, IH), 3.71 (dd, J= 10.8, 6.0 Hz, IH), 1.60-1.57 (m, 6H), 1.24-1.02 (m, 9H)3 0.86-0.76 (m, 2H); 13C NMR (100 MHz, DMSO-^) δ 166.0, 158.1, 157.2, 153,2, 146.5, 130.0, 117,6, 114.9, 113.8, 98.5, 68.9, 54.5, 37.4, 29.69, 29.61, 27.5, 26.4, 25.9, 19.87, 19.67.
Figure imgf000040_0002
Cyclohexylmethyl 4-(3-hydroxyphenyl)-2-oxo-6-propyl-l,2,3,4-tetrahydropyrimidine-5- carboxylate (13)
1H NMR (400 MHz, OMSO-d6) δ 9.31 (s, IH), 9.08 (s, IH), 7.59 (s, IH), 7.04 (t, J= 8.0 Hz, IH), 6.62-6.57 (m, 3H), 5.01 (d, J= 3.6 Hz, IH), 3.78 (dd, J= 10.8, 6.0 Hz, IH), 3.68 (dd, J= 10.8, 6.0 Hz, IH), 2.64-2.56 (m, 2H), 1.54-1.40 (m, 8H), 1.13-0.99 (m, 3H), 0.89-0.74 (m, 5H); 13C NMR (IOO MHZ, DMSO-^) δ 165.8, 158.1, 153.1, 152.9, 146.8, 129.9, 117.5, 114.8, 113.8, 99.4, 68.9, 54.6, 37.4, 33.0, 29.75, 29.69, 26.4, 25.9, 22.3, 14.4.
Figure imgf000040_0003
Cyclohexylmethyl 4-(3-hydroxyphenyl)-2-oxo-6-phenyl-l,23,4-tetrahydropyrimidine-5- carboxylate (14)
1H NMR (400 MHz, OMSO-d6) δ 9.43 (s, IH), 9.23 (s, IH), 7.79 (s, IH), 7.41-7.38 (m, 3H), 7.33-7.31 (m, 2H), 7.15 (t, J= 7.6 Hz, IH), 6.83-6.81 (m, 2H), 6.66 (dd, J= 8.2, 1.8 Hz, IH), 5.15 (d, J= 3.2 Hz, IH), 3.56-3.47 (m, 2H), 1.51-1.49 (m, 3H), 1.22-0.97 (m, 6H), 0.58-0.52 (m, 2H); 13C NMR (100 MHz, OMSO-d6) δ 165.9, 158.1, 152.7, 149.6, 146.4, 135.9, 130.1, 129.5, 129.0, 128.5, 117.6, 115.0, 100.9, 69.2, 54.7, 37.0, 29.47, 29.37, 26.3, 25.9.
Figure imgf000041_0001
Cyclohexylmethyl 4-(3-hydroxyphenyl)-2-oxo-6-(2-(triisopropylsilyIoxy)ethyl)-l,2,3,4- tetrahydropyrimidine-5-carboxylate (15)
1H NMR (400 MHz, CD3OD) δ 7.07 (t, J= 7.6 Hz, IH), 6.78-6.74 (m, 2H), 6.65 (d, J= 7.2 Hz, IH), 5.24 (s, IH), 3.99 (s, 2H), 3.89-3.87 (m, IH), 3.74-3.72 (m, IH), 3.19 (t, J= 6.8 Hz, IH), 2.92 (t, J= 6.4 Hz, IH), 1.60-1.44 (m, 8H), 1.07 (s, 21H), 0.91-0.80 (m, 3H); 13C NMR (100 MHz, CD3OD) δ 165.9, 157.6, 153.6, 149.3, 145.6, 129.4, 117.5, 114.4, 113.5, 101.4, 69.0, 62.0, 55.2, 37.4, 34.1, 29.6, 26.2, 25.7, 17.4, 11.9; TLC i?/(CH2Cl2:Me0H 10:1) = 0.68.
Figure imgf000041_0002
Cyclohexylmethyl 6-(2-hydroxyethyI)-4-(3-hydroxyphenyl)-2-oxo-l,2,3,4-tetrahydro- pyrimidine-5-carboxylate (16)
1H NMR (400 MHz, CD3OD) δ 7.07 (t, J= 7.6 Hz, IH), 6.77-6.74 (m, 2H), 6.65 (d, J= 8.0 Hz, IH), 5.23 (s, IH), 3.89 (dd, J= 10.4, 6.0 Hz, IH), 3.81 (t, J= 6.4 Hz, 2H), 3.71 (dd, J= 10.4, 6.0 Hz, IH), 3.02 (t, J= 6.4 Hz, 2H), 1.59-1.40 (m, 6H), 1.46-1.11 (m, 3H), 0.80-0.78 (m, 2H); 13C NMR (IOO MHZ, CD3OD) δ 166.0, 157.6, 153.6, 149.2, 145.6, 129.5, 117.7, 114.5, 113.3, 101.4, 69.0, 60.3, 55.2, 37.4, 34.0, 29.4, 26.1, 25.6; TLC 2^(CH2Cl2MeOH 10:1) = 0.45.
Figure imgf000042_0001
Cyclohexylmethyl 6-(chloromethyl)-4-(3-hydroxyphenyl)-2-oxo-l,2,3,4-tetrahydropyri- midine-5-carboxylate (17)
1H NMR (400 MHz5 CD3OD) δ 7.12 (t, J= 7.6 Hz, IH), 6.77 (t, J= 7.6 Hz, 2H), 6.68 (d, J= 8.0 Hz, IH), 5.27 (s, IH), 4.72 (d, J= 11.2 Hz, IH), 3.97-3.94 (m, IH), 3.80-3.76 (m, IH), 1.62-1.46 (m, 6H), 1.28-1.09 (m, 3H), 0.89-0.80 (m, 2H); 13C NMR (100 MHz, CD3OD) δ 165.0, 157.7, 153.6, 145.5, 144.9, 129.5, 117.5, 114.7, 113.4, 103.0, 69.5, 55.0, 38.3, 37.3, 29.4, 26.1, 25.7; TLC R1 (CH2Cl2: MeOH 10:1) = 0.25.
Figure imgf000042_0002
CyclohexyImethyl 4-(3-hydroxyphenyl)-l,6-dimethyl-2-oxo-l,2,3,4- tetrahy dropyrimidine-5-carboxylate (18)
1H NMR (400 MHz, CD3OD) δ 7.11 (t, J= 7.8 Hz, IH), 6.65-6.74 (m, 3H), 3.94 (dd, J= 10.8, 5.8 Hz, IH), 3.80 (dd, J= 10.8, 5.6 Hz, IH), 3.20 (s, 3H), 2.67 (s, 3H), 1.48-1.67 (m, 6H), 1.10-1.23 (m, 3H), 0.83-0.88 (m, 2H); 13C NMR (IOO MHz, CD3OD) δ 167.8, 159.0, 151.7, 146.4, 130.8, 118.7, 115.7, 114.3, 105.5, 70.5, 54.6, 38.7, 30.6, 27.0, 16.6.
Figure imgf000042_0003
Cyclohexylmethyl 6-ethyl-4-(3-hydroxyphenyl)-l-methyl-2-oxo-l,2,3>4- tetrahydropyrimidine-5-carboxylate (19)
1U NMR (400 MHz, CDCl3) δ 7.05 (t, J= 8.0 Hz, IH), 6.66-6.74 (m, 3H), 6.31-6.34 (m, IH), 5.22 (s, IH), 3.16 (s, 3H), 2.83-2.97 (m, 2H), 1.48-1.64 (m, 6H), 1.05-1.27 (m, 6H), 3.80-3.89 (m, 2H), 0.82-0.87 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 165.9, 156.8, 155.1, 154.6, 144.7, 129.9, 117.8, 115.0, 113.1, 103.8, 69.7, 53.2, 37.2, 29.7, 26.3, 25.7, 22.6, 14.2, 12.9.
Figure imgf000043_0001
Cyclohexylmethyl l-ethyl-4-(3-hydroxyphenyl)-6-methyl-2-oxo-l,2,354- tetrahydropyrimidine-5-carboxylate (20)
1H NMR (400 MHz, CD3OD) δ 7.08 (t, J= 7.8 Hz, IH), 6.66-6.74 (m, 3H), 6.61 (bs, IH), 5.71 (bs, IH), 5.24 (s, IH), 3.75 (m, 3H), 3.65-3.74 (m, IH), 2.49 (s, 3H), 1.48-1.67 (m, 6H), 1.05-1.19 (m, 6H), 0.80-0.86 (m, 2H); 13C NMR (100 MHz, CD3OD) δ 166.4, 156.8, 154.1, 148.4, 144.9, 129.9, 117.9, 115.0, 113.2, 104.8, 69.7, 53.8, 38.0, 37.3, 29.8, 29.7, 26.3, 25.7, 16.0, 15.0.
Figure imgf000043_0002
Cyclohexylmethyl l,6-diethyl-4-(3-hydroxyphenyl)-2-oxo-l,2,3?4-tetrahydropyrimidine- 5-carboxylate (21)
1H NMR (400 MHz, CDCl3) δ 7.09 (t, J= 7.8 Hz, IH), 6.67-6.75 (m, 3H), 5.84 (bs IH), 5.22 (s, IH), 3.94 (dd, J= 14.0, 6.8 Hz, IH), 3.61 (dd, J= 14.0, 6.8 Hz, IH), 3.02-3.07 (m, IH), 2.77-2.82 (m, IH), 1.50-1.65 (m, 6H), 1.06-1.26 (m, 9H), 0.78-0.85 (m, 2H).
Figure imgf000044_0001
Cyclohexylmethyl 4-(3-hydroxyphenyl)-6-methyl-2-oxo-l-propyl-l,2,354- tetrahydropyrimidine-5-carboxylate (22)
1H NMR (400 MHz, CD3OD) δ 7.11 (t, J= 7.8 Hz, IH), 6.66-6.75 (m, 3H), 5.22 (s, IH), 3.93
(dd, J= 10.8, 5.6 Hz, IH), 3.81-3.89 (m, IH), 3.78 (dd, J= 10.8, 5.6 Hz, IH), 3.52-3.59 (m,
IH), 1.44-1.66 (m, 8H), 1.08-1.25 (m, 3H), 0.78-0.92 (m, 2H); 13C NMR (100 MHz, CD3OD) δ 167.9, 158.9, 155.6, 150.9, 146.4, 130.7, 118.6, 115.6, 114.4, 105.5, 70.5, 54.6, 45.2, 38.7,
30.7, 27.4, 26.9, 24.2, 16.3, 11.4.
CyclohexylmethyI 6-ethyl-4-(3-hydroxyphenyl)-2-oxo-l-propyl-l,2,3»4- tetrahydropyrimidine-5-carboxylate (23)
1H NMR (400 MHz, CDCl3) δ 7.08 (t, J= 7.8 Hz, IH), 6.66-6.75 (m, 3H), 5.84 (bs, IH), 5.22 (s, IH), 3.81-3.92 (m 3H), 3.36-3.42 (m, IH), 3.08-3.20 (m, IH), 2.62-2.66 (m, IH), 0.78- 1.65 (m, 18H).
Figure imgf000044_0003
Cyclohexylmethyl 4-(3-hydroxyphenyl)-6-methyl-2-oxo-l-phenyl-l,2,3,4- tetrahydropyrimidine-5-carboxyIate (24) 1H NMR (400 MHz, CD3OD) δ 7.41-7.50 (m, 3H), 7.18-7.26 (m, 3H), 6.87-6.90 (m, 2H), 6.71-6.74 (m, IH), 5.35 (s. IH), 3.95 (dd, J= 10.6, 5.8 Hz, IH), 3.82 (dd, J= 10.6, 5.8 Hz, IH), 2.16 (s, 3H), 1.49-1.67 (m, 6H), 1.13-1.22 (m, 3H), 0.83-0.88 (m, 2H).
Figure imgf000045_0001
(S)-Cyclohexylmethyl 4-(3-acetoxyphenyl)-l-acetyl-6-ethyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (25)
1H NMR (400 MHz, CDCl3) δ 7.84 (s, IH), 7.30 (t, J= 7.8 Hz, IH), 7.16 (d, J= 7.6 Hz, IH), 7.00-7.98 (m, 2H), 5.82 (s, IH), 5.36 (d, J= 2.0 Hz, IH), 3.86 (dd, J= 11.0, 6.2 Hz, IH), 3.78 (dd, J= 11.0, 6.2 Hz, IH), 2.83-2.78 (m, IH), 2.69-2.64 (m, IH), 2.26 (s, 3H), 1.66-1.44 (m, 6H), 1.22-1.06 (m, 6H), 0.87-0.77 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 169.5, 165.4, 153.4, 151.1, 145.5, 130.0, 124.1, 121.4, 120.0, 100.3, 69.7, 55.6, 37.3, 29.89, 29.87, 26.5, 25.9, 25.6, 21.4, 12.7.
Figure imgf000045_0002
Cyclohexylmethyl l-benzyI-4-(3-hydroxyphenyl)-6-methyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (26)
1H NMR (400 MHz, CDCl3) δ 7.21-7.30 (m, 3H), 7.10-7.15 (m, 3H), 6.69-6.77 (m, 3H), 5.31 (s, IH), 3.93 (dd, J= 10.8, 5.8 Hz, IH), 3.79 (dd, J= 10.8, 5.8 Hz, IH), 2.44 (s, 3H), 1.11- 1.65 (m, 9H), 0.80-0.84 (m, IH).
Figure imgf000046_0001
Cyclohexylmethyl l-benzyl-6-ethyI-4-(3-hydroxyphenyl)-2-oxo-l,2,3?4- tetrahydropyrimidine-5-carboxylate (27)
1H NMR (400 MHz, CDCl3) δ 7.06-7.24 (m, 6H), 6.65-6.75 (m, 3H), 6.02 (bs, IH), 5.28 (s, IH), 5.23 (d, J= 16.2 Hz, IH), 4.74 (d, J= 16 Hz, IH), 3.80 (m 2H), 2.96-3.12 (m, IH), 2.65- 2.69 (m, IH), 0.93-1.64 (m, 12H), 0.80-0.85 (m, 2H).
Figure imgf000046_0002
28
Cyclohexylmethyl l-(2,4-dimethoxybenzyl)-4-(3-methoxyphenyl)-6-methyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (28)
Figure imgf000046_0003
28
To a solution of 2,4-dimethoxybenzylamine hydrochloride (5.44 g, 26.7 mmol) in water (111 mL) was added urea (6.4 g, 1.07 mmol) and concentrated HCl (31 mL, 0.374 mmol) and the mixture was then refluxed for 6 h. The resulting mixture was cooled to room temperature and further cooled with ice. The precipitate formed was filtered off to give 2,4- dimethoxybenzylurea as a white solid (2.58 g, 46%): 1H NMR (400 MHz, OM&O-dβ) δ 7.11 (d, J= 8.8 Hz, IH), 6.57 (d, J= 2.0 Hz, IH), 6.50 (dd, J= 8.2, 2.0 Hz, IH), 6.14 (t. J= 5.8 Hz, IH), 5.50 (bs, 2H), 4.08 (d, J= 6.0 Hz, 2H), 2.12 (bs, IH).
A mixture of 3-methoxybenzaldehyde (863 mg, 6.34 mmol), β-ketoester (1.25 g, 6.34 mmol), 2,4-dimethoxybenzylurea (2.0 g, 9.51 mmol) and acetic acid (0.54 mL, 9.51 mmol) was heated with stirring at 90 °C for 12 h. The mixture was cooled to room temperature and water (10 mL) was added. The mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography to afford Biginelli adduct 28 (2.28 g, 71%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.12 (d, J= 8.0 Hz, IH), 6.92 (d, J= 8.2 Hz, IH), 6.68-6.72 (m, 3H), 6.37-6.38 (m, 2H), 5.25 (s, IH), 4.97 (d, J = 16.0 Hz, IH), 4.80 (d, J= 16.0 Hz, IH), 3.82-3.92 (m, 2H), 3.70 (s, 3H), 3.77 (s, 3H), 3.67 (s, 3H), 1.50-1.64 (m, 6H), 1.08-1.18 (m, 3H), 0.80-0.89 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 166.5, 160.2, 158.9, 157.8, 154.6, 150.3, 142.6, 129.6, 128.9, 119.2, 118.6, 113.0, 112.8, 104.2, 103.8, 98.4, 69.7, 55.5, 55.3, 55.2, 42.1, 37.3, 34.8, 30.0, 29.8, 25.9, 25.7, 16.1.
Figure imgf000047_0001
29
Cyclohexylmethyl l-(2,4-dimethoxybenzyl)-4-(3-methoxyphenyI)-3,6-dimethyl-2-oxo- l,2,3?4-tetrahydropyrimidine-5-carboxylate (29)
1H NMR (400 MHz, CDCl3) δ 7.11 (d, J= 8.0 Hz, IH), 7.01 (d, J= 9.2 Hz, IH), 6.70-6.75 (m, 3H), 6.37-6.38 (m, 2H), 5.21 (s, IH), 4.95 (d, J= 16.4 Hz, IH), 4.84 (d, J= 16 Hz, IH), 3.84- 3.90 (m, 2H), 3.76 (s, 3H), 3.69 (s, 3H), 3.67 (s, 3H), 2.92 (s, 3H), 2.43 (s, 3H), 1.55- 1.65 (m, 6H), 1.11-1.20 (m, 3H), 0.86-0.92 (m, 2H); 13C NMR (400 MHz, CDCl3) δ 166.5, 160.2, 159.9, 157.7, 153.8, 150.1, 142.6, 129.6, 129.1, 119.2, 118.6, 113.0, 112.8, 104.2, 103.8, 98.4, 69.7, 61.0, 55.5, 55.3, 55.2, 42.1, 37.3, 34.8, 30.0, 29.9, 25.9, 25.8, 16.5.
Figure imgf000048_0001
30
Cyclohexylmethyl 3-benzyl-l-(2,4-dimethoxyben2yl)-4-(3-methoxyphenyl)-6-methyl-2- oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate (30)
1H NMR (400 MHz, CDCl3) δ 7.21-7.30 (m, 5H), 7.01- 7.19 (m, 2H), 6.62- 6.72 (m, 3H), 6.33- 6.37 (m, 2H), 5.32 (d, J= 15.2 Hz, IH), 5.17 (s, IH), 4.97 (d, J= 16 Hz, IH), 4.83 (d, J = 16 Hz, IH), 3.78- 3.83 (m, IH), 3.75 (s, 3H), 3.65- 3.70 (m, 3H), 3.64 (s, 3H), 3.60 (s, 3H), 2.43 (s, 3H), 1.56- 1.58 (m, 3H), 1.36- 1.44 (m, 3H), 1.03- 1.10 (3H), 0.69- 0.75 (m, 2H); 13C NMR (400 MHz, CDCl3) δ 166.0, 160.0, 159.6, 157.6, 153.9, 150.0, 142.4, 136.6, 129.4, 129.2, 128.0, 127.3, 118.9, 118.2, 112.7, 112.5, 103.9, 103.8, 98.2, 69.1, 56.4, 55.2, 54.9, 54.9, 48.9, 42.0, 36.9, 29.5, 29.4, 26.1, 25.7, 25.6, 16.1.
Figure imgf000048_0002
31
Cyclohexylmethyl l-(2,4-dimethoxybenzyl)-4-(3-hydroxyphenyl)-6-methyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxyIate (31)
1U NMR (400 MHz, CDCl3) δ 7.16- 7.20 (m, IH), 6.89 (d, J= 8.0 Hz, IH), 6.79 (t, J= 7.8 Hz, 2H), 6.74 (s, IH), 6.47 (s, IH), 6.38 (d, J= 8.4 Hz, IH), 5.00 (d. J= 16 Hz, IH), 5.31 (s, IH), 4.76 (d, J= 16 Hz, IH), 3.81- 3.95 (m, 2H), 3.81 (s, 3H), 3.78 (s, 3H), 3.70 (s, 3H), 2.20 (s, 3H), 1.48- 1.65 (m, 6H), 1.07-1.19 (m, 3H), 0.81-0.90 (m, 2H); 13C NMR (400 MHz, CDCl3) δ 166.5, 160.6, 160.1, 157.9, 156.9, 150.6, 145.1, 129.4, 128.7, 118.4, 118.0, 112.5, 112.1, 104.1, 97.9, 69.2, 54.5, 54.3, 40.7, 37.4, 29.5, 29.4, 26.0, 25.6, 15.1.
Figure imgf000049_0001
Cyclohexylmethyl 4-(3-hydroxyphenyl)-3,6-dimethyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (32)
1R NMR (400 MHz, CDCl3) δ 7.07 (t, J= 7.8 Hz, IH), 6.81 (d, J= 8.0 Hz, IH), 6.67- 6.73
(m, 2H), 6.22-6.30 (m, IH), 5.19 (s IH), 3.93 (dd, J= 10.8, 6.4 Hz, IH), 3.79 (dd, J= 10.8,
5.6 Hz, IH), 2.92 (s, 3H), 2.49 (s, 3H), 1.48- 1.64 (m, 6H), 1.12- 1.22 (m 3H), 0.82- 0.88 (m,
2H).
Figure imgf000049_0002
Cyclohexylmethyl 3-benzyI-4-(3-hydroxyphenyl)-6-methyl-2-oxo-l,2,3?4- tetrahydropyrimidine-5-carboxylate (33)
1H NMR (400 MHz, CDCl3) δ 7.19-7.29 (m, 5H), 6.97 (t, J= 7.4 Hz, IH), 6.85 (d, J=8.0 Hz, IH), 6.22-6.61 (m, 3H), 6.62 (m IH), 5.24 (d, J= 15.2 Hz, IH), 5.07 (s, IH), 3.74 (dd, J = 11.0, 6.2 Hz, IH), 3.68 (d, J= 15.2 Hz, IH), 3.63 (dd, J= 10.8, 6.0 Hz, IH), 2.47 (s, 3H), 1.53-1.60 (m, 3H), 1.32-1.41 (m, 3H), 0.96-1.07 (m, 3H), 0.63-0.72 (m, 2H).
Figure imgf000049_0003
34
CycIohexylmethyI 3-ethyl-l-(2,4-dimethoxybenzyl)-4-(3-methoxyphenyl)-6-methyl-2- oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate (34) 1H NMR (400 MHz, CDCl3) δ 7.08 (t, J= 8.0 Hz, IH), 6.98 (d, J= 9.2 Hz, IH), 6.69-6.74 (m, 3H), 6.34-6.37 (m, 2H), 5.34 (s, IH), 4.98 (d, J= 16.0 Hz, IH), 4.79 (d, J= 16.0 Hz, IH), 3.91 (d, J= 6.4 Hz, 2H), 3.77-3.84 (m, IH), 3.76 (s, 3H), 3.67 (s, 3H), 3.62 (s, 3H), 2.94-3.00 (m, IH), 2.42 (s, 3H), 1.57-1.70 (m, 7H), 1.08-1.27 (m, 8H), 0.86-0.90 (m, 3H).
Figure imgf000050_0001
CyclohexyImethyl 3-ethyl-4-(3-hydroxyphenyl)-6-methyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxyIate (35)
1H NMR (400 MHz, CDCl3) δ 7.05 (t, J= 7.8 Hz, IH), 6.65-6.78 (m. 4H), 6.20-6.30 (m, IH), 5.30 (s, IH), 3.94 (dd, J= 10.8, 6.0 Hz, IH), 3.85 (dd, J= 10.8, 6.0 Hz, IH), 3.65-3.72 (m, IH), 3.08-3.13 (m, IH), 2.46 (s, 3H), 1.27-1.68 (m, 6H), 1.16-1.22 (m, 3H), 1.10 (t, J= 7.0 Hz, 3H), 0.88-0.92 (m, 2H).
General procedure for nitrogen/sulfur containing derivatives
Figure imgf000050_0002
.AcOH
The β-keto ester (0.50 mmol, 1.0 equiv), aldehyde (0.45 mmol, 0.9 equiv), guanidine (0.54 mmol, 1.1 equiv), and NaHCO3 (1.83 mmol, 3.7 equiv) were dissolved in DMF (1.0 mL) and stirred under Ar for 2-24 h at 70 0C. After cooling to room temperature, the crude reaction mixture was poured into water and extracted with CH2Cl2 (3 x 10 mL). The combined organic layers were washed with brine (10 mL) and dried over Na2SO4. After filtration and concentration in vacuo, the residue was purified by flash column chromatography on silica gel.
Figure imgf000051_0001
The β-keto ester (0.82 mmol, 1.0 equiv), aldehyde (0.82 mmol, 1.0 equiv), thiourea (1.23 mmol, 1.5 equiv), and VCl3 (0.082 mmol, 0.1 equiv) were dissolved in acetonitrile (2 mL) and stirred under Ar for 4 h at 90 °C. After cooling to room temperature, the crude reaction mixture was quenched with a saturated aqueous NaHCO3 (2 mL), and then extracted with CH2Cl2 (3 x 5 mL). The combined organic layers were washed with brine (5 mL) and dried over Na2SO4. After filtration and concentration in vacuo, the residue was purified via flash column chromatography (SiO2, «-Hexanes/EtOAc = 2:1) to give corresponding Biginelli adducts.
Figure imgf000051_0002
36
Cyclohexylmethyl 2-amino-6-(3-hydroxyphenyl)-4-methyl-l,6-dihydropyrimidine-5- carboxylate acetate (36)
1H NMR (400 MHz, CD3OD) δ 7.06 (t, J= 8.0 Hz, IH), 6.82-6.62 (m, 3H), 5.26 (s, IH), 3.88-3.83 (m, IH), 3.68-3.64 (m, IH), 2.35 (s, IH), 1.82 (s, IH), 1.55-1.52 (m, 3H), 1.44-1.39 (m, 3H), 1.06-1.03 (m, 4H), 0.74-0.69 (m, IH); 13C NMR (100 MHz, CD3OD) δ 179.6, 165.1, 158.0, 151.5, 144.8, 143.6, 129.8, 117.5, 115.1, 113.3, 103.2, 69.3, 53.3, 37.3, 29.4, 26.1, 25.6, 22.8, 16.6; TLC Rf (EtO Ac: MeOH: AcOH 9:1 :0.5) = 0.23.
Figure imgf000051_0003
37 CyclohexyImethyl 6-ethyl-4-(3-hydroxyphenyl)-2-(lH-pyrazol-l-yl)-l,4-dihydropyrimi- dine-5-carboxylate (37)
1H NMR (400 MHz, CD3OD) δ 7.64 (s, IH), 7.56 (s, IH), 7.06 (t, J= 7.6 Hz, IH), 6.82 (m, 2H), 6.65 (d, J= 8.0 Hz, IH), 6.42 (s, IH), 6.29 (s, IH), 5.55 (s, IH), 3.92-3.88 (m, IH), 3.76- 3.72 (m, IH), 2.92-2.83 (m, 2H), 1.63-1.03 (m, HH), 0.88-0.80 (m, 3H); 13C NMR (100 MHz, CD3OD) δ 173.2, 169.3, 166.6, 157.6, 146.1, 142.4, 129.4, 128.2, 118.0, 114.5, 113.8, 108.7, 104.5, 102.2, 78.4, 63.7, 54.4, 37.4, 29.2, 26.5, 12.1; TLC i?/(«-Hexanes:EtOAc 5:1) = 0.18.
Figure imgf000052_0001
CyclohexylmethyI 6-ethyl-4-(3-hydroxyphenyl)-2-(lH-pyrazol-l-yl)-l,4-dihydropyrimi- dine-5-carboxylate (38)
1H NMR (400 MHz, CD3OD) δ 7.64 (s, IH), 7.56 (s, IH), 7.06 (t, J= 7.6 Hz, IH), 6.82 (m, 2H), 6.65 (d, J= 8.0 Hz, IH), 6.42 (s, IH), 6.29 (s, IH), 5.55 (s, IH), 3.92-3.88 (m, IH), 3.76- 3.72 (m, IH), 2.92-2.83 (m, 2H), 1.63-1.03 (m, HH), 0.88-0.80 (m, 3H); 13C NMR (100 MHz, CD3OD) δ 173.2, 169.3, 166.6, 157.6, 146.1, 142.4, 129.4, 128.2, 118.0, 114.5, 113.8, 108.7, 104.5, 102.2, 78.4, 63.7, 54.4, 37.4, 29.2, 26.5, 12.1; TLC J?/(ra-Hexanes:EtOAc 5:1) = 0.18.
Figure imgf000052_0002
Cyclohexylmethyl 4-(3-hydroxyphenyl)-6-methyl-2-thioxo-l,2,3,4-tetrahydropyrimi- dine-5-carboxylate (39)
1U NMR (400 MHz, CD3OD) δ 7.11 (t, J= 4.0 Hz, IH), 6.75-6.66 (m, 3H), 5.46 (s IH), 3.94- 3.90 (m, IH), 3.76-3.72 (m, IH), 2.35 (s. 3H), 1.96-1.45 (m, 3H), 1.30-1.11 (m, 5H), 0.89- 0.78 (m, 3H); 13C NMR (100 MHz, CD3OD) δ 174.6, 174.1, 166.2, 157.7, 144.9, 144.7, 129.6, 117.9, 114.8, 113.5, 101.7, 69.2, 55.3, 37.4, 29.5, 26.2, 25.7, 19.6, 16.6.
Figure imgf000053_0001
Cyclohexylmethyl 6-ethyl-4-(3-hydroxyphenyl)-2-thioxo-l,2,3,4-tetrahydropyrimidine-5- carboxylate (40)
1H NMR (400 MHz, CD3OD) δ 7.11 (t, J= 8.0 Hz, IH), 6.75-6.66 (m, 3H), 5.21 (s, IH), 3.94-3.90 (m, IH), 3.77-3.73 (m, IH)5 2.84-2.70 (m, 2H), 1.65-1.45 (m, 3H), 1.30-1.08 (m, 5H), 0.90-0.79 (m, 3H); 13C NMR (100 MHz, CD3OD) δ 175.1, 165.7, 157.7, 150.5, 144.7, 129.5, 117.8, 114.7, 113.5, 100.8, 69.2, 55.2, 37.4, 31.5, 29.5, 25.9, 23.9, 22.5, 13.2, 12.0.
Figure imgf000053_0002
Cyclohexylmethyl 4-(3-hydroxyphenyl)-6-methyl-2-oxo-l,2-dihydropyrimidine-5- carboxylate (41)
1 (50 mg, 0.15 mmol), NaHCO3 (63 mg, 0.75 mmol) and acetone (1.50 mL) were added to a 50 mL round bottom flask containing a stir bar. To this suspension was added a solution of CAN (247 mg, 0.45 mmol) in water (0.20 mL), and the mixture was stirred for 1 h at -5 °C followed by overnight stirring at room temperature under Argon. The resulting mixture was diluted with CH2Cl2 (10 mL) and filtered. The residue was washed with CH2Cl2 (2 x 10 mL). The combined CH2Cl2 layers were washed with saturated NH4Cl (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography to afford 41 (10 mg, 20%): 1H NMR (400 MHz, CD3OD) δ 8.12 (d, J= 6.4 Hz, IH), 7.25 (s, IH) 7.11 (d, J= 8.0 Hz, IH), 6.94 (s, IH), 3.78-3.82 (m, 2H), 1.07-1.60 (m, 9H), 0.67-0.71 (m, 2H).
Figure imgf000054_0001
Ethyl 6-(4-methoxyphenyl)-2,4-dioxo-l ,2,3,4-tetrahy dropyrimidine-5-carboxyIate (42)
1H NMR (400 MHz, CD3OD) δ 7 .42 (d, J= 8.8 Hz, 2H), 7.04 (d, J= 8.8 Hz, 2H), 4.03 (q, J = 7.2 Hz, 2H), 3.86 (s, 3H), 1.01 (t, J= 7.2 Hz, 3H).
Figure imgf000054_0002
Ethyl 6-(chIoromethyl)-4-(3-hydroxyphenyl)-2-oxo-l,2,3?4-tetrahydropyrimidine-5- carboxylate (43)
1H NMR (400 MHz, CD3OD) δ 7.10 (t, J= 7.6 Hz, IH), 6.77 (d, J= 8.0 Hz, IH), 6.76 (bs, IH), 6.67 (dd, J= 8.0, 2.0 Hz, IH), 5.27 (s, IH), 4.81 (d, J= 11.6 Hz, IH), 4.65 (d, J= 11.6 Hz, IH), 4.10-4.06 (m, 2H), 1.15 (t, J= 6.8 Hz, 3H); 13C NMR (100 MHz, CD3OD) δ 165.0, 157.6, 153.8, 145.1, 145.1, 129.6, 117.6, 114.7, 113.3, 103.4, 60.5, 55.0, 38.5, 13.2; TLC R1 (CH2Cl2:Me0H 10:1) = 0.36.
Figure imgf000054_0003
4-(3-Hydroxyphenyl)-3,4-dihydrofuro[3,4-d]pyrimidine-2,5(l/ir,7H)-dione (44)
Biginelli adduct 43 (1.0 mmol) was heated neat in an oil bath at 210 °C (bath temperature) for approximately 6 min. The resulting solid was purified by recrystallization from MeOH to afford furopyrimidine 44: 1K NMR (400 MHz, CD3OD) δ 7.14 (t, J= 8.0 Hz, IH), 6.82 (bd, J = 8.0 Hz, IH), 6.79 (bs, IH), 6.72-6.69 (m, IH), 5.23 (s, IH), 4.83-4.73 (m, 2H); 13C NMR (100 MHz, CD3OD) δ 171.4, 159.3, 157.7, 143.5, 129.7, 117.6, 115.1, 113.3, 98.4, 65.6, 53.5; TLC i?/(CH2Cl2:Me0H 10:1) = 0.14.
Figure imgf000055_0001
Ethyl 4-(3-hydroxyphenyl)-2-oxo-6-(2-(triisopropylsilyloxy)ethyl)-l,2,3>4- tetrahydropyrimidine-5-carboxylate (45)
1. NaH1 THF (COCI)2 10 mol% SnCI2
HO^^^OH
2. TIPSCI Tipscr "OH
DMSO, Et3N* TIPSO H N2^CO2Et 92 % CH2CI2
45-a 93% 45-b CH2CI2
25 °C, 16 h
86%
Figure imgf000055_0002
45
Sodium hydride (60% dispersion in mineral oil, 1.66 g, 41.5 mmol) was suspended in THF (41 mL) and a solution of 1,3-propandiol (3 rnL, 41.5 mmol) in THF (20 mL plus 2 niL rinse) was added slowly via a cannula over 10 min at 25 °C. The white suspension was stirred for 45 min, and then a solution of triisopropylsilyl chloride (8.0 g, 41.5 mmol) in THF (20 mL) was added via a cannula over 5 min. The resulting white suspension was stirred for 7 h, and then quenched with a mixture of saturated aqueous NaHCO3 (50 mL) and H2O (30 mL). The mixture was extracted with Et2O (3 x 100 mL) and dried over Na2SO4. After filtration and concentration in vacuo, the residue was purified by flash column chromatography (SiO2, n- Hexanes/Et2O = 10:1 -→ 2:1) to give compound 45-a (8.86 g, 92%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 3.91 (t, J= 5.2 Hz, 2H), 3.81 (t, J= 5.6 Hz, 2H), 1.79-1.77 (m, 2H), 1.12-1.04 (m, 21H); 13C NMR (100 MHz, CDCl3) δ 63.7, 62.8, 34.1, 17.9, 11.8; TLC R1 (rc-Hexanes:Et2O 5:1) = 0.11.
To a -78 0C solution of oxalyl chloride (3.15 mL, 36.7 mmol) in CH2Cl2 (240 mL) was added slowly dimethyl sulfoxide (5.21 mL, 73.4 mmol). Gas evolution was observed. After 15 min, a solution of compound 45-a (7.11 g, 30.6 mmol) in CH2Cl2 (50 mL plus 2 niL rinse) was added via a cannula over 8 min. The cloudy solution was stirred at -78 0C for 30 min, and then Et3N (16.6 mL, 119.3 mmol) was added via a syringe over 7 min. The resulting solution was stirred at -78 °C for 50 min, and then warmed to 25 °C and stirred for an additional 30 min. The mixture was quenched at 25 °C with saturated aqueous NH4Cl (150 mL). The organic layer was washed with brine (100 mL) and dried over Na2SO4. After filtration and concentration in vacuo, the residue was purified by flash column chromatography (SiO2, n- Hexanes/Et2O = 10:1) to give aldehyde 45-b (6.55 g, 93%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 9.82 (t, J= 1.6 Hz, IH), 4.08-4.04 (m, 2H), 2.61-2.57 (m, 2H), 1.10-0.98 (m, 21H); 13C NMR (100 MHz, CDCl3) δ 202.2, 57.9, 46.7, 17.9, 11.9; TLC i?/(«-Hexanes:Et2O 5:1) - 0.42.
To a 0 "C suspension of aldehyde 45-b (2.0 g, 8.68 mmol) and tin (II) chloride (165 mg, 0.867 mmol) in CH2Cl2 (87 mL) was added slowly ethyl diazoacetate (1.28 mL, 12.15 mmol) via a syringe over 15 min. Significant gas evolution was observed. The bright yellow suspension was stirred at 25 0C for 16 h, and then additional ethyl diazoacetate (91 μL, 0.87 mmol) was added. Since no additional gas evolution was observed, the mixture was quenched by the addition of IN HCl (50 mL) and extracted with CH2Cl2 (50 mL). The combined organic layers were washed with IN HCl (50 mL), and dried over Na2SO4. After filtration and concentration in vacuo, the residue was purified by flash column chromatography (SiO2, n- Hexanes only → n-Hexanes/Et2O = 10:1) to give β-keto ester 45-c (2.36 g, 86%) as a pale yellow oil: 1H NMR (400 MHz, CDCl3) δ 4.17 (q, J= 7.2 Hz, 2H), 3.97 (t, J= 6.4 Hz, 2H), 3.50 (s, 2H), 2.73 (t, J= 6.4 Hz, 2H), 1.25 (t, J= 7.2 Hz, 3H), 1.06-1.00 (m, 21H); 13C NMR (100 MHz, CDCl3) δ 202.3, 167.2, 61.3, 59.1, 50.2, 46.0, 17.9, 14.1, 11.9; TLC Rf(n- Hexanes:Et2O 2:1) = 0.59.
The β-keto ester 45-c (200 mg, 0.632 mmol), 3-hydroxybenzaldehyde (77 mg, 0.632 mmol), urea (57 mg, 0.948 mmol), and Yb(OTf)3 (39 mg, 0.063 mmol) were dissolved in acetonitrile (1.6 mL) and stirred under Argon for 24 h at 90 °C. After cooling to room temperature, the reaction was quenched by the addition of saturated aqueous NaHCO3 (10 mL) and extracted with CH2Cl2 (4 x 20 mL). The combined organic layers were dried over Na2SO4. After filtration and concentration in vacuo, the residue was purified by flash column chromatography (SiO2, «-Hexanes/EtOAc = 5:1 → 1 :1 then CH2Cl2/Me0H = 20:1) to give Biginelli adduct 45 (164 mg, 56%) as a yellow solid: 1U NMR (400 MHz, CD3OD) δ 7.88 (s, IH), 7.01 (t, J= 7.6 Hz, IH), 6.76-6.73 (m, 2H), 6.64 (d, J= 8.0 Hz, IH), 6.39 (s, IH), 5.22 (s, IH), 4.04-3.94 (m, 4H), 3.07-2.97 (m, 2H), 1.12-1.02 (m, 24H); 13C NMR (100 MHz, CD3OD) δ 165.7, 156.5, 153.1, 148.8, 144.9, 129.7, 117.8, 114.9, 113.7, 101.5, 62.0, 60.1, 55.1, 33.6, 17.9, 14.0; TLC ^7(CH2Cl2MeOH 10:1) = 0.42.
Figure imgf000057_0001
Ethyl 6-(2-hydroxyethyl)-4-(3-hydroxyphenyl)-2-oxo-l,2,3»4-tetrahydropyrimidine-5- carboxylate (46)
To a solution of 45 (110 mg, 0.237 mmol) in THF (2.4 niL) was added TBAF (1.0 M in THF, 476 μL, 0.476 mmol) at room temperature. After sitting overnight, the reaction mixture was quenched by the addition of saturated aqueous NaHCO3 (5 mL) and extracted with CH2Cl2 (3 χ lθ mL). The combined organic layers were dried over Na2SO4. After filtration and concentration in vacuo, the residue was purified via flash column chromatography (SiO2, CH2Cl2 only → CH2Cl2MeOH = 10:1) to give 46 (58 mg, 80%) as a pale yellow oil: 1H NMR (400 MHz, CD3OD) δ 7.10 (t, J= 7.6 Hz, IH), 6.77 (d, J= 8.0 Hz, IH), 6.75 (d, J= 2.0 Hz, IH), 6.65 (d, J= 8.0 Hz, IH), 5.25 (s, IH), 4.08-4.01 (m, 2H), 3.79 (t, J= 6.8 Hz, 2H), 3.03-2.94 (m, 2H), 1.13 (t, J= 6.8 Hz, 3H); D 13C NMR (IOO MHz, CD3OD) δ 166.0, 157.6, 153.8, 148.7, 145.8, 129.4, 117.7, 114.5, 113.3, 101.7, 60.3, 60.0, 55.1, 34.1, 13.3; TLC R1 (CH2Cl2:Me0H 10:1) = 0.30.
Figure imgf000057_0002
4-(3-Hydroxyphenyl)-3,4,7,8-tetrahydro-l//-pyraiio [4,3-</] pyrimidine-2,5-dione (47) Compound 46 (55 mg, 0.179 mmol) and dibutyltinoxide (58 mg, 0.233 mmol) were dissolved in MeOH (6 mL). The reaction mixture was heated to reflux for 24 h. After cooling to room temperature, the reaction was concentrated in vacuo and then directly subjected to flash column chromatography (SiO2, CH2Cl2 only → CH2Cl2MeOH = 10:1) to give lactone 47 (44 mg, 95%) as a white solid: 1U NMR (400 MHz, CD3OD) δ 7.12 (t, J= 7.6 Hz, IH), 6.82-6.78 (m, 2H), 6.67 (ddd, J= 8.4, 2.4, 0.8 Hz, IH), 5.25 (s, IH), 4.39-4.34 (m, IH), 4.25 (dt, J= 11.2, 4.0 Hz, IH), 2.82-2.73 (m, IH), 2.48 (dt, J= 17.6, 4.0 Hz, IH); 13C NMR (100 MHz, CD3OD) δ 166.1, 157.6, 152.9, 149.7, 145.3, 129.6, 117.4, 114.6, 113.1, 98.7, 64.6, 53.8, 24.9; TLC #/(CH2Cl2:Me0H 10:1) = 0.13.
Figure imgf000058_0001
Ethyl 6-(2-hydroxyethyI)-4-(3-hydroxyphenyl)-2-thioxo-l,2,3,4-tetrahydropyrimidine-5- carboxylate (48)
1H NMR (400 MHz, CD3OD) δ 7.10 (t, J= 8.0 Hz, IH), 6.77-6.73 (m, 2H), 6.67 (d, J= 8.0 Hz, IH), 5.24 (s, IH), 4.08-4.03 (m, 2H), 3.78 (t, J= 8.0 Hz, 2H), 3.02-2.98 (m, 2H). 1.13 (t, J= 7.2 Hz, 3H); 13C NMR (100 MHz, CD3OD) δ 174.8, 165.8, 157.6, 145.7, 144.8, 129.6, 117.9, 114.8, 113.4, 102.8, 60.3, 60.2, 55.3, 33.4,. 13.3.
Figure imgf000058_0002
4-(3-hydroxyphenyl)-2-thioxo-3,4,7,8-tetrahydro-lHr-pyrano[4,3-<flpyrimidin-5(2H)-one (49)
1H NMR (400 MHz, CD3OD) δ 7.15-7.09 (m, IH), 6.80-6.75 (m, 2H), 6.69-6.65 (m, IH), 5.24 (s, IH), 4.41-4.36 (m,lH), 4.29-4.22 (m, IH), 2.83-2.74 (m, IH), 2.56-2.50 (m, IH); 13C NMR (100 MHz, CD3OD) δ 175.3, 166.0, 157.7, 146.1, 129.7, 117.6, 114.9, 113.3, 99.6, 64.6, 53.9, 24.4.
General procedure for lactam derivatives
Figure imgf000059_0001
To a solution of Biginelli adduct (0.16 mmol, 1.0 equiv) and amine (0.16 mmol, 1.0 equiv) in acetonitrile (800 μL) was added triethylamine (0.12 mmol, 0.75 equiv) at 25 0C. The reaction temperature was warmed to 90 0C and the resulting mixture was further stirred for 15 h. After the starting material disappeared, the reaction mixture was cooled to 25 °C and quenched by the addition of water (10 mL) and extracted with CH2Cl2 (3 x 10 mL). The combined organic layers were washed with brine (10 mL) and dried over Na2SO4. After filtration and concentration in vacuo, the residue was purified by flash column chromatography on silica gel.
Figure imgf000059_0002
Ethyl 6-((benzylamino)methyl)-4-(3-hydroxyphenyl)-2-oxo-l,2,3»4-tetrahydropyrimi- dine-5-carboxylate (50)
1U NMR (400 MHz, CD3OD) δ 7.29-7.22 (m, 5H), 7.09 (t, J= 8.0 Hz, IH), 6.77-6.75 (m, 2H), 6.65 (d, J= 7.2 Hz, IH), 5.24 (s, IH), 4.05-4.00 (m, 2H), 3.85 (s, 2H), 3.72 (s, 2H), 1.18 (t, J= 6.8 Hz, 3H); 13C NMR (100 MHz, CD3OD) δ 169.8, 157.7, 153.5, 150.2, 144.4, 137.4, 129.5, 128.6, 127.6, 127.4, 117.6, 114.8, 113.3, 104.5, 53.9., 46.1, 45.3; TLC Rf (CH2Cl2:Me0H 10:1) = 0.25.
Figure imgf000059_0003
6-Benzyl-4-(3-hydroxyphenyl)-3,4,6,7-tetrahydro-l/f-pyrrolo[3,4-</]pyriinidine-2,5-dione
(51)
1H NMR (400 MHz, CD3OD) δ 7.29-7.10 (m, 6H), 6.83-6.79 (m, 2H), 6.68-6.66 (m, IH), 5.24 (s, IH), 4.53 (d, J= 15.2 Hz, IH), 4.42 (d, J= 15.2 Hz, IH), 3.91-3.84 (m, 2H); 13C NMR (IOO MHz, CD3OD) δ 169.8, 157.7, 153.5, 150.2, 144.4, 137.4, 129.5, 128.6, 127.6, 127.4, 117.6, 114.8, 113.3, 104.5, 53.9., 46.1, 45.3; TLC i?/ (CH2Cl2 :MeOH 10:1) = 0.18.
Figure imgf000060_0001
6-(2,4-DimethoxybenzyI)-4-(3-hydroxyphenyl)-3,4,6,7-tetrahydro-lH-pyrrolo[3,4- rf]pyrimidine-2,5-dione (52)
1H NMR (400 MHz, CD3OD) δ 7.13 (d, J= 7.6 Hz, IH), 7.03 (d, J= 8.4 Hz, IH), 6.85-6.80 (m, 2H), 6.70-6.68 (m, IH), 6.51 (d, J= 2.4 Hz, IH), 6.46-6.43 (m, IH), 5.24 (s, IH), 4.45- 4.44 (m, 2H), 3.87-3.75 (m, 6H); 13C NMR (IOO MHz, CD3OD) δ 169.6, 165.9, 161.1, 158.7, 157.6, 153.6, 149.9, 145.8, 144.5, 130.4, 129.4, 117.6, 117.3, 114.7, 113.2, 104.6, 98.2, 54.6, 53.9, 40.2, 13.2; TLC R1 (CH2Cl2 :MeOH 10:1) = 0.43.
Figure imgf000060_0002
6-(Cyclohexylmethyl)-4-(3-hydroxyphenyI)-3,4,6,7-tetrahydro-liϊ-pyrrolo[3,4- </]pyrimidine-2,5-dione (53)
1H NMR (400 MHz, CD3OD) δ 7.13 (t, J= 7.6 Hz, IH), 6.84-6.79 (m, 2H), 6.68-6.67 (m, IH), 5.23 (s, IH), 4.09-3.99 (m, 2H), 3.20-3.14 (m, 2H), 1.70-1.59 (m, 6H), 1.23-1.18 (m, 5H), 0.93-0.91 (m, 2H); 13C NMR (100 MHz, CD3OD) δ 170.0, 157.6, 153.6, 149.8, 144.4, 129.4, 117.5, 114.7, 113.2, 104.7, 103.5, 53.8, 37.2, 30.6, 26.3, 25.6; TLC Rf (CH2Cl2 :MeOH 10:1) = 0.65. General procedure for fused lactone analogs
Figure imgf000061_0001
The β-keto ester (1.50 mmol, 1.0 equiv), aldehyde (1.50 mmol, 1.0 equiv), urea (1.80 mmol, 1.2 equiv), and KHSO4 (0.38 mmol, 0.25 equiv) were dissolved in glycol (6 mL) and stirred for 2 h at 100 0C. After cooling to room temperature, the crude reaction mixture was poured into ice-water. The solids were filtered and washed with ice-water and 95% EtOH to give the pure Biginelli adducts.
Figure imgf000061_0002
4-(3-Methoxyphenyl)-3,4-dihy dro-l-fiT-chromeno [4,3-</] pyrimidine-2,5-dione (54)
1H NMR (400 MHz, DMSO-^) δ 7.98 (d, J= 8.0 Hz, IH), 7.60 (t, J= 7.6 Hz, IH), 7.37-7.33 (m, 2H), 7.16 (t, J= 8.0 Hz, IH), 7.14-7.00 (m, IH), 6.81-6.80 (m, 2H)5 6.75-6.73(m, IH), 6.37-6.35 (m, IH), 3.79 (s, 3H); 13C NMR (IOO MHz, OMSO~d6) δ 162.5, 161.8, 159.8, 152.9, 144.2, 133.0, 129.7, 124.8, 124.5, 118.8, 117.0, 116.8, 112.8, 111.8, 107.3, 55.6, 47.8.
Figure imgf000061_0003
4-(3-HydroxyphenyI)-3,4-dihydro-lH-chromeno[43-^pyrimidine-2,5-dione (55) 1H NMR (400 MHz, DMSO-^) δ 8.93 (s,lH), 7.82 (d, J= 8.0, IH), 7.34-7.31 (m,lH), 7.10- 7.02 (m, 2H), 6.93-6.89 (m, IH), 6.83-6.61 (m, 2H), 6.41 (d, J= 8.0, IH), 6.13(bs, IH), 5.72 (bs, IH).
General procedure for cyclic ketone analogs
Figure imgf000062_0001
The β-keto ester (1.50 mmol, 1.0 equiv), 3-methoxybenzaldehyde (1.50 mmol, 1.0 equiv), urea (2.25 mmol, 1.5 equiv), and H3BO3 (0.30 mmol, 0.2 equiv) were dissolved in glacial acetic acid (3 niL) and stirred for 2 h at 100 °C. After cooling to room temperature, the reaction mixture was poured into ice-water. The solids were filtered and washed with ice- water and 95% EtOH to give Biginelli adducts.
Figure imgf000062_0002
4-(3-MethoxyphenyI)-3,4,7,8-tetrahydroquinazoline-2,5(lJHr,6JHr)-dione (56)
1H NMR (400 MHz, OMSO-d6) δ 9.43 (s, IH), 7.70 (s, IH), 7.18 (t, J= 8.0 Hz, IH), 6.77- 6.75 (m, 3H), 5.11 (s, IH), 3.68 (s, 3H), 2.47-2.41 (m, 2H), 2.22-2.17 (m, 2H), 1.92-1.86 (m, IH), 1.79-1.77 (m, IH).
Figure imgf000062_0003
4-(3-Hydroxyphenyl)-3,4,7,8-tetrahydroquinazoline-2,5(lH,6fi)-dione (57) 1H NMR (400 MHz, OMSO-d6) δ 9.40 (s, IH), 9.28 (s, IH), 7.66 (s, IH), 7.03 (t, J= 8.0 Hz, IH), 6.65-6.63 (m, 2H), 6.55 (d, J= 8.0 Hz, IH), 5.04 (s, IH), 2.43-2.38 (m, 2H), 2.21-2.18 (m, 2H), 1.90-1.88 (m, IH), 1.88-1.86 (m, IH); 13C NMR (IOO MHz, OMSO-d6) δ 193.8, 157.9, 154.9, 152.6, 146.7, 129.9, 117.5, 114.6, 113.8, 109.3, 52.1, 37.0, 26.5, 21.4.
Dihydropyrimidine analogs at C-5 ester position.
Figure imgf000063_0001
Neopentyl 4-(3-hydroxyphenyl)-6-methyl-2-oxo-l,2,3?4-tetrahydropyrimidine-5- carboxylate (58)
1H NMR (400 MHz, DMSO-tf*) δ 9.34 (s, IH), 9.18 (s, IH), 7.68 (s, IH), 7.09 (t, J= 7.6 Hz, IH), 6.68-6.63 (m, 2H), 6.61 (d, J= 6.8 Hz, IH), 5.08 (d, J= 3.2 Hz,lH), 3.64 (dd, J= 30.2, 10.6 Hz, 2H), 2.29 (s, 3H), 0.77 (s, 9H); 13C NMR (100 MHz, DMSO-J6) δ 166.1, 158.1, 152.7, 149.5, 146.4, 130.0, 117.6, 114.9, 113.7, 99.4, 73.2, 55.6, 54.4, 39.5, 31.6, 26.9, 18.5.
Figure imgf000063_0002
Benzyl 4-(3-hydroxyphenyl)-6-methyl-2-oxo-l,2,3?4-tetrahydropyrimidine-5-carboxylate
(59)
1H NMR (400 MHz, CDCl3) δ 8.19 (bs, IH), 7.24-7.26 (m, 3H), 7.09-7.12 (m, 2H), 7.01 (t, J = 7.8 Hz, IH), 6.36-6.71 (m, 3H), 6.36 (bs, IH), 5.21 (s, IH), 5.06 (d, J= 12.4 Hz, IH), 4.97 (d, J= 12.2 Hz, IH).
Figure imgf000064_0001
Benzyl 6-ethyI-4-(3-hydroxyphenyl)-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate (60)
1H NMR (400 MHz, CD3OD) δ 7.26 (s, 3H), 7.13-7.07 (m, 3H), 6.74-6.68 (m, 3H), 5.26 (s, IH), 5.06 (dd, J= 33.8, 12.6 Hz, 2H), 2.75 (m, 2H), 1.20 (t, J= 7.4 Hz, 3H); 13C NMR (100 MHz, CD3OD) δ 169.5, 161.6, 157.9, 157.8, 149.8, 140.4, 133.4, 132.1, 131.7, 121.7, 118.4, 117.2, 103.5, 69.5, 58.9, 28.4, 16.0.
Figure imgf000064_0002
Octyl 4-(3-hydroxyphenyI)-6-methyl-2-oxo-l,2,3»4-tetrahydropyrimidine-5-carboxyIate (61)
1H NMR (400 MHz, DMSO-cfc) δ 9.34 (s, IH), 9.15 (s, IH), 7.67 (s, IH), 7.08 (t, J= 8.0 Hz, IH), 6.66-6.60 (m, 3H), 5.05 (d, J= 3.2 Hz, IH), 3.98-3.89 (m, 2H), 2.25 (s, 3H), 1.50-1.43 (m, 2H), 1.26-1.19 (m, 10H), 0.85 (t, J= 7.0 Hz, 3H); 13C NMR (100 MHz, DMSO-J6) δ 166.9, 158.9, 153.6, 149.8, 147.6, 130.7, 118.3, 115.6, 114.5, 100.6, 64.6, 55.3, 32.7, 30.1, 30.0, 29.7, 26.9, 23.6, 19.2, 15.4.
Figure imgf000064_0003
Adamantanemethyl ester (62)
1H NMR (400 MHz, DMSO-^) δ 9.31 (s, IH), 9.14 (s, IH), 7.62 (s, IH), 7.06 (t, J= 7.8 Hz, IH), 6.64-6.57 (m, 3H), 5.03 (d, J= 3.2 Hz, IH), 3.61 (d, J= 10.8 Hz, IH), 3.39 (d, J= 10.4 Hz, IH), 2.26 (s, 3H), 1.80 (s, 3H), 1.52 (dd, J= 39.2, 11.6 Hz, 6H), 1.26 (dd, J= 24.0, 12.0 Hz, 6H); 13C NMR (IOO MHZ, DMSO-J6) δ 166.0, 158.2, 152.6, 149.6, 146.4, 130.0, 117.6, 114.8, 113.8, 99.3, 73.3, 54.6, 37.0, 33.4, 28.1, 18.4.
Figure imgf000065_0001
(l-Benzylpiperidin-4-yl)methyl 4-(3-hydroxyphenyl)-6-methyl-2-oxo-l,2,3?4- tetrahydropyrimidine-5-carboxylate acetate (63)
1H NMR (400 MHz, CD3OD) δ 7.37-7.40 (m, 5H), 7.11 (t, J= 7.8 Hz, IH), 6.77 (d, J= 7.6 Hz, IH), 6.74 (s, IH), 6.65 (d, J= 7.8 Hz, IH), 5.23 (s, IH), 3.98 (dd, J= 11.2, 6.8 Hz, IH), 3.87 (s, 2H), 3.82 (dd, J= 11.2, 6.0 Hz, IH), 3.06-3.13 (m, IH), 2.34-2.44 (m, 2H), 2.35 (s, 3H), 1.94 (s, 3H), 1.59-1.66 (m, 2H), 1.45-1.69 (m, IH), 1.21-1.35 (m, 2H).
Figure imgf000065_0002
(l-(BenzyloxycarbonyI)piperidin-4-yl)methyl 4-(3-hydroxyphenyl)-6-methyl-2-oxo- l,2,3,4-tetrahydropyrimidine-5-carboxylate (64)
Figure imgf000065_0003
To a stirred solution of 4-hydroxymethylpiperidine (1.0 g, 8.7 mmol, 1.0 equiv) in dry CH2Cl2 (50 mL) was added Et3N (2.4 mL, 17.4 mmol, 2.0 equiv) and benzylchoroformate (1.85 niL, 17.4 mmol, 2.0 equiv) at 0 "C. The mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was washed with water (20 mL) and the aqueous phase was extracted with CH2Cl2 (2 x 25 mL). The combined organic phases were washed with brine (15mL), dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel to afford compound 64-a (1.95 g, 89%) as a clear oil: 1H NMR (400 MHz, CDCl3) δ 5.10 (s, 2H), 4.20 (br d, J= 11.2 Hz, 2H), 3.48 (d, J= 6.4 Hz, 2H), 2.77 (t, J= 12.8 Hz, 2H), 1.62-1.70 (m, 3H), 1.10-1.20 (m, 2H).
To a stirred mixture of compound 64-a (1.80 g, 7.22 mmol, 1.0 equiv) in CH2Cl2 (14 mL) was added 3-oxobutanoic acid (0.81 g, 7.94 mmol, 1.1 equiv), EDC (2.08 g, 10.85 mmol, 1.5 equiv), and DMAP (0.44 g, 3.61 mmol, 0.5 equiv). After stirring for 12 h at 25 0C, the mixture was diluted with CH2Cl2 (50 mL), washed with water (20 mL), sat. NH4Cl (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel to afford β-ketoester 64-b (2.24 g, 93%): 1H NMR (400 MHz, CDCl3) δ 5.10 (s, 2H), 4.20 (bd, J= 9.2 Hz, 2H), 3.99 (d, J= 6.4 Hz, 2H), 3.44 (s, 2H), 2.76 (t, J= 12.2 Hz, 2H), 2.24 (s, 3H), 1.78-1.88 (m, IH), 1.69 (bd, J= 12.8 Hz, 2H), 1.13-1.25 (m, 2H).
A mixture of 3-hydroxybenzaldehyde (0.50 g, 4.09 mmol, 1.0 equiv), β-ketoester 64-b (1.36 g, 4.09 mmol, 1.0 equiv), urea (0.37 g, 6.14 mmol, 1.5 equiv) and acetic acid (0.35 mL) was heated with stirring at 90 °C for 12 h. The mixture was cooled to room temperature and water (7 mL) was added. The mixture was extracted with EtOAc (3 >< 10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography to afford Biginelli adduct 64 (1.47 g, 75%) as a white solid: 1U NMR (400 MHz, CD3OD) δ 7.28-7.38 (m, 5H), 7.10 (t, J= 7.8 Hz, IH), 6.73-6.77 (m, 2H), 6.67 (d, J= 8.0 Hz, IH), 5.22 (s, IH), 3.99-4.07 (m, 3H), 3.75 (dd, J= 10.8, 6.0 Hz, IH), 2.60-2.81 (m, 2H), 3.36 (s, 3H), 1.62-1.70 (m, IH), 1.22-1.46 (m, 2H), 0.90-1.03 (m, 2H).
Figure imgf000066_0001
Cycloheptylmethyl 6-ethyl-4-(3-hydroxyphenyl)-2-oxo-l,2,354-tetrahydropyriinidine-5- carboxylate (65) 1H NMR (400 MHz, CD3OD) δ 7.10 (t, J= 8.0 Hz, IH), 6.76-6.73 (m, 2H), 6.67-6.64 (m,
IH), 5.22 (s, IH), 3.90-3.85 (m, IH), 3.73-3.69 (m, IH), 2.79-2.73 (m, 2H), 1.66-1.32 (m,
1 IH), 1.22 (t, J= 8.0 Hz, 3H), 1.08-1.04 (m, 2H); 13C NMR (100 MHz, CD3OD) δ 166.0,
157.7, 154.0, 153.7, 145.8, 129.5, 117.6, 114.4, 113.3, 99.6, 69.2, 55.0, 38.9, 30.8, 28.3, 28.2,
26.4, 26.4, 24.4, 12.1.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 25% i-
PrOH in rø-Hexanes, 0.85 mL/min): 65a ΪR = 8.5 min, 65b ΪR = 15.6 min.
Figure imgf000067_0001
2-Cyclohexylethyl 6-ethyl-4-(3-hydroxyphenyl)-2-oxo-l,2,3,4-tetrahydropyrimidine-5- carboxylate (66)
1H NMR (400 MHz, CD3OD) δ 7.10 (t, J= 8.0 Hz, IH), 6.76-6.72 (m, 2H), 6.67-6.64 (m, IH), 5.21 (s, IH), 4.14-4.08 (m. IH), 3.99-3.93 (m, IH), 2.81-2.69 (m, 2H), 1.64-1.57 (m, 5H), 1.41-1.27 (m, 2H), 1.21 (t, J= 8.0 Hz, 3H), 1.17-1.05 (m, 3H), 0.85-0.77 (m, 3H); 13C NMR (IOO MHz, CD3OD) δ 166.0, 157.7, 154.1, 153.5, 145.8, 129.5, 117.6, 114.5, 113.2, 99.7, 61.6, 55.0, 36.0, 34.1, 33.1, 32.8, 26.4, 26.0, 26.0, 24.4, 12.1.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 25% i- PrOH in «-Hexanes, 0.85 mL/min): 66a (R = 7.7 min, 66b ΪR = 15.3 min.
Figure imgf000067_0002
67
((R)-Tetrahydrofuran-2-yl)methyl 6-ethyI-4-(3-hydroxyphenyl)-2-oxo-l,2,3,4- tetrahydro-pyrimidine-5-carboxylate (67)
1H NMR (400 MHz, CD3OD) δ 7.08 (t, J= 7.6 Hz, IH), 6.78-6.75 (m, 2H), 6.65 (d, J= 7.6 Hz, IH), 5.25 (s, IH), 4.07-3.93 (m, 3H), 3.73-3.65 (m, 2H), 2.75-2.70 (m, 2H), 1.82-1.74 (m, 3H), 1.44-1.40 (m, 3H), 1.20 (t, J- 7.2 Hz, 3H); 13C NMR (100 MHz, CD3OD) δ 165.6, 157.6, 154.1, 145.8, 129.5, 117.6, 114.4, 113.2, 99.6, 76.8, 68.0, 65.4, 54.8, 27.6, 27.4, 25.4, 19.7, 12.1; TLC i?/(«-Hexanes: EtOAc 1 :3) = 0.21.
Figure imgf000068_0001
((S)-T etrahydrofuran-2-yl)methyl 6-ethyl-4-(3-hydroxyphenyl)-2-oxo-l,2,354-tetrahydro- pyrimidine-5-carboxylate (68)
1H NMR (400 MHz, CD3OD) δ 7.09 (t, J= 7.6 Hz, IH), 6.77-6.73 (m, 2H), 6.66-6.63 (m, IH), 5.25 (s, IH), 4.02-3.96 (m, 3H), 3.74-3.67 (m, 2H), 2.77-2.70 (m, 2H), 1.82-1.76 (m, 3H), 1.46-1.39 (m, IH), 1.22-1.18 (m, 3H); 13C NMR (IOO MHz, CD3OD) δ 165.6, 157.6, 154.1, 145.7, 117.6, 114.4, 113.2, 99.4, 76.8, 68.0, 65.4, 65.1, 54.8, 27.6, 27.4, 25.4, 24.5, 12.0; TLC i?/(«-Hexanes:EtOAc 1 :3) = 0.21.
Figure imgf000068_0002
2-(Piperidin-l-yl)ethyl 6-ethyl-4-(3-hydroxyphenyl)-2-oxo-l,2,3,4-tetrahydropyrimidine- 5-carboxylate (69)
1H NMR (400 MHz, CD3OD) δ 7.09 (t, J= 7.6 Hz, IH), 6.77-6.73 (m, 2H), 6.67-6.64 (m, IH), 5.24 (s, IH), 4.17-4.12 (m, 2H), 2.75 (t, J= 8.0 Hz, 2H), 2.54 (t, J= 5.2 Hz, 2H), 2.33 (bs, 4H), 1.53-1.47 (m, 4H), 1.38 (d, J= 5.2 Hz, 2H), 1.22-1.19 (m, 3H); 13C NMR (IOO MHz, CD3OD) δ 165.5, 157.6, 154.1, 154.0, 145.7, 129.5, 117.6, 114.5, 113.3, 99.3, 61.1, 56.9, 54.7, 54.3, 25.1, 24.5, 23.5, 12.1; TLC i?/(CH2Cl2:Me0H 10:1) = 0.12. Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 15% i- PrOH in «-Hexanes, 0.80 mL/min): 69a tR = 17.2 min, 69b tR = 32.5 min.
Figure imgf000069_0001
Phenethyl 6-ethyl-4-(3-hydroxyphenyI)-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxy- late (70)
1H NMR (400 MHz, CD3OD) δ 7.21-7.18 (m, 2H), 7.14-7.13 (m, IH), 7.08-7.05 (m, 3H),
6.74 (bs, IH), 6.67 (t, J= 8.0 Hz, 2H), 5.18 (s, IH), 4.23-4.19 (m, 2H), 2.79 (t, J= 4.0 Hz,
2H), 2.64-2.61 (m, 2H), 1.10 (t, J= 8.0 Hz, 3H); 13C NMR (100 MHz, CD3OD) δ 165.9,
157.6, 154.2, 153.5, 145.8, 129.5, 128.7, 126.3, 117.7, 114.5, 113.2, 99.8, 64.6, 54.8, 34.8,
24.5, 12.1.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 25% /-
PrOH in n-Hexanes, 0.85 mL/min): 70a tR = 13.9 min, 70b tR = 20.7 min.
Figure imgf000069_0002
2-Morpholino-2-oxoethyl 4-(3-(te^-butyIdimethylsilyloxy)phenyl)-6-ethyI-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (71)
1H NMR (400 MHz, CD3OD) δ 6.99 (t, J= 8.0 Hz, IH), 6.77 (d, J= 7.6 Hz, IH), 6.67 (t, J= 2.0 Hz, IH), 6.56-6.54 (m, IH), 5.17 (s, IH), 4.65 (d, J= 14.4 Hz, IH), 4.49 (d, J= 14.4 Hz, IH), 3.44-3.40 (m, 8H), 2.66-2.58 (m, 2H), 1.05 (t, J= 8.0 Hz, 3H), 0.80 (s, 9H), 0.00 (s, 6H); 13C NMR (IOO MHZ, CD3OD) δ 166.7, 165.2, 156.1, 154.8, 154.1, 145.9, 129.5, 119.7, 119.3, 117.9, 99.3, 66.4, 66.3, 61.0, 54.4, 45.0, 42.2, 25.1, 25.0, 24.7, 17.9, 12.2, -5.3; TLC Rf (CH2Cl2:Me0H 10:1) = 0.70.
Figure imgf000069_0003
2-Morpholino-2-oxoethyl 6-ethyl-4-(3-hydroxyphenyl)-2-oxo-l,2,3,4-tetrahydropyrimi- dine-5-carboxylate (72)
1H NMR (400 MHz, CD3OD) δ 7.09 (t, J= 8.0 Hz, IH), 6.80-6.75 (m, 2H), 6.66-6.64 (m,
IH), 5.29 (s, IH), 4.80 (d, J= 14.4 Hz, IH), 4.65 (d, J= 14.4 Hz, IH), 3.61-3.50 (m, 8H),
2.79-2.70 (m, 2H), 1.21 (t, J= 8.0 Hz, 3H); 13C NMR (100 MHz, CD3OD) δ 166.9, 165.2,
157.6, 154.8, 154.1, 145.8, 129.5, 117.6, 114.4, 113.2, 99.2, 66.4, 66.2, 61.0, 54.6, 53.6, 45.1,
42.2, 24.6, 12.0.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 20% i-
PrOH in rc-Hexanes, 0.80 mL/min): 72a tR = 41.0 min, 72b tR = 52.9 min.
Figure imgf000070_0001
2-(Pyrrolidin-l-yl)ethyl 6-ethyl-4-(3-hydroxyphenyl)-2-oxo-l,2,354-tetrahydropyrimi- dine-5-carboxylate (73)
1H NMR (400 MHz, CD3OD) δ 7.09 (t, J= 7.6 Hz, IH), 6.77-6.73 (m, 2H), 6.67-6.64 (m,
IH), 5.26 (s, IH), 4.16-4.12 (m, 2H), 2.77-2.71 (m, 2H), 2.68-2.64 (m, 2H), 2.44 (s, 4H), 1.70
(s, 4H), 1.03 (t, J= 7.6 Hz, 3H); 13C NMR (100 MHz, CD3OD) δ 165.6, 157.6, 154.1, 154.0,
145.7, 129.5, 117.6, 114.5, 113.3, 99.4, 62.4, 54.7, 54.2, 54.1, 24.4, 23.0, 12.0; TLC R1
(CH2Cl2:Me0H 10:1) = 0.10.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 15% i-
PrOH in rc-Hexanes, 0.80 mL/min): 73a tR = 17.7 min, 73b tR = 31.8 min.
Figure imgf000070_0002
(S)-(Tetrahydro-2H-pyran-4-yl)methyl 6-ethyI-4-(3-hydroxyphenyl)-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (74a) 1H NMR (400 MHz, CD3OD) δ 7.07 (t, J= 8.0 Hz, IH), 6.74-6.70 (m, 2H), 6.64-6.61 (m, 2H), 5.19 (s, IH), 3.82-3.72 (m. 3H), 3.30-3.21 (m, 2H), 2.77-2.68 (m, 2H), 1.70-1.68 (m, IH), 1.36-1.08 (m, 8H); 13C NMR (100 MHz, CD3OD) δ 165.7, 157.6, 153.8, 145.9, 129.5, 117.6, 114.4, 113.3, 99.4, 68.0, 67.3, 55.0, 34.6, 29.3, 29.2, 24.2, 12.0; TLC Rf (CH2Cl2MeOH 20:1) = 0.45.
Figure imgf000071_0001
75
2-Oxo-2-(piperidin-l-yl)ethyl 4-(3-(te^-butyldimethylsilyloxy)phenyl)-6-ethyl-2-oxo- 1 ,2,3,4-tetrahydropyrimidine-5-carboxylate (75)
1H NMR (400 MHz, CD3OD) δ 6.99 (t, J= 8.0 Hz, IH), 6.78-6.55 (m, IH), 6.56 (t, J= 1.2 Hz, IH), 5.54-5.31 (m, IH), 5.17 (s, IH), 4.65 (d, J= 14.4 Hz, IH), 4.47 (d, J= 14.4 Hz, IH), 3.32-3.31 (m, 2H), 3.12-3.11 (m, 2H), 2.62-2.58 (m, 2H), 1.49-1.44 (m, 2H), 1.40-1.32 (m, 4H), 1.05 (t, J= 8.0 Hz, 3H), 0.80 (s, 9H), 0.00 (s, 6H); 13C NMR (100 MHz, CD3OD) δ 166.2, 165.2, 156.1, 154.6, 145.9, 129.5, 119.7, 119.2, 117.9, 99.4, 54.4, 45.6, 43.0, 31.5, 26.0, 25.3 ,25.0, 24.6, 22.5, 17.9, 13.2, 12.1, -5.4.
Figure imgf000071_0002
(,S)-2-Oxo-2-(piperidin-l-yl)ethyl 6-ethyl-4-(3-hydroxyphenyl)-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (76a)
1U NMR (400 MHz, CD3OD) δ 7.08 (t, J= 6.0 Hz, IH), 6.80-6.76 (m, 2H), 6.66-6.63 (m, IH), 5.30 (s, IH), 4.79 (d, J= 14.4 Hz, IH), 4.62 (d, J= 14.4 Hz, IH), 3.47-3.44 (m, 2H), 3.25-3.22 (m, 2H), 2.80-2.70 (m, 2H), 1.61-1.53 (m, 2H), 1.50-1.48 (m, 4H), 1.21 (t, J= 4.0 Hz, 3H); 13C NMR (100 MHz, CD3OD) δ 166.3, 165.3, 157.6, 154.6, 154.2, 145.8, 129.5, 117.6, 114.4, 113.2, 99.4, 61.1, 54.6, 45.6, 43.0, 26.0, 25.3, 24.7, 24.1, 12.0.
Figure imgf000072_0001
2-(Cyclohexyloxy)ethyl 6-ethyl-4-(3-hydroxyphenyI)-2-oxo-l,2,3j4- tetrahydropyrimidine-5-carboxylate (77)
1H NMR (400 MHz, CD3OD) δ 7.09 (t, J= 8.0 Hz, IH), 6.79-6.75 (m, 2H), 6.66-6.63 (m,
IH), 5.25 (s, IH), 4.17-4.07 (m, 2H), 3.57 (t, J= 4.8 Hz, 2H), 3.21-3.19 (m, IH), 2.79-2.68
(m, 2H), 1.84-1.79 (m, 2H), 1.69-1.68 (m, 2H), 1.51-1.49 (m, IH), 1.27-1.19 (m, 9H); 13C
NMR (IOO MHz, CD3OD) δ 165.9, 157.6, 154.3, 153.5, 145.9, 129.4, 117.6, 114.4, 113.2,
.99.9, 77.9, 65.7, 63.5, 54.8, 32.0, 32.0, 25.7, 24.6, 23.8, 12.1.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 20% i-
PrOH in «-Hexanes, 0.80 mL/min): 77a ^ = 11.8 min, 77b tR = 20.2 min.
Figure imgf000072_0002
2-Phenoxyethyl 6-ethyl-4-(3-hydroxyphenyl)-2-oxo-l,2,3?4-tetrahydropyrimidine-5- carboxylate (78)
1H NMR (400 MHz, CD3OD) δ 7.24-7.01 (m, 2H), 6.99 (t, J= 8.0 Hz, IH), 6.90 (t, J= 8.0 Hz, IH), 6.86-6.84 (m, 2H), 6.77-6.74 (m, 2H), 6.63-6.61 (m, IH), 5.24 (s, IH), 4.33-4.30 (m, 2H), 4.07-4.03 (m, 2H), 2.74-2.67 (m, 2H), 1.17 (t, J= 8.0 Hz, 3H); 13C NMR (100 MHz, CD3OD) δ 165.8, 158.8, 157.6, 154.2, 153.6, 145.9, 129.3, 129.3, 120.8, 117.7, 114.5, 114.4, 113.10, 99.9, 65.8, 62.5, 54.9, 24.6, 12.0; TLC ^(π-Hexanes: EtOAc 1 :3) = 0.33. Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 25% i- PrOH in «-Hexanes, 0.85 mL/min): 78a tR = 14.7 min, 78b tR = 26.0 min.
79
Cyclopentyl 6-ethyl-4-(3-hydroxyphenyl)-2-oxo-l,2,3,4-tetrahydropyrimidine-5- carboxylate (79)
1H NMR (400 MHz, CD3OD) δ 7.09 (t, J= 8.0 Hz, IH), 6.75-6.66 (m, 2H), 6.64 (d, J= 2.0 Hz, IH), 5.18 (s, IH), 5.09-5.06 (m, IH), 2.78-2.67 (m, 2H), 1.79-1.39 (m, 8H), 1.20 (t, J= 8.0 Hz, 3H); 13C NMR (100 MHz, CD3OD) δ 165.7, 157.6, 154.0, 153.1, 146.0, 129.4, 117.6, 114.4, 113.3, 100.1, 77.0, 55.2, 32.3, 24.5, 23.4, 23.2, 12.1.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 25% i- PrOH in «-Hexanes, 0.85 mL/min): 79a tR = 8.6 min, 79b tR = 15.0 min.
Figure imgf000073_0002
80
Cyclohexyl 6-ethyl-4-(3-hydroxyphenyl)-2-oxo-l,2,3»4-tetrahydropyrimidiiie-5-carboxy- late (80)
1H NMR (400 MHz, CD3OD) δ 7.09 (d, J=8.0 Hz, IH), 6.77-6.66 (m, 2H), 6.66-6.64 (m, IH), 5.23 (s, IH), 4.71-4.67 (m, IH), 2.80-2.68 (m, 2H), 1.78-1.73 (m, IH), 1.66-1.55 (m, 3H), 1.45-1.32 (m, 4H), 1.30-1.19 (m, 5H); 13C NMR (IOO MHz, CD3OD) δ 165.4, 157.6, 154.1, 153.1, 145.9, 129.4, 117.7, 114.4, 113.3, 100.2, 72.2, 55.1, 31.4, 31.1, 25.3, 24.5, 23.3, 23.1, 12.1.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 25% i- PrOH in «-Hexanes, 0.85 mL/min): 80a tR = 8.5 min, 80b tR = 14.7 min.
Figure imgf000074_0001
81
Cyclopentylmethyl 6-ethyl-4-(3-hydroxyphenyl)-2-oxo-l,2,3,4-tetrahydropyrimidine-5- carboxylate (81)
1H NMR (400 MHz, CD3OD) δ 7.09 (t, J =8.0 Hz, IH), 6.76-6.73 (m, 2H), 6.66-6.64 (m, IH),
5.22 (s, IH), 3.96-3.91 (m, IH), 3.88-3.83 (m, IH), 2.81-2.69 (m, 2H), 2.09-2.03 (m, IH),
1.64-1.47 (m, 5H), 1.23 (t, J =8.0 Hz, 3H), 1.19-1.07 (m, 3H); 13C NMR (IOO MHZ5 CD3OD) δ 166.1, 157.6, 154.1, 153.4, 145.8, 129.4, 117.6, 114.4, 113.3, 99.8, 57.7, 55.0, 38.8, 29.1,
25.1, 24.5, 12.1.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 25% i-
PrOH in «-Hexanes, 0.85 mL/min): 81a tR = 8.6 min, 81b tR = 14.5 min.
Figure imgf000074_0002
82a
(4S)-1-Cyclohexylethyl 4-(3-(fer^butyldimethylsilyloxy)phenyI)-6-ethyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (82a)
1H NMR (400 MHz, CD3OD) δ 7.93 (bs, IH), 7.90 (bs, IH), 7.16-7.12 (m, IH), 6.84 (t, J= 6.2 Hz, IH), 6.75-6.70 (m, 2H), 5.70 (bs, IH), 5.31-5.28 (m, IH), 4.72-4.67 (m, IH), 2.85- 2.69 (m, 2H), 1.72-1.15 (m, 10H), 1.12 (d, J= 11.2 Hz, 3H), 0.94 (s, 9H), 0.87 (t, J= 6.8 Hz, 3H), 0.15 (s, 6H); 13C NMR (100 MHz, CD3OD) δ 165.0, 164.9, 156.4, 156.2, 152.3, 145.3, 145.2, 129.9, 129.8, 119.8, 119.7, 119.6, 118.4, 118.3, 100.8, 100.3, 74.5, 55.8, 55.7, 42.8,
42.7, 31.8, 28.8, 28.7, 28.5, 28.3, 26.6, 26.4, 26.3, 26.2, 25.9, 25.4, 22.8, 18.4, 17.3, 16.8, 14.3,
12.8, -4.1, -4.2; TLC i?/(n-Hexanes:EtOAc 1:2) = 0.60.
Figure imgf000075_0001
83a
(4S)-l-Cyclohexylethyl 6-ethyl-4-(3-hydroxyphenyl)-2-oxo-l,2,3?4-tetrahydropyrimidine- 5-carboxylate (83a)
1H NMR (400 MHz, CD3OD) δ 7.11 (t, J= 7.0 Hz, 2H), 6.76-6.73 (m, 4H), 6.65 (d, J- 8.0 Hz, 2H ), 5.22 (s, IH), 5.19 (s, IH), 4.68-4.63 (m, 2H), 3.03 (s, IH), 2.90 (s, IH), 2.82-2.70 (m, 4H), 1.71-0.90 (m, 32H); 13C NMR (IOO MHz, CD3OD) δ 165.6, 165.4, 157.7, 157.5, 153.9, 152.6, 145.9, 145.7, 129.5, 129.3, 117.8, 117.7, 114.4, 114.3, 113.5, 113.3, 100.3, 99.5, 74.3, 74.1, 55.2, 55.0, 42.9, 42.8, 28.7, 28.5, 28.3, 27.8, 26.3, 26.1, 26.0, 24.4, 24.3, 16.4, 15.9, 12.1, 12.0; TLC i?/(CH2Cl2:Me0H 10:1) = 0.45.
Figure imgf000075_0002
4-(3-HydroxyphenyI)-6-methyI-2-oxo-l,2,3?4-tetrahydropyrimidine-5-carboxylic acid
(84)
1H NMR (400 MHz, CD3OD) δ 7.11 (t, J= 7.8 Hz, IH), 6.80 (d, J= 8.0 Hz, IH), 6.78 (d, J- 1.2 Hz, IH), 6.66 (d, J= 8.0 Hz, IH), 5.25 (s, IH), 2.33 (s, 3H); 13C NMR (100 MHz, CD3OD) δ 157.5, 147.1, 145.9, 129.3, 117.6, 114.3, 113.1, 101.5, 55.0, 16.9.
Figure imgf000075_0003
85
Allyl 4-(3-chloro-4-hydroxyphenyl)-6-ethyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5- carboxylate (85) 1H NMR (400 MHz, CD3OD) δ 7.21 (s, IH), 7.05 (d, J= 7.6 Hz, IH), 6.84 (d, J= 8.4 Hz, IH), 5.83-5.76 (m, IH), 5.12-5.08 (m, 2H), 4.55-4.44 (m, 2H), 2.73-2.72 (m, 2H), 1.07 (t, J= 11.4 Hz, 3H); 13C NMR (IOO MHz, CD3OD) δ 165.4, 154.1, 153.7, 152.6, 136.8, 132.4, 128.2, 126.2, 126.1, 120.4, 117.1, 116.6, 99.7, 64.6, 54.2, 24.7, 12.4; TLC i?/(«-Hexanes:EtOAc 1:2) = 0.31.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 20% /-PrOH in rc-Hexanes, 4.0 mL/min): 85a tR = 42.2 min, 85b tR = 59.1 min.
Figure imgf000076_0001
86
4-(3-Chloro-4-hydroxyphenyl)-6-ethyl-2-oxo-l,2,354-tetrahydropyrimidine-5-carboxylic acid (86)
Allyl ester (31 mg, 0.093 mmol), 5 mol% Pd(PPh3)4 (5 mg, 0.005 mmol), and piperidine (92 μL, 0.09 mmol) was added to a solution of THF (0.5 mL) and stirred for 5 h at 25 0C. And then the reaction mixture was evaporated to dryness under reduced pressure and solid residue was treated with 0.5 M KOH solution (0.5 mL), vigorously stirred, and filtered. The filtrate was acidified by IN HCl till pH 2-3 and the resulting precipitates were collected by filtration. The product was white solid (18 mg, 66%): 1H NMR (400 MHz, CD3OD) δ 7.01 (s, IH), 6.86 (d, J= 8.0 Hz, IH), 6.63 (d, J= 8.4 Hz, IH), 5.00 (s, IH), 2.59-2.47 (m, 2H), 1.00 (t, J= 7.4 Hz, 3H); 13C NMR (100 MHz, CD3OD) δ 167.7, 154.3, 153.2, 152.5, 136.9, 128.0, 125.9, 120.3, 116.4, 100.2, 54.1, 24.5, 12.1; TLC i?/(«-Hexanes:EtOAc 1 :2) = 0.32.
iV-(CyclohexylmethyI)-4-(3-hydroxyphenyl)-6-methyI-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxamide (87) 1H NMR (400 MHz, OMSO-d6) δ 8.45 (s, IH), 7.50 (t, J= 5.4 Hz, IH), 7.36 (s, IH), 7.04 (t, J - 7.6 Hz, IH), 6.68 (s, IH), 6.61 (d, J= 6.8 Hz, 2H), 5.14 (s, IH), 3.42 (bs, IH), 2.92-2,86 (m, IH), 2.83-2.76 (m, IH), 1.96 (s, 3H), 1.56 (m, 4H), 1.31-1.25 (m, 2H), 1.05 (m, 3H), 0.73-0.70 (m, 2H); 13C NMR (100 MHz, DMSO- d6) δ 167.0, 158.4, 153.4, 146.4, 136.9, 129.6, 117.4, 114.8, 114.0, 106.1, 55.7, 45.6, 38.1, 31.1, 26.7, 26.1, 17.5.
Figure imgf000077_0001
6-Ethyl-4-(3-hydroxyphenyl)-iV-methoxy-ΛLmethyl-2-oxo-l,2,3,4-tetrahydropyriinidine- 5-carboxamide (88)
1H NMR (400 MHz, CD3OD) δ 7.13 (t, J= 8.0 Hz, IH), 6.73 (bs, 2H), 6.68 (d, J= 8.0 Hz, 2H), 5.25 (s, IH), 3.40 (s, 3H), 3.01 (s, 3H), 2.25-2.07 (m, 2H), 0.98 (t, J= 7.2 Hz, 3H); 13C NMR (IOO MHz, CD3OD) δ 167.7, 157.9, 154.7, 144.8, 139.1, 129.7, 117.3, 114.9, 113.1, 103.9, 60.3, 57.0, 32.9, 23.6, 11.3; TLC R1 (CH2Cl2 :MeOH 10:1) = 0.20.
General procedure for reduced Biginelli adducts
Figure imgf000077_0002
To a -78 °C solution of thiol ester (0.15 mmol, 1.0 equiv) in CH2Cl2 (2 mL) was added DIBAL-H (1.0 M in CH2Cl2, 400 μL, 0.40 mmol, 2.7 equiv) under Argon. After 3 h at -78 0C, the reaction was warmed to 25 "C and quenched by the addition of water (5 mL), saturated aqueous NH4Cl (5 mL) and extracted with CH2Cl2 (3 x 10 mL). The combined organic layers were washed with brine (5 mL) and dried over Na2SO4. After filtration and concentration in vacuo, the residue was purified by flash column chromatography on silica gel to give reduced Biginelli adducts.
Figure imgf000078_0001
89 6-Ethyl-5-(hydroxymethyl)-4-(3-methoxyphenyl)-3,4-dihydropyrimidin-2(l//)-one (89)
1H NMR (400 MHz, CD3OD) δ 7.22 (t, J= 8.0 Hz, IH), 6.90-6.86 (m, 2H), 6.82-6.80 (m, IH), 5.40 (s, IH), 4.15 (d, J= 12.0 Hz, IH), 3.75 (s, 3H), 3.57 (d, J= 12.4 Hz, IH), 2.24-2.17 (m, 2H), 1.13 (t, J= 7.6 Hz, 3H); 13C NMR (100 MHz, CD3OD) δ 160.3, 155.3, 145.6, 136.0, 129.5, 119.1, 133.0, 112.5, 106.9, 61.0, 56.9, 54.4, 21.9, 12.3; TLC Rf (CH2Cl2MeOH 10:1) = 0.11.
Figure imgf000078_0002
90 6-Ethyl-5-(hydroxymethyl)-4-(3-hydroxyphenyl)-3,4-dihydropyrimidin-2(ljH)-one (90)
1H NMR (400 MHz, CD3OD) δ 7.12 (t, J= 8.0 Hz, IH), 6.70-6.73 (m, 2H), 6.68-6.66 (m,
IH), 4.56 (s, IH), 3.95 (d, J = 11.6 Hz, IH), 3.75 (s, 3H), 3.53 (d, J= 11.6 Hz, IH), 2.24-2.22 (m, 2H), 1.12 (t, J= 7.6 Hz, 3H); 13C NMR (IOO MHz, CD3OD) δ 157.7, 155.2, 145.4, 137.2, 129.4, 118.0, 114.6, 113.6, 104.1, 67.4, 57.2, 22.0, 12.2J TLC iJ7(CH2Cl2)MeOH 10:1) = 0.85.
General procedure for benzyl derivatives from Biginelli adducts
Figure imgf000078_0003
To a 0 °C solution of ketone (0.59 mmol, 1.0 equiv) and CeCl3 7H2O (1.77 mmol, 3.0 equiv) in MeOH (5 niL) was added NaBH4 (0.88 mmol, 1.5 equiv). The reaction temperature was warmed to 25 0C and stirred overnight for 12 h. The reaction mixture was quenched by the addition of water (10 mL), NH4Cl (10 mL) and extracted with CH2Cl2 (3 x 10 mL). The combined organic layers were washed with brine (10 mL) and dried over Na2SO4. After filtration and concentration in vacuo, the residue was purified via flash column chromatography on silica gel to give reduced alcohols.
To a solution of alcohol (0.059 mmol, 1.0 equiv) in EtOAc/MeOH (1 mL:l mL) added 10% Pd on carbon (72 mg) at room temperature. The reaction mixture was hydrogenated with H2 gas (3 bar) for 1 h at 25 ° C. The resulting mixture was filtered through a pad of Celite and rinsed with EtOAc, and then concentrated in vacuo. The residue was purified via flash column chromatography (SiO2, EtOAc only) to give deoxygenated products.
Figure imgf000079_0001
91
6-EthyI-5-(hydroxy(phenyl)methyl)-4-(3-methoxyphenyl)-3,4-dihydropyrimidin-2(l//)- one (91)
1NMR (400 MHz, CD3OD) δ 7.09-7.06 (m, 2H), 6.96-6.88 (m, 4H), 6.58 (d, J= 7.6 Hz, IH), 6.57-6.51 (m, IH), 6.42 (t, J= 2.0 Hz, IH), 5.61 (s, IH), 4.86 (s, IH), 3.59 (s, 3H), 2.53-2.45 (m, 2H), 1.23 (t, J= 7.6 Hz, 3H); 13C NMR (100 MHz, CD3OD) δ 159.5, 156.1, 145.5, 142.2, 136.9, 128.9, 127.3, 126.3, 126.0, 119.1, 112.7, 112.1, 110.6, 69.5, 54.8, 54.2, 22.3, 12.3; TLC Rf (EtOAc only) = 0.10.
Figure imgf000079_0002
92 5-Benzyl-6-ethyl-4-(3-methoxyphenyl)-3,4-dihydropyrimidin-2(lH)-one (92)
1H NMR (400 MHz, CD3OD) δ 7.26-7.09 (m, 6H), 6.82-6.79 (m, 2H), 6.57 (s, IH), 4.54 (s, IH), 3.73 (s, IH), 3.56 (d, J= 15.6 Hz, IH), 2.81 (d, J= 15.6 Hz, IH), 2.32-2.87 (m, 2H), 1.15 (t, J= 7.6 Hz, 3H); 13C NMR (100 MHz, CD3OD) δ 164.2, 159.2, 149.3, 143.3, 137.8, 133.5, 132.3, 132.2, 130.0, 123.1, 117.0, 116.4, 110.0, 62.0, 58.3, 37.0, 26.2, 15.9; TLC R1 (EtOAc only) = 0.78.
93 5-Benzyl-6-ethyl-4-(3-hydroxyphenyl)-3,4-dihydropyrimidin-2(liϊ)-one (93)
1H NMR (400 MHz, CD3OD) δ 7.27-7.24 (m, 2H), 7.18-7.09 (m, 4H), 6.70-6.67 (m, 3H), 4.48 (s, IH), 3.56 (d, J= 15.6 Hz, IH), 2.81 (d, J- 15.6 Hz, IH), 2.30-2.28 (m, 2H), 1.15 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CD3OD) δ 157.7, 155.3, 145.4, 139.4, 133.6, 129.4, 128.3, 128.2, 126.1, 11831, 114.6, 113.7, 106.2, 58.1, 33.0, 22.3, 12.0; TLC Rf (CH2Cl2MeOH 20:1) = 0.25.
Dihydropyrimidine analogs at C-4 phenyl position. General procedure for the deprotection of acetate group
Figure imgf000080_0002
Acetyl protected Biginelli product (9.8 μmol, 1.0 equiv) was suspended in MeOH (1 mL) and was added potassium carbonate (6.8 mg, 49 μmol, 5.0 equiv) and water (200 μL). The reaction was stirred at 25 °C for 30 min. The reaction was quenched with aqueous 2 N HCl and the mixture was extracted with CH2Cl2 (3 x 5 mL) and dried over MgSO4. After filtration and concentration in vacuo, the crude residue was purified via flash column chromatography on silica gel.
Figure imgf000081_0001
Ethyl 6-methyl-2-oxo-4-phenyl-l ,2,3>4-tetrahy dropyrimidine-5-carboxylate (94)
1U NMR (400 MHz, OMSO-Cl6) δ 9.21 (bs, IH), 7.76 (bs, IH), 7.26-7.37 (m, 5H), 5.17 (s, IH), 4.01 (q, J= 7.2 Hz, 2H), 2.28 (s, 3H), 1.12 (t, J= 7.0 Hz, 3H); 13C NMR (100 MHz, DMSO-J6) δ 165.2, 152.1,148.3, 144.8, 128.3, 127.2, 126.2, 99.2, 59.1, 53.9, 17.7, 14.0.
Figure imgf000081_0002
95 Ethyl 4-(4-methoxyphenyl)-6-methyl-2-oxo-l,2,3?4-tetrahydropyrimidine-5-carboxyIate
(95)
1H NMR (400 MHz, DMSO-J6) δ 9.18 (bs, IH), 7.65 (bs, IH), 7.18 (d, J= 8.4 Hz, 2H), 6.91 (d, J= 8.4 Hz, 2H), 4.02 (q, J= 6.8 Hz, 2H), 3.36 (s, 3H), 2.28 (s, 3H), 1.14 (t, J= 7.0 Hz, 3H); 13C NMR (100 MHz, DMSO-J6) δ 165.3, 158.4, 152.1 ,147.9, 137.0, 127.3, 113.6, 99.5, 59.1, 55.0, 53.3, 17.7, 14.0.
Figure imgf000081_0003
Ethyl 4-(3-methoxyphenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate (96)
1H NMR (400 MHz, DMSO-J6) δ 9.21 (bs, IH), 7.76 (bs, IH), 7.28 (t, J= 7.8 Hz, IH), 6.01- 687 (m, 3H), 5.15 (s, IH), 4.04 (q, J= 7.2 Hz, 2H), 3.76 (s, 3H), 2.28 (s, 3H), 1.15 (t, J= 7.2 Hz, 3H); 13C NMR (IOO MHZ, DMSO-J6) δ 165.3, 159.1, 152.2, 148.4, 146.3, 129.5, 118.2, 112.3, 112., 99.1, 59.2, 54.9, 53.7, 17.7, 14.1.
Figure imgf000082_0001
Ethyl 4-(3-hydroxyphenyI)-6-methyl-2-oxo-l,2,3j4-tetrahydropyrimidine-5-carboxylate
(97)
1H NMR (400 MHz, OMSO-d6) δ 9.35 (bs, IH), 9.14 (s, IH), 7.67 (s, IH), 7.09 (t, J= 8.0 Hz, IH), 6.68-6.60 (m, 3H), 5.06 (d, J= 3.6 Hz, IH), 3.99 (q, J= 6.8 Hz, 2H), 2.23 (s, 3H), 1.12 (t, J- 7.2 Hz, 3H); 13C NMR (100 MHz, OMSO-d6) δ 165.4, 157.3, 152.2, 148.1, 146.3, 129.3, 116.9, 114.2, 113.1, 99.4, 59.2, 53.8, 17.8, 14.1.
Figure imgf000082_0002
Ethyl 6-methyl-4-(3-nitrophenyl)-2-oxo-l,2,3?4-tetrahydropyrimidine-5-carboxylate (98)
1H NMR (400 MHz, OMSO-d6) δ 8.17 (d, J= 7.6 Hz, IH), 8.12 (s, IH), 7.93 (bs, IH), 7.67- 7.74 (m, 2H), 5.33 (s, IH), 4.00-4.07 (m, 2H), 2.31 (s, 3H), 1.13 (t, J= 7.0 Hz, 3H).
Figure imgf000082_0003
CyclohexyImethyl 6-methyl-2-oxo-4-phenyl-l,2,3,4-tetrahydropyrimidine-5-carboxylate (99)
1H NMR (400 MHz, CD3OD) δ 7.23-7.34 (m, 5H), 5.31 (s, IH), 3.89 (dd. J= 10.8, 6.0 Hz, IH), 3.74 (dd, J= 10.6, 5.8 Hz, IH), 2.37 (s, 3H), 1.43-1.66 (m, 6H), 1.08-1.21 (m, 3H), 0.79- 0.87 (m, 2H); 13C NMR (100 MHz, CD3OD) δ 167.6, 149.4, 145.6, 129.7, 128.8, 127.8, 101.7, 70.3, 56.7, 38.6, 30.8, 30.7, 27.4, 26.9, 18.2.
Figure imgf000083_0001
CycIohexylmethyl 4-(2-hydroxyphenyI)-6-methyl-2-oxo-l,2,3?4-tetrahydropyrimidine-5- carboxylate (100)
1H NMR (400 MHz, CD3OD) δ 7.01 (d, J= 7.6 Hz, IH), 6.74-7.00 (m, 2H), 5.71 (bs, IH), 5.49 (s, IH), 3.90 (dd, J= 10.6, 5.8 Hz, IH), 3.68 (dd, J= 10.6, 5.8 Hz, IH), 2.40 (s, 3H), 1.57-1.62 (m, 3H), 1.29-1.44 (m, 3H), 1.02-1.18 (m, 3H), 0.69-0.79 (m, 2H).
Figure imgf000083_0002
Cyclohexylmethyl 4-(4-hydroxyphenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5- carboxylate (101)
1H NMR (400 MHz, CD3OD) δ 7.11 (d, J= 6.8 Hz, 2H), 6.72 (d, J= 6.4 Hz, 2H), 5.22 (s, IH), 3.90 (dd, J= 10.6, 6.0 Hz, IH), 3.73 (dd, J= 10.6, 5.8 Hz, IH), 3.35 (s, IH), 2.33 (s, 3H), 1.44-1.68 (m, 6H), 1.10-1.21 (m, 3H), 0.80-0.86 (m, 2H).
Figure imgf000083_0003
Cyclohexylmethyl 4-(3-methoxyphenyl)-6-methyI-2-oxo-l,2,3»4-tetrahydropyrimidine-5- carboxylate (102) 1H NMR (400 MHz, CD3OD) δ 7.23 (t, J= 7.8 H, IH) 6.81-6.89 (m, 2H), 5.28 (s, IH), 3.92 (dd, J= 10.8, 5.6 Hz, IH), 3.77 (s, 3H), 3.74 (dd, J= 10.8, 5.6 Hz, IH), 2.36 (s, 3H), 1.43- 1.66 (m, 6H), 1.11-1.20 (m, 3H), 0.79-0.85 (m, 2H).
Figure imgf000084_0001
Cyclohexylmethyl 6-methyl-2-oxo-4-(pyridin-3-yl)-l,2,3>4-tetrahydropyrimidine-5- carboxylate (103)
1H NMR (400MHz, DMSO-J6) δ 9.32 (s, IH), 8.46-8.44 (m, 2H), 7.78 (s, IH), 7.60 (d, J= 7.6 Hz, IH), 7.37 (dd, J= 7.8, 4.6 Hz, IH), 5.19 (d, J= 2.8 Hz, IH), 3.82 (dd, J= 10.6, 6.0 Hz, IH), 3.70 (dd, J= 10.6, 6.0 Hz, IH), 2.29 (s, 3H), 1.56-1.37 (m, 6H), 1.12-1.00 (m, 3H), 0.79-0.72 (m, 2H); 13C NMR (100MHz, DMSO-J6) δ 165.7, 152.4, 150.2, 149.3, 148.7, 134.6, 124.5, 98.6, 68.9, 52.8, 37.3, 29.69, 29.61, 26.4, 25.86, 25.85, 18.5.
Figure imgf000084_0002
3-(5-((CyclohexyImethoxy)carbonyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidiii-4- yl)pyridine 1-oxide (104)
1H NMR (400 MHz, CD3OD) δ 8.16 (d, J= 4.0 Hz, 2H), 7.49-7.45 (m, 2H), 5.27 (s, IH), 3.85 (dd, J= 10.8, 6.0 Hz, IH), 3.72 (dd, J= 10.8, 6.0 Hz, IH), 2.28 (s, 3H), 1.61-1.37 (m, 6H), 1.19-1.02 (m, 3H), 0.82-0.76 (m, 2H).
Figure imgf000084_0003
105 Cyclohexylmethyl 6-ethyl-4-(4-hydroxyphenyl)-2-oxo-l,2,3,4-tetrahydropyrimidine-5- carboxylate (105)
1H NMR (400 MHz, CD3OD) δ 7.12-7.09 (m, 2H), 6.74-6.70 (m, 2H), 5.22 (s, IH), 3.91 (dd, J= 11.0, 6.2 Hz, IH), 3.74 (dd, J= 11.0, 6.2 Hz, IH), 2.81-2.72 (m, 2H), 1.68-1.43 (m, 6H), 1.25-1.10 (m, 6H), 0.88-0.81 (m, 2H); 13C NMR (IOO MHz, CD3OD) δ 166.0, 157.0, 154.0, 153.2, 135.5, 127.7, 115.1, 100.1, 69.0, 54.6, 37.5, 29.51, 29.45, 26.2, 25.7, 24.4, 12.1. Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 25% i- PrOH in rc-Hexanes, 0.85 mL/min): 105a tR = 7.70 min, 105b tR = 14.51 min.
Figure imgf000085_0001
106a
(S)-Cyclohexylmethyl 4-(3-acetoxyphenyl)-6-ethyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5- carboxylate (106a)
1U NMR (400 MHz, CDCl3) δ 7.84 (s, IH), 7.30 (t, J= 7.8 Hz, IH), 7.16 (d, J= 7.6 Hz, IH), 7.00-7.98 (m, 2H), 5.82 (s, IH), 5.36 (d, J= 2.0 Hz, IH), 3.86 (dd, J= 11.0, 6.2 Hz, IH), 3.78 (dd, J= 11.0, 6.2 Hz, IH), 2.83-2.78 (m, IH), 2.69-2.64 (m, IH), 2.26 (s, 3H), 1.66-1.44 (m, 6H), 1.22-1.06 (m, 6H), 0.87-0.77 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 169.5, 165.4, 153.4, 151.1, 145.5, 130.0, 124.1, 121.4, 120.0, 100.3, 69.7, 55.6, 37.3, 29.89, 29.87, 26.5, 25.9, 25.6, 21.4, 12.7.
Figure imgf000085_0002
107a
(S)-Cyclohexylmethyl 6-ethyl-2-oxo-4-(3-(pivaloyloxy)pb.enyl)-l,2,3>4- tetrahydropyrimidine-5-carboxylate (107a) 1H NMR (400 MHz, CDCl3) δ 7.60 (s, IH), 7.30 (t, J= 8.0 Hz, IH), 7.14 (d, J= 8.0 Hz, IH), 6.96-6.94 (m, 2H), 5.77 (s, IH), 5.35 (d, J= 2.4 Hz, IH), 3.84-3.76 (m, 2H), 2.82-2.67 (m, 2H), 1.66-1.44 (m, 6H), 1.32 (s, 9H), 1.28-1.06 (m, 6H), 0.87-0.79 (m, 2H).
Figure imgf000086_0001
(S)-Cyclohexylmethyl 4-(3-(benzoyloxy)phenyl)-6-ethyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (108a)
1H NMR (400 MHz, CDCl3) δ 8.16 (d, J= 8.0 Hz, 2H), 7.80 (s, IH), 7.62 (t, J= 7.4 Hz, IH), 7.48 (t, J= 7.6 Hz, 2H), 7.36 (t, J= 7.8 Hz, IH), 7.20 (d, J= 8.0 Hz, IH), 7.14-7.11 (m, 2H), 5.88 (s, IH), 5.39 (d, J= 2.0 Hz, IH), 3.88 (dd, J= 11.0, 6.2 Hz, IH), 3.79 (dd, J= 11.0, 6.2 Hz, IH), 2.85-2.64 (m, 2H), 1.64-1.46 (m, 6H), 1.26-1.04 (m, 6H), 0.89-0.78 (m, 2H); 13C NMR (IOO MHz, CDCl3) δ 165.4, 165.2, 153.4, 152.3, 151.4, 145.6, 133.9, 130.4, 130.1, 129.7, 128.8, 124.2, 121.6, 120.3, 100.3, 69.7, 55.7, 37.3, 29.92, 29.88, 26.5, 25.9, 25.6, 12.7.
Figure imgf000086_0002
(S)-Cyclohexylmethyl 4-(4-acetoxyphenyl)-6-ethyl-2-oxo-l,2,3?4-tetrahydropyrimidine-5- carboxylate (109)
1H NMR (400 MHz, CDCl3) δ 7.80 (s, IH), 7.29 (d, J= 8.8 Hz, 2H), 7.02 (d, J= 8.8 Hz, 2H), 5.74 (s, IH), 5.37 (d, J= 2.4 Hz, IH), 3.87-3.78 (m, 2H), 2.81-2.67 (m, 2H), 2.27 (s, 3H), 1.68-1.44 (m, 6H), 1.23-1.06 (m, 6H), 0.87-0.78 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 169.6, 165.5, 153.5, 152.1, 150.5, 141.3, 127.9, 122.1, 100.6, 69.7, 55.4, 37.3, 29.9, 26.5, 25.85, 25.83, 25.6, 21.4, 12.7.
Figure imgf000087_0001
110a
(S)-CyclohexylmethyI 6-ethyl-2-oxo-4-(4-(pivaloyloxy)phenyl)-l,2,3,4- tetrahydropyrimidine-5-carboxylate (110a)
1H NMR (400 MHz, CDCl3) δ 7.81 (s, IH), 7.29 (d, J= 8.4 Hz, 2H), 6.99 (d, J= 8.4 Hz, 2H), 5.78 (s, IH), 5.37 (d, J= 2.0 Hz, IH), 3.81 (d, J= 6.0 Hz, 2H), 2.80-2.68 (m, 2H), 1.71-1.44 (m, 6H), 1.37-1.06 (m, 15H), 0.87-0.79 (m, 2H).
Figure imgf000087_0002
111a
(S)-Cyclohexylmethyl 4-(4-(benzoyloxy)phenyl)-6-ethyl-2-oxo-l,2,3j4- tetrahydropy rimidine-5-carboxylate (Ilia)
1H NMR (400 MHz, CDCl3) δ 8.12 (d, J= 8.4 Hz, 2H), 7.57 (t, J= 6.8 Hz, IH), 7.44 (t, J= 7.6 Hz, 2H), 7.31 (d, J= 8.0 Hz, 2H), 7.11 (d, J= 8.0 Hz, 8.4), 5.52 (s, IH), 5.37 (s, IH), 3.84-3.77 (m, 2H), 2.77-2.66 (m, 2H), 1.67-1.47 (m, 6H), 1.21-1.03 (m, 6H), 0.82-0.76 (m, 2H).
Figure imgf000087_0003
(S)-Cyclohexylmethyl 4-(4-(tert-butoxycarbonyloxy)phenyl)-6-ethyl-2-oxo-l,2,3?4- tetrahy dropy rimidine-5-carboxylate (112a)
1H NMR (400 MHz, CDCl3) δ 7.29 (d, J= 8.4 Hz, 2H), 7.17-7.09 (m, 3H), 5.47 (s, IH), 5.38 (d, J= 2.4 Hz, IH), 3.87-3.78 (m, 2H), 2.81-2.68 (m, 2H), 1.74-1.45 (m, 15H), 1.24-1.03 (m, 6H), 0.86-0.78 (m, 2H).
Figure imgf000088_0001
(5)-CycIohexylmethyl 4-(4-((S)-2-(fer/-butoxycarbonylamino)propanoyloxy)phenyI)-6- ethyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate (113a)
1H NMR (400 MHz, CDCl3) δ 8.15 (s, IH), 7.29 (d, J- 8.8 Hz, 2H), 7.01 (d, J= 8.8 Hz, 2H), 5.94 (s, IH), 5.36 (d, J= 2 Hz, IH), 5.13 (s, IH), 4.51 (s, IH), 3.86-3.76 (m, 2H), 2.80-2.64 (m, 2H), 1.65-1.34 (m, 18H), 1.27-1.02 (m, 6H), 0.90-0.76 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 165.5, 152.4, 150.3, 141.7, 127.9, 121.8, 100.4, 69.6, 55.3, 37.3, 29.9, 28.5, 26.5, 25.8, 25.5, 18.6, 12.8.
Figure imgf000088_0002
114a
(S)-Cyclohexylmethyl 4-(4-((S)-2-aminopropanoyloxy)phenyl)-6-ethyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate hydrochloride (114a)
1H NMR (400 MHz, CD3OD) δ 7.39 (d, J= 8.4 Hz, 2H), 7.16 (d, J= 8.4 Hz, 2H), 5.35 (s, IH), 4.39 (q, J= 7.2 Hz, IH), 3.90 (dd, J= 10.6, 5.8 Hz, IH), 3.78 (dd, J= 10.6, 5.8 Hz, IH), 2.85-2.71 (m, 2H), 1.71-1.45 (m, 9H), 1.26-1.10 (m, 6H), 0.90-0.82 (m, 2H); 13C NMR (IOO MHz, CD3OD) δ 168.7, 165.7, 154.1, 149.7, 143.1, 127.9, 121.3, 99.4, 69.1, 57.2, 37.4, 29.5, 26.2, 25.6, 24.5, 15.0, 12.1.
Figure imgf000089_0001
115a
(S)-Cyclohexylmethyl 6-ethyl-4-(4-(isonicotinoyloxy)phenyl)-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (115a)
1U NMR (400 MHz, CDCl3) δ 8.85 (bs, 2H), 8.00 (d, J= 9.2 Hz, 2H), 7.37 (d, J= 8.4 Hz, 2H), 7.16 (d, J= 8.4 Hz, 2H), 5.94 (s, IH), 5.42 (d, J= 2.4 Hz, IH), 3.89-3.79 (m, 2H), 2.83- 2.68 (m, 2H), 1.70-1.46 (m, 6H), 1.24-1.03 (m, 6H), 0.89-0.79 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 165.5, 163.5, 153.6, 152.4, 150.24, 150.20, 142.2, 137.7, 128.2, 123.8, 121.9, 100.4, 69.7, 55.3, 37.4, 29.9, 26.5, 25.9, 25.6, 128.
Figure imgf000089_0002
116a
(5)-CycIohexylmethyl 6-ethyl-4-(4-(nicotinoyloxy)phenyl)-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (116a)
1H NMR (400 MHz, CDCl3) δ 9.36 (s, IH), 8.85 (s, IH), 8.50 (d, J= 8.0 Hz, IH), 7.73 (s, IH), 7.53 (s, IH), 7.36 (d, J= 8.8 Hz, 2H), 7.15 (d, J= 8.8 Hz, 2H), 5.81 (s, IH), 5.40 (s, IH), 3.87-3.77 (m, 2H), 2.80-2.69 (m, 2H), 1.66-1.48 (m, 6H), 1.23-1.05 (m, 6H), 0.84 (m, 2H).
Figure imgf000090_0001
117
Cyclohexylmethyl 4-(3-acetoxyphenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5- carboxylate (117)
1H NMR (400 MHz, CDCl3) δ 8.48 (s, IH), 7.29 (t, J= 7.6 Hz, IH), 7.19 (dd, J= 27.4, 7.8 Hz, IH), 7.00-6.98 (m, 2H), 6.14 (s, IH), 5.36 (d, J= 2.0 Hz, IH), 3.86 (dd, J= 10.6, 6.2 Hz, IH), 3.77 (dd, J= 10.6, 6.2 Hz, IH), 2.33 (s, 3H), 2.26 (s, 3H), 1.65-1.44 (m, 6H), 1.25-1.05 (m, 3H), 0.86-0.77 (m, 2H).
Figure imgf000090_0002
Cyclohexylmethyl 4-(3-(benzoyloxy)phenyl)-6-methyl-2-oxo-l,2,3»4- tetrahydropyrimidine-5-carboxylate (118)
1H NMR (400 MHz, CDCl3) δ 8.62 (s, IH), 8.17 (d, J= 8.4 Hz, 2H), 7.64-7.60 (m, IH), 7.49 (t, J= 7.8 Hz, 2H), 7.35 (t, J= 7.8 Hz, IH), 7.26-7.11 (m, 3H), 6.37 (s, IH), 5.40 (d, J= 2.4 Hz, IH), 3.89 (dd, J= 10.8, 6.0 Hz, IH), 3.78 (dd, J= 10.8, 6.0 Hz, IH), 2.34 (s, 3H), 1.64- 1.49 (m, 6H), 1.65-1.05 (m, 3H), 0.88-0.80 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 165.9, 165.2, 154.0, 151.4, 147.3, 145.6, 133.9, 130.4, 130.1, 129.7, 129.3, 128.8, 128.5, 124.3, 121.6, 120.2, 101.0, 69.7, 55.5, 37.3, 29.9, 26.5, 25.9, 18.9.
Figure imgf000090_0003
119 Cyclohexylmethyl 6-methyl-2-oxo-4-(3-(pivaloyloxy)phenyl)-l,2,3j4- tetrahydropyrimidine-5-carboxylate (119)
1H NMR (400 MHz, CDCl3) δ 8.62 (s, IH), 7.30-7.22 (m, IH), 7.16-7.14 (m, IH), 6.96-6.93 (m, 2H), 6.25 (s, IH), 5.34 (d, J= 2.8 Hz, IH), 3.85 (dd, J- 10.6, 6.2 Hz, IH), 3.77 (dd, J = 10.6, 6.2 Hz, IH), 2.33 (s, 3H), 1.66-1.45 (m, 6H), 1.33-1.06 (m, 12H), 0.87-0.79 (m, 2H); 13C NMR (IOO MHZ, CDCl3) δ 177.1, 165.8, 153.8, 151.4, 147.2, 145.5, 129.9, 124.0, 121.3, 120.0, 100.9, 69.6, 55.6, 39.3, 37.3, 29.91, 29.88, 27.4, 26.5, 25.9, 18.8.
Figure imgf000091_0001
120a
(S)-Cyclohexylmethyl 4-(3-(te^-butoxycarbonyloxy)phenyl)-6-ethyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (120a)
To a mixture of 2a (10 mg, 0.028 mmol, 1.0 equiv) in CH2Cl2 (0.5 mL) was added DIPEA (7.3 μL, 0.042 mmol, 2.0 equiv), (Boc)2O (7.3 mg, 0.034 mmol, 1.2 equiv), and DMAP (1.7 mg, 0.014 mmol, 0.5 equiv), and the reaction mixture was stirred for 3 h at 0 0C. The mixture was diluted with CH2Cl2 (5 mL), washed with water (1 mL), dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (10% MeOH/CH2Cl2) to afford 120 (6.9mg, 54%): 1H NMR (400 MHz, CD3OD) δ 7.33 (t, J = 8.0 Hz, IH), 7.18 (d, J = 7.6 Hz, IH), 7.03 (m, 2H), 5.30 (s, IH), 3.88 (dd, J= 10.8, 6.2 Hz, IH), 3.76 (dd, J= 10.8, 6.0 Hz, IH), 2.76 (q, J = 7.6 Hz, 2H), 1.66-1.43 (m, 15H), 1.27-1.11 (m, 6H), 0.93-0.81 (m, 2H); 13C NMR (100 MHz, CD3OD) δ 167.1, 155.5, 155.2, 153.4, 153.0, 147.5, 130.9, 125.0, 121.7, 120.8, 100.7, 84.5, 70.5, 56.0, 38.7, 30.9, 28.0, 27.5, 27.0, 25.8, 13.4.
Figure imgf000091_0002
(5)-CyclohexyImethyl 6-ethyl-4-(3-(isonicotinoyloxy)phenyI)-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (121a) 1H NMR (400 MHz, CDCl3) δ 8.85 (d, J = 5.2 Hz, 2H), 7.97 (d, J = 5.2 Hz, 2H), 7.56 (s, IH), 7.37 (t, J = 7.6 Hz, IH), 7.26 (s, IH), 7.15 (t, J = 7.2 Hz, 2H), 5.73 (s, IH), 5.41 (d, J = 2.8 Hz, IH), 3.89 (dd, J = 10.8, 6.0 Hz, IH), 3.81 (dd, J = 10.6, 6.2 Hz, IH), 2.83 (m, IH), 2.69 (m, IH), 1.65-1.50 (m, 6H), 1.55-1.03 (m, 6H), 0.86-0.80 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 165.4, 163.8, 153.1, 152.3, 151.1, 145.9, 137.0, 130.3, 124.7, 123.4, 121.2, 119.9, 100.3, 68.8, 55.7, .37.4, 29.92, 29.90, 26.5, 25.9, 25.7, 12.7.
Figure imgf000092_0001
(S)-Cyclohexylmethyl 6-ethyl-4-(3-(nicotinoyloxy)phenyl)-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (122a)
1H NMR (400 MHz, CDCl3) δ 9.38 (t, J = 1.0 Hz, IH), 8.86 (d, J = 5.2 Hz, IH), 8.43 (d, J = 8.0 Hz, IH), 7.77 (bs, IH), 7.47 (dd, J = 8.0, 4.8 Hz, IH), 7.40 (t, J = 7.8 Hz, IH), 7.25 (d, J = 8.0 Hz, IH), 7.17 (m, 2H), 5.85 (bs, IH), 5.42 (d, J = 2.8 Hz, IH), 3.90 (dd, J = 11, 6.2 Hz, IH), 3.82 (dd, J = 10.6, 6.2 Hz, IH), 2.83 (m, IH), 2.70 (m, IH), 1.67-1.51 (m, 6H), 1.31- 1.07 (m, 6H), 0.88-0.81 (m, 2H).
Figure imgf000092_0002
(5)-Cyclohexylmethyl 4-(3-((5)-2-(tert-butoxycarbonylamino)propanoyloxy)phenyl)-6- ethyl-2-oxo-l,2,3?4-tetrahydropyrimidine-5-carboxylate (123a)
To a mixture of 2a (20 mg, 0.056 mmol, 1.0 equiv) in CH2Cl2 (0.5 niL) was added Boc-L- alanine (18 mg, 0.095mmol, 1.7 equiv), DIPEA (24.3 μL, 0.14mmol, 2.5 equiv), EDC (13.9 mg, 0.073mmol, 1.3 equiv), and DMAP (3.4 mg, 0.028mmol, 0.5 equiv), and the reaction mixture was stirred for 4 h at 35 °C. The resulting mixture was diluted with CH2Cl2 (5 mL), washed with water (1 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by preparative TLC (5% MeOH/ CH2Cl2) to afford 123 (13.1 mg, 44%): 1H NMR (400 MHz, CD3OD) δ 7.35 (t, J = 7.8 Hz, IH), 7.19 (d, J = 7.6 Hz, IH), 7.02 (t, J = 8.2 Hz, 2H), 5.30 (s, IH), 4.31 (q, J = 7.6 Hz, IH), 3.88 (dd, J = 10.4, 6.0 Hz, IH), 3.74 (dd, J = 10.4, 5.6 Hz, IH), 2.77 (m, 2H), 1.65-1.39 (m, 18H), 1.31-1.07 (m, 6H), 0.86-0.78 (m, 2H).
Figure imgf000093_0001
(S)-Cyclohexylmethyl 4-(3-((<S)-2-aminopropanoyloxy)phenyl)-6-ethyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate hydrochloride (124a)
1H NMR (400 MHz, CD3OD) δ 7.32 (t, J = 7.6 Hz, IH), 7.18 (d, J = 7.6 Hz, IH), 7.02 (d, J = 8.0 Hz, 2H), 5.26 (s, IH), 4.30 (q, J = 6.8 Hz, IH), 3.81 (dd, J= 10.8, 6.0 Hz, IH), 3.68 (dd, J = 10.8, 6.0 Hz, IH), 2.73 (m, IH), 2.62 (m, IH), 1.64-1.36 (m, 9H), 1.22-0.99 (m, 6H), 0.79-0.72 (m, 2H).
Figure imgf000093_0002
Cyclohexylmethyl 6-ethyl-4-(4-nitrophenyl)-2-oxo-l,2,3,4-tetrahydropyrimidine-5- carboxylate (125)
1H NMR (400 MHz, CD3OD) δ 8.19 (d, J= 7.2 Hz, 2H), 7.53 (d, J= 7.2 Hz, 2H), 5.40 (s, IH), 3.88 (dd, J= 10.6, 6.2 Hz, IH), 3.76 (dd, J= 10.6, 6.2 Hz, IH), 2.86-2.67 (m, 2H), 1.61- 1.39 (m, 6H), 1.26-1.05 (m, 6H), 0.84-0.75 (m, 2H); 13C NMR (100 MHz, CD3OD) δ 165.5, 161.6, 154.7, 151.5, 148.2, 147.6, 127.8, 123.7, 98.6, 69.1, 54.6, 37.4, 29.52, 29.47, 26.1, 25.58, 25.54, 24.5, 12.1.
Figure imgf000094_0001
Cyclohexylmethyl 4-(4-aminophenyl)-6-ethyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5- carboxylate hydrochloride (126)
1H NMR (400 MHz, CD3OD) δ 7.46 (d, J= 11.2 Hz, 2H), 7.35 (d, J= 11.2 Hz, 2H), 5.35 (s, IH), 3.85 (dd, J= 10.8, 6.0 Hz, IH), 3.78 (dd, J= 10.8, 6.0 Hz, IH), 2.84-2.68 (m, 2H), 1.68- 1.45 (m, 6H), 1.24-1.01 (m, 6H), 0.90-0.80 (m, 2H); 13C NMR (100 MHz, CD3OD) δ 165.7, 154.4, 153.7, 145.7, 130.2, 128.4, 123.1, 99.1, 69.2, 54.4, 37.4, 29.57, 29.54, 26.2, 25.6, 24.5, 12.1.
Figure imgf000094_0002
127
Cyclohexylmethyl 4-(4-aminophenyl)-6-ethyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5- carboxylate (127)
1H NMR (400 MHz, CD3OD) δ 7.00 (d, J= 8.4 Hz, 2H), 6.64 (d, J= 8.4 Hz, 2H), 5.16 (s, IH), 3.86 (dd, J= 10.8, 6.0 Hz, IH), 3.73 (dd, J= 10.8, 6.0 Hz, IH), 2.77-2.70 (m, 2H), 1.67- 1.45 (m, 6H), 1.22-1.09 (m, 6H), 0.88-0.81 (m, 2H); 13C NMR (100 MHz, CD3OD) δ 166.1, 154.1, 152.9, 147.3, 142.1, 134.0, 127.4, 115.3, 100.2, 69.0, 57.1, 54.7, 37.4, 29.54, 29.51, 26.2, 25.7, 24.4, 17.2, 12.1.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 25% i- PrOH in fl-Hexanes, 0.85 mL/min): 127a tR = 20.0 min, 127b tR = 50.0 min.
Figure imgf000095_0001
128
CyclohexyImethyl 6-ethyl-4-(3-nitrophenyl)-2-oxo-l,2,3,4-tetrahydropyrimidine-5- carboxylate (128)
1H NMR (400 MHz, CDCl3) δ 8.27 (s, IH), 8.14 (s, IH), 8.11 (d, J= 8.4 Hz, IH), 7.63 (d, J= 7.6 Hz, IH), 7.48 (t, J= 7.6 Hz, IH), 6.37 (s, IH), 5.47 (s, IH), 3.82 (m, 2H), 2.55 (m, 2H), 1.62-1.44 (m, 6H), 1.24-1.03 (m, 6H), 0.85-0.76 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 161.2, 149.7, 149.3, 144.7, 142.0, 129.0, 126.2, 119.2 118.0, 95.7, 65.9, 51.3, 33.3, 26.0, 22.5, 21.8, 21.6, 8.9.
Figure imgf000095_0002
Cyclohexylmethyl 4-(3-aminophenyl)-6-ethyl-2-oxo-l,2,354-tetrahydropyrimidine-5- carboxylate hydrochloride (129)
1H NMR (400 MHz, CD3OD) δ 7.50 (t, J= 7.8 Hz, IH), 7.43 (d, J= 8.0 Hz, IH), 7.36 (s, IH), 7.30 (d, J= 8.0 Hz, IH), 5.73 (s, IH), 4.08 (dd, J= 14.4, 7.2 Hz, IH), 3.83 (m, IH), 2.84 (m, IH), 2.69 (m, IH), 1.67-1.46 (m, 6H), 1.24-1.09 (m, 6H), 0.90-0.80 (m, 2H); 13C NMR (100 MHz, CD3OD) δ 169.6, 158.4, 157.6, 151.2, 135.1, 134.4, 131.6, 126.2, 124.9, 103.0, 73.2, 58.5, 41.3, 33.52, 33.49, 30.1, 29.5, 28.5, 16.1.
Figure imgf000095_0003
130
Cyclohexylmethyl 4-(3-aminophenyl)-6-ethyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5- carboxylate (130) 1H NMR (400 MHz, CD3OD) δ 7.03 (t, J= 7.6 Hz, IH), 6.67-6.60 (m, 3H), 5.20 (s, IH), 3.89
(dd, J= 10.4, 6.0 Hz, IH), 3.75 (dd, J= 10.4, 6.0 Hz, IH), 2.84-2.68 (m, 2H), 1.67-1.49 (m,
6H), 1.29-1.10 (m, 6H), 0.90-0.85 (m, 2H); 13C NMR (100 MHz, CD3OD) δ 166.0, 154.0,
153.4, 148.0, 145.1, 129.1, 116.3, 114.8, 113.4, 99.7, 69.0, 55.2, 37.4, 29.54, 29.49, 26.2,
25.7, 24.4, 12.1.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 25% i-
PrOH in n-Hexanes, 0.85 mL/min) : 130a tR = 16.93 min, 1303b tR = 40. ,77 min.
Figure imgf000096_0001
131
Cyclohexylmethyl 4-(3-aminophenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyriinidine-5- carboxylate (131)
Cyclohexylmethyl 4-6-methyl-(3-nitrophenyl)-2-oxo-l,2,3,4-tetrahydropyrimidine-5- carboxylate was synthesized by the Biginelli reaction: 1H NMR (400 MHz, DMSO-^6) δ 9.41 (bs, IH), 8.19 (d, J= 7.2 Hz, IH), 8.11 (bs, IH), 7.89 (bs, lH)m 7.69-7.75 (m, 2H), 5.33 (d, J = 2.8 Hz, IH), 3.87 (dd, J= 10.8, 6.0 Hz, IH), 3.72 (dd, J= 10.8, 6.0 Hz, IH), 2.34 (s, 3H), 1.37-1.60 (m, 6H), 1.00-1.15 (m, 3H), 0.72-0.83 (m, 2H); 13C NMR (100 MHz, DMSO-<4) δ 164.6, 151.2, 149.5, 147.3, 146.5, 132.7, 130.0, 122.1, 120.8, 97.5, 67.9, 53.3, 38.5, 36.3, 28.7, 28.6, 25.3, 24.8, 24.7, 17.4.
To a mixture of the above nitro compounds (100 mg, 0.27 mmol) in MeOH (3 mL) was added 10% Pd on carbon (7 mg), and the reaction mixture was stirred for 3 h at room temperature under hydrogen balloon. The catalyst was filtered through a plug of Celite and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography to give 131 (86 mg, 93%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 8.43 (bs, IH), 6.65 (d, J= 7.2 Hz), 6.59 (s, IH), 6.55 (d, J= 8.0 Hz, IH), 5.98 (bs, IH), 5.25 (s, IH), 3.86 (dd, J= 10.8, 6.0 Hz, IH), 3.76 (dd, J= 10.8, 6.0 Hz, IH), 3.26 (bs, 2H), 2.31 (s, 3H), 1.03-1.64 (m, 9H), 0.81-0.85 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 165.9, 153.7, 146.6, 144.9, 129.7, 117.0, 114.9, 113.3, 101.1, 69.4, 55.6, 37.2, 28.8, 26.7, 26.4, 25.8, 18.7.
Figure imgf000097_0001
132
Cyclohexylmethyl 6-ethyl-4-(4-(methylamino)phenyl)-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (132)
1H NMR (400 MHz, CDCl3) δ 7.93 (s, IH), 7.08 (d, J= 6.8 Hz, 2H), 6.54 (d, J= 6.8 Hz, 2H),
5.82 (s, IH), 5.25 (s, IH), 3.85-3.74 (m, 2H), 2.83 (s, 3H), 2.79-2.68 (m, 2H), 1.64-1.47 (m,
6H), 1.27-1.05 (m, 6H), 0.85-0.77 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 165.7, 154.0,
151.2, 148.7, 133.3, 127.8, 113.1, 101.2, 69.5, 55.5, 37.4, 31.2, 29.9, 26.5, 25.9, 25.4, 21.1,
12.7.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 25% i-
PrOH in rc-Hexanes, 0.85 mL/min): 132a tR = 12.2 min, 132b tR = 27.2 min.
Figure imgf000097_0002
Cyclohexylmethyl 4-(4-(dimethylamino)phenyl)-6-ethyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (133)
1H NMR (400 MHz, CDCl3) δ 7.52 (bs, IH), 7.14 (d, J= 8.4 Hz, 2H), 6.63 (d, J= 8.4 Hz, 2H), 5.44 (bs, IH), 5.27 (s, IH), 3.85 (dd, J= 10.8, 6.0 Hz, IH), 3.77 (dd, J= 10.8, 6.0 Hz, IH), 2.90 (s, 6H), 2.68-2.79 (m, IH), 1.41-1.66 (m, 6H), 1.07-1.23 (m, 6H), 0.78-0.92 (m, 2H).
Figure imgf000098_0001
Cyclohexylmethyl 6-ethyl-4-(4-(ethylamino)phenyl)-2-oxo-l,2,3,4-tetrahydropyrimidine- 5-carboxylate (134)
1U NMR (400 MHz, CDCl3) δ 7.81 (s, IH), 7.07 (d, J= 8.4 Hz, 2H), 6.50 (d, J= 8.4 Hz, 2H), 5.55 (s, IH), 5.24 (d, J = 2.4 Hz, IH), 3.84 (dd, J= 11.0, 6.2 Hz, IH), 3.77 (dd, J= 11.0, 6.2 Hz, IH), 3.11 (q, J= 7.2 Hz, 2H), 2.77-2.66 (m, 2H), 1.66-1.44 (m, 6H), 1.28-1.06 (m, 9H), 0.88-0.78 (m, 2H); 13C NMR (IOO MHz, CDCl3) δ 165.8, 153.6, 151.3, 148.3, 132.8, 127.8, 112.9, 101.1, 69.4, 55.6, 38.7, 37.4, 29.9, 26.5, 25.92, 25.91, 25.5, 15.0, 12.8. Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 25% i- PrOH in rc-Hexanes, 0.85 mL/min): 134a tR = 9.9 min, 134b tR = 24.9 min.
Figure imgf000098_0002
135
Cyclohexylmethyl 6-ethyl-4-(3-(methylamino)phenyl)-2-oxo-l,2,3?4- tetrahydropyrimidine-5-carboxylate (135)
To a stirred solution of 130 (50.0 mg, 0.14 mmol) in CH2C12/DMF (3:1, 0.40 niL) were added /-Pr2NEt (24.0 μL, 0.14 mmol) and MeI (9.00 μL, 0.14 mmol) at 0 0C. The mixture was allowed to warm to room temperature and stirred for 12 h. The resulting mixture was diluted with CH2Cl2 (10 mL), washed with brine (3 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography to afford the desired product 135 (20.6 mg, 42%): 1H NMR (400 MHz, CDCl3) δ 7.78 (bs, IH), 7.10 (t, J- 7.6 Hz, IH), 6.61 (d, J= 7.2 Hz, IH)5 6.46-6.50 (m, 2H), 5.68 (bs, IH), 5.28 (s, IH), 3.84 (dd. J= 10.8, 6.2 Hz, IH)5 3.76 (dd, J= 10.8, 6.2 Hz, IH), 2.78 (s, 3H), 2.76 (q, J= 7.6 Hz, 2H), 1.46-1.66 (m, 6H), 1.02-1.64 (m, 8H), 0.81-0.86 (m, 2H). Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 20% i- PrOH in rc-Hexanes, 0.8 mL/min): 135a tR = 16.0 min, 135b tR = 30.6 min.
Figure imgf000099_0001
Cyclohexylmethyl 6-ethyl-4-(3-(ethylamino)phenyl)-2-oxo-l,2,354-tetrahydropyrimidine- 5-carboxylate (136)
To a mixture of 130 (50.0 mg, 0.14 mmol), acetaldehyde (7.80 μL, 0.14 mmol) and AcOH (16.0 μL, 0.28 mmol) in CH2Cl2 (0.5 mL) was added NaBH(OAc)3 (41.5 mg, 1.4 mmol), and the resulting mixture was stirred at room temperature for 12 h under Argon. After quenching with saturated NaHCO3 (5 mL), the mixture was extracted with CH2Cl2 (2 x 10 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography to give 136 (42 mg, 78%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.84 (bs, IH), 7.08 (t, J= 7.8 Hz, IH), 6.59 (d, J= 7.6 Hz, IH), 6.47 (d, J= 8.4 Hz, 2H), 5.74 (bs, IH), 5.28 (s, IH), 3.86 (dd, J= 10.8, 6.0 Hz, IH), 3.78 (dd, J= 10.8, 6.0 Hz, IH), 3.10 (q, J= 10.6 Hz, 2H), 2.74 (q, J= 10.8 Hz, 2H), 2.00-2.04 (m, 2H), 1.05-1.64 (m, 13H), 0.76-0.90 (m, 4H).
Figure imgf000099_0002
137
Cyclohexylmethyl 6-ethyl-2-oxo-4-(3-(propylamino)phenyl)-l,2,3,4- tetrahydropyrimidine-5-carboxylate (137)
1H NMR (400 MHz, CDCl3) δ 8.10 (bs, IH), 7.21 (bs, IH), 7.04 (t, J= 7.6 Hz, IH), 6.55 (d, J = 7.6 Hz, IH), 6.42-6.45 (m, 2H), 5.73 (bs, IH), 5.22 (s, IH) 3.82 (dd, J= 10.8, 6.0 Hz, IH), 3.74 (dd, J= 10.8, 6.0 Hz, IH), 2.99 (t, J= 6.8 Hz, 2H), 2.64-2.72 (m, 2H), 1.45-1.59 (m, 6H), 1.02-1.21 (m, 9H), 0.93 (t, J= 7.4 Hz, 3H), 0.79-0.83 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 165.6, 153.8, 151.9, 128.9, 144.7, 129.7, 115.3, 112.1, 110.8, 100.3, 69.3, 55.9, 45.8, 37.3, 29.7, 26.4, 25.8, 25.3, 22.8, 12.7, 11.7.
Figure imgf000100_0001
138
Cyclohexylmethyl 4-(4-(diethylamino)phenyl)-6-ethyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (138)
1U NMR (400 MHz, CDCl3) δ 8.19 (s, IH), 7.10 (d, J= 8.4 Hz, 2H), 6.56 (d, J= 8.4 Hz, 2H), 5.75 (s, IH), 5.25 (d, J- 2.4 Hz, IH), 3.86 (dd, J= 10.8, 6.0 Hz, IH), 3.76 (dd, J= 10.8, 6.0 Hz, IH), 3.30 (q, J= 7.2 Hz, 2H), 2.78-2.67 (m, 2H), 1.65-1.45 (m, 6H), 1.23-1.05 (m, 12H), 0.87-0.79 (m, 2H); 13C NMR (IOO MHz, CDCl3) δ 172.2, 161.9, 150.1, 147.5, 143.7, 126.8, 123.9, 107.9, 97.1, 65.5, 51.4, 40.6, 33.5, 25.9, 22.6, 22.0, 21.5, 17.3, 8.9. Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 20% i- PrOH in rc-Hexanes, 0.80 mL/min): 138a tR = 7.2 min, 138b ^ = 13.0 min.
Figure imgf000100_0002
139
Cydohexylmethyl 6-ethyI-2-oxo-4-(4-(propylamino)phenyl)-l,2,3,4- tetrahydropyrimidine-5-carboxylate (139)
1H NMR (400 MHz, CDCl3) δ 8.04 (s, IH), 7.06 (d, J= 8.4 Hz, 2H), 6.52 (d, J= 8.4 Hz, 2H), 5.73 (s, IH), 5.24 (d, J= 2.8 Hz, IH), 3.84 (dd, J= 10.8, 6.0 Hz, IH), 3.77 (dd, J = 10.8, 6.0 Hz, IH), 3.03 (t, J= 12 Hz, 2H), 2.77-2.66 (m, 2H), 1.65-1.45 (m, 8H), 1.28-1.06 (m, 6H), 0.98-0.78 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 165.8, 153.9, 151.5, 147.9, 133.1, 127.8, 113.2, 101.0, 69.4, 55.5, 46.3, 37.4, 31.8, 29.9, 26.5, 25.9, 25.5, 22.9, 22.8, 14.3, 12.8, 11.8. Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 10-30 % /-PrOH in rc-Hexanes gradient, 0.85-1.0 mL/min): 139a tR = 17.8 min, 139b tR = 33.3 min.
Figure imgf000101_0001
140
Cyclohexylmethyl 4-(4-(benzylamino)phenyl)-6-ethyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (140)
1H NMR (400 MHz, CDCl3) δ 7.53 (s, IH), 7.33-7.24 (m, 5H), 7.07 (d, J= 7.6 Hz, 2H), 6.67 (d, J= 7.6 Hz, 2H), 5.82 (s, IH), 5.24 (d, J= 2.4 Hz, IH), 4.30 (s, 2H), 3.85-3.76 (m, 2H), 2.79-2.69 (m, 2H), 1.66-1.44 (m, 6H), 1.28-1.06 (m, 6H), 0.86-0.81 (m, 2H).
Figure imgf000101_0002
Cyclohexylmethyl 6-ethyl-2-oxo-4-(4-(pentylamino)phenyl)-l,2,3,4- tetrahydropyrimidine-5-carboxylate (141)
1H NMR (400 MHz, CDCl3) δ 7.77 (bs, IH), 7.06 (d, J= 8.0 Hz, 2H), 6.49 (d, J= 8.0 Hz, 2H), 5.55 (bs, IH), 5.28 (bs, IH), 5.23 (s, IH), 3.84 (dd, J= 10.6, 5.8 Hz, IH), 3.77 (dd, J = 10.8, 6.4 Hz, IH), 3.05 (t, J= 7.2 Hz, 2H), 2.67-2.78 (m, 2H), 0.82-1.65 (m, 23H).
Figure imgf000101_0003
142 Cyclohexylmethyl 6-ethyl-4-(4-(octylamino)phenyl)-2-oxo-l,2,3?4-tetrahydropyrimidine- 5-carboxylate (142)
1H NMR (400 MHz, CDCl3) δ 8.02 (bs, IH), 7.06 (d, J= 8,4 Hz, 2H), 6.49 (d, J= 8.4 Hz, 2H), 5.27 (bs, IH), 5.24 (s, IH), 3.84 (dd, J= 10.8, 6.0 Hz, IH), 3.77 (dd, J= 10.8, 6.0 Hz, IH), 3.05 (t, J= 7.2 H, 2H), 2.70-2.74 (m, 2H), 0.81-1.65 (m, 29H); 13C NMR (100 MHz, CDCl3) δ 165.7, 153.8, 151.2, 148.4, 132.4, 127.7, 112.7, 101.3, 69.3, 55.4, 44.1, 37.3, 31.9, 29.8, 29.6, 29.5, 27.2, 26.4, 25.8, 25.3, 22.7, 14.2, 12.6.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 20% z-PrOH in «-Hexanes, 6.5 mL/min): 142a ΪR = 5.4 min, 142b fø = 7.8 min. oc
Figure imgf000102_0001
143
Cyclohexylmethyl 4-(4-(5-(tert-butoxycarbonylamino)pentylamino)phenyl)-6-ethyl-2- oxo-1 ,2,354-tetrahy dropy rimidine-5-carboxylate (143)
1H NMR (400 MHz, CDCl3) δ 8.41 (bs, IH), 7.04 (d, J= 8.0 Hz, 2H), 6.48 (d, J= 8.0 Hz, 2H), 5.93 (s, IH), 5.25 (s, IH), 4.59 (s, IH), 3.84-3.73 (m, 2H), 3.19-3.03 (m, 4H), 2.85-2.62 (m, 2H), 1.63-1.34 (m, 16H), 1.27-1.02 (m, 8H), 0.98-0.77 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 165.8, 156.3, 154.1, 151.7, 148.1, 133.0, 129.2, 128.4, 127.8, 125.5, 113.0, 100.9, 79.3, 69.4, 55.4, 44.1, 40.6, 37.4, 30.1, 29.9, 29.2, 28.6, 26.5, 25.9, 25.4, 24.5, 21.3, 14.3, 12.8.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 15- 40% z-PrOH in «-Hexanes gradient, 6.5 mL/min): 143a tR = 38.5 min, 143b tR = 69.2 min.
Figure imgf000102_0002
Cyclohexylmethyl 4-(4-(5-aminopentylamino)phenyl)-6-ethyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate hydrochloride (144)
1H NMR (400 MHz, CD3OD) δ 7.53 (d, J= 9.2 Hz, 4H), 5.38 (s, IH), 3.88 (dd, J- 10.8, 6.0 Hz, IH), 3.81 (dd, J= 10.8, 6.0 Hz, IH), 3.40 (t, J= 7.4 Hz, 2H), 2.95 (t, J= 7.0 Hz, 2H), 2.86-2.80 (m, IH), 2.77-2.70 (m, IH), 1.81-1.51 (m, 12H), 1.25-1.11 (m, 6H), 0.92-0.84 (m, 2H); 13C NMR (100 MHz, CD3OD) δ 165.6, 154.5, 153.7, 146.4, 135.0, 128.6, 122.9, 99.0, 69.2, 54.4, 51.8, 39.2, 37.4, 29.58, 29.55, 26.8, 26.2, 25.6, 25.4, 24.5, 23.2, 12.2.
Figure imgf000103_0001
Cyclohexylmethyl 4-(4-acetamidophenyl)-6-ethyI-2-oxo-l,2,3,4-tetrahydropyrimidine-5- carboxylate (145)
1H NMR (400 MHz, CD3OD) δ 7.50 (d, J= 8.8 Hz, 2H), 7.23 (d, J= 8.8 Hz, 2H), 5.27 (s, IH), 3.90 (dd, J= 10.8, 5.6 Hz, IH), 3.75 (dd, J= 10.8, 5.6 Hz, IH), 2.75-2.80 (m, 2H), 2.10 (s, 3H), 1.45-1.67 (m, 6H), 1.13-1.23 (m, 6H), 0.82-0.85 (m, 2H); 13C NMR (I OO MHZ, CDCl3) δ 171.7, 167.1, 155.2, 154.9, 141.4, 139.6, 128.2, 121.3, 100.9, 70.3, 55.9, 38.7, 30.7, 26.9, 25.7, 23.9, 13.4.
Figure imgf000103_0002
146
Cyclohexylmethyl 4-(4-butyramidophenyl)-6-ethyl-2-oxo-l,2,3,4-tetrahydropyrimidine- 5-carboxyIate (146)
1H NMR (400 MHz, CD3OD) δ 7.52 (d, J= 8.4 Hz, 2H), 7.24 (d, J= 8.4 Hz, 2H), 5.27 (s, IH), 3.92 (dd, J= 10.6, 5.8 Hz, IH), 3.74 (dd, J= 10.6, 5.8 Hz, IH), 2.74-2.80 (m, 2H), 2.33 (t, J= 7.4 Hz, 2H), 1.43-1.74 (m, 4H), 1.23 (t, J= 7.4 Hz, 3H), 1.11-1.19 (m 3H), 0.99 (t, J= 7.4 Hz, 3H), 0.80-0.84 (m, 2H).
Figure imgf000104_0001
147
Cyclohexylmethyl 6-ethyl-2-oxo-4-(4-propionamidophenyl)-l,2,354- tetrahydropyrimidine-5-carboxylate(147)
To a stirred solution of 127 (50 mg, 0.14 mmol, 1.0 equiv) in CH2Cl2 (0.3 ml) was added i- Pr2NEt (27.0 μL, 0.15 mmol, 1.07 equiv) and propionyl chloride (9.0 μL, 0.154 mmol, 1.1 equiv) at 0 0C. After stirring for 1 h at 0 °C, the mixture was diluted with CH2Cl2 (30 mL), washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography to afford the desired product 147 (52.6 mg, 99 %): 1H NMR (400 MHz, CD3OD) δ 7.51 (d, J= 8.8 Hz, 2H), 7.24 (d, J= 8.8 Hz, 2H), 5.27 (s, IH), 3.90 (dd, J= 10.8, 6.0 Hz, IH), 3.75 (dd, J= 10.8, 6.0 Hz, IH), 2.73-2.81 (m, 2H), 2.37 (q, J= 8.0 Hz, 2H), 1.44-1.66 (m, 6H), 1.09-1.25 (m, 9H), 0.80-0.85 (m, 2H).
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 15- 30% i-PrOH in «-Hexanes gradient, 0.8 niL/min): 147a tR = 1st band, 147b tR = 2nd band.
Figure imgf000104_0002
148
CyclohexyImethyl 6-ethyl-2-oxo-4-(4-pentanamidophenyl)-l,2,3,4-tetrahydropyrimidine- 5-carboxylate (148) 1H NMR (400 MHz, DMSO-J6) δ 10.00 (s, IH), 9.16 (s, IH), 7.64 (s, IH), 7.54 (d, J= 8.4 Hz, 2H), 7.11 (d, J= 8.4 Hz, 2H), 5.07 (d, J= 2.8 Hz, IH), 3.80 (dd, J= 10.6, 6.2 Hz, IH), 3.70 (dd, J= 10.6, 6.2 Hz, IH), 2.73-2.60 (m, 2H), 2.29 (t, J= 7.4 Hz, 2H), 1.58-0.98 (m, 16H), 0.92-0.76 (m, 5H); 13C NMR (100 MHz, DMSO-J15) δ 171.9, 165.6, 154.7, 152.9, 139.9, 139.2, 127.2, 119.6, 98.9, 68.8, 54.2, 37.4, 36.7, 29.71, 29.65, 28.0, 26.4, 25.9, 24.7, 22.4, 14.4, 13.7.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 15- 30% /-PrOH in n-Hexanes gradient, 0.8 mL/min): 148a tR = 1st band, 148b tR = 2nd band.
Figure imgf000105_0001
149
Cyclohexylmethyl 6-ethyl-4-(4-octanamidophenyl)-2-oxo-l,2,3,4-tetrahydropyrimidine- 5-carboxylate (149)
1H NMR (400 MHz, DMS-J15) δ 9.84 (s, IH), 9.15 (s,lH), 7.62 (s, IH), 7.51 (d, J= 8.4 Hz, 2H), 7.12 (d, J= 8.4 Hz, 2H), 5.07 (d, J= 3.2 Hz, IH), 3.81 (dd, J= 10.6, 6.2 Hz, IH), 3.70 (dd, J= 10.6, 6.2 Hz, IH), 2.74-2.60 (m, 2H), 2.26 (t, J= 7.4 Hz, 2H), 1.56-1.01 (m, 22H), 0.99-0.73 (m, 5H); 13C NMR (IOO MHz, DMSO-J6) δ 171.8, 165.6, 154.7, 152.9, 139.9, 139.2, 127.2, 119.6, 98.8, 68.8, 54.3, 37.4, 37.0, 31.9, 29.71, 29.65, 29.3, 29.1, 26.5, 25.9, 25.8, 24.7, 22.7, 14.6, 13.7.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 15- 30% i-PrOH in rc-Hexanes gradient, 0.8 mL/min): 149a tR = 1st band, 149b tR = 2nd band.
Figure imgf000105_0002
Cyclohexylmethyl 4-benzyl-6-ethyI-2-oxo-l,2,3>4-tetrahydropyrimidine-5-carboxylate (150) 1H NMR (400 MHz, CDCl3) δ 7.82 (s, IH), 7.30-7.15 (m, 5H), 5.40 (s, IH), 4.47-4.44 (m, IH), 3.97 (d, J= 6.0 Hz, 2H), 2.93 (dd, J= 13.2, 3.2 Hz, IH), 2.75-2.69 (m, 2H), 2.64-2.57 (m, IH), 1.79-1.65 (m, 6H), 1.33-0.86 (m, 8H); 13C NMR (IOOMHZ, CDCl3) δ 165.8, 154.6, 153.1, 137.1, 130.0, 128.9, 127.1, 100.5, 69.8, 53.7, 43.3, 37.7, 30.31, 30.27, 26.7, 26.0, 25.5, 12.8.
Figure imgf000106_0001
151
Cyclohexylmethyl 4-(4-cyanophenyI)-6-ethyl-2-oxo-l,2,354-tetrahydropyrimidine-5- carboxylate (151)
1H NMR (400 MHz, CDCl3) δ 8.58 (bs, IH), 7.60 (d, J= 8.4Hz, 2H), 7.42 (d, J= 8.4 Hz, 2H), 6.58 (bs, IH), 5.42 (d, J= 3.2 Hz, IH), 3.88 (dd, J= 10.6, 6.2 Hz, IH), 3.82 (dd, J= 10.6, 6.2Hz, IH), 2.80 (m, IH), 2.67 (m, IH), 1.65-1.47 (m, 6H), 1.27-1.07 (m, 6H), 0.83 (m, 2H); 13C NMR (IOO MHZ, CDCl3) δ 165.2, 153.9, 153.1, 148.8, 132.8, 127.5, 118.6, 111.9, 99.5, 69.7, 55.3, 37.2, 29.8, 26.3, 25.7, 25.4, 12.8.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 10- 15% /-PrOH in «-Hexanes, 6.5 mL/min): 151a fa = 22.1 min, 151b fa = 26.9 min.
Figure imgf000106_0002
4-(5-((Cyclohexylmethoxy)carbonyl)-6-ethyl-2-oxo-l,2,3,4-tetrahydropyrimidin-4- yl)benzoic acid (152)
To a solution of benzyl ester 156 (100 mg, 0.21 mmol, 1.0 equiv) in MeOH (3 mL) was added 10% Pd on carbon (10 mg) at room temperature. The reaction mixture was hydrogenated with H2 gas (3 bar) for 3 h at 25 °C. The mixture was filtered through a plug of Celite and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel to give acid 152 (70 mg, 86%) as a white solid: 1H NMR (400 MHz, OMSO-d6) δ 9.29 (bs, IH), 7.92 (d, J= 8.0 Hz, 2H), 7.79 (bs, IH), 7.32 (d, J= 8.0 Hz, 2H), 5.21 (s, IH), 3.87 (dd, J = 10.6, 5.8 Hz, IH), 3.74 (dd, J= 10.6, 5.8 Hz, IH), 2.77-2.82 (m, IH), 2.63-2.68 (m, IH), 1.42-1.61 (m, 6H), 1.08-1.19 (m, 6H), 0.80-0.83 (m, 2H); 13C NMR (100 MHz, OMSO-d6) δ 164.7, 154.7, 152.0, 149.1, 129.6, 126.4, 97.5, 68.2, 53.8, 36.6, 29.0, 28.9, 25.7, 25.1, 24.0, 13.0.
Figure imgf000107_0001
Cyclohexylmethyl 6-ethyl-4-(4-(methoxycarbonyl)phenyl)-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (153)
1H NMR (400 MHz, CDCl3) δ 7.98 (d, J= 8.0 Hz, 2H), 7.41 (d, J= 8.0 Hz, 2H), 5.37 (s, IH), 3.90 (s, 3H), 3.31-3.89 (m. 2H), 2.81-2.83 (m, IH), 2.73-2.75 (m, IH), 1.43-1.65 (m, 6H), 1.24 (t, J= 7.6 Hz, 3H), 1.10-1.23 (m, 3H), 0.79-0.82 (m 2H); 13C NMR (100 MHz, CDCl3) δ 168.3, 166.9, 155.6, 154.9, 150.8, 131.1, 130.7, 128.0, 100.3, 79.6, 79.3, 78.9, 70.4, 56.1, 52.7, 38.6, 30.8, 30.7, 27.4, 26.9, 26.8, 25.8, 13.4.
Figure imgf000107_0002
Cyclohexylmethyl 4-(4-(ethoxycarbonyl)phenyl)-6-ethyl-2-oxo-l,2,3?4- tetrahydropyrimidine-5-carboxyIate (154)
1H NMR (400 MHz, CDCl3) δ 7.97 (d, J= 8.0 Hz, 2H), 7.34 (d, J= 8.0 Hz, 2H), 6.01 (bs, IH), 5.41 (s, IH), 4.34 (q, J= 6.8 Hz, 2H), 3.75-3.84 (m, 2H), 2.69-2.78 (m, 2H), 1.04-1.60 (m, 15H), 0.77-0.81 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 166.3, 165.2, 153.5, 152.5, 148.4, 130.2, 126.6, 99.9, 69.5, 61.1, 55.5, 37.2, 29.7, 26.3, 25.7, 25.4, 14.4, 12.6.
Figure imgf000108_0001
Cyclohexylmethyl 6-ethyl-2-oxo-4-(4-(propoxycarbonyl)phenyl)-l,2,3?4- tetrahydropyrimidine-5-carboxylate (155)
1H NMR (400 MHz, CDCl3) δ 7.52 (d, J= 8.0 Hz, 2H), 7.24 (d, J= 8.0 Hz, 2H), 5.28 (s, IH), 3.91 (dd, J= 10.8, 6.0 Hz, IH), 3.75 (dd, J= 10.8, 6.0 Hz, IH), 2.72-2.83 (m, 2H) , 2.37 (q, J = 7.6 Hz, 2H), 1.53 -1.64 (m, 7H), 1.09-1.48 (m, HH), 0.78-0.90 (m, 3H); 13C NMR (IOO MHz, CDCl3) δ 175.4, 167.2, 154.9, 155.1, 154.9, 141.3, 139.7, 128.2, 121.3, 101.0, 70.3, 55.9, 38.7, 31.1, 30.9, 30.8, 27.4, 26.9, 25.7, 13.4, 10.3.
Figure imgf000108_0002
Cyclohexylmethyl 4-(4-(benzyloxycarbonyl)phenyl)-6-ethyl-2-oxo-l,2,3>4- tetrahydropyrimidine-5-carboxylate (156)
1H NMR (400 MHz, CDCl3) 5 8.01 (d, J= 8.0 Hz, 2H), 7.86 (bs, IH), 7.31-7.41 (m, 7H), 5.81 (bs, IH), 5.41 (s, IH), 5.33 (s, 2H), 3.78-3.83 (m, 2H), 2.72-2.76 (m, 2H), 1.42-1.60 (m, 3H), 1.21 (t, J= 6.8 Hz, 3H), 1.07-1.18 (m, 3H), 0.76-0.81 (m, 2H); 13C NMR (IOO MHz, CDCl3) δ 166.0, 165.2, 153.2, 152.4, 148.6, 136.1, 130.4, 129.9, 128.7, 128.2, 126.7, 99.9, 69.5, 66.8, 55.6, 37.2, 29.7, 26.3, 25.7, 25.4, 12.6.
Figure imgf000109_0001
Cyclohexylmethyl 6-ethyl-4-(3-(methoxycarbonyl)phenyl)-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (157)
1H NMR (400 MHz, CDCl3) δ 8.14 (s, IH), 7.94-7.90 (m, 2H), 7.48 (dd, J= 4.6, 3.4 Hz, IH), 7.37 (t, J= 7.8, IH), 5.96 (s, IH), 5.41 (d, J= 2.4 Hz, IH), 3.82 (dd, J= 10.6, 6.2 Hz, IH), 3.75 (dd, J= 11.0, 6.2 Hz, IH), 2.82-2.70 (m, 2H), 1.62-1.40 (m, 6H), 1.24-1.02 (m, 6H), 0.81-0.72 (m, 2H); 13C NMR (100MHz, CDCl3) δ 166.9, 165.3, 153.5, 152.8, 144.3, 131.3, 130.8, 129.4, 129.2, 128.1, 100.0, 69.6, 55.7, 52.4, 37.3, 29.8, 26.4, 25.8, 25.5, 12.7.
Figure imgf000109_0002
158
3-(5-((Cyclohexylmethoxy)carbonyl)-6-ethyl-2-oxo-l,2,3,4-tetrahydropyrimidin-4- yl)benzoic acid (158)
1U NMR (400 MHz, CD3OD) δ 8.00 (s, IH), 7.93 (d, J= 7.6 Hz, IH), 7.55 (d, J= 7.6 Hz, IH), 7.45 (t, J= 7.8 Hz, IH), 5.37 (s, IH), 3.91 (dd, J= 10.6, 6.2 Hz, IH), 3.74 (dd, J= 10.8, 6.0 Hz, IH), 2.84-2.77 (m, 2H), 1.65-1.42 (m, 6H), 1.39-1.07 (m, 6H), 0.9-0.78 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 169.7, 167.0, 155.6, 155.1, 146.3, 132.50, 132.46, 130.2, 130.1, 129.4, 100.6, 70.4, 56.3, 48.7, 48.5, 38.7, 30.85, 30.82, 27.5, 26.9, 25.8, 13.4; TLC R1 (CH2Cl2:Et0Ac + 0.5% MeOH 1 :1) = 0.54.
Figure imgf000110_0001
Cyclohexylmethyl 6-ethyl-4-(4-fluorophenyl)-2-oxo-l,2,3,4-tetrahydropyrimidine-5- carboxylate (159)
1H NMR (400 MHz, CDCl3) δ 8.36 (s, IH), 7.25-7.21 (m, 2H), 7.00-6.99 (m, 2H), 6.16 (s, IH), 5.34 (s, IH), 3.85 (dd, J= 10.6, 6.2 Hz, IH), 3.77 (dd, J= 10.8, 6.0 Hz, IH), 2.79-2.65 (m, 2H), 1.65-1.41 (m, 6H), 1.30-1.04 (m, 6H), 0.86-0.74 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 165.5, 163.8, 161.3, 153.9, 152.3, 139.82, 139.78, 128.5, 128.4, 115.9, 115.7, 100.4, 69.6, 55.2, 37.3, 29.8, 26.4, 25.82, 25.81, 25.4, 12.8.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 10% /-PrOH in π-Hexanes, 6.5 mL/min): 159a tR = 12 A min, 159b tR = 21.4 min.
Figure imgf000110_0002
160
Cyclohexylmethyl 4-(4-chIorophenyl)-6-ethyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5- carboxylate (160)
1H NMR (400 MHz, CDCl3) δ 8.60 (s, IH), 7.20 (m, 4H), 6.55 (s, IH), 5.30 (s, IH), 3.84 (dd, J= 10.6, 6.2 Hz, IH), 3.76 (dd, J= 10.2, 6.6 Hz, IH), 2.76-2.61 (m, 2H), 1.64-1.43 (m, 6H), 1.33-1.00 (m, 6H), 0.80-0.74 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 165.4, 154.2, 152.6, 142.4, 133.8, 129.0, 128.1, 100.1, 69.6, 55.0, 37.3, 29.8, 26.4, 25.8, 25.8, 25.4, 12.8. Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 10% /-PrOH in «-Hexanes, 6.5 mL/min): 160a fø = 12.5 min, 160b tR = 22.5 min.
Figure imgf000111_0001
CycIohexylmethyl 6-ethyl-4-(3-fluorophenyl)-2-oxo-l,2,3,4-tetrahydropyrimidine-5- carboxylate (161)
1H NMR (400 MHz, CD3OD) δ 7.35 (dd, J = 13.8, 7.8 Hz, IH), 7.11 (d, J = 7.6 Hz, IH), 6.96 (m, 2H), 5.30 (s, IH), 3.90 (dd, J = 10.8, 6.0 Hz, IH), 3.74 (dd, J = 10.8, 5.6 Hz, IH), 2.76 (m, 2H), 1.65-1.43 (m, 6H), 1.26-1.06 (m, 6H), 0.88-0.78 (m, 2H); 13C NMR (100 MHz, CD3OD) δ 170.0, 155.5, 148.5, 131.7, 123.6, 115.6, 115.4, 114.7, 114.5, 100.5, 70.4, 55.9, 38.7, 30.9, 30.8, 27.5, 27.0, 25.8, 13.4.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 10% /-PrOH in rø-Hexanes, 6.5 mL/min): 161a ΪR = 14.8 min, 161b ΪR = 22.2 min.
Figure imgf000111_0002
Cyclohexylmethyl 4-(3-chlorophenyl)-6-ethyl-2-oxo-l,2,3?4-tetrahydropyrimidme-5- carboxylate (162)
1H NMR (400 MHz, CD3OD) δ 7.30-7.21 (m, 4H), 5.28 (s, IH), 3.90 (dd, J = 10.8, 6.0 Hz, IH), 3.72 (dd, J = 10.8, 5.6 Hz, IH), 2.76 (m, 2H), 1.64-1.48 (m, 6H), 1.45-1.07 (m, 6H), 0.86-0.76 (m, 2H); 13C NMR (100 MHz, CD3OD) δ 166.9, 155.6, 155.1, 148.0, 135.5, 131.5, 128.9, 128.2, 126.1, 100.4, 70.4, 56.0, 38.7, 30.9, 30.8, 27.5, 27.0, 25.8, 13.5. Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 10% /-PrOH in «-Hexanes, 6.5 mL/min): 162a ΪR = 17.0 min, 162b ΪR = 23.0 min.
Figure imgf000112_0001
Cyclohexylmethyl 4-(2-chlorophenyI)-6-ethyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5- carboxylate (163)
1K NMR (400 MHz, CD3OD) δ 7.39-7.21 (m, 4H), 5.82 (s, IH), 3.84 (dd, J = 10.8, 6.0 Hz, IH), 3.65 (dd, J = 10.6, 5.6 Hz, IH), 2.82 (m, 2H), 1.58-1.02 (m, 12H), 0.78-0.65 (m, 2H); 13C NMR (100 MHz, CD3OD) δ 166.7, 156.5, 154.9, 142.1, 134.0, 131.1, 130.5, 129.5, 128.9, 99.3, 70.3, 53.2, 38.7, 30.7, 30.6, 27.4, 27.03, 37.01, 25.7, 13.4.
Figure imgf000112_0002
Cyclohexylmethyl 4-(3-bromophenyl)-6-ethyl-2-oxo-l,2,3j4-tetrahydropyrimidine-5- carboxylate (164)
1H NMR (400 MHz, CD3OD) δ 7.40 (m, 2H), 7.25 (m, 2H), 5.26 (s, IH), 3.91 (dd, J = 10.8, 6.2 Hz, IH), 3.72 (dd, J = 10.8, 5.6 Hz, IH), 2.75 (m, 2H), 1.66-1.42 (m, 6H), 1.27-1.10 (m, 6H), 0.83-0.78 (m, 2H); 13C NMR (IOO MHz, CD3OD) δ 166.9, 155.7, 155.0, 148.3, 131.9, 131.8, 131.2, 126.6, 123.6, 100.4, 70.4, 56.0, 38.8, 30.90, 30.86, 27.5, 27.0, 25.8, 13.4.
Figure imgf000112_0003
Cyclohexylmethyl 4-(4-chloro-3-hydroxyphenyl)-6-ethyI-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (165) 1H NMR (400 MHz, CD3OD) δ 7.20 (d, J = 8.4H, IH), 6.86 (d, J = 1.6 Hz, IH), 6.74 (dd, J = 8.4, 1.8 Hz, IH), 5.20 (s, IH), 3.92 (dd, J = 10.8, 6.2 Hz, IH), 3.72 (dd, J = 10.8, 5.6 Hz, IH), 2.75 (m, 2H), 1.61-1.41 (m, 6H), 1.26-1.06 (m, 6H), 0.81-0.78 (m, 2H); 13C NMR (100 MHz, CD3OD) δ 167.1, 155.1, 154.6, 145.9, 131.2, 121.0, 119.9, 116.0, 100.7, 70.4, 56.0, 38.8, 30.9, 30.8, 27.5, 26.98, 26.96, 25.8, 13.4.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 15% i- PrOH in ra-Hexanes, 0.80 mL/min): 165a tR= 11.22 min, 165b tR= 20.97 min.
Figure imgf000113_0001
Cyclohexylmethyl 4-(3-chloro-4-hydroxyphenyI)-6-ethyl-2-oxo-l,2,3,4- tetrahydropy rimidine-5-carboxylate (166)
1H NMR (400 MHz, DMSO-J6) δ 10.10 (s, IH), 9.19 (s, IH), 7.62 (s, IH)), 7.12 (s, IH), 6.99-6.90 (m, 2H), 5.02 (d, J= 3.2 Hz, IH), 3.85 (dd, J= 10.6, 6.2 Hz, IH), 3.69 (dd, J= 10.6, 6.2 Hz, IH), 2.74-2.60 (m, 2H), 1.58-1.41 (m, 6H), 1.18-1.02 (m, 6H), 0.85-0.74 (m, 2H); 13C NMR (100 MHz, DMSO-^6) δ 165.5, 154.9, 152.9, 152.7, 137.3, 128.6, 126.5, 119.9, 117.3, 98.6, 68.8, 53.8, 37.4, 29.73, 29.65, 26.4, 25.9, 24.6, 13.7. Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 25% i- PrOH in «-Hexanes, 0.85 mL/min): 166a fø = 6.86 min, 166b fø = 9.14 min.
Figure imgf000113_0002
Cyclohexylmethyl 4-(2-chloro-4-hydroxyphenyl)-6-ethyI-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (167)
1K NMR (400 MHz, CD3OD) δ 7.08 (d, J = 8.4 Hz, IH), 6.80 (d, J = 2.0 Hz, IH), 6.66 (dd, J = 8.4, 2.0 Hz, IH), 5.70 (s, IH), 3.88 (dd, J = 10.8, 6.0 Hz, IH), 3.64 (dd, J = 10.8, 6.0 Hz, IH), 2.79 (m, 2H), 1.59 (m, 3H), 1.42 (m, 6H), 1.24 (t, J = 7.4 Hz, 3H), 0.73 (m, 2H); 13C NMR (IOO MHz, CD3OD) δ 165.2, 152.8, 152.4, 134.7, 134.2, 133.7, 115.3, 113.9, 112.5, 98.9, 68.1, 53.9, 36.7, 29.11, 29.08, 25.8, 25.24, 25.22, 24.0, 13.1
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 10% i- PrOH in n-Hexanes, 0.85 mL/min) : 167a tR = 16.40 min, 167b tR = 26.61 min.
Figure imgf000114_0001
Cyclohexylmethyl 6-ethyl-4-(2-fluoro-5-hydroxyphenyl)-2-oxo-l,2,3>4- tetrahydropyrimidine-5-carboxyIate (168)
1H NMR (400 MHz, DMSO-J6) δ 9.32 (s, IH), 9.23 (s, IH), 7.63 (s, IH), 6.93 (t, J= 10.0 Hz, IH), 6.64-6.60 (m, 2H), 5.36 (d, J= 3.2 Hz, IH), 3.81 (dd, J= 10.8, 6.0 Hz, IH), 3.66 (dd, J= 10.8, 6.0 Hz, IH), 2.74-2.66 (m, 2H), 1.57-1.36 (m, 6H), 1.63-1.05 (m, 6H), 0.79-0.73 (m, 2H); 13C NMR (100 MHz, DMSO-J6) δ 165.3, 155.5, 154.4, 154.27, 154.25, 152.5, 152.0, 132.6, 132.5, 116.6, 116.4, 116.0, 115.9, 114.63, 114.59, 97.2, 68.8, 48.6, 37.4, 29.60, 29.50, 26.4, 25.9, 24.6, 13.7.
Figure imgf000114_0002
169
CyclohexylmethyL 4-(4-acetoxy-3-chlorophenyl)-6-ethyl-2-oxo-l,2,3,4- tetrahy dropy rimidine-5-carboxylate (169)
To a solution of phenol 166 (50 mg, 0.13mmol, 1.0 equiv) in CH2Cl2 (0.5 mL) was added acetic anhydride (14.4 μl, 0.15 mmol, 1.15 equiv) and DMAP (7.8 mg, 0.06 mmol, 0.5 equiv), and the resulting mixture was stirred for 4 h at 0 °C. The mixture was diluted with CH2Cl2 (10 mL), washed with water (2 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (10% MeOHZCH2Cl2) to afford 169 (32 mg, 57%): 1H NMR (400 MHz, CD3OD) δ 7.37 (d, J = 2.0 Hz, IH), 7.26 (dd, J = 8.4, 2.0 Hz, IH), 7.15 (d, J = 8.4 Hz, IH), 5.29 (s, IH), 3.92 (dd, J = 10.8, 6.0 Hz, IH) 3.75 (dd, J = 10.8, 5.6 Hz, IH), 2.82 (m, IH), 2.72 (m, IH), 2.29 (s, 3H), 1.66-1.43 (m, 6H), 1.31-1.08 (m, 6H), 0.90-0.80 (m, 2H).
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 15% i- PrOH in n-Hexanes, 0.85 mL/min): 169a tR = 10.19 min, 169b tR= 15.15 min.
Figure imgf000115_0001
170
Cyclohexylmethyl 4-(3-acetoxy-4-chlorophenyl)-6-ethyI-2-oxo-l,2,3?4- tetrahy dropy rimidine-5-carboxyIate (170)
1H NMR (400 MHz, CD3OD) δ 7.43 (d, J = 8.4 Hz, IH), 7.18 (dd, J = 8.4, 1.6 Hz, IH), 7.10 (d, J = 1.6 Hz, IH), 5.29 (s, IH), 3.90 (dd, J = 10.8, 6.0 Hz, IH), 3.75 (dd, J = 10.8, 5.6 Hz, IH), 2.80 (m, IH), 2.69 (m, IH), 2.29 (s, 3H), 1.63-1.43 (m, 6H), 1.30-1.04 (m, 6H), 0.90- 0.78 (m, 2H); 13C NMR (IOO MHz, CD3OD) δ 169.9, 166.9, 155.7, 155.0, 148.7, 146.4, 131.5, 127.2, 126.6, 123.5, 100.3, 70.5, 55.6, 38.7, 30.91, 30.89 , 27.5, 26.9, 25.8, 20.5, 13.4. Enantiomeric pure forms were obtained by chiral HPLC (OD-H analytical column, 10% i- PrOH in o-Hexanes, 0.85 mL/min): 170a tR = 14.81 min, 170b tR = 21.80 min.
Figure imgf000115_0002
(S)-Cyclohexylmethyl 4-(4-((5)-2-(te/Y-butoxycarbonylamino)propanoyloxy)-3- chlorophenyl)-6-etb.yl-2-oxo-l,2,3j4-tetrab.ydropyrimidine-5-carboxylate (171a)
1H NMR (400 MHz, CD3OD) δ 7.38 (s, IH), 7.27 (d, J = 8.4 Hz, IH), 7.18 (d, J = 8.4 Hz, IH), 5.29 (s, IH), 4.38 (q, J = 7.6 Hz, IH), 3.92 (dd, J = 10.6, 6.2 Hz, IH), 3.74 (dd, J = 10.6, 5.8 Hz, IH), 2.80 (m, IH), 2.71 (m, IH), 1.65-1.41 (m, 18H), 1.32-1.07 (m, 6H), 0.88- 0.76 (m, 2H); 13C NMR (100 MHz, CD3OD) δ 172.7, 166.9, 155.8, 155.0, 147.8, 145.5, 129.8, 127.9, 127.5, 125.4, 100.3, 70.5, 55.6, 51.0, 38.8, 30.93, 30.89, 28.9, 27.5, 27.0, 25.8, 17.7, 13.4.
Figure imgf000116_0001
(S)-Cyclohexylmethyl 4-(4-((5)-2-aminopropanoyIoxy)-3-chIorophenyI)-6-ethyl-2-oxo- l,2,3?4-tetrahydropyrimidine-5-carboxylate hydrochloride (172a)
1H NMR (400 MHz, DMSO-J6) δ 9.28 (bs, IH), 8.65 (bs, 3H), 7.74 (bs, IH), 7.33 (t, J= 9.2 Hz, 2H), 7.24 (d, J= 8.0Hz, IH), 5.13 (s, IH), 4.44 (m, IH), 3.81 (dd, J= 10.4, 5.2 Hz, IH), 3.66 (dd, J= 10.2, 5.0 Hz, IH), 2.72 (m, IH), 2.57 (m, IH), 1.58-1.54 (m, 6H), 1.44-1.31 (m, 3H), 1.15-0.95 (m, 6H), 0.81-0.71 (m, 2H).
Figure imgf000116_0002
(S)-Cyclohexylmethyl 4-(4-acetoxy-3-chlorophenyl)-6-ethyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (173a)
1H NMR (400 MHz, CD3OD) δ 7.37 (s, IH), 7.25 (d, J= 8.4 Hz, IH), 7.15 (d, J= 8.8 Hz, IH), 5.28 (s, IH), 3.92 (dd, J= 10.4, 6.0 Hz, IH), 3.74 (dd, J= 10.4, 5.6Hz, IH), 2.81(m, IH), 2.72 (m, IH), 2.29 (s, 3H), 1.63-1.45 (m, 6H), 1.36-1.05 (m, 6H), 0.88-0.77 (m, 2H).
Figure imgf000117_0001
(S)-Cyclohexylmethyl 4-(4-(benzoyloxy)-3-chlorophenyl)-6-ethyl-2-oxo-l,2,3?4- tetrahy dropy rimidine-5-carboxylate (174a)
1H NMR (400 MHz, CD3OD) δ 8.09 (d, J = 7.2 Hz, 2H), 7.87 (d, J = 6.8 Hz, IH), 7.61 (t, J = 7.6 Hz, IH), 7.47 (t, J = 8.0 Hz, 2H), 7.38 (s, IH), 7.28 (t, J = 7.6 Hz, IH), 5.25 (s, IH), 3.86 (dd, J = 10.4, 5.6 Hz, IH), 3.70 (dd, J = 10.8, 5.6 Hz, IH), 2.75 (m, IH), 2.65 (m, IH), 1.59- 142 (m, 6H), 1.23-1.03 (m, 6H), 0.81-0.77 (m, 2H).
Figure imgf000117_0002
175a
(S)-CyclohexylmethyI 4-(3-chloro-4-(pivaloyloxy)phenyl)-6-ethyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (175a)
1H NMR (400 MHz, CD3OD) δ 7.37 (d, J = 2.0 Hz, IH), 7.26 (dd, J = 8.4, 2.0 Hz, IH), 7.10 (d, J = 8.4 Hz, IH), 5.29 (s, IH), 3.91 (dd, J = 10.8, 6.0 Hz, IH), 3.75 (dd, J - 10.8, 6.0 Hz, IH), 2.82 (m, IH), 2.70 (m, IH), 1.63-1.46 (m, 6H), 1.38-1.12 (m, 15H), 0.88-0.79 (m, 2H).
Figure imgf000117_0003
176a (S)-Cyclohexylmethyl 4-(3-chloro-4-(isonicotinoyloxy)phenyI)-6-ethyl-2-oxo-l,2,3>4- tetrahydropy rimidine-5-carboxylate (176a)
To a mixture of 166a (6.0 mg, 15.2 μmol, 1.0 equiv) in THF was added isonicotinoyl chloride hydrochloride (3.5 mg, 19.7 μmol, 1.3 equiv), and DIPEA (9.3 μL, 53.4 μmol, 3.5 equiv), and the reaction mixture was allowed to stir overnight at room temperature. The mixture was subjected to preparative TLC (5% MeOH/CH2Cl2) to afford 176a (6.4 mg, 85%): 1H NMR (400 MHz, CDCl3) δ 8.87 (dd, J = 4.4, 1.6 Hz, 2H), 8.01 (dd, J = 4.4, 1.6 Hz, 2H), 7.44 (s, IH), 7.29 (m, 2H), 7.15 (s, IH), 5.59 (s, IH), 5.41 (s, IH), 3.91 (dd, J = 10.6, 5.8 Hz, IH), 3.84 (dd, J = 10.2, 5.8 Hz, IH), 2.85 (m, IH), 2.71 (m, IH), 1.70-1.42 (m, 6H), 1.27-1.09 (m, 6H), 0.92-0.87 (m, 2H).
Figure imgf000118_0001
177a
(S)-Cyclohexylmethyl 4-(3-chloro-4-(nicotinoyloxy)phenyl)-6-ethyl-2-oxo-l,2,354- tetrahy dropyrimidine-5-carboxyIate (177a)
1H NMR (400 MHz, CDCl3) δ 9.41 (d, J = 2.0 Hz, IH), 8.88 (dd, J = 4.8 Hz, 1.2 Hz, IH), 8.47 (dd, J = 8.4, 2.0 Hz, IH), 7.69 (s, IH), 7.52-7.45 (m, 2H), 7.38-7.25 (m, 2H), 5.85 (s, IH), 5.42 (s, IH), 3.92 (dd, J = 10.8, 6.0 Hz, IH), 3.85 (dd, J = 10.8, 6.0 Hz, IH), 2.86 (m, IH), 2.71 (m, IH), 1.71-1.43 (m, 6H), 1.34-1.07 (m, 6H), 0.93-0.84 (m, 2H).
Figure imgf000118_0002
Cyclohexylmethyl 6-ethyl-4-(3-fluoro-4-hydroxyphenyl)-2-oxo-l,2,354- tetrahydropyrimidine-5-carboxylate (178) 1H NMR (400 MHz, CD3OD) δ 6.92 (ddd, J= 15.4, 10.2, 2.0 Hz, 2H), 6.83 (t, J= 8.4 Hz, IH), 5.19 (s, IH), 3.91 (dd, J= 10.8, 6.4Hz, IH), 3.73 (dd, J= 10.6, 5.8 Hz, IH), 2.76 (m, 2H), 1.64(m, 3H), 1.47 (m, 3H), 1.21-1.08 (m, 6H), 0.82 (m, 2H); 13C NMR (100 MHz, CD3OD) δ 167.2, 155.1, 154.1, 151.7, 145.9, 137.8, 123.8, 118.9, 115.4, 101.0, 70.4, 55.6, 38.8, 30.9, 30.8, 27.5, 27.00, 26.98, 25.8, 13.4.
Enantiomeric pure forms were obtained by chiral HPLC (OD-H preparative column, 10% i- PrOH in «-Hexanes, 6.5 mL/min): 178a tR = 32.0 min, 178b tR = 48.7 min.
Figure imgf000119_0001
Cyclohexylmethyl 4-(4-acetoxy-2-fluorophenyl)-6-ethyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (179)
1H NMR (400 MHz, CDCl3) δ 8.30 (bs, IH), 7.21 (t, J= 8.6Hz, IH), 6.86 (t, J= 8.6Hz, 2H), 5.72 (s, 2H), 3.86 (dd, J= 10.8, 5.6Hz, IH), 3.77 (dd, J= 10.6, 5.8Hz, IH), 2.85 (m, 2H), 2.29 (s, 3H), 1.63 (m, 3H), 1.45 (m, 3H), 1.28-1.04 (m, 6H), 0.80 (m, 2H); 13C NMR(IOOMHz, CDCl3) δ 169.0, 165.1, 161.5, 159.0, 154.1, 153.5, 128.6, 127.6, 117.9, 110.1, 97.7, 69.5, 49.13, 49.10, 37.3, 29.73, 29.70, 26.4, 25.8, 25.4, 21.3, 12.8. Enantiomeric pure forms were obtained by chiral HPLC (OD-H preparative column, 10% i- PrOH in w-Hexanes, 6.5 mL/min): 179a tR = 19.6 min, 179b tR = 28.4 min.
Figure imgf000119_0002
Cyclohexylmethyl 6-ethyl-4-(2-fluoro-4-hydroxyphenyl)-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (180)
Enantiomerically pure forms were obtained from 179a/179b by hydrolysis using K2CO3 in MeOH. 1H NMR (400 MHz, CD3OD) δ 7.03 (t, J= 8.8 Hz, IH), 6.49 (ddd, J= 23.0, 10.2, 2.4 Hz, 2H), 5.52 (s, IH), 3.89 (dd, J= 10.8, 6.0 Hz, IH), 3.68 (dd, J= 10.8, 5.6 Hz, IH), 2.76 (m, 2H), 1.62 (m, 3H), 1.44 (m, 3H), 1.23-1.07 (m, 6H), 0.79 (m, 2H); 13C NMR (100 MHz, CD3OD) δ 167.0, 163.5, 161.1, 160.2, 155.4, 130.2, 123.1, 112.6, 103.8, 99.4, 70.3, 50.03, 50.00, 38.8, 30.8, 30.7, 27.5, 27.0, 25.7, 13.4.
Figure imgf000120_0001
Cyclohexylmethyl 6-ethyl-4-(3-hydroxy-4-methoxyphenyl)-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (181)
1K NMR (400 MHz, CD3OD) δ 6.84 (d, J= 9.6 Hz, IH), 6.78 (s, IH), 6.76 (d, J= 10.8 Hz, IH), 5.20 (s, IH), 3.92 (dd, J= 10.8, 5.6Hz, IH), 3.81 (s, 3H), 3.73 (dd, J= 10.8, 5.6 Hz, IH), 2.73-2.81 (m, 2H), 1.45-1.67 (m, 6H), 10.9-1.25 (m, 6H), 0.80-0.86 (m, 2H). Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 20% i- PrOH in π-Hexanes, 0.85 mL/min): 181a tR = 14.67 min, 181b tR = 65.58 min.
Figure imgf000120_0002
182
Cyclohexylmethyl 6-ethyl-4-(4-hydroxy-3-methoxyphenyl)-2-oxo-l,2,3»4- tetrahy dropy rimidine-5-carboxy late (182)
1H NMR (400 MHz, CD3OD) δ 6.85 (s, IH), 6.73 (s, 2H), 5.23 (s, IH), 3.93 (dd, J= 10.6, 5.4 Hz, IH), 3.82 (s, 3H), 3.74 (dd, J= 10.6, 5.4 Hz, IH), 2.71-2.86 (m, 2H), 1.43-1.66 (m, 6H), 1.05-1.34 (m, 6H), 0.80-0.86 (m, 2H).
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 20% i- PrOH in «-Hexanes, 0.85 mL/min): 182a tR = 15.59 min, 182b tR = 39.79 min.
Figure imgf000121_0001
Cyclohexylmethyl 6-ethyl-4-(4-fluoro-3-hydroxyphenyl)-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (183)
1H NMR (400 MHz, CDCl3) δ 7.89 (s, IH), 6.94-6.90 (m, 2H), 6.73-6.70 (m, IH), 6.10 (s, IH), 5.27 (d, J= 1.6 Hz, IH), 3.87 (dd, J= 10.8, 6.0 Hz, IH), 3.79 (dd, J= 10.8, 6.0 Hz, IH), 2.79-2.63 (m, 2H), 1.66-1.41 (m, 6H), 1.19-1.06 (m, 6H), 0.84-0.78 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 165.5, 153.9, 152.3, 151.8, 149.9, 144.4, 144.3, 140.4, 118.8, 116.1, 115.9, 115.7, 100.8, 69.8, 55.3, 37.3, 29.86, 29.84, 26.5, 25.9, 25.5, 12.7.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 15% i- PrOH in n-Hexanes, 0.8 mL/min): 183a tR = 14.12 min, 183b tR = 24.70 min.
Figure imgf000121_0002
CyclohexylmethyM^benzoIdUl^ldioxol-S-y^-o-ethyl-l-oxo-l^^^- tetrahy dropyrimidine-5-carboxylate (184)
1H NMR (400 MHz, CDCl3) δ 8.00 (bs, IH), 6.69 (m, 3H), 5.91 (s, 2H), 5.75 (bs, IH), 5.27 (s, IH), 3.87 (dd, J= 10.4, 6.0 Hz, IH), 3.77 (dd, J= 10.4, 6.0 Hz, IH), 2.68-2.78 (m, 2H), 1.47-1.65 (m, 6H), 1.21 (t, J= 7.4 Hz, 3H), 1.06-1.14 (m, 3H), 0.79-0.84 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 165.4, 153.4, 151.9, 148.1, 147.3, 137.9, 120.1, 108.3, 107.1, 101.2, 100.4, 69.4, 55.7, 37.3, 29.8, 29.7, 26.4, 25.8, 25.7, 25.4, 12.6.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 20% z-PrOH in n-Hexanes, 8.0 mL/min): 184a tR = 11.4 min, 184b tR = 17.5 min.
Figure imgf000122_0001
185
Cyclohexylmethyl 4-(4-(difluoromethoxy)-3-hydroxyphenyl)-6-ethyl-2-oxo-l,2,3,4- tetrahy dropyrimidine-5-carboxylate (185)
1H NMR (400 MHz, CDCl3) δ 8.10 (s, IH), 6.96 (d, J= 8.0 Hz, IH), 6.91 (d, J= 2.0 Hz, IH), 6.72 (dd, J= 8.2, 1.8 Hz, IH), 6.45 (t, J= 74.2 Hz, IH), 6.36 (s, IH), 5.25 (d, J = 2.8 Hz, IH), 3.87 (dd, J= 10.6, 6.2 Hz, IH), 3.77 (dd, J= 11.0, 5.8 Hz, IH), 2.77-2.72 (m, IH), 2.64-2.59 (m, IH), 1.64-1.44 (m, 6H), 1.25-1.04 (m, 6H), 0.86-0.78 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 165.6, 154.2, 152.2, 148.2, 142.4, 138.24, 138.22, 138.19, 121.1, 119.0, 118.7, 115.3, 100.5, 69.8, 55.1, 37.3, 29.83, 29.81, 26.4, 25.8, 25.5, 12.7; TLC £/(Hexanes:EtOAc + 0.5% MeOH 1 :1) = 0.12.
Figure imgf000122_0002
Cyclohexylmethyl 4-(4-(benzyloxy)-3-hydroxyphenyI)-6-ethyl-2-oxo-l,2,3,4- tetrahy dropyrimidine-5-carboxylate (186)
1R NMR (400 MHz, CDCl3) δ 8.13 (bs, IH), 7.38 (s, 5H), 6.90 (s, IH), 6.83 (d, J= 8.0Hz, IH), 6.75 (d, J= 8.4 Hz, IH), 5.82 (d, J= 17.2 Hz, 2H), 5.28 (s, IH), 5.06 (s, 2H), 3.87 (dd, J =10.4, 6.0 Hz, IH), 3.78 (dd, J= 11.2, 5.2 Hz, IH), 2.78 (m, IH), 2.69 (m, IH), 1.63-1.48 (m, 6H), 1.26-1.07 (m, 6H), 0.85 (m, 2H); 13C NMR (IOO MHz, CDCl3) δ 165.6, 153.7, 152.1, 146.3, 145.7, 137.8, 136.5, 128.9, 128.6, 128.0, 118.4, 113.3, 112.4, 100.4, 71.4, 69.4, 55.5, 37.4, 29.84, 29.82, 26.5, 25.9, 25.5, 12.7.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 15- 50% /-PrOH in «-Hexanes, 6.5 mL/min): 186a tR = 37.1 min, 186b tR = 75.0 min.
Figure imgf000123_0001
Cyclohexylmethyl 4-(3,4-dihydroxyphenyl)-6-ethyl-2-oxo-l,2,3,4-tetrahydropyrimidine- 5-carboxylate (187)
1H NMR (400 MHz, CDCl3) δ 6.75 (s, IH), 6.72 (d, J- 17.2 Hz, IH), 6.62 (d, J= 8.4 Hz, IH), 5.17 (s, IH), 3.92 (dd, J= 10.8, 6.0 Hz, IH), 3.74 (dd, J= 10.8, 6.0 Hz, IH), 2.71-2.82 (m, 2H), 1.45-1.68 (m, 6H), 1.10-1.25 (m, 6H), 0.81-0.90 (m, 2H); 13C NMR (IOO MHZ, CDCl3) δ 167.4, 155.3, 154.3, 146.6, 146.1, 137.4, 119.3, 116.3, 114.9, 101.4, 70.2, 56.1, 38.8, 30.8, 30.7, 27.4, 27.0, 25.7, 13.4.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 25- 30% /-PrOH in «-Hexanes, 0.85 mL/min): 187a tR = 9.5 min, 187b tR = 38.1 min.
Figure imgf000123_0002
CycIohexylmethyI 6-ethyI-4-(3-hydroxy-4-nitrophenyl)-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxyIate (188)
1U NMR (400 MHz, CD3OD) δ 8.03 (d, J = 8.8 Hz, IH), 7.04 (d, J = 2.0 Hz, IH), 6.96 (dd, J = 8.4, 2.0 Hz, IH), 5.30 (s, IH), 3.91 (dd, J = 10.6, 6.2 Hz, IH), 3.76 (dd, J = 10.8, 6.0 Hz, IH), 2.81 (m IH), 2.70 (m, IH), 1.65-1.43 (m, 6H), 1.27-1.07 (m, 6H), 0.89-0.77 (m, 2H); 13C NMR (100 MHz, CD3OD) δ 165.5, 154.8, 154.6, 153.7, 153.6, 133.8, 125.7, 118.2, 117.6, 98.4, 69.2, 54.5, 37.4, 29.6, 29.5, 26.1, 25.61, 25.59, 24.5, 12.1.
Figure imgf000124_0001
CyclohexyImethyl 4-(4-amino-3-hydroxyphenyl)-6-ethyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (189)
To a mixture of 188 (65.6 mg, O.lόmmol, 1.0 equiv) in MeOH (2 niL) was added Pd/C (10%, 7 mg), and the reaction mixture was stirred for 3 h at room temperature under hydrogen balloon. The catalyst was filtered through a plug of Celite and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative TLC (3% MeOH/Et2O) to afford 189 (26 mg, 73%): 1H NMR (400 MHz, CD3OD) δ 6.67 (m, 2H), 6.58 (d, J = 7.6 Hz, IH), 5.13 (s, IH), 3.87 (dd, J = 10.8, 6.0 Hz, IH), 3.73 (dd, J = 10.8, 6.0 Hz, IH), 2.72 (m, 2H), 1.67-1.50 (m, 6H), 1.48-1.12 (m, 6H), 10.9-0.78 (m, 2H); 13C NMR (IOO MHz, CD3OD) δ 167.5, 155.4, 154.1, 146.8, 136.7, 136.1, 119.6, 117.2, 114.0, 101.6, 70.3, 56.2, 38.8, 30.92, 30.86, 27.5, 27.0, 25.7, 13.4.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 25% i- PrOH in «-Hexanes, 0.85 niL/min): 189a tR= 15.45 min, 189b tR = 31.49 min.
Figure imgf000124_0002
190
Cyclohexylmethyl 4-(4-chloro-3-nitrophenyl)-6-ethyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (190)
1H NMR (400 MHz, CDCl3) δ 7.88 (s, IH), 7.79 (s, IH), 7.50-7.44 (m, 2H), 6.20 (s, IH), 5.42 (d, J= 2.8 Hz, IH), 3.88 (dd, J= 10.8, 6.4 Hz, IH), 3.82 (dd, J= 10.8, 6.4 Hz, IH), 2.84-2.77 (m, IH), 2.72-2.65 (m, IH), 1.70-1.47 (m, 6H), 1.28-1.05 (m, 6H), 0.88-0.78 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 165.0, 153.23, 153.12, 148.1, 144.2, 132.6, 131.4, 126.7, 124.1, 99.6, 70.0, 54.8, 37.3, 31.8, 29.97, 29.93, 26.4, 25.77, 25.75, 25.69, 12.7. Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 10% i- PrOH in rc-Hexanes, 0.85 mL/min): 190a tR = 16.57 min, 190b tR = 22.63 min.
Figure imgf000125_0001
Cyclohexylmethyl 4-(3-amino-4-chlorophenyl)-6-ethyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (191)
190 (100 mg, 0.24 mmol, 1.0 equiv), Zn (93 mg, 1.42 mmol, 5.9 equiv), AcOH (0.9 mL) and concentrated HCl (0.1 mL) was added to a 20 mL round-bottom flask. After stirring at 80 °C for 1 h, the reaction mixture was cooled to 0 0C and aqueous saturated K2CO3 (5 mL) was added. The mixture was extracted with EtOAc (3 x 5 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (n-Hexanes/EtOAc/AcOH = 50:50:0.5) to afford 191 (82 mg, 88%): 1H NMR (400 MHz, CD3OD) δ 7.13 (d, J= 8.0 Hz, IH), 6.77 (s, IH), 6.57 (dd, J= 8.0, 1.6 Hz, IH), 5.19 (s, IH), 3.94 (dd, J= 10.6, 5.8 Hz, IH), 3.74 (dd, J= 10.6, 5.8 Hz, IH), 2.86-2.79 (m, IH), 2.74-2.67 (m, IH), 1.67-1.44 (m, 6H), 1.30-1.09 (m, 6H), 0.88-0.78 (m, 2H); 13C NMR (IOO MHz, CD3OD) δ 165.9, 153.8, 153.7, 144.4, 144.1, 129.1, 117.9, 116.3, 114.0, 99.4, 69.0, 54.8, 37.5, 29.54, 29.45, 26.2, 25.67, 25.65, 24.4, 12.1.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 25% i- PrOH in rc-Hexanes, 0.85 mL/min): 191a tR = 10.0 min, 191b tR = 23.1 min.
Figure imgf000125_0002
Cyclohexylmethyl 6-ethyl-4-(3-fluoro-4-nitrophenyl)-2-oxo-l,2,3j4- tetrahydropyrimidine-5-carboxylate (192) 1U NMR (400 MHz, CD3OD) δ 8.10 (t, J= 8.4 Hz, IH), 7.35-7.31 (m, 2H), 5.40 (s, IH), 3.95 (dd, J= 10.8, 6.4 Hz, IH), 3.80 (dd, J= 10.8, 6.4 Hz, IH), 2.89-2.82 (m, IH), 2.75-2.68 (m, IH), 1.69-1.45 (m, 6H), 1.26-1.10 (m, 6H), 0.89-0.80 (m, 2H); 13C NMR (100 MHz, CD3OD) δ 165.4, 156.8, 155.1, 154.2, 153.36, 153.31, 153.24, 126.60, 126.58, 122.84, 122.80, 116.4, 116.2, 98.2, 69.3, 54.4, 37.4, 29.58, 29.50, 26.1, 25.58, 25.55, 24.55, 12.1. Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 10% i- PrOH in rc-Hexanes, 0.85 mL/min): 192a tR = 18.5 min, 192b tR = 24.8 min.
Figure imgf000126_0001
Cyclohexylmethyl 4-(4-amino-3-fluoropheiiyl)-6-ethyl-2-oxo-l,2,3?4- tetrahydropyrimidine-5-carboxylate (193)
1K NMR (400 MHz, CD3OD) δ 6.89-6.84 (m, 2H), 6.77 (t, J= 8.6 Hz, IH), 5.18 (s, IH), 3.92 (dd, J= 10.6, 6.2 Hz, IH), 3.76 (dd, J= 10.6, 6.2 Hz, IH), 2.82-2.72 (m, 2H), 1.70-1.46 (m, 6H), 1.25-1.11 (m, 6H), 0.91-0.83 (m, 2H); 13C NMR (IOO MHZ, CD3OD) δ 166.0, 154.0, 153.4, 152.9, 150.5, 135.3, 135.1, 134.5, 134.4, 122.49, 122.46, 116.91, 116.88, 113.2, 113.0, 99.8, 69.0, 54.3, 37.5, 29.55, 29.48, 26.2, 25.66, 25.64, 24.4, 12.1.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 25% i- PrOH in rc-Hexanes, 0.85 mL/min): 193a tR = 13.3 min, 193b tR = 22.0 min.
Figure imgf000126_0002
Cyclohexylmethyl 6-ethyl-4-(2-fluoro-5-nitrophenyl)-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (194)
1H NMR (400 MHz, DMSO-^) δ 9.46 (s, IH), 8.26-8.22 (m, IH), 8.09-8.07 (m, IH), 7.83 (s, IH), 7.52 (t, J= 9.2 Hz, IH), 5.51 (d, J= 2.8 Hz, IH), 3.80 (dd, J= 10.8, 6.4 Hz, IH), 3.66 (dd, J= 10.8, 6.0 Hz, IH), 2.79-2.66 (m, 2H), 1.59-1.21 (m, 6H), 1.17-0.95 (m, 6H), 0.77- 0.66 (m, 2H); 13C NMR (IOO MHz, DMSO-J6) δ 164.5, 164.3, 161.9, 155.8, 151.4, 143.93, 143.9, 133.3, 133.1, 125.5, 125.4, 124.5, 124.4, 117.7, 117.4, 95.3, 68.3, 49.0, 36.6, 29.0, 28.9, 25.7, 25.2, 25.1, 24.0, 13.0.
Figure imgf000127_0001
Cyclohexylmethyl 4-(5-amino-2-fluorophenyl)-6-ethyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (195)
1H NMR(400 MHz, CD3OD) δ 6.82 (t, J= 9.2 Hz, IH), 6.66-6.59 (m, 2H), 5.57 (s, IH), 3.89 (dd, J= 10.4, 6.0 Hz, IH), 3.71 (dd, J= 10.8, 5.6 Hz, IH), 2.91-2.84 (m, IH), 2.76-2.70 (m, IH), 1.66-1.43 (m, 6H), 1.35-1.09 (m, 6H), 0.88-0.75 (m, 2H); 13C NMR (100 MHz, CD3OD) δ 167.0, 156.0, 155.9, 155.1, 153.7, 145.49, 145.47, 132.4, 132.2, 117.3, 117.2, 117.0, 116.8, 115.9, 115.8, 99.1, 70.3, 38.7, 30.8, 30.7, 27.5, 27.0, 25.7, 13.4.
Figure imgf000127_0002
CyclohexylmethyI 6-ethyl-4-(4-fluoro-3-nitrophenyl)-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (196)
1H NMR (400 MHz, CDCl3) δ 7.99-7.95 (m, 2H), 7.60-7.56 (m, IH), 7.26-7.21 (m, IH), 6.22 (s, IH), 5.44 (d, J= 3.2 Hz, IH), 3.89-3.80 (m, 2H), 2.84-2.77 (m, IH), 2.74-2.67 (m, IH), 1.70-1.48 (m, 6H), 1.30-1.06 (m, 6H), 0.88-0.79 (m,2H); 13C NMR (100 MHz, CDCl3) δ 165.1, 156.5, 153.9, 153.3, 153.1, 141.1, 141.0, 133.9, 133.8, 124.62, 124.59, 119.3, 119.1, 99.8, 70.0, 54.8, 37.3, 31.8, 30.0, 29.9, 26.4, 25.78, 25.76, 25.68, 22.9, 14.3, 12.8.
Figure imgf000128_0001
197
Cyclohexylmethyl 4-(3-amino-4-fluorophenyl)-6-ethyl-2-oxo-l,2,3,4- tetrahy dropy rimidine-5-carboxyIate (197)
1E NMR(400 MHz, CD3OD) δ 6.90-6.85 (m, IH), 6.79 (d, J= 8.8 Hz, IH), 6.58-6.55 (m, IH), 5.20 (s, IH), 3.92 (dd, J= 10.8, 6.0 Hz, IH), 3.75 (dd, J= 10.6, 5.8 Hz, IH), 2.85-2.75 (m, IH), 2.73-2.68 (m, IH), 1.68-1.44 (m, 6H), 1.29-1.09 (m, 6H), 0.90-0.79 (m, 2H); 13C NMR (100 MHz, CD3OD) δ 167.3, 155.2, 154.8, 153.9, 151.5, 142.0, 141,98, 137.2, 137.0, 117.23, 117.17, 116.6, 116.5, 116.1, 115.9, 101.0, 70.4, 56.1, 38.8, 30.9, 30.8, 27.5, 27.0, 25.8, 13.4. Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 15- 25% z-PrOH in «-Hexanes, 6.5 mL/min): 197a tR = 25.5 min, 197b tR = 43.4 min.
Figure imgf000128_0002
198
Cyclohexylmethyl 4-(3-chloro-4-nitrophenyl)-6-ethyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (198)
1H NMR (400 MHz, CD3OD) δ 7.92 (d, J = 8.4 Hz, IH), 7.52 (d, J = 1.2 Hz, IH), 7.43 (dd, J = 8.4, 1.6 Hz, IH), 5.36 (s, IH), 3.94 (dd, J = 10.8, 6.0 Hz, IH), 3.74 (dd, J = 10.8, 5.6 Hz, IH), 2.83 (m, IH), 2.71 (m, IH), 1.63 (m, 3H), 1.53-1.39 (m, 3H), 1.30-1.07 (m, 6H), 0.89- 0.76 (m, 2H); 13C NMR (IOO MHz, CD3OD) δ 166.6, 156.5, 154.7, 151.9, 148.8, 131.3, 127.7, 127.5, 127.4, 99.5, 70.6, 55.7, 38.8, 30.94, 30.87, 27.5, 27.0, 25.9, 13.4.
Figure imgf000129_0001
Cyclohexylmethyl 4-(4-amino-3-chlorophenyl)-6-ethyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (199)
1U NMR (400 MHz, CD3OD) δ 7.09 (d, J = 2.0 Hz, IH), 6.96 (dd, J = 8.4 Hz, 2.0 Hz, IH), 6.75 (d, J = 8.4 Hz, IH), 5.14 (s, IH), 3.91 (dd, J = 10.6, 6.2 Hz, IH), 3.72 (dd, J = 10.6, 5.8 Hz, IH), 2.75 (m, 2H), 1.67-1.42 (m, 6H), 1.27-1.08 (m, 6H), 0.88-0.78 (m, 2H). Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 15- 30% /-PrOH in rc-Hexanes, 6.5 mL/min): 199a tR = 1st band, 199b tR = 2nd band.
Figure imgf000129_0002
Cyclohexylmethyl 4-(2-chloro-5-nitrophenyl)-6-ethyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (200)
1U NMR (400MHz,
Figure imgf000129_0003
δ 9.48 (s, IH), 8.14 (m, IH), 8.05 (d, J= 2.8 Hz, IH), 7.88 (s, IH), 7.77 (d, J= 8.8 Hz, IH), 5.68 (d, J= 3.6 Hz, IH), 3.78 (dd, J= 10.8, 6.4 Hz, IH), 3.64 (dd, J= 10.6, 5.8 Hz, IH), 2.90-2.87 (m, IH), 2.68-2.63 (m, IH), 1.53-1.39 (m, 6H), 1.37- 0.96 (m, 6H), 0.73-0.65 (m, 2H); 13C NMR (100 MHz, OMSO-d6) δ 164.2, 156.1, 151.2, 146.7, 143.1, 138.9, 131.3, 123.9, 123.2, 95.8, 68.3, 51.7, 36.6, 28.9, 28.8, 25.7, 25.1, 23.9, 12.0.
Figure imgf000129_0004
Cyclohexylmethyl 4-(5-amino-2-chloropheiiyl)-6-ethyl-2-ox()-l,2,3,4- tetrahydropyrimidine-5-carboxylate (201)
1H NMR(400 MHz, CD3OD) δ 7.08 (d, J= 8.4 Hz, IH), 6.67 (d, J= 2.8 Hz, IH), 6.59 (dd, J = 8.4, 2.8 Hz, IH), 5.72 (s, IH), 3.88 (dd, J= 10.8, 6.0 Hz, IH), 3.67 (dd, J= 10.8, 5.2 Hz, IH), 2.98-2.93 (m, IH), 2.74-2.69 (m, IH), 1.63-1.34 (m, 6H), 1.30-1.07 (m, 6H), 0.82-0.72 (m, 2H); 13C NMR (IOO MHZ, CD3OD) δ 166.7, 156.0, 154.8, 148.9, 142.0, 131.1, 121.5, 117.0, 115.4, 99.2, 70.1, 53.0, 38.5, 30.5, 30.4, 27.2, 26.88, 26.87, 25.4, 13.2. Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 10- 20% /-PrOH in n-Hexanes, 6.5 mL/min): 201a tR = 53.8 min, 201b tR = 59.9 min.
Figure imgf000130_0001
Cyclohexylmethyl 4-(3,4-dinitrophenyl)-6-ethyl-2-oxo-l,2,354-tetrahydropyrimidiiie-5- carboxylate (202)
1H NMR (400 MHz, CD3OD) δ 8.06 (d, J = 8.4 Hz, IH), 7.93 (d, J = 1.6 Hz, IH), 7.79 (dd, J = 8.4, 1.6 Hz, IH), 5.46 (s, IH), 3.94 (dd, J = 10.8, 6.4 Hz, IH), 3.77 (dd, J = 10.8, 6.0 Hz, IH), 2.86 (m, IH), 2.69 (m, IH), 1.65 (m, 3H), 1.51 (m, 3H), 1.22 (m, 6H), 0.90-0.76 (m, 2H); 13C NMR (100 MHz, CD3OD) δ 165.2, 155.6, 153.1, 151.5, 131.7, 126.0, 123.6, 97.9, 69.3, 54.3, 37.3, 29.59, 29.56, 26.1, 25.55, 25.52, 24.6, 12.1.
Figure imgf000130_0002
Cyclohexylmethyl 4-(3,4-diaminophenyl)-6-ethyI-2-oxo-l,2,354-tetrahydropyrimidine-5- carboxylate (203)
To a mixture of 202 (33 mg, 0.076 mmol, 1.0 equiv) in MeOH (2 mL) was added 10% Pd/C (7 mg), and the reaction mixture was stirred for 2 h at room temperature under hydrogen balloon. The catalyst was filtered through a plug of Celite and the filtrate was concentrated under reduced pressure. The residue was purified by preparative. TLC (3% MeOHTEt2O) to afford 203 (26 mg, 73%): 1H NMR (400 MHz, DMSO-J6) δ 8.92 (d, J = 1.2 Hz, IH), 7.36 (t, J = 2.4 Hz, IH), 6.35 (m, 2H), 6.22 (dd, J = 8.0, 2.0 Hz, IH), 4.86 (d, J = 3.2 Hz, IH), 4.36 (s, 2H), 4.32 (s, 2H), 3.72 (m, 2H), 2.68 (m, IH), 2.54 (m, IH), 1.60-1.42 (m, 6H), 1.20-1.02 (m, 6H), 0.85 (m, 2H); 13C NMR (100 MHz, DMSO-^6) δ 165.2, 152.8, 152.4, 134.7, 134.2, 133.7, 115.3, 113.9, 112.5, 98.9, 68.1, 53.9, 36.7, 29.11, 29.08, 25.8, 25.24, 25.22, 24.0, 13.1. Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 35% i- PrOH in π-Hexanes, 0.85 mL/min): 203a tR = 21.36 min, 203b tR = 56.14 min.
Figure imgf000131_0001
204
Cyclohexylmethyl 4-(3,4-difluorophenyl)-6-ethyI-2-oxo-l,2,3?4-tetrahydropyrimidine-5- carboxylate (204)
1H NMR (400 MHz, CDCl3) δ 8.44 (s, IH), 7.10-6.98 (m, 3H), 6.40 (s, IH), 5.32 (s, IH), 3.87 (dd, J= 10.8, 6.0 Hz, IH), 3.79 (dd, J= 10.6, 6.2 Hz, IH), 2.82-2.73 (m, IH), 2.70-2.61 (m, IH), 1.69-1.43 (m, 6H), 1.26-1.02 (m, 6H), 0.87-0.76 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 165.3, 154.0, 152.7, 151.9, 151.7, 151.4, 151.3, 149.4, 149.3, 148.9, 148.8, 140.95, 140.92, 140.87, 122.72, 122.69, 122.66, 122.62, 117.8, 117.6, 115.9, 115.7, 100.1, 69.7, 54.9, 37.3, 29.9, 26.4, 25.80, 25.77, 25.5, 12.8.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 10% /-PrOH in «-Hexanes, 6.5 mL/min): 204a tR = 8.8 min, 204b tR = 18.1 min.
Figure imgf000131_0002
Cyclohexylmethyl 4-(3,5-bis(trifluoromethyl)phenyl)-6-ethyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (205)
1H NMR (400 MHz, CDCl3) δ 8.04 (s, IH), 7.77 (s, IH), 7.72 (s, 2H), 6.21 (s, IH), 5.51 (d, J = 2.4 Hz, IH), 3.86 (dd, J= 10.8, 6.0 Hz, IH), 3.79 (dd, J= 10.8, 6.0 Hz, IH), 2.83-2.72 (m, 2H), 1.62-1.42 (m, 6H), 1.24-1.03 (m, 6H), 0.86-0.74 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 164.9, 153.5, 153.2, 146.3, 132.9, 132.6, 132.2, 131.9, 127.4, 127.1, 124.7, 122.3, 122.0, 99.3, 69.9, 55.3, 37.2, 29.9, 29.8, 26.4, 25.7, 25.6, 12.7.
Figure imgf000132_0001
206
Cyclohexylmethyl 4-(3,5-dibromophenyl)-6-ethyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5- carboxylate (206)
1H NMR (400 MHz, CDCl3) δ 8.50 (s, IH), 7.52 (s, IH), 7.24 (s, IH), 6.48 (s, IH), 5.27 (d, J = 2.8 Hz, IH), 3.89 (dd, J= 10.8, 6.0 Hz, IH), 3.75 (dd, J= 10.8, 6.0 Hz, IH), 2.85-2.78 (m, IH), 2.66-2.59 (m, IH), 1.67-1.45 (m, 6H), 1.23-1.03 (m, 6H), 0.86-0.76 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 165.1, 153.8, 153.4, 147.5, 133.8, 128.8, 123.5, 99.3, 69.8, 55.0, 37.3, 29.96, 29.92, 26.5, 25.9, 25.5, 12.8.
Figure imgf000132_0002
Cyclohexylmethyl 4-(3,5-difluorophenyl)-6-ethyl-2-oxo-l,2,3?4-tetrahydropyrimidine-5- carboxylate (207)
1H NMR (400 MHz, CDCl3) δ 8.43 (s, IH), 6.80 (t, J= 6.2 Hz, 2H), 6.70-6.65 (m, IH), 6.39 (s, IH), 5.33 (d, J- 2.8 Hz, IH), 3.89 (dd, J= 10.6, 6.2 Hz, IH), 3.79 (dd, J= 10.6, 6.2 Hz, IH), 2.82-2.75 (m, IH), 2.70-2.63 (m, IH), 1.65-1.44 (m, 6H), 1.21-1.02 (m, 6H), 0.87-0.76 (m, 2H); 13C NMR (IOO MHZ, CDCl3) δ 165.2, 164.7, 164.6, 162.2, 162.1, 153.9, 153.1, 147.6, 109.76, 109.70, 109.58, 109,51, 103.8, 103.6, 103.3, 99.6, 69.8, 55.1, 37.4, 29.9, 29.9, 26.4, 25.82, 25.81, 25.5, 12.8.
Figure imgf000133_0001
Cyclohexylmethyl 4-(3,4-dichlorophenyl)-6-ethyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5- carboxylate (208)
1H NMR (400 MHz, CDCl3) δ 8.44, 7.35-7.33 (m, 2H), 7.12-7.09 (m, IH), 6.47 (s, IH), 5.30 (d, J= 2.8 Hz, IH), 3.88 (dd, J= 10.8, 6.0 Hz, IH), 3.77 (dd, J= 10.8, 6.0 Hz, IH), 2.80-2.73 (m, IH), 2.69-2.62 (m, IH), 1.66-1.44 (m, 6H), 1.27-1.05 (m, 6H), 0.85-0.76 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 165.2, 153.9, 152.9, 144.1, 132.9, 132.2, 131.0, 128.9, 126.1, 99.8, 69.8, 54.9, 37.4, 29.9, 26.4, 25.84, 25.82, 25.5, 12.8.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 15- 30% /-PrOH in w-Hexanes gradient, 0.8 mL/min): 208a tR = 1st band, 208b tR = 2nd band.
Figure imgf000133_0002
Cyclohexylmethyl 4-(4-acetoxy-3,5-dichlorophenyl)-6-ethyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (209)
1H NMR (400 MHz, CDCl3) δ 7.92 (bs, IH), 7.30 (s, 2H), 6.03 (bs, IH), 5.36 (s, IH), 3.93 (dd, J= 10.8, 6.0 Hz, IH), 3.83 (dd, J= 10.8, 6.0 Hz, IH), 2.88 (m, IH), 2.68 (m, IH), 2.38 (s, 3H), 1.71-1.54 (m, 6H), 1.43-1.07 (m, 6H), 0.88 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 167.4, 165.1, 153.3, 153.0, 143.8, 143.4, 129.3, 127.1, 99.7, 70.0, 55.0, 37.3, 30.01, 29.99, 26.5, 25.8, 25.6, 20.4, 12.7.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 10- 15% /-PrOH in «-Hexanes, 6.5 mL/min): 209a tR = 15.3 min, 209b tR = 21.3 min.
Figure imgf000134_0001
Cyclohexylmethyl 4-(3,5-dichloro-4-hydroxyphenyl)-6-ethyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (210)
Enantiomeric pure forms were obtained from 209a/209b by hydrolysis using K2CO3 in
MeOH.
1H NMR (400 MHz, CD3OD) δ 7.16 (s, 2H), 5.18 (s, IH), 3.95 (dd, J= 10.6, 5.8 Hz, IH),
3.71 (dd, J= 10.8, 5.6 Hz, IH), 2.76 (m, 2H), 1.62-1.42 (m, 6H), 1.26-1.07 (m, 6H), 0.80 (m,
2H); 13C NMR (IOO MHZ, CD3OD) δ 166.9, 155.6, 154.9, 150.4, 138.5, 128.0, 123.6, 100.3,
70.4, 55.3, 38.8, 30.9, 30.8, 27.5, 27.0, 25.8, 13.4.
Figure imgf000134_0002
211
Cyclohexylmethyl 4-(3-chloro-4,5-dihydroxyphenyI)-6-ethyl-2-oxo-l,2,354- tetrahydropyrimidine-5-carboxylate (211)
1H NMR (400 MHz, DMSO-sfc) δ 9.17 (bs, IH), 7.59 (bs, IH), 6.67 (s, IH), 6.65 (s, IH), 5.00 (s, IH), 3.88 (dd, J= 10.8, 6.0 Hz, IH), 3.73 (dd, J= 10.8, 6.0 Hz, IH), 3.22 (bs, 2H), 2.72- 2.79 (m, IH), 2.62-2.68 (m, IH), 1.46-1.66 (m, 6H), 1.11-1.23 (m, 6H), 0.81-0.89 (m, 2H); 13C NMR (100 MHz, DMSO-J6) δ 164.7, 153.8, 152.0, 146.3, 147.9, 135.9, 119.4, 117.8, 111.7, 97.9, 68.0, 53.3, 38.8, 36.6, 29.0, 28.8, 25.7, 25.1, 23.9, 12.9.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 25% i- PrOH in «-Hexanes, 0.8 mL/min): 211a tR = 19.0 min, 211b tR = 25.3 min.
Figure imgf000135_0001
212
Cyclohexylmethyl 6-ethyI-4-(3-fluoro-4,5-dihydroxyphenyl)-2-oxo-l,2,3)4- tetrahydropyrimidine-5-carboxylate (212)
1H NMR (400 MHz, DMSO-J6) δ 9.46 (bs, IH), 9.16 (s, IH), 8.91 (bs, IH), 7.60 (s, IH), 6.51 (d, J= 1.6 Hz, IH), 6.41 (dd, J= 11.4, 2.2 Hz, IH), 4.96 (d, J= 3.2 Hz, IH), 3.85 (dd, J= 10.8, 6.0 Hz, IH), 3.71 (dd, J- 10.8, 6.0 Hz, IH), 2.74-2.59 (m, 2H), 1.61-1.40 (m, 6H), 1.18-1.03 (m, 6H), 0.87-0.78 (m, 2H); 13C NMR (IOO MHz, DMSO-J15) δ 165.6, 154.7, 153.4, 152.9, 151.1, 148.14, 148.08, 135.83, 135.77, 133.06, 132.9, 109.8, 105.3, 105.1, 98.7, 68.8, 54.0, 37.5, 29.74, 29.65, 26.4, 25.93, 25.91, 24.6, 13.7.
Enantiomeric pure forms were obtained by chiral HPLC (OD-H analytical column, 25% i- PrOH in rc-Hexanes, 0.8 mL/min): 212a tR = 18.2 min, 212b tR = 32.6 min.
Figure imgf000135_0002
213
Cyclohexylmethyl 6-ethyl-2-oxo-4-(3,4,5-trihydroxyphenyl)-l,2,3,4- tetrahydropyrimidine-5-carboxyIate (213)
1H NMR (400 MHz, CDCl3 + DMSO-J6) δ 6.29 (s, 2H), 5.10 (s, IH), 3.83 (dd, J= 10.8, 6.4 Hz, IH), 3.75 (dd, J= 10.8, 6.4 Hz, IH), 2.58-2.74 (m, 2H), 1.45-1.63 (m, 6H), 1.03-1.18 (m, 6H), 0.78-0.82 (m, 2H); 13C NMR (IOO MHz, CDCl3 + DMSO-J6) δ 166.0, 151.3, 145.1, 135.3, 105.6, 100.9, 69.6, 55.1, 37.2, 29.7, 26.3, 25.7, 25.2, 12.4.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 30% i- PrOH in n-Hexanes, 0.8 mL/min): 213a tR = 21.0 min, 213b tR = 36.9 min.
Figure imgf000136_0001
214
Cyclohexylmethyl 6-ethyl-4-(3-fluoro-4-hydroxy-5-methoxyphenyl)-2-oxo-l,2,3»4- tetrahydropyrimidine-5-carboxylate (214)
1H NMR (400 MHz, CD3OD) δ 6.70 (s, IH), 6.62 (d, J= 10.8 Hz, IH), 5.23 (s, IH), 3.96 (dd, J= 10.8, 5.6 Hz, IH), 3.84 (s, 3H), 3.75 (dd, J= 10.8, 5.6 Hz, IH), 2.72-2.85 (m, 2H), 1.46- 1.68 (m, 6H), 1.11-1.27 (m, 6H); 13C NMR (IOO MHz, CD3OD) δ 167.1, 154.2, 151.1, 135.5, 135.4, 107.9, 106.9, 100.7, 70.3, 56.9, 55.9, 38.8, 30.7, 27.4, 27.0, 25.7, 13.5.
Figure imgf000136_0002
CycIohexylmethyl 4-(3-chloro-4,5-dimethoxyphenyl)-6-ethyl-2-oxo-l,2,354- tetrahydropyrimidine-5-carboxylate (215)
1H NMR (400 MHz, CDCl3) δ 8.59 (bs, IH), 6.84 (s, IH), 6.71 (s, IH), 6.38 (bs, IH), 5.26 (s, IH), 3.87 (dd, J= 10.6, 5.8 Hz, IH), 3.78 (s, 3H), 3.76 (s, 3H), 3.74 (dd, J= 10.6, 5.8 Hz, IH), 2.72 (q, J= 7.2 Hz, 2H), 1.45-1.62 (m, 6H), 1.02-1.25 (m, 6H), 0.79-0.81 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 165.2, 154.0, 153.8, 152.6, 145.0, 140.1, 128.4, 119.9, 109.2, 99.6, 69.5, 60.6, 56.0, 55.0, 37.2, 29.7, 26.3, 25.7, 25.2, 12.7.
Figure imgf000136_0003
216 Cyclohexylmethyl 4-(3-bromo-4,5-dihydroxyphenyl)-6-ethyl-2-oxo-l,2,3,4- tetrahy dropy rimidine-5-carboxylate (216)
1H NMR (400 MHz, DMSOd6) δ 9.18 (s, IH), 7.60 (s, IH), 6.76 (d, J= 1.6 Hz, IH), 6.67 (d, J= 1.6 Hz, IH), 4.95 (d, J= 3.2 Hz, IH), 3.85 (dd, J= 10.6, 5.8 Hz, IH), 3.69 (dd, J= 10.6, 5.8 Hz, IH), 2.74-2.59 (m, 2H), 1.62-1.41 (m, 6H), 1.14-1.03 (m, 6H), 0.87-0.76 (m, 2H); 13C NMR (100 MHz, DMSOd6) δ 164.9, 154.1, 152.1, 146.3, 142.2, 136.7, 120.9, 112.4, 109.1, 98.1, 68.2, 53.4, 36.8, 29.14, 29.08, 25.8, 25.3, 24.0, 13.1.
Figure imgf000137_0001
CyclohexyImethyl 6-ethyl-4-(2-fluoro-4,5-dihydroxyphenyl)-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (217)
1R NMR (400 MHz, DMSOd6) δ 9.21 (bs, 2H), 8.89 (s, IH), 7.53 (s, IH), 6.57 (d, J= 7.6 Hz, IH), 6.46 (d, J= 11.2 Hz, IH), 5.30 (d, J= 2.8 Hz, IH), 3.80 (dd, J= 10.6, 6.2 Hz, IH), 3.66 (dd, J= 10.6, 6.2 Hz, IH), 2.74-2.62 (m, 2H), 1.60-1.39 (m, 6H), 1.16-1.02 (m, 6H), 0.84-0.72 (m, 2H); 13C NMR (IOO MHZ, DMSOd6) δ 165.4, 154.9, 153.9, 152.7, 151.6, 146.3, 146.2, 142.26, 142.24, 121.9, 121.7, 114.4, 114.3, 103.5, 103.2, 97.7, 68.8, 48.1, 37.4, 29.6, 29.5, 26.4, 25.97, 25.94, 24.6, 13.7.
Figure imgf000137_0002
CyclohexyImethyI 4-(l-bromonaphthalen-2-yl)-6-ethyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (218)
1H NMR (400 MHz, DMSOd6) δ 9.36 (s, IH), 8.28 (d, J= 8.4 Hz, IH), 7.96 (d, J= 8.8 Hz, IH), 7.73 (d, J= 8.0 Hz, IH), 7.74 (s, IH), 7.69 (t, J= 7.6 Hz, IH), 7.59 (t, J= 7.4 Hz, IH), 7.41 (d, J= 8.4 Hz, IH), 5.96 (d, J= 2.8 Hz, IH), 3.76 (dd, J= 10.8, 6.8 Hz, IH), 3.53 (dd, J = 10.8, 6.8 Hz, IH), 2.82-2.72 (m, 2H), 1.35-1.13 (m, 9H), 0.94-0.63 (m, 3H), 0.54-0.42 (m, 2H); 13C NMR (100 MHz, DMSO-J15) δ 165.2, 156.1, 152.1, 141.8, 134.3, 132.3, 129.5, 128.8, 128.6, 127.9, 127.4, 125.6, 122.7, 97.7, 68.8, 55.7, 37.3, 29.6, 29.2, 26.2, 25.8, 25.6, 24.7, 13.7.
Figure imgf000138_0001
Cyclohexylmethyl 4-(4-(tert-butoxycarbonylamino)-3,5-dichlorophenyl)-6-ethyl-2-oxo- l,2,3,4-tetrahydropyrimidine-5-carboxylate (219)
1H NMR (400 MHz, CDCl3) δ 8.22 (bs, IH), 7.28 (s, 2H), 6.44 (bs, IH), 6.36 (bs, IH), 5.31
(d, J= 3.2 Hz, IH), 3.87 (m, 2H), 2.84 (dd, J= 13.2, 7.6 Hz, IH), 2.64(dd, J= 13.4, 7.4 Hz,
IH), 1.71-1.45 (m, 15H), 1.28-1.07 (m, 6H), 0.90 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
D 165.2, 153.5, 153.3, 144.3, 134.1, 132.0, 126.8, 99.4, 81.4, 72.4, 54.8, 37.3, 30.02, 29.97,
28.4, 26.5, 25.9, 25.5, 12.7.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 5-
10% /-PrOH in rc-Hexanes, 6.5 mL/min): 219a tR = 49.8 min, 219b tR = 53.4 min.
Figure imgf000138_0002
Cyclohexylmethyl 4-(4-amino-3,5-dichlorophenyl)-6-ethyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (220)
1U NMR (400 MHz, CD3OD) δ 7.08 (s, 2H), 5.13 (s, IH), 3.96 (dd, J= 10.6, 6.2 Hz, IH), 3.71 (dd, J= 11.0, 5.8 Hz, IH), 2.77 (m, 2H), 1.66-1.43 (m, 6H), 1.27-1.08 (m, 6H), 0.84 (m, 2H); 13C NMR (100 MHz, CD3OD) δ 167.0, 155.3, 155.0, 141.9, 135.5, 127.5, 120.3, 100.5, 70.4, 55.4, 38.8, 30.9, 30.8, 27.5, 27.0, 25.7, 13.4. Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 20% z-PrOH in rc-Hexanes, 6.5 mL/min): 220a tR = 12.2 min, 220b tR = 15.5 min.
Figure imgf000139_0001
221
Cyclohexylmethyl 4-(2,3-dibromo-4,5-dihydroxyphenyl)-6-ethyl-2-oxo-l,2,3j4- tetrahydropyrimidine-5-carboxylate (221)
1H NMR (400 MHz, DMSO-J6) δ 10.04 (bs, IH), 9.54 (bs, IH), 9.28 (s, IH), 7.49 (s, IH), 6.73 (s, IH), 5.56 (d, J= 2.8 Hz, IH), 3.83 (dd, J= 10.8, 6.4 Hz, IH), 3.57 (dd, J= 10.8, 6.4 Hz, IH), 2.83-2.26 (m, 2H), 1.53-1.22 (m, 6H), 1.20-0.95 (m, 6H), 0.72-0.60 (m, 2H); 13C NMR (100 MHz, DMSO-^5) δ 164.6, 154.9, 151.6, 145.5, 144.3, 135.3, 114.0, 113.2, 113.1, 97.5, 68.1, 55.2, 54.9, 38.9, 36.8, 29.1, 28.7, 25.7, 25.4, 23.9, 13.0.
Dihydropyrimidine aryl ketone analogs at C-5 position.
General procedure for the synthesis of β-keto thiol esters
Figure imgf000139_0002
To a 0 0C solution of diisopropylamine (707 μL, 5.00 mmol, 1.1 equiv) in THF (10 mL) was added n-BuLi (2.5 M in «-Hexanes, 2.0 mL, 5.00 mmol, 1.1 equiv) via a syringe under Ar. After 30 min at 0 0C, the reaction was cooled to -78 °C and then treated with a solution of thiol ester (4.54 mmol, 1.0 equiv) in THF (2 mL) via a cannula. After 30 min at -78 °C, aldehyde (4.54 mmol, 1.0 equiv) was added dropwise, and the whole reaction mixture was allowed to stir at -78 °C for another 10 min. The reaction was then quenched by the addition of saturated aqueous NH4Cl (10 mL), and the reaction mixture was extracted with CH2Cl2 (3 x 20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, π-Hexanes/Et2O = 5:1→ 2:1) to give β -hydroxy thiol esters.
To a 0 °C solution of the above β-hydroxy thiol ester (1.00 mmol, 1.0 equiv) and NaHCO3 (253 mg, 3.00 mmol, 3.0 equiv) in CH2Cl2 (10 mL) was added Dess-Martin periodinane solution (15% by wt in CH2Cl2, 2.5 mL, 1.20 mmol, 1.2 equiv). After 5 min at 0 0C, the reaction was warmed to 25 ° C and then further stirred for 1 h. The resulting mixture was diluted with n-Hexanes (10 mL) and filtered through a pad of silica gel (rinsed with n- Hexanes/EtOAc = 2:1). After concentrated in vacuo, the residue was purified via flash column chromatography (SiO2, rø-Hexanes/Et2O = 15:1) to give β-keto thiol esters.
General procedure for Biginelli reaction with β-keto thiol esters
Figure imgf000140_0001
The β-keto thiol ester (0.573 mmol, 1.0 equiv), aldehyde (0.573 mmol, 1.0 equiv), urea (0.860 mmol, 1.5 equiv), and Yb(OTf)3 (0.057 mmol, 0.1 equiv) were dissolved in THF (2 mL) and stirred under Ar for 16 h at 75 "C. After cooling to room temperature, the reaction was quenched by the addition of saturated aqueous NaHCO3 (10 mL) and extracted with CH2Cl2 (4 x 20 mL). The combined organic layers were dried over Na2SO4. After filtration and concentration in vacuo, the residue was purified via flash column chromatography on silica gel to give Biginelli adducts.
General procedure for ketone analogs using Pd-eatalvzed cross couplings
Figure imgf000140_0002
Thiol ester (0.13 mmol, 1.0 equiv), boronic acid (0.26 mmol, 2.0 equiv), CuTC (0.39 mmol, 3.0 equiv), Pd(OAc)2 (10 mol%) and PPh3 (20 mol%) were added to a sealed tube and flushed with Ar. Then anhydrous THF was added. The reaction mixture was heated for overnight at 75 °C. After cooling to 25 0C, the reaction mixture was diluted with EtOAc and washed with 10% aqueous NH3, and then dried over MgSO4. After filtration and concentration in vacuo, the residue was purified via flash column chromatography (SiO2, CH2Cl2ZMeOH = 10:1) to give ketone analogs.
Figure imgf000141_0001
S-Ethyl 6-ethyl-4-(3-hydroxyphenyl)-2-oxo-l,2,354-tetrahydropyrimidine-5-carbothioate
(222)
1H NMR (400 MHz, CD3OD) δ 7.10 (t, J= 8.0 Hz, IH), 6.79-6.67 (m, 2H), 6.66-6.65 (m, IH), 5.36 (s, IH), 2.85-2.79 (m, 2H), 2.76-2.65 (m, 2H), 1.22 (t, J= 8.0 Hz, 3H), 1.15 (t, J= 8.0 Hz, 3H).
Figure imgf000141_0002
223
5-Benzoyl-6-ethyl-4-(3-methoxyphenyl)-3,4-dihydropyrimidin-2(lJjT)-one (223) 1H NMR (400 MHz, CD3OD) δ 7.52-7.48 (m, 3H), 7.43-7.39 (m, 2H), 7.18 (t, J= 7.6 Hz, IH), 6.78 (t, J= 7.6 Hz, IH), 6.71 (s, IH), 5.43 (s, IH), 3.71 (s, 3H), 2.09 (q, J= 7.6 Hz, 2H), 1.04 (t, J= 7.6 Hz, 3H); 13C NMR (100 MHz, CD3OD) δ 196.5, 160.1, 154.3, 148.5, 145.1, 140.6, 131.9, 129.6, 128.4, 127.9, 118.3, 113.0, 111.8, 110.0, 56.6, 54.4 ,24.1, 11.9; TLC Rf («-Hexanes:EtOAc 1 :1) = 0.27.
Figure imgf000142_0001
223 5-Benzoyl-6-ethyl-4-(3-hydroxyphenyl)-3,4-dihydropyrimidin-2(ljF/)-one (224)
1H NMR (400 MHz, CD3OD) δ 7.50-7.47 (m, 3H), 7.41-7.37 (m, 2H), 7.05 (t, J= 8.0 Hz, IH), 6.66-6.61 (m, 3H), 5.38 (s, IH), 2.13-2.09 (m, 2H), 1.02 (t, J=8.0 Hz, 3H). Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 10% i- PrOH in rc-Hexanes, 0.85 mL/min): 224a tR = 63.4 min, 224b tR = 86.9 min.
Figure imgf000142_0002
225 6-Ethyl-4-(3-hydroxyphenyl)-5-(4-methyIbenzoyl)-3,4-dihydropyrimidin-2(lH)-one (225)
1H NMR (400 MHz, CD3OD) δ 7.42 (d, J= 8.0 Hz, 2H), 7.22 (d, J= 8.0 Hz, 2H), 7.06 (t, J=
7.6 Hz, IH), 6.68-6.63 (m, 3H), 5.40 (s, IH), 2.36 (s, 3H), 2.15-2.00 (m, 2H), 1.03 (t, J= 7.6
Hz, 3H); 13C NMR (IOO MHZ, CD3OD) δ 196.5, 157.6, 154.5, 146.8, 145.2, 143.2, 137.7,
129.5, 129.0, 128.3, 117.2, 114.5, 112.9, 110.3, 56.8, 24.0, 20.3, 11.8; TLC R1 (EtO Ac only) =
0.18.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 10% i-
PrOH in n-Hexanes, 0.80 mL/min): 225a tR = 50.9 min, 225b tR = 64.9 min.
Figure imgf000142_0003
226 6-Ethyl-5-(4-ethylbenzoyl)-4-(3-hydroxyphenyl)-3,4-dihydropyrimidin-2(l/7)-one (226) 1U NMR (400 MHz, CD3OD) δ 7.43 (d, J= 8.4 Hz, 2H), 7.23 (d, J= 8.0 Hz, 2H), 7.04 (t, J= 7.6 Hz, IH), 6.67-6.60 (m, 3H), 5.38 (s, IH), 2.68-2.62 (m, 2H), 2.66 (q, J= 7.6 Hz, 2H), 1.20 (t, J= 7.6 Hz, 3H), 1.01 (t, J= 7.6 Hz, 3H); 13C NMR (100 MHz, CD3OD) δ 196.6, 157.6, 154.5, 149.5, 146.8, 145.2, 137.9, 129.5, 128.4, 127.9, 117.2, 114.5, 112.9, 110.4, 56.8, 28.6, 24.0, 14.5, 11.8; TLC ^7(EtOAc only) = 0.16.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 10% i- PrOH in rc-Hexanes, 0.80 mL/min): 226a tR = 45.6 min, 226b tR = 58.2 min.
Figure imgf000143_0001
227 5-(3,5-Dimethylbenzoyl)-6-ethyl-4-(3-hydroxyphenyl)-3,4-dihydropyrimidin-2(ljBF)-oiie
(227)
1H NMR (400 MHz, CD3OD) δ 7.23 (s, 2H), 7.14 (s, IH), 7.08-7.00 (m, IH), 6.66-6.63 (m,
3H), 5.32 (s, IH), 2.31 (s, 6H), 2.14-2.07 (m, 2H), 1.01 (t, J= 7.6 Hz, 3H); 13C NMR (100
MHz, CD3OD) δ 197.1, 157.7, 154.5, 147.6, 145.2, 140.7, 138.3, 133.4, 129.5, 125.6, 117.2,
114.5, 112.9, 110.5, 56.6, 24.0 ,19.9, 11.6; TLC i?/(EtOAc only) = 0.15.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 10% i-
PrOH in ra-Hexanes, 0.80 mL/min): 227a tR = 47.9 min, 227b tR = 59.3 min.
Figure imgf000143_0002
228 6-Ethyl-5-(4-fluorobenzoyl)-4-(3-hydroxyphenyl)-3,4-dihydropyrimidin-2(lJH)-one (228)
1H NMR (400 MHz, CD3OD) δ 7.60-7.54 (m, 2H), 7.15-7.10 (m, 2H), 7.05 (t, J= 8.0 Hz, IH), 6.64-6.61 (m, 3H), 5.36 (s, IH), 2.17-2.10 (m, 2H), 1.04 (t, J= 8.0 Hz, 3H). Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 10% i- PrOH in rc-Hexanes, 0.80 mL/min): 228a tR = 49.0 min, 228b tR = 71.8 min.
Figure imgf000144_0001
229 5-(4-Chlorobenzoyl)-6-ethyl-4-(3-hydroxyphenyl)-3,4-dihydropyrimidin-2(lH)-one (229)
1U NMR (400 MHz, CD3OD) δ 7.45 (d, J= 8.4 Hz, 2H), 7.40 (d, J= 8.4 Hz, 2H), 7.05 (t, J= 8.0 Hz, IH), 6.64-6.61 (m, 3H),5.35 (s, IH), 2.16-2.10 (m, 2H), 1.04 (t, J= 8.0 Hz, 3H); 13C NMR (100 MHz, CD3OD) δ 195.1, 157.7, 154.3, 148.3, 145.1, 139.1, 138.1, 131.9, 131.8, 129.7, 129.6, 128.8, 128.7, 117.3, 114.6, 113.0, 109.9, 56.7, 24.2, 11.8. Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 15% i- PrOH in rc-Hexanes, 0.80 mL/min): 229a tR = 22.0 min, 229b tR = 31.9 min.
Figure imgf000144_0002
230
5-(4-tert-Butylbenzoyl)-6-ethyl-4-(3-hydroxyphenyl)-3,4-dihydropyrimidin-2(liϊ)-one
(230)
1K NMR (400 MHz, CD3OD) δ 7.45 (bs, 4H), 7.05 (t, J= 8.0 Hz, IH), 6.66-6.61 (m, 3H), 5.38 (s, IH), 2.13-2.06 (m, 2H), 1.31 (s, 9H), 1.02 (t, J= 8.0 Hz, 3H).
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 10% i- PrOH in rc-Hexanes, 0.80 mL/min): 230a tR = 33.7 min, 230b tR = 46.1 min.
Figure imgf000144_0003
231
6-Ethyl-4-(3-hydroxyphenyl)-5-(4-methoxybenzoyl)-3,4-dihydropyrimidin-2(lJϊ)-one
(231) 1H NMR (400 MHz, CD3OD) δ 7.53 (dd, J= 9.4, 2.0 Hz, 2H), 7.04 (t, J= 8.0 Hz, IH), 6.91 (dd, J= 9.4, 2.0 Hz, 2H), 6.67-6.60 (m, 3H), 5.37 (s, IH), 2.09-2.01 (m, 2H), 1.02 (t, J= 8.0 Hz, 3H).
Dihydropyrimidine aliphatic ketone analogs at C-5 position.
Figure imgf000145_0001
4-(3-Chloro-4-hydroxyphenyl)-5-(2-(cyclohexyIoxy)acetyl)-6-ethyl-3,4- dihydropyrimidin-2(llϊ)-one (232)
1H NMR (400 MHz, CD3OD) δ 7.12 (d, J= 2.4 Hz, IH), 7.06 (dd, J= 4.2, 2.0 Hz, IH), 6.83 (d, J= 8.4 Hz, IH), 5.58 (s, IH), 4.92-4.83 (m, 2H), 3.67-3.60 (m, IH), 2.70-2.60 (m, 2H), 1.85-1.01 (m, 10H), 0.99 (t, J= 7.2 Hz, 3H); 13C NMR (IOO MHz, CD3OD) δ 210.0, 155.9, 153.8, 136.1, 131.2, 129.7, 128.8, 126.8, 121.8, 117.6, 113.2, 81.2, 53.9, 33.9, 33.5, 33.2, 26.7, 24.7, 24.6, 8.2; TLC i?/(«-Hexanes:EtOAc 1:2) = 0.23.
Figure imgf000145_0002
233
4-(3-Chloro-4-hydroxyphenyl)-6-(cyclohexyloxymethyl)-5-propionyl-3,4- dihydropyrimidin-2(l//)-one (233)
1H NMR (400 MHz, CD3OD) δ 7.23 (s, IH), 7.06 (d, J= 8.4 Hz, IH), 6.87 (d, J= 8.4 Hz, IH), 5.36 (s, IH), 4.70 s, 2H), 3.46-3.40 (m, IH), 2.56-2.47 (m, IH), 2.18-2.10 (m, IH), 1.98- 1.94 (m, 2H), 1.77-1.74 (m, 2H), 1.45-1.23 (m, 6H), 0.88 (t, J= 7.2 Hz, 3H); 13C NMR (100 MHz, CD3OD) δ 199.3, 153.3, 152.8, 148.5, 135.3, 128.4, 126.3, 120.9, 116.9 107.3, 78.6, 65.1, 54.4, 33.3, 31.9, 25.6, 23.7, 7.0; TLC i?/(n-Hexanes:EtOAc 1:2) = 0.35.
Figure imgf000146_0001
234
2-ChIoro-4-(5-(3-cyclopentylpropanoyl)-6-ethyl-2-oxo-l,2,3,4-tetrahydropyrimidin-4- yl)phenyl acetate (234)
1H NMR (400 MHz, CD3OD) δ 7.42 (d, J= 2.0 Hz, IH), 7.29 (dd, J= 8.4 Hz, 2.0 Hz, IH), 7.19 (d, J= 8.4 Hz, IH), 5.43 (s, IH), 2.70 (m, 2H), 2.52 (m, IH), 2.31 (m, 4H), 1.65-1.36 (m, 9H), 1.26 (t, J= 7.6 Hz, 3H), 0.91 (m, 2H); TLC i?/(CH2Cl2:Me0H 19:1) = 0.64.
Figure imgf000146_0002
235
4-(3-Chloro-4-hydroxyphenyl)-5-(3-cycIopentylpropanoyl)-6-ethyl-3,4- dihydropyrimidin-2(l/?)-oiie (235)
1H NMR (400 MHz, CD3OD) δ 7.21 (d, J= 2.0 Hz, IH), 7.05 (dd, J= 8.4 Hz, 2.0Hz, IH), 6.86 (d, J= 8.4 Hz, IH), 5.30 (s, IH), 2.67 (q, J= 8.4 Hz, 2H), 2.43 (m, IH), 2.25 (m, IH), 1.61-1.33 (m, 10H), 1.23 (t, J= 7.4 Hz, 3H), 0.92 (m, 3H); TLC i?/(CH2Cl2:Me0H 19:1) = 0.25.
Figure imgf000146_0003
236 2-Chloro-4-(6-(2-cyclopentylethyl)-2-oxo-5-propionyI-l,2,3,4-tetrahydropyrimidin-4- yl)phenyl acetate (236)
1H NMR (400 MHz, CD3OD) δ 7.42 (d, J- 2.0 Hz, IH), 7.28 (dd, J= 8.4 Hz, 2.0 Hz, IH), 7.19 (d, J= 8.4 Hz, IH), 5.43 (s, IH), 2.73 (m, 2H), 2.59 (m, IH), 2.28 (m, 4H), 1.86 (m, 3H), 1.67 (m, 3H), 1.56 (m, 2H), 1.25 (m, 3H), 0.96 (t, J= 7.2 Hz, 3H); TLC ^/(CH2Cl2 :MeOH 19:1) = 0.64.
Figure imgf000147_0001
4-(3-Chloro-4-hydroxyphenyl)-6-(2-cyclopentylethyl)-5-propionyI-3,4- dihydropyrimidin-2(l//)-one (237)
1H NMR (400 MHz, CD3OD) δ 7.21 (d, J= 2.0 Hz, IH), 7.04 (dd, J= 8.4, 2.4 Hz, IH), 6.85 (d, J= 8.4 Hz, IH), 5.30 (s, IH), 2.70 (m, 2H), 2.51 (dd, J= 17.2, 7.2 Hz, IH), 2.20 (dd, J = 17.2, 7.2 Hz, IH), 1.86 (m, 3H), 1.66-1.54 (m, 5H), 1.23 (m, 5H), 0.91 (t, J= 7.2 Hz, 3H); TLC i?/(CH2Cl2:Me0H 19:1) = 0.25.
Figure imgf000147_0002
238
4-(3-Chloro-4-hydroxyphenyI)-6-ethyl-5-(3-phenylpropanoyl)-3,4-dihydropyrimidin- 2(li7)-one (238)
1U NMR(400MHz, CD3OD) δ 7.15 (m, 3H), 7.09 (d, J= 7.6 Hz, IH), 6.99 (m, 3H), 6.84 (d, J = 8.4 Hz, IH), 5.27 (s, IH), 2.78-2.62 (m, 5H), 2.59-2.51 (m, IH), 1.21 (t, J= 7.6 Hz, 3H); 13C NMR(IOOMHZ, CD3OD) δ 197.8, 153.2, 152.9, 144.3, 141.0, 135.4, 128.1, 127.8, 127.8, 126.0, 125.4, 120.5, 116.5, 108.1, 54.0, 41.9, 29.9, 24.6, 11.7; TLC i?/(CH2Cl2:Me0H 95:5) =0.16. Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 15- 40% i-PrOH in rc-Hexanes gradient, 4.0 mL/min): 238a tR = 89.1 min, 238b fø = 131.4 min.
Figure imgf000148_0001
4-(3-Chloro-4-hydroxyphenyl)-6-phenethyI-5-propionyl-3,4-dihydropyrimidin-2(lH)- one (239)
1H NMR (400 MHz, CD3OD) δ 7.31-7.22 (m, 5H), 7.17 (t, J= 7.0 Hz, IH), 6.99 (dd, J= 2.0, 8.4 Hz, IH), 6.84 (d, J= 8.4 Hz, IH), 5.30 (s, IH), 2.94 (m, 4H), 2.44 (m, IH), 2.14 (m, IH), 0.88 (t, J= 7.2 Hz, 3H); TLC i?/(CH2Cl2:Me0H 95:5) = 0.16.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 15- 40% z-PrOH in rc-Hexanes gradient, 4.0 mL/min): 239a tR = 73.6 min, 239b tR = 115.2 min.
Figure imgf000148_0002
(S)-4-(3-Chloro-4-hydroxyphenyl)-5-(3-cyclohexylpropanoyl)-6-ethyl-3,4- dihydropyrimidin-2(lH)-one (240a)
1H NMR (400 MHz, CD3OD) δ 7.21 (d, J= 1.6 Hz, IH), 7.06-7.04 (m, IH), 6.86 (d, J= 8.4 Hz, IH), 5.29 (s, IH), 2.69-2.64 (m. 2H), 2.39-2.35 (m, IH), 2.30-2.26 (m, IH), 2.05-1.99 (m, IH), 1.62-1.51 (m, 2H), 1.48-0.98 (m, 10H), 0.88-0.71 (m, 3H); 13C NMR (IOO MHz, CD3OD) δ 199.7, 153.5, 153.1, 152.8, 135.8, 128.4, 126.3, 120.7, 116.7, 108.4, 61.0, 54.4, 38.0, 37.3, 33.1, 32.8, 31.7, 26.4, 26.1, 24.9, 12.0; TLC i?/(«-Hexanes:EtOAc 1 :1) = 0.24. Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 15% i- PrOH in rc-Hexanes, 0.80 mL/min): 240a ^ = 17.2 min.
Figure imgf000149_0001
(S)-4-(3-Chloro-4-hydroxyphenyl)-6-(2-cyclohexylethyI)-5-propionyl-3,4- dihydropyrimidin-2(lH)-one (241a)
1H NMR (400 MHz, CD3OD) δ 7.20 (s, IH), 7.03 (d, J= 9.2 Hz, IH), 6.84 (d, J= 8.4 Hz, IH), 5.29 (s, IH), 2.74-2.64 (m. 2H), 2.54-2.48 (m, IH), 2.23-2.17 (m, IH), 2.05-1.99 (m, IH), 1.81-1.64 (m, 2H), 1.54-0.96 (m, 10H), 0.92-0.86 (m, 3H); 13C NMR (100 MHz, CD3OD) δ 199.5, 153.6, 153.5, 152.2, 135.6, 128.4, 126.1, 120.8, 116.7, 108.4, 61.0, 54.2, 38.1, 36.0, 33.8, 33.1, 33.0, 29.3, 26.5, 26.2, 7.4; TLC i?/(Hexanes: EtOAc 1:1) = 0.24. Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 15% i- PrOH in «-Hexanes, 0.80 niL/min): 241a tn = 15.3 min.
Figure imgf000149_0002
242a
(5)-2-Chloro-4-(5-(3-cycloheptylpropanoyl)-6-ethyl-2-oxo-l,2,3,4-tetrahydropyrimidin- 4-yl)phenyl acetate (242a)
1U NMR (400 MHz, CD3OD) δ 7.42(d, J= 2.0 Hz, IH), 7.29 (dd, J= 8.4, 2.0 Hz, IH), 7.20 (d, J= 8.4 Hz, IH), 5.43 (s, IH), 2.71 (m, 2H), 2.47 (m, IH), 2.31 (m, 4H), 1.55-1.24 (m, HH), 1.20-0.87 (m, 4H); TLC i?/(CH2Cl2:Me0H 19:1) = 0.50.
Figure imgf000149_0003
243a (S)-4-(3-Chloro-4-hydroxyphenyl)-5-(3-cycloheptylpropanoyl)-6-ethyI-3,4- dihydropyrimidin-2(lH)-one (243a)
1H NMR (400 MHz, CD3OD) δ 7.22 (d, J= 2.0 Hz, IH), 7.05 (dd, J= 8.4 Hz, 1.6 Hz, IH), 6.87 (d, J= 8.4 Hz, IH), 5.29 (s, IH), 2.67 (q, J= 7.2 Hz, 2H), 2.38 (m, IH), 2.25 (m, IH), 1.52 (m, 8H), 1.32 (m, 8H), 1.05 (m, 2H); TLC i?/(rc-Hexanes:EtOAc 1 :1 + 2% MeOH) = 0.29.
Figure imgf000150_0001
(-S)-2-Chloro-4-(6-(2-cycIoheptylethyl)-2-oxo-5-propionyI-l,2,3j4-tetrahydropyrimidin-4- yl)phenyl acetate (244a)
1H NMR (400 MHz, CD3OD) δ 7.42 (d, J= 2.0 Hz, IH), 7.28 (dd, J= 8.4 Hz, 2.0 Hz, IH), 7.18 (d, J= 8.4 Hz, IH), 5.43 (s, IH), 2.74 (m, 2H), 2.60 (m, IH), 2.31 (s, 3H), 2.26 (m, IH), 1.82 (m, 2H), 1.69 (m, 2H), 1.56 (m, 5H), 1.31 (m, 3H), 0.96 (t, J= 7.2 Hz, 3H); TLC Rf (CH2Cl2:Me0H 19:1) = 0.50.
Figure imgf000150_0002
(S)-4-(3-Chloro-4-hydroxyphenyl)-6-(2-cycloheptylethyl)-5-propionyl-3,4- dihydropyrimidin-2(ljH)-one (245a)
1H NMR (400 MHz, CD3OD) δ 7.21 (d, J= 2.0 Hz, IH), 7.04 (dd, J= 8.4, 2.4 Hz, IH), 6.85 (d, J= 8.4Hz, IH), 5.30 (s, IH), 2.70 (m, 2H), 2.51 (m, IH), 2.19 (m, IH), 1.79 (m, 2H), 1.69 (m, 2H), 1.53 (m, 10H), 1.24 (m, 5H), 0.91 (t, J= 7.2 Hz, 3H); TLC i?/(«-Hexanes:EtOAc + 0.5% MeOH) = 0.29.
Figure imgf000151_0001
(S)-4-(3-Chloro-4-hydroxyphenyl)-5-(2-cyclopentylacetyl)-6-ethyl-3,4- dihydropyrimidin-2(lH)-one (246a)
1H NMR (400 MHz, CD3OD) δ 7.20 (d, J= 2.0 Hz, IH ), 7.04 (dd, J= 8.4, 2.4 Hz, IH), 6.86 (d, J= 8.4 Hz, IH), 5.30 (s, IH), 2.69-2.63 (m, 2H), 2.53-2.47 (m, IH), 2.25-2.11 (m, IH), 1.67-1.39 (m, 9H), 0.99 (t, J= 8.2 Hz, 3H); 13C NMR (100 MHz, CD3OD) δ 199.3, 156.2, 153.6, 153.1, 135.8, 128.4, 126.3, 120.7, 116.7, 108.8, 35.5, 54.4, 36.0, 32.3, 32.0, 24.9, 24.6, 24.5, 12.1; TLC i?/(«-Hexanes:EtOAc 1:2) = 0.42.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 15% /-PrOH in «-Hexanes, 0.80 mL/min): 246a tR = Yl 2 min.
Figure imgf000151_0002
(5)-4-(3-ChIoro-4-hydroxyphenyl)-6-ethyl-5-(2-phenylacetyl)-3,4-dihydropyrimidin-
2(U2)-one (247a)
1H NMR (400 MHz, CD3OD) δ 7.15-7.08 (m, 4H), 6.98 (dd, J= 8.4, 2 Hz, IH ), 6.89 (d, J=
7.2 Hz, 2H), 6.78 (d, J= 8.4 Hz, IH), 5.27 (s, IH), 3.68 (d, J= 15.6 Hz, IH ), 3.46 (d, J=
15.6 Hz, IH ), 2.60-2.58 (m, 2H), 1.13 (t, J= 7.4 Hz, 3H ); 13C NMR (100 MHz, CD3OD) δ
196.7, 154.1, 153.4, 153.1, 135.5, 135.0, 129.0, 128.4, 128.3, 126.5, 126.3, 120.8, 116.8,
108.0, 54.2, 24.9, 24.0, 12.0; TLC i?/(rc-Hexanes:EtOAc 1 :2) = 0.28.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 15%
/-PrOH in rc-Hexanes, 0.80 mL/min): 247a tR = 26.3 min.
Figure imgf000152_0001
(S)-6-Benzyl-4-(3-chloro-4-hydroxyphenyl)-5-propionyl-3,4-dihydropyrimidin-2(lH)- one (248a)
1H NMR (400 MHz, CD3OD) δ 7.26-7.19 (m, 4H), 7.15-7.13 (m, 2H), 6.96 (dd, J= 8.4, 2 Hz, IH ), 6.76 (d, J= 8.4 Hz, IH), 5.29 (s, IH), 4.08-3.98 (m, 2H), 2.50-2.43 (m, IH), 2.17-2.06 (m IH), 0.81 (t, J= 7.2 Hz, 3H ); 13C NMR (100 MHz, CD3OD) δ 199.7, 160.1, 153.1, 152.6, 148.4, 137.3, 135.7, 128.6, 128.0, 126.7, 126.6, 120.8, 116.7, 110.1, 54.3, 36.2, 33.9, 7.3; TLC i?/(«-Hexanes:EtOAc 1:2) = 0.28.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 15% i- PrOH in ra-Hexanes, 0.80 mL/min): 248a tR = 29.2 min.
Figure imgf000152_0002
4-(3-Chloro-4-hydroxyphenyl)-5-(2-cyclohexylacetyl)-6-ethyl-3,4-dihydropyrimidin- 2(LH)-OiIe (249)
1H NMR (400 MHz, CD3OD) δ 7.19 (d, J= 2.4 Hz, IH), 7.04-7.02 (m, IH), 6.85 (d, J= 8.4 Hz, IH), 5.27 (s, IH), 2.67-2.62 (m. 2H), 2.34-2.23 (m, IH), 2.11-2.04 (m, IH), 1.68-1.03 (m, HH), 0.92-0.64 (m, 3H); 13C NMR (IOO MHz, CD3OD) δ 199.1, 153.6, 153.0, 152.5, 135.7, 128.4, 126.3, 120.7, 116.7, 109.0, 54.3, 34.5, 33.1, 32.9, 26.1, 26.0, 24.9, 12.1; TLC Rf(n- Hexanes:EtOAc 1 :1) = 0.36.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 15% /- PrOH in «-Hexanes, 0.80 mL/min): 249a tR = 17.2 min, 249b tR = 30.8 min.
Figure imgf000153_0001
250
4-(3-Chloro-4-hydroxyphenyl)-6-ethyl-5-(2-(4-methylcyclohexyl)acetyI)-3,4- dihydropyrimidin-2(l/f)-one (250)
1H NMR (400 MHz, CD3OD) δ 7.22 (d, J= 2.4 Hz, IH), 7.07-7.05 (m, IH), 6.88 (d, J= 8.4 Hz, IH), 5.30 (s, IH), 2.68 (q, J= 7.6 Hz, 2H), 2.37-2.32 (m, IH), 2.09 (dd, J= 15.6, 6.8 Hz, IH), 1.63-1.56 (m, 4H), 1.46-1.40 (m, IH), 1.34-1.14 (m, 6H), 0.94-0.71 (m, 5H); 13C NMR (100 MHz, CD3OD) 6 200.4, 154.9, 154.3, 153.8, 137.0, 129.6, 127.5, 121.9, 117.9, 110.2, 55.5, 49.5, 36.2, 36.1, 35.6, 34.2, 34.1, 33.7, 31.8, 31.3, 30.4, 26.1, 23.0, 13.3; TLC Rf(n- Hexanes:EtOAc 1:1 + 2% MeOH) = 0.24.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 15% z-PrOH in n-Hexanes, 6.5 mL/min): 250a ΪR = 18.1 min, 250b fø = 36.2 min.
Figure imgf000153_0002
4-(3-Chloro-4-hydroxyphenyl)-6-ethyl-5-(2-(4-methylenecyclohexyl)acetyl)-3,4- dihydropyrimidin-2(lH)-one (251)
1H NMR (400 MHz, CD3OD) δ 7.20 (s, IH), 7.03 (d, J= 7.6 Hz, IH), 6.84 (d, J= 8.0 Hz, IH), 5.29 (s, IH), 4.55 (s, 2H), 2.64 (q, J= 6.8 Hz, 2H), 2.33 (dd, J= 15.4 Hz, 5.8 Hz, IH), 2.27-1.78 (m, 6H), 1.66 (d, J= 10.8 Hz, IH), 1.49 (d, J= 11.2 Hz, IH), 1.21 (t, J= 6.8 Hz, 3H), 0.90-0.70 (m, 2H); 13C NMR (100 MHz, CD3OD) δ 198.7, 153.7, 153.0, 152.6, 148.9, 135.8, 128.4, 126.3, 120.8, 116.8, 109.0, 106.4, 54.3, 34.3, 34.2, 34.1, 33.9, 25.0, 12.2; TLC tf/(«-Hexanes:EtOAc 1 :1 + 2% MeOH) = 0.25.
Figure imgf000154_0001
4-(3-Chloro-4-hydroxyphenyl)-6-ethyl-5-(2-(4-ethylcyclohexyl)acetyl)-3,4- dihydropyrimidin-2(lH)-one (252)
1K NMR (400 MHz, CD3OD) δ 7.22 (d, J- 2.0 Hz, IH), 7.09-7.05 (m, IH), 6.88 (d, J= 8.8
Hz, IH), 5.30 (s, IH), 2.68 (q, J= 7.6 Hz, 2H), 2.37-2.32 (m, IH), 2.10 (dd, J= 15.4, 7.0 Hz,
IH), 1.72-1.58 (m, 4H), 1.48-1.45 (m, IH), 1.35-1.12 (m, 8H), 0.95-0.70 (m, 5H); 13C NMR
(100 MHz, CD3OD) δ 200.2, 152.6, 135.8, 128.4, 126.3, 120.7, 116.7, 109.0, 54.3, 48.3, 39.5,
34.8, 33.1, 32.9, 32.6, 32.5, 29.8, 24.9, 12.1, 10.6; TLC i?/(«-Hexanes:EtOAc 1 :1 +2%
MeOH) = 0.23.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 15%
Z-PrOH in rc-Hexanes, 6.5 mL/min): 252a tR = 20.0 min, 252b tR = 38.6 min.
Figure imgf000154_0002
253
4-(3-Chloro-4-hydroxyphenyl)-6-ethyl-5-(2-(3-methylcyclohexyl)acetyl)-3,4- dihydropyrimidin-2(l//)-oiie (253)
1H NMR (400 MHz, CD3OD) δ 6.99 (s, IH), 6.83 (d, J= 8.0 Hz, IH), 6.65 (d, J= 8.4Hz, IH), 5.08 (s, IH), 2.45 (q, J= 7.2 Hz, 2H), 2.11 (m, IH), 1.89 (m, IH), 1.52-1.30 (m, 5H), 1.18- 1.00 (m, 8H), 0.92 (d, J= 6.0 Hz, 3H); 13C NMR (100 MHz, CD3OD) δ 199.2, 153.7, 153.1, 152.5, 135.8, 128.5, 126.4, 120.7, 116.7, 109.1, 54.4, 41.8, 34.8, 34.7, 32.7, 32.5, 26.0, 24.9, 22.0, 12.2; TLC R1 (CH2Cl2: MeOH 95:5) = 0.12.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 25- 40% /-PrOH in ra-Hexanes gradient, 4.0 mL/min): 253a tR = 29.7 min, 253b tR = 52.6 min.
Figure imgf000155_0001
254
4-(3-Chloro-4-hydroxyphenyI)-6-ethyl-5-(2-(4-(propan-2-ylidene)cyclohexyl)acetyl)-3,4- dihydropyrimidin-2(l/?)-one (254)
1H NMR (400 MHz, CD3OD) δ 7.20 (d, J= 2.0 Hz, IH), 7.04 (dd, J= 8.2 Hz, 2.2 Hz, IH), 6.86 (d, J= 8.4 Hz, IH), 5.29 (s, IH), 2.66 (q, J= 7.6 Hz, 2H), 2.56 (m, 2H), 2.33 (dd, J= 15.4, 6.2 Hz, IH), 2.10 (dd, J= 15.4, 7.0 Hz, IH), 1.81 (m, IH), 1.68-1.56 (m, 9H), 1.24 (t, J = 7.6 Hz, 3H), 0.83 (m, 3H); 13C NMR (100 MHz, CD3OD) δ 198.8, 153.4, 152.8, 152.4, 135.6, 130.7, 128.2, 126.1, 120.5, 120.0, 116.5, 108.8, 54.1, 34.4, 33.8, 33.6, 28.9, 28.94, 28.86, 24.7, 18.7, 18.60, 18.58, 11.9; TLC i?/(CH2Cl2:Me0H 9:1) = 0.50.
Figure imgf000155_0002
255
4-(3-Chloro-4-hydroxyphenyl)-6-ethyl-5-(2-(4-isopropylcyclohexyl)acetyl)-3,4- dihydropyrimidin-2(l//)-one (255)
1U NMR (400 MHz, CD3OD) δ 7.17 (d, J= 6.4 Hz, IH), 7.00 (d, J= 7.2 Hz, IH), 6.82 (d, J= 8.0 Hz, IH), 5.24 (s, IH), 2.61 (q, J= 7.6 Hz, 2H), 2.28 (dd, J= 15.2, 6.0 Hz, IH), 2.03 (dd, J = 15.0, 6.6 Hz, IH), 1.49 (m, 4H), 1.26 (m, 7H), 0.82 (m, 12H); 13C NMR (100 MHz, CD3OD) δ 199.2, 153.7, 153.0, 152.6, 135.8, 128.4, 126.3, 120.7, 116.7, 109.0, 54.3, 44.0, 34.8, 33.2, 33.1, 32.8, 29.5, 29.4, 24.9, 19.0, 12.1; TLC i?/(n-Hexanes:EtOAc 1 :1 + 2% MeOH) = 0.15.
Figure imgf000156_0001
4-(3-Chloro-4-hydroxyphenyl)-5-(2-cycIoheptylacetyl)-6-ethyl-3,4-dihydropyrimidin- 2(lH)-one (256)
1H NMR (400 MHz, CD3OD) δ 7.21 (d, J= 2.0 Hz, IH), 7.05-7.03 (m, IH), 6.85 (d, J= 8.8 Hz, IH), 5.28 (s, IH), 2.68-2.62 (m, 2H), 2.35-2.30 (m, IH), 2.17-2.12 (m, IH), 1.59-1.31 (m, 14H), 1.29-0.90 (m, 2H); 13C NMR (400 MHz, CD3OD) δ 199.2, 153.0, 152.5, 135.8, 128.4, 126.3, 120.7, 116.7, 109.0, 60.3, 54.3, 35.8, 34.5, 34.2, 28.1, 26.2, 26.0, 24.9, 19.6, 13.2, 12.1; TLC i?/(«-Hexanes: EtOAc 1 :1) = 0.67.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 15% i- PrOH in «-Hexanes, 0.80 mL/min): 256a tR = 16.0 min, 256b tR = 35.9 min.
Figure imgf000156_0002
257
4-(3-Chloro-4-hydroxyphenyl)-6-ethyl-5-(2-(4-ethyIidenecyclohexyI)acetyl)-3,4- dihydropyrimidin-2(lH)-one (257)
1H NMR (400 MHz, CD3OD) δ 7.20 (d, J= 2.0 Hz, IH), 7.04 (dd, J= 8.4, 2.0 Hz, IH), 6.86 (d, J= 8.4 Hz, IH), 5.28 (s, IH), 2.65 (q, J= 7.6 Hz, 2H), 2.32 (dd, J= 15.2, 6.4 Hz, IH), 2.08 (dd, J= 15.2, 6.8 Hz, IH), 1.64 (m, 3H), 1.45 (m, IH), 1.23 (m, 3H), 1.14 (m, 2H), 0.96 (m, IH), 0.83 (m, 6H); TLC i?/(CH2Cl2:Me0H 9:1) = 0.36.
Figure imgf000157_0001
258
4-(3-Chloro-4-hydroxyphenyl)-6-ethyl-5-(2-(4-methoxycyclohexyl)acetyl)-3,4- dihydropyrimidin-2(liϊ)-one (258)
1HNMR (400 MHz, CD3OD) δ 7.21(d, J= 2.4 Hz, IH), 7.05 (dd, J= 8.4, 2.0 Hz, IH), 6.86 (d, J= 8.0 Hz, IH), 5.30 (s, IH), 3.29 (m, IH), 3.21 (s, 3H), 2.66 (q, J= 7.6 Hz, 2H), 2.34 (dd, J= 15.8, 6.6 Hz, IH), 2.12 (dd, J= 15.8, 7.0 Hz, IH), 1.72 (m, 3H), 1.38 (m, 4H), 1.21 (m, 5H); TLC ^(CH2Cl2IMeOH 19:1) = 0.07.
Figure imgf000157_0002
259
4-(3-Chloro-4-hydroxyphenyl)-6-((4-methoxycycIohexyl)methyl)-5-propionyI-3,4- dihydropyrimidin-2(liϊ)-one (259)
1U NMR (400 MHz, CD3OD) δ 7.21 (s, IH), 7.04 (d, J= 8.0 Hz, IH), 6.84 (d, J= 8.4 Hz, IH), 5.32 (s, IH), 3.26 (m, IH), 3.11 (s, 3H), 2.62 (m, 2H), 2.51 (m, IH), 2.20 (m, IH), 1.87- 1.24 (m, 9H), 0.90 (t, J= 7.2 Hz, 3H); TLC i?/(CH2Cl2:Me0H 19:1) = 0.07.
Dihydropyrimidine bioisostere analogs at C-5 position General procedure for oxazoline bioisosteres CHO 250C
Figure imgf000158_0001
Figure imgf000158_0002
Aldehyde (500 mg, 4.46 mmol, 1.0 equiv) was added to a stirred solution OfNaHSO3 (1.02 g, 9.81 mmol, 2.2 equiv) in H2O (3.5 mL) at 25 °C to afford a white solid. The reaction mixture was stirred for 1 h. To the resulting suspension, was cooled at 0 0C, a solution of KCN (0.64 g, 9.81 mmol, 2.2 equiv) in H2O (2.4 mL) was added dropwise. After stirring at 25 °C for 10 min, the reaction mixture was warmed to 25 °C. The precipitate gradually disappeared. The reaction mixture was extracted with Et2O (2 x 100 mL). The organic layer was washed with brine (100 mL) and dried over MgSO4. After filtration and concentration in vacuo, the residue was purified by flash column chromatography (SiO2, n-Hexanes/EtOAc = 3:1) to give corresponding 2-cyclohexyl-2-hydroxyacetonitrile (620 mg, 99%): 1H NMR (400 MHz, CDCl3) 54.25 (d, J= 6.0 Hz, IH), 1.90-1.68 (m, 6H), 1.31-1.05 (m, 5H); 13C NMR (IOO MHz, CDCl3) δ 119.3, 66.6, 42.5, 28.3, 28.0, 26.1,25.7, 25.6; TLC i?/(rc-Hexanes:EtOAc 5:1) = 0.33.
The solution of 2-cyclohexyl-2-hydroxyacetonitrile (0.6 g, 4.31 mmol, 1.0 equiv) in dry THF (5 mL) was added dropwise to a LiAlH4 (0.36 g, 9.48 mmol, 2.2 equiv) in THF (20 mL) at 0 °C. After warmed to 25 0C and stirred for 6 h, the reaction mixture was quenched with H2O until hydrogen evolution ceased. MgSO4 was added and the reaction mixture filtered and the solvent removed in vacuo to give a white solid. Trituration with hexane gave the 2-amino-l- cyclohexylethanol (510 mg, 83%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 3.24 (m, IH), 2.71 (dd, J= 13.0, 3.0 Hz, IH), 2.53 (dd, J= 13.0, 8.6 Hz, IH), 1.96-1.64 (m, 6H), 1.38- 1.02 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 76.2, 44.9, 42.1, 29.2, 28.8, 26.7, 26.4, 26.3; TLC i?/(n-Hexanes:EtOAc 5:1) = 0.02.
To a stirring (S)-4-(3-(tert-butyldimethylsilyloxy)phenyl)-6-ethyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylic acid (100 mg, 0.27 mmol, 1.0 equiv) and 2-amino-l- cyclohexylethanol (76 mg, 0.54 mmol, 2.0 equiv) in DMF (1.0 mL) was added EDC (100 mg, 0.54 mmol, 2.0 equiv) and DMAP (65 mg, 0.54 mmol, 2.0 equiv) in one portion at 25 0C. After stirred for overnight, the reaction mixture was extracted with EtOAc (2 x 100 mL). The organic layers were washed with brine (100 mL) and dried over MgSO4. After filtration and concentration in vacuo, the residue was purified by flash column chromatography (SiO2, CH2Cl2/Me0H = 40:1 → 20:1) to give corresponding (S)-4-(3-(tert- butyldimethylsilyloxy)phenyl)-N-(2-cyclohexyl-2-hydroxyethyl)-6-ethyl-2-oxo- 1 ,2,3 ,4- tetrahydropyrimidine-5-carboxamide (127 mg, 95%): 1H NMR (400 MHz, CD3OD) δ 7.24- 7.19 (m, IH), 6.93 (t, J= 6.2 Hz, IH), 6.84 (d, J= 2.0 Hz, IH), 6.76 (d, J= 8.0 Hz, IH), 5.25 (s, IH), 3.41-3.36 (m, IH), 3.29-3.25 (m, IH), 3.17-2.99 (m, IH), 2.58-2.41 (m, 2H), 1.94-
1.52 (m, 6H), 1.29-1.10 (m, 6H), 1.04-0.95 (m, HH), 0.20 (s, 6H); 13C NMR (IOO MHZ, CD3OD) δ 169.5, 157.5, 157.4, 155.7, 146.2, 146.1, 144.5, 143.7, 131.0, 130.9, 120.8, 120.8, 119.2, 106.4, 106.1, 75.5, 75.4, 57.5, 57.4, 44.2, 42.7, 42.6, 30.3, 28.9, 28.7, 27.3, 27.2, 27.1, 26.2, 24.9, 24.8, 19.1, 13.3, -4.2, -4.22; TLC £/(CH2Cl2:Me0H 40:1) = 0.16.
A solution of (<S)-4-(3-(tert-butyldimethylsilyloxy)phenyl)-N-(2-cyclohexyl-2-hydroxyethyl)- 6-ethyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxamide (120 mg, 0.24 mmol, 1.0 equiv) and Burgess reagent (85 mg, 0.36 mmol, 1.5 equiv) in dry THF (12 mL) was stirred at 70 0C for 1 h. After concentration in vacuo, the residue was purified via flash column chromatography (SiO2, π-Hexanes/EtOAc + 2% MeOH = 1:1) to give corresponding (5)-4-(3- (tert-butyldimethylsilyloxy)phenyl)-5-((i?)-5-cyclohexyl-4,5-dihydrooxazol-2-yl)-6-ethyl-3,4- dihydropyrimidin-2(lH)-one 261-a (27 mg, 23%) and (5)-4-(3-(tert- butyldimethylsilyloxy)phenyl)-5-((5)-5-cyclohexyl-4,5-dihydrooxazol-2-yl)-6-ethyl-3,4- dihydropyrimidin-2(lH)-one 262-a (33 mg, 29%): 261-a 1H NMR (400 MHz, CD3OD) δ 7.17 (t, J= 7.8 Hz, IH), 6.94 (d, J= 7.6 Hz, IH), 6.83 (t, J= 2.0 Hz, IH), 6.74-6.71 (m, IH), 5.28 (s, IH), 4.34-4.28 (m, IH), 3.80-3.74 (m, IH), 3.56-3.51 (m, IH), 2.76-2.65 (m, 2H), 1.74-
1.53 (m, 6H), 1.41-1.13 (m, 6H), 1.02-0.82 (m, HH), 0.19 (s, 6H); 13C NMR (IOO MHz, CD3OD) δ 165.1, 157.2, 155.9, 148.7, 146.4, 130.6, 121.0, 120.5, 119.2, 98.6, 85.1, 57.0, 56.4, 43.8, 29.4, 28.9, 27.4, 26.9, 26.8, 26.2, 25.5, 19.1, 13.6, -4.2; TLC i?/(Hexanes:EtOAc 1:1 + 2% MeOH) = 0.27; 262-a 1H NMR (400 MHz, CD3OD) δ 7.17 (t, J= 7.8 Hz, IH), 6.94 (d, J = 7.6 Hz, IH), 6.83 (t, J= 2.0 Hz, IH), 6.74-6.71 (m, IH), 5.27 (s, IH), 4.38-4.32 (m, IH), 3.82-3.73 (m, IH), 3.48-3.42 (m, IH), 2.71-2.55 (m, 2H), 1.71-1.50 (m, 6H), 1.38-1.12 (m, 6H), 1.00-0.82 (m, HH), 0.18 (s, 6H); 13C NMR (100 MHz, CD3OD) δ 165.4, 157.1, 155.9, 148.2, 146.4, 130.5, 121.1, 120.4, 119.2, 98.9, 85.3, 56.9, 56.6, 43.6, 29.3, 28.7, 27.4, 26.9, 26.8, 26.2, 25.7, 19.1, 13.7, -4.2; TLC i?/(Hexanes:EtOAc 1 :1 + 2% MeOH) = 0.17.
Figure imgf000160_0001
260 iV-(2-CyclohexyI-2-hydroxyethyl)-6-ethyl-4-(3-hydroxyphenyl)-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxamide (260)
1H NMR (400 MHz, CD3OD) δ 7.15 (t, J= 7.8 Hz, IH), 6.80-6.78 (m, 2H), 6.70 (d, J= 7.2 Hz, IH), 5.23 (s, IH), 3.30-3.26 (m, IH), 3.16-3.09 (m, IH), 3.07-3.01 (m, IH), 2.61-2.52 (m, IH), 2.43-2.35 (m, IH), 1.82-1.52 (m, 6H), 1.27-1.11 (m, 6H), 1.07-0.87 (m, 2H); 13C NMR (100 MHz, CD3OD) δ 168.5, 157.9, 154.5, 144.9, 142.8, 129.7, 117.6, 114.8, 105.4, 105.0, 74.3, 56.6, 42.3, 41.3, 39.3, 29.15, 19.12, 27.7, 27.5, 26.3, 26.1, 26.0, 25.9, 23.7, 23.6, 12.0; TLC i?/(EtOAc:MeOH 15:1) = 0.55.
Figure imgf000160_0002
261
(S)-5-((i?)-5-cyclohexyl-4,5-dihydrooxazol-2-yI)-6-ethyl-4-(3-hydroxyphenyl)-3,4- dihydropyrimidin-2(lH)-one (261)
To a solution of 261-a (27 mg, 0.056 mmol, 1.0 equiv) in THF (0.11 niL) was added TBAF (1.0 M in THF, 0.112 niL, 0.112 mmol, 2.0 equiv) at 0 0C. After stirred at 25 0C for 15 min, the reaction mixture was quenched by the addition of saturated aqueous NaHCO3 (10 mL) and extracted with EtOAc (20 mL). The organic layer was dried over MgSO4. After filtration and concentration in vacuo, the residue was purified via flash column chromatography (SiO2, n- Hexanes/EtOAc + 2% MeOH = 1 :1 → EtOAc/MeOH = 15:1) to give 261 (16 mg, 92%): 1H NMR (400 MHz, CD3OD) δ 7.11 (t, J= 7.8 Hz, IH), 6.81 (s, IH), 6.79-6.79-6.77 (m, IH), 6.68-6.65 (m, IH), 5.26 (s, IH), 4.34-4.28 (m, IH), 3.80-3.74 (m, IH), 3.55-3.50 (m, IH), 2.82-2.73 (m, IH), 2.66-2.58 (m, IH), 1.74-1.51 (m, 6H), 1.39-1.10 (m, 6H), 1.02-0.82 (m, 2H); 13C NMR (IOO MHZ, CD3OD) δ 165.2, 158.8, 155.8, 148.5, 146.3, 130.6, 119.0, 115.7, 114.6, 98.6, 85.0, 56.9, 56.7, 43.8, 29.3, 28.9, 27.4, 26.9, 26.8, 25.5, 13.5; TLC Rf(n- Hexanes:EtOAc + 2% MeOH 1 :1) = 0.52.
Figure imgf000161_0001
262
(»S)-5-((5)-5-cyclohexyl-4,5-dihydrooxazoI-2-yl)-6-ethyl-4-(3-hydroxyphenyl)-3,4- dihydropyrimidin-2(lH)-one (262)
1H NMR (400 MHz, CD3OD) δ 7.10 (t, J= 7.8 Hz, IH), 6.78 (s, IH), 6.78-6.77 (m, IH), 6.67-6.65 (m, IH), 5.25 (s, IH), 4.37-4.31 (m, IH), 3.81-3.75 (m, IH), 3.49-3.43 (m, IH), 2.64-2.58 (m, 2H), 1.73-1.50 (m, 6H), 1.40-1.09 (m, 6H), 1.02-0.08 (m, 2H); 13C NMR (IOO MHz, CD3OD) δ 165.5, 158.7, 155.9, 147.8, 146.3, 130.5, 118.9, 115.6, 114.6, 98.9, 85.2, 56.9, 56.8, 43.6, 29.2, 28.7, 27.4, 26.9, 26.8, 25.6, 13.6; TLC i?/(«-Hexanes:EtOAc + 2% MeOH 1 :1) = 0.50.
General procedure for oxazole/thiazole/imidazole bioisosteres
Figure imgf000161_0002
then reflux, 4 h
Figure imgf000161_0003
To a solution of PhI(OAc)2 (2.0 g, 6.24 mmol, 1,5 equiv) in CH3CN (20 mL) was added slowly CF3SO3H (1.09 ml, 11.6 mmol, 1.9 equiv) at 25 0C. The suspension was stirred at 25 °C for 30 min, and then a solution of acetophenone (0.50 g, 4.16 mmol, 1.0 equiv) in CH3CN (5 mL) added via cannula at 25 °C. The resulting solution was refiuxed for 4 h, and then quenched with a mixture of saturated aqueous Na2CO3 (20 mL) and H2O (20 mL). The mixture was extracted with CH2Cl2 (3 * 20 mL) and dried over Na2SO4. After filtration and concentration in vacuo, the residue was purified via flash column chromatography on silica gel.
To a solution of ΛζiV-diisopropylamine (0.88 ml, 6.25 mmol, 5.0 equiv) in THF (1 mL) was added slowly R-BuLi (2.5M in n-Hexanes, 2.5 ml, 6.25 mmol, 5.0 equiv) at 0 0C. The suspension was stirred at 0 "C for 15 min, and then a solution of 2-methyl-5-phenyloxazole (0.20 g, 1.25 mmol, 1.0 equiv) in THF (1 mL) added via cannula at -78 0C. The suspension was stirred at -78 "C for 30 min, and then a solution of ethyl propionate (0.21 ml, 1.875 mmol, 1.5 equiv) in THF (1 mL) added via cannula at -78 0C, and the resulting solution was stirred at 25 0C for 3 h, then quenched with a mixture of saturated aqueous NH4Cl (10 mL) solution and H2O (10 mL). The mixture was extracted with CH2Cl2 (3 x 20 mL) and dried over Na2SO4. After filtration and concentration in vacuo, the residue was purified via flash column chromatography on silica gel.
General procedure for oxazole/thiazole/imidazole bioisosteres
Figure imgf000162_0001
In a sealed tube was added 2-bromo-l-cyclohexylethanone (1.0 equiv) and amide (3.0 equiv) and stirred at 130 0C for 2 h. To the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with saturated aqueous Na2CO3, brine, and then dried over MgSO4. After filtration and concentration in vacuo, the residue was purified via flash column chromatography (SiO2, «-Hexanes:EtOAc 19:1) to give cyclized products.
Figure imgf000163_0001
To a solution of acetamidine (5.0 equiv) in methanol was added sodium hydroxide (5.0 equiv) and stirred at 0 °C for 3 hours. After filtration and concentration in vacuo, the residue was dissolved in acetonitrile. To the reaction mixture was added potassium carbonate (2.0 equiv) in H2O and 2-bromo-l-cyclohexylethanone (1.0 equiv) in acetonitrile and stirred at room temperature for 12 h. To the reaction mixture was added water and extracted with methylene chloride (x 3). The organic layer was washed with brine (x 1), and then dried over MgSO4. After filtration and concentration in vacuo, the residue was suspended in methylene chloride and was crystallized by slowly adding diethyl ether. The resulting solid was filtered and washed with diethyl ether.
Figure imgf000163_0002
To a solution of 4-cyclohexyl-2-methyl-lH-imidazole (1.0 equiv) in DMF was added trityl chloride (1.3 equiv) and triethyl amine (2.2 equiv) and stirred at room temperature for 6 h. After the reaction mixture was concentration in vacuo, it was treated with saturated aqueous ammonium chloride solution and extracted with ethyl acetate (x 3). The combined organic layers were washed with brine (x 1), and then dried over MgSO4. After filtration and concentration in vacuo, the residue was purified via flash column chromatography (SiO2, n- Hexanes:EtOAc 7:l → 1:1).
4-Cy clohexy 1-2-methy 1- 1 -trityl- lH-imidazole
1H NMR (400 MHz, CD3OD) δ 7.35 (m, 9H), 7.12 (m, 6H), 6.39 (s, IH), 2.41 (m, IH), 1.92 (m, 2H), 1.77-1.65 (m, 3H), 1.56 (s, 3H), 1.40-1.18 (m, 5H); LRMS (electrospray) m/z calculated for C29H30N2 (M+H)+ 407.56, found 407.32.
Figure imgf000164_0001
To a solution of diethylamine (2.6 equiv) in THF (0.6 M) at -78 0C was added slowly n-BuLi (2.4 equiv) and stirred for 10 min at 0 0C then cooled back to -78 0C. A solution of oxazole (or thiazole, 1.0 equiv) in THF (0.6 M) was added to the reaction mixture using cannula at -78 °C and further stirred for 30 min. The reaction mixture was warmed to 25 °C and further stirred for 3 h. The reaction was quenched by the addition of saturated aqueous NH4Cl and extracted with EtOAc (3 x). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified via flash column chromatography (SiO2, n- Hexanes:EtOAc 9:1).
Figure imgf000164_0002
To a solution of 4-cyclohexyl-2-methyl-l-trityl-l //-imidazole (1.0 equiv) in distilled THF at -78 0C was added rc-BuLi (1.6 M in hexanes, 2.0 equiv) and stirred at -78 0C for 30 min then further stirred at room temperature for 30 min. The reaction mixture was cooled back to -78 0C and added ethyl propionate (3.0 equiv) and stirred at room temperature for 12 h. The reaction was quenched with methanol and concentration in vacuo, the residue was purified via flash column chromatography (SiO2, rø-Hexanes:EtOAc 3:1).
l-(4-Cyclohexyl-l-trityl-li/-imidazol-2-yl)butan-2-one
1H NMR (400 MHz, CDCl3) δ 7.32 (m, 9H), 7.13 (m, 6H), 6.41 (s, IH), 3.19 (s, 2H), 2.45 (m, IH), 2.01-1.88 (m, 4H), 1.76-1.65 (m, 3H), 1.35-1.24 (s, 5H), 0.74 (t, J = 7.6 Hz, 3H); LRMS (electrospray) m/z calculated for C32H34N2O (M+H)+ 463.63, found 463.37.
Figure imgf000165_0001
To a mixture of benzaldehyde (1.0 equiv), urea (1.5 equiv), and β-keto oxazole (thiazole, or imidazole) (1.0 equiv) was added acetic acid (0.2 M) and stirred at 110 0C for 16 h. The reaction was slowly quenched with saturated aqueous K2CO3 (caution: gas evolution) and extracted with EtOAc (3 x). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was redissolved with CH2Cl2 and crystallized by the slow addition of hexanes. The resulting precipitate was filtered and washed with cold CH2Cl2 :«-Hexanes (1 :1) solution. Alternatively, the concentrated residue was directly subjected to flash column chromatography (SiO2, CH2Cl2:Me0H = 19:1) to give Biginelli adducts.
General procedure for reduction of nitro groups
Figure imgf000165_0002
X = O1 S
Y = O , S1 NH
To a solution of nitro compound (1.0 equiv) in AcOH:HCl (cone.) (9:1, 0.1 M) was added zinc dust (6.0 equiv) and stirred at 80 "C for 1 h. After cooling to 25 0C, the reaction mixture was quenched with water and extracted with EtOAc (3 x). The combined organic layers were washed with saturated aqueous K2CO3 solution and then dried over MgSO4. After filtration and concentration in vacuo, the residue was redissolved in CH2Cl2/Me0H and crystallized by slowly adding n-Hexanes. The resulting solid was filtered and washed with cold CH2Cl2:hexanes (1:1) solution.
General procedure for reductive aminations
Figure imgf000166_0001
To a solution of aniline compound (1.0 equiv) in THF (0.1 M) was added molecular sieve, benzaldehyde (2.0 equiv), and AcOH (2.0 equiv) and was stirred at room temperature for 2 h. Then the reaction mixture was treated with sodium triacetoxyborohydride (2.0 equiv) and further stirred overnight at 25 °C. The reaction was quenched by the addition of water and extracted with EtOAc (3 x). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified via flash column chromatography (SiO2, CH2Cl2IMeOH 9:1) to give reductive animation products.
General procedure for amide coupling
Figure imgf000166_0002
To a mixture of Biginelli compound (1.0 equiv), amine (or acid) (1.2 equiv), DMAP (0.2 equiv), and EDC (1.3 equiv) was added DMF (or CH2Cl2) (0.3 M) and DIPEA (1.5 equiv) and the resulting mixture was stirred at room temperature overnight. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution and extracted with CH2Cl2 (3 x). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified via flash column chromatography (SiO2, CH2Cl2:Me0H = 19:l).
2-Methyl-5-phenyloxazoIe
1H NMR (400 MHz, CDCl3) δ 7.35-7.33 (m, 2H), 7.14-7.10 (m, 2H), 7.05-7.01 (m, IH), 6.97 (s, IH), 2.23 (s, IH); TLC i?/(«-Hexanes:EtOAc 3:1) = 0.52.
l-(5-Phenyloxazol-2-yl)butan-2-one
1U NMR (400 MHz, CD3OD) δ 7.66-7.63 (m, 2H), 7.42-7.40 (m, 3H), 7.38-7.31 (m, IH), 4.04 (s, 2H), 2.64-2.59 (m, 2H), 1.05 (t, J= 7.2 Hz, 3H);13C NMR (400 MHz, CD3OD) δ
204.7, 158.7, 152.4, 128.8, 127.7, 124.0, 123.6, 121.5, 41.1, 35.3, 6.7; TLC Rf(n- Hexanes:EtOAc 5:1) = 0.17.
5-(4-Bromophenyl)-2-methyIoxazole
1H NMR (400 MHz, CDCl3) δ 7.53-7.51 (m, 2H), 7.47-7.45 (m, 2H), 7.20 (s, IH), 2.52 (s, 3H); TLC i?/(n-Hexanes: EtOAc 3:1) = 0.48.
l-(5-(4-BromophenyI)oxazol-2-yl)butan-2-one
1H NMR (400 MHz, CD3OD) δ 7.51-7.49 (m, 4H), 7.41 (s, IH), 4.03 (s, 2H), 2.63-2.58 (m, 2H), 1.03 (t, J= 7.2 Hz, 3H); 13C NMR (400 MHz, CD3OD) δ 204.9, 159.1, 151.4, 132.0,
126.8, 125.6, 125.2, 121.5, 41.3, 35.3, 6.6; TLC £/(rc-Hexanes:EtOAc 5:1) = 0.32.
Figure imgf000167_0001
263
4-(3-ChIoro-4-hydroxyphenyl)-6-ethyl-5-(5-phenyloxazol-2-yI)-3,4-dihydropyrimidin- 2(117)-one (263)
1H NMR (400 MHz, DMSO-^) δ 9.07 (s, IH), 7.63 (s, IH), 7.58-7.56 (m, 3H), 7.42-7.38 (m, 2H), 7.29-7.24 (m, 2H), 7.08-7.05 (m, IH), 6.86 (d, J= 8.4 Hz, IH), 5.32 (d, J= 3.2 Hz, IH), 2.80-2.72 (m, 2H), 1.20 (t, J= 7.2 Hz, 3H);13C NMR (400 MHz, DMSO-^) δ 160.2, 153.1, 153.0, 149.3, 146.1, 137.1, 129.7, 128.6, 128.3, 126.7, 124.1, 124.0, 119.9, 117.3, 96.7, 54.3, 24.6, 13.3.
S-CyclohexyW-methyloxazole
1H NMR (400 MHz, CDCl3) δ 7.17 (d, J= 1.2 Hz, IH), 2.38 (s, 3H), 1.96-1.94 (m, 2H), 1.77- 1.70 (m, 4H), 1.35-1.27 (m, 5H); TLC i?/(«-Hexanes:EtOAc 5:1) = 0.48.
l-(5-Cyclohexyloxazol-2-yI)butan-2-one
1H NMR (400 MHz, CDCl3) δ 7.26 (d, J= 1.2 Hz, IH), 3.82 (s, 2H), 2.51-2.45 (m, 3H), 2.01- 1.96 (m, 3H), 1.77-1.66 (m, 5H), 1.36-1.30 (m, 2H), 1.19-1.16 (m, 3H); TLC Rf(n- Hexanes:EtOAc 5:1) = 0.43.
Figure imgf000168_0001
264
4-(3-Chloro-4-hydroxyphenyl)-5-(5-cyclohexyloxazol-2-yl)-6-ethyl-3,4- dihydropyrimidin-2(lJfiT)-one (264)
1H NMR (400 MHz, CD3OD) δ 7.38 (d, J= 1.2 Hz, IH), 7.23 (d, J= 2.0 Hz, IH), 7.07-7.04 (m, IH), 6.78 (d, J= 8.4 Hz, IH), 5.42 (s, IH), 2.76-2.63 (m, 2H), 1.94-1.67 (m, 6H), 1.42- 1.18 (m, 8H);13C NMR (400 MHz, CD3OD) 6 159.8, 154.7, 152.6, 146.6, 143.5, 136.3, 131.7, 128.2, 125.9, 120.2, 116.3, 98.1, 54.8, 35.8, 32.1, 26.0, 25.9, 25.8, 23.9, 11.8; TLC R/ (CH2Cl2: MeOH 10:1) = 0.52.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 205% z-PrOH in n-Hexanes, 8.0 mL/min): 264a tR = 18.2 min, 264b tR = 25.3 min.
4-Cyclohexyl-2-methyloxazole
1H NMR (400 MHz, CDCl3) δ 7.16 (s, IH), 2.42 (m, IH), 2.38 (s, 3H), 1.92 (m, 2H), 1.77- 1.61 (m, 4H), 1.38-1.21 (m, 4H); TLC i?/(n-Hexanes:EtOAc 9:1) = 0.25.
l-(4-CycIohexyloxazol-2-yl)propan-2-one 1H NMR (400 MHz, CDCl3) δ 7.28 (s, IH), 3.83 (s, 2H), 2.48 (m, IH), 2.20 (s, 3H), 2.00 (m, 2H), 1.78-1.62 (m, 3H), 1.39-1.17 (m, 5H); TLC i?/(n-Hexanes:EtOAc 4:1) = 0.27.
Figure imgf000169_0001
4-(3-Chloro-4-hydroxyphenyl)-5-(4-cyclohexyloxazoϊ-2-yl)-6-methyl-3,4- dihydropyrimidin-2(lH)-one (265)
1H NMR (400 MHz, CD3OD) δ 7.39 (s, IH), 7.23 (d, J= 2.0 Hz, IH), 7.06 (dd, J= 8.4, 2.0 Hz, IH), 6.78 (d, J= 8.4 Hz, IH), 5.43 (s, IH), 2.44 (m, IH), 2.28 (s, 3H), 1.96 (m, 2H), 1.73 (m, 3H), 1.39-1.22 (m, 5H); TLC i?/(CH2Cl2:Me0H 19:1) = 0.28.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 20% z-PrOH in «-Hexanes, 6.5 mL/min): 265a tR = 20.1 min, 265b tR = 23.9 min.
l-(4-Cyclohexyloxazol-2-yl)butan-2-one
1H NMR (400 MHz, CDCl3) δ 7.27 (s, IH), 3.83 (s, 2H), 2.50 (q, J= 7.2 Hz, 2H), 2.48 (m, IH), 1.99 (m, 2H), 1.76 (m, 2H), 1.69 (m, IH), 1.37-1.22 (m, 5H), 1.05 (t, J= 7.2 Hz, 3H); TLC i?/(rc-Hexanes:EtOAc 4:1) = 0.30.
Figure imgf000169_0002
266
4-(3-Chloro-4-hydroxyphenyl)-5-(4-cyclohexyloxazol-2-yl)-6-ethyl-3,4- dihydropyrimidin-2(lH)-one (266)
1H NMR (400 MHz, CD3OD) δ 7.34 (s, IH), 7.25 (d, J= 2.4 Hz, IH), 7.07 (dd, J= 8.4, 2.0 Hz, IH), 6.80 (d, J= 8.0 Hz, IH), 5.44 (s, IH), 2.70 (m, 2H), 2.40 (m, IH), 1.92 (m, 2H), 1.72 (m, 2H), 1.65 (m, IH), 1.35-1.24 (m, 5H), 1.94 (t, J= 7.4 Hz, 3H); 13C NMR (100 MHz, CD3OD) δ 159.6, 152.4, 146.4, 143.3, 136.1, 131.5, 128.0, 125.8, 120.1, 116.2, 98.0, 54.6, 35.6, 31.9, 31.4, 25.8, 25.7, 23.8, 20.2, 11.7.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 20% /-PrOH in n-Hexanes, 6.5 mL/min): 266a tβ = 20.5 min, 266b tj? = 25.3 min.
l-(4-Cyclohexyloxazol-2-yI)pentan-2-one
1H NMR (400 MHz, CDCl3) δ 7.30 (s, IH), 3.84 (s, 2H), 2.50 (m, IH), 2.47 (t, J= 7.2 Hz5 2H), 2.00 (m, 2H), 1.78 (m, 2H), 1.67 (m, IH), 1.61 (m, 2H), 1.39-1.25 (m, 5H), 0.90 (t, J= 7.2 Hz, 3H); TLC i?/(«-Hexanes:EtOAc 4:1) = 0.40.
Figure imgf000170_0001
4-(3-Chloro-4-hydroxyphenyl)-5-(4-cyclohexyloxazoI-2-yl)-6-propyl-3,4- dihydropyrimidin-2(lH)-one (267)
1H NMR (400 MHz, CD3OD) δ 7.38 (s, IH), 7.24 (d, J= 2.0 Hz, IH), 7.06 (dd, J= 8.4, 2.0
Hz, IH), 6.78 (d, J= 8.4 Hz, IH), 5.43 (s, IH), 2.67 (m, 2H), 2.43 (m, IH), 1.94 (bs, 2H),
1.76-1.59 (m, 5H), 1.42-1.23 (m, 5H), 0.97 (t, J= 7.4 Hz, 3H); TLC i?/(CH2Cl2:Me0H 9:1) =
0.62.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 20%
/-PrOH in «-Hexanes, 6.5 mL/min): 267a tR = 18.8 min, 267b tR = 24.5 min.
2-(4-CycIohexyIoxazol-2-yl)-l-cyclopropylethanone
1H NMR (400 MHz, CDCl3) δ 7.28 (s, IH), 3.97 (s, 2H), 2.49 (m, IH), 2.02-1.94 (m, 3H), 1.76 (m, 2H), 1.69 (m, IH), 1.37-1.19 (m, 5H), 1.09 (m, 2H), 0.91 (m, 2H); TLC Rf(n- Hexanes:EtOAc 4: 1) = 0.31.
Figure imgf000171_0001
268
4-(3-ChIoro-4-hydroxyphenyl)-5-(4-cyclohexyloxazol-2-yI)-6-cyclopropyl-3,4- dihydropyrimidin-2(lH)-one (268)
1U NMR (400 MHz, CD3OD) δ 7.40 (s, IH), 7.21 (d, J= 2.0 Hz, IH), 7.04 (dd, J= 8.4, 2.0 Hz, IH), 6.78 (d, J= 8.4 Hz, IH), 5.41 (s, IH), 2.57 (m, 2H), 2.44 (m, IH), 1.96 (bs, 2H), 1.77-1.67 (m, 3H), 1.42-1.20 (m, 5H), 0.87 (d, J= 6.8 Hz, 4H).
Enantiomerically pure forms were obtained by crural HPLC (OD-H preparative column, 20% i-PrOH in «-Hexanes, 6.5 mL/min): 268a tR = 33.4 min, 268b tR = 45.9 min.
l-(4-Cyclohexyloxazol-2-yl)-3-methylbutan-2-one
1H NMR (400 MHz, CDCl3) δ 7.41 (s, IH), 3.89 (s, 2H), 2.70 (m, IH), 2.47 (m, IH), 1.97 (m, 2H), 1.78-1.62 (m, 3H), 1.36-1.19 (m, 5H), 1.11 (d, J= 5.2 Hz, 6H); TLC Rf{n- Hexanes:EtOAc 4:1) = 0.38.
Figure imgf000171_0002
269
4-(3-Chloro-4-hydroxyphenyl)-5-(4-cyclohexyIoxazol-2-yI)-6-isopropyl-3,4- dihydropyrimidin-2(l//)-one (269)
1H NMR (400 MHz, CD3OD) δ 7.38 (s, IH), 7.20 (d, J= 2.0 Hz5 IH), 7.03 (dd, J= 8.4, 2.0
Hz5 IH), 6.78 (d, J= 8.4 Hz, IH), 5.39 (s, IH), 2.43 (m, IH), 2.20 (m, IH), 1.94 (m, 2H)5
1.77-1.66 (m, 3H), 1.40-1.11 (m, 5H), 0.89 (d, J= 6.4 Hz, 6H); TLC i?/(CH2Cl2:Me0H 9:1) =
0.57.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 20% z-PrOH in «-Hexanes, 6.5 mL/min): 269a tR = 19.3 min, 269b tR = 21.8 min. 4-Cyclohexyl-2-methyIthiazole
1H NMR (400 MHz, CDCl3) δ 6.64 (s, IH), 2.69 (m, IH), 2.66 (s, 3H), 2.02 (bs, 2H), 1.79 (m, 2H), 1.70 (m, IH), 1.43-1.21 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 165.0, 162.5, 110.3, 40.6, 32.9, 26.3, 26.1, 19.1; TLC i?/(«-Hexanes:EtOAc 4:1) = 0.56.
l-(4-Cyclohexylthiazol-2-yl)butan-2-one
1H NMR (400 MHz, CDCl3) δ 6.79 (s, IH), 4.08 (s, 2H), 2.72 (m, IH), 2.56 (q, J= 7.2 Hz, 2H), 2.03 (m, 2H), 1.79 (m, 2H), 1.69 (m, IH), 1.43-1.16 (m, 5H), 1.06 (t, J- 7.4 Hz, 3H); TLC i?/(«-Hexanes:EtOAc 4:1) = 0.45.
Figure imgf000172_0001
4-(3-Chloro-4-hydroxyphenyl)-5-(4-cyclohexylthiazol-2-yl)-6-ethyl-3,4- dihydropyrimidin-2(lJϊ)-one (270)
1H NMR (400 MHz, CD3OD) δ 7.22 (d, J= 2.0 Hz, IH), 7.06 (dd, J= 8.2, 2.2 Hz, IH), 6.86 (s, IH), 6.79 (d, J= 8.4 Hz, IH), 5.39 (s, IH), 2.63 (m, 3H), 1.96 (m, 2H), 1.79 (m, 2H), 1.71 (d, J= 12.4 Hz, IH), 1.46-1.25 (m, 5H), 1.22 (t, J= 7.6 Hz, 3H); TLC ^/(CH2Cl2 :MeOH 19:1) = 0.42.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 20% /-PrOH in «-Hexanes, 6.5 mL/min): 270a tR = 18.1 min, 270b tR = 27.5 min.
Figure imgf000172_0002
5-(4-Cyclohexylthiazol-2-yl)-6-ethyl-4-phenyl-3,4-dihydropyrimidin-2(lH)-one (271) 1K NMR (400 MHz, CD3OD) δ 7.31-7.19 (m, 5H), 6.85 (s, IH), 5.47 (s, IH), 2.64 (m, 3H), 1.97 (m, 2H), 1.78 (m, 2H), 1.70 (m, IH), 1.45-1.26 (m, 5H)5 1.22 (t, J= 7.6 Hz, 3H); TLC R1 (CH2Cl2:Me0H 19:1) = 0.33.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 15% z-PrOH in rc-Hexanes, 6.5 mL/min): 271a tR = 20.0 min, 271b tR = 33.3 min.
Figure imgf000173_0001
272 4-Benzyl-5-(4-cyclohexylthiazol-2-yl)-6-ethyl-3,4-dihydropyrimidin-2(lH)-one (272)
1H NMR (400 MHz, CD3OD) δ 7.19 (m, 3H), 7.12 (m, 2H), 6.95 (s, IH), 4.78 (t, J= 5.0 Hz, IH), 2.84 (d, J= 5.2 Hz, 2H), 2.74 (m, IH), 2.50 (m, 2H), 2.06 (m, 2H), 1.83 (m, 2H), 1.74 (m, IH), 1.53-1.28 (m, 5H), 1.07 (t, J= 7.4 Hz, 3H); TLC ^(CH2Cl2MeOH 19:1) = 0.24.
Figure imgf000173_0002
273
4-(l-Bromonaphthalen-2-yl)-5-(4-cyclohexylthiazol-2-yl)-6-ethyl-3,4-dihydropyrimidin- 2(lH)-one (273)
1H NMR (400 MHz, CD3OD) δ 8.31 (d, J= 8.31 Hz, IH), 7.85 (dd, J= 8.0, 4.8 Hz, 2H), 7.57 (m, 3H), 6.81 (s, IH), 6.34 (s, IH), 5.49(s, IH), 2.64 (q, J= 7.6 Hz, 2H), 2.62 (m, IH), 1.91 (m, IH), 1.85 (m, IH), 1.67 (m, 3H), 1.40-1.23 (m, 8H); TLC i?/(CH2Cl2:Me0H 19:1) = 0.27. Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 25% /-PrOH in n-Hexanes, 6.5 mL/min): 273a tR = 12.5 min, 273b tR = 16.0 min.
Figure imgf000174_0001
274 5-(4-Cyclohexylthiazol-2-yl)-6-ethyl-4-(4-hydroxyphenyI)-3,4-dihydropyrimidin-2(lJHr)- one (274)
1H NMR (400 MHz, DMSO-<4) δ 9.29 (s, IH), 8.78 (s, IH), 7.43 (s, IH), 7.05 (d, J= 8.4 Hz,
2H), 6.92 (s, IH), 6.63 (d, J= 8.4 Hz, 2H), 5.12 (d, J= 3.2 Hz, IH), 2.66 (m, 2H), 2.54 (m,
IH), 1.88 (m, 2H), 1.71 (m, 2H), 1.62 (m, IH), 1.31 (m, 5H), 1.14 (t, J= 7.4 Hz, 3H); TLC Rf
(CH2Cl2:Me0H 19:1) = 0.17.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 20% i-
PrOH in «-Hexanes, 1.0 niL/min): 274a tR = 5.8 min, 274b tR = 8.7 min.
Figure imgf000174_0002
275 5-(4-Cyclohexylthiazol-2-yl)-6-ethyl-4-(3-hydroxyphenyl)-3,4-dihydropyrimidin-2(lJϊ)- one (275)
1H NMR (400 MHz, DMSO-J6) δ 9.30 (bs, IH), 8.82 (s, IH), 7.50 (s, IH), 7.03 (t, J= 7.8 Hz,
IH), 6.94 (s, IH), 6.69 (d, J= 7.2 Hz, 2H), 6.57 (d, J= 8.0 Hz, IH), 5.19 (d, J= 3.2 Hz, IH),
2.66 (m, 2H), 2.57 (m, IH), 1.90 (m, 2H), 1.69 (m, 2H), 1.63 (m, IH), 1.36-1.28 (m, 5H),
1.15 (t, J= 7.4 Hz, 3H); TLC ^/(CH2Cl2: MeOH 19:1) = 0.11.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 20% i-
PrOH in «-Hexanes, 1.0 mL/min): 275a tR = 7.9 min, 275b tR = 15.9 min.
Figure imgf000175_0001
5-(4-Cyclohexylthiazol-2-yl)-6-ethyl-4-(3-fluoro-4-hydroxyphenyl)-3,4- dihydropyrimidin-2(lH)-one (276)
1H NMR (400 MHz, CD3OD) δ 7.00 (dd, J= 12.0, 2.0 Hz, IH), 6.95 (dd, J= 8.4, 2.0 Hz, IH), 6.90 (s, IH), 6.82 (t, J= 8.6 Hz, IH), 5.42 (s, IH), 2.66 (m, 3H), 2.00 (m, 2H), 1.83 (m, 2H), 1.75 (d, J= 12.4 Hz, IH), 1.49-1.41 (m, 4H), 1.31 (m, IH), 1.25 (t, J= 7.6 Hz, 3H); TLC i?/(CH2Cl2:Me0H 19:1) = 0.14.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 25% z-PrOH in π-Hexanes, 6.5 mL/min): 276a tR = 15.6 min, 276b tR = 36.1 min.
Figure imgf000175_0002
4-(2-ChIoro-4-hydroxyphenyI)-5-(4-cyclohexylthiazol-2-yl)-6-ethyl-3,4- dihydropyrimidin-2(liϊ)-one (277)
1H NMR (400 MHz, CD3OD) δ 7.20 (s, IH), 6.89 (s, IH), 6.77 (d, J= 2.4 Hz, IH), 6.67 (dd,
J= 8.4, 2.4 Hz, IH), 5.84 (s, IH), 2.67 (m, IH), 2.63 (q, J= 7.6 Hz, 2H), 1.98 (m, IH), 1.85-
1.71 (m, 3H), 1.57-1.27 (m, 5H), 1.25 (t, J= 7.4 Hz, 3H); TLC i?/(CH2Cl2:Me0H 19:1) =
0.12.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 25%
/-PrOH in n-Hexanes, 6.5 mL/min): 277a tR = 10.9 min, 277b tR = 12.9 min.
Figure imgf000176_0001
278
5-(4-Cyclohexylthiazol-2-yl)-6-ethyl-4-(4-fluoro-3-hydroxyphenyI)-3,4- dihydropyrimidin-2(lH)-one (278)
1H NMR (400 MHz, CD3OD) δ 6.91 (m, 2H), 6.83 (s, IH), 6.72 (m, IH), 5.38 (s, IH), 2.62 (m, 3H), 1.98 (m, 2H), 1.78 (m, 2H), 1.71 (m, IH), 1.44-1.26 (m, 5H), 1.22 (t, J= 7.6 Hz, 3H); TLC i?/(CH2Cl2:Me0H 19:1) = 0.29.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 25% /-PrOH in «-Hexanes, 6.5 mL/min): 278a tR = 15.1 min, 278b tR = 24.28 min.
Figure imgf000176_0002
5-(4-Cyclohexylthiazol-2-yl)-6-ethyl-4-(2-methoxyphenyl)-3,4-dihydropyrimidin-2(liϊ)- one (279)
1K NMR (400 MHz, CD3OD) δ 7.21 (m, IH), 7.17 (dd, J- 7.6, 2.0 Hz, IH), 6.95 (d, J= 8.4 Hz, IH), 6.82 (m, 2H), 5.77 (s, IH), 3.83 (s, 3H), 2.68 (q, J= 7.2 Hz, 2H), 2.64 (m, IH), 1.95 (m, 2H), 1.79 (m, 2H), 1.70 (m, IH), 1.44-1.33 (m, 5H), 1.24 (t, J= 7.6 Hz, 3H); TLC Rf (CH2Cl2:Me0H 19:1) = 0.28.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 20% /-PrOH in «-Hexanes, 6.5 mL/min): 279a tR = 15.1 min, 279b tR = 20.6 min.
Figure imgf000177_0001
5-(4-CycIohexylthiazol-2-yI)-6-ethyl-4-(3-methoxyphenyl)-3,4-dihydropyrimidin-2(lfi)- one (280)
1H NMR (400 MHz, CD3OD) δ 7.16 (t, J= 8.0 Hz, IH), 6.88-6.83 (m, 3H), 6.76 (dd, J= 8.4, 2.4 Hz, IH), 5.45 (s, IH), 3.71 (s, 3H), 2.64 (m, 3H), 1.98 (m, 2H), 1.79 (m, 2H), 1.71 (m, IH), 1.45-1.34 (m, 4H), 1.27 (m, IH), 1.22 (t, J= 7.4 Hz, 3H); TLC #/(CH2Cl2:Me0H 19:1) = 0.35.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 20% /-PrOH in n-Hexanes, 6.5 mL/min): 280a tR = 15.2 min, 280b tR = 23.4 min.
Figure imgf000177_0002
5-(4-CyclohexylthiazoI-2-yl)-6-ethyl-4-(4-methoxyphenyl)-3,4-dihydropyrimidin-2(liϊ)- one (281)
1H NMR (400 MHz, CD3OD) δ 7.21 (d, J= 8.8 Hz, 2H), 6.84 (s, IH), 6.80 (d, J= 8.8 Hz, 2H), 5.39 (s, IH), 3.72 (s, 3H), 2.63 (m, 3H), 1.98 (m, 2H), 1.79 (m, 2H), 1.71 (m, IH), 1.45- 1.34 (m, 4H), 1.26 (m, IH), 1.21 (t, J= 7.4 Hz, 3H); TLC i?/(CH2Cl2:Me0H 19:1) = 0.31. Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 20% Z-PrOH in «-Hexanes, 6.5 mL/min): 281a tR = 13.8 min, 281b tR = 22.1 min.
4-(Benzyloxy)benzaldehyde
1H NMR (400 MHz, CDCl3) δ 9.87 (s, IH), 7.82 (d, J= 8.8 Hz, 2H), 7.43-7.34 (m, 5H), 7.06 (d, J= 8.8 Hz, 2H), 5.14 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 190.9, 163.9, 136.2, 132.2, 130.4, 128.9, 128.5, 127.7, 115.4, 70.5; TLC i?/(«-Hexanes:EtOAc 7:3) = 0.58.
Figure imgf000178_0001
4-(4-(Benzyloxy)phenyl)-5-(4-cyclohexylthiazol-2-yl)-6-ethyI-3,4-dihydropyrimidin- 2(lH)-one (282)
1H NMR (400 MHz, CD3OD) δ 7.37 (d, J= 6.8 Hz, 2H), 7.32 (t, J= 7.0 Hz, 2H), 7.26 (d, J= 6.8 Hz, IH), 7.21 (d, J= 8.8 Hz, 2H), 6.87 (d, J= 8.8 Hz, 2H), 6.84 (s, IH), 5.39 (s, IH), 5.01 (s, 2H), 2.63 (m, 3H), 1.97 (m, 2H), 1.78 (m, 2H), 1.71 (m, IH), 1.44-1.27 (m, 5H), 1.21 (t, J = 7.4 Hz, 3H); TLC i?/(CH2Cl2:Me0H 19:1) = 0.35.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 25% /-PrOH in «-Hexanes, 6.5 mL/min): 282a tR = 23.5 min, 282b tR = 31.7 min.
Figure imgf000178_0002
283
4-(4-(Benzyloxy)-3-chlorophenyl)-5-(4-cyclohexylthiazol-2-yl)-6-ethyI-3,4- dihydropyrimidin-2(l#)-one (283)
1H NMR (400 MHz, CD3OD) δ 7.40 (d, J= 7.2 Hz, 2H), 7.32 (t, J= 7.4 Hz, 3H), 7.27 (d, J= 7.6 Hz, IH), 7.16 (dd, J= 8.4, 2.0 Hz, IH), 7.00 (d, J= 8.8 Hz, IH), 6.86 (s, IH), 5.45 (s, IH), 5.10 (s, 2H), 2.63 (m, 3H), 1.96 (m, 2H), 1.79 (m, 2H), 1.71 (m, IH), 1.46-1.27 (m, 5H), 1.22 (t, J= 7.6 Hz, 3H); TLC i?/(CH2Cl2:Me0H 19:1) = 0.27.
Figure imgf000179_0001
5-(4-CycIohexyIthiazol-2-yI)-6-ethyI-4-(4-phenoxyphenyl)-3,4-dihydropyrimidin-2(lH)- one (284)
1H NMR (400 MHz, CD3OD) δ 7.29 (m, 4H), 7.06 (t, J= 7.2 Hz, IH), 6.91 (d, J= 7.6 Hz, 2H), 6.87 (s, IH), 6.86 (d, J= 8.4 Hz, 2H), 5.47 (s, IH), 2.64 (m, 3H), 1.96 (m, 2H), 1.79 (t, J = 4.0 Hz, 2H), 1.71 (d, J= 11.6 Hz, IH), 1.45-1.26 (m, 5H), 1.22 (t, J= 7.4 Hz, 3H); TLC Rf (CH2Cl2:Me0H 19:1) = 0.41.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 25% z-PrOH in «-Hexanes, 6.5 mL/min): 284a tR = 17.5 min, 284b tR = 34.1 min.
Figure imgf000179_0002
4-(5-(4-Cyclohexylthiazol-2-yl)-6-ethyl-2-oxo-l,2,3,4-tetrahydropyrimidin-4- yl)benzonitrile (285)
1H NMR (400 MHz, CD3OD) δ 7.63 (d, J= 8.4 Hz, 2H), 7.48 (d, J= 8.4 Hz, 2H), 6.88 (s, IH), 5.66 (s, IH), 2.64 (m, 3H), 1.95 (m, 2H), 1.79 (m, 2H), 1.71 (m, IH), 1.43-1.26 (m, 5H), 1.23 (t, J= 7.4 Hz, 3H); TLC i?/(CH2Cl2:Me0H 19:1) = 0.34.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 10% i- PrOH in n-Hexanes, 1.0 mL/min): 285a tR = 14.5 min, 285b tR = 20.9 min.
Figure imgf000180_0001
4-(5-(4-CyclohexyIthiazol-2-yl)-6-ethyl-2-oxo-l,2,3,4-tetrahydropyrimidin-4-yl)-2- fluorobenzonitrile (286)
1H NMR (400 MHz, CD3OD) δ 7.67 (dd, J= 7.8, 7.0 Hz, IH), 7.31 (m, 2H), 6.92 (s, IH), 5.73 (s, IH), 2.65 (m, 3H), 1.96 (m, 2H), 1.81 (m, 2H), 1.73 (m, IH), 1.45-1.28 (m, 5H), 1.25 (t, J= 7.6 Hz, 3H); TLC i?/(CH2Cl2:Me0H 19:1) = 0.32.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 25% /-PrOH in π-Hexanes, 6.5 mL/min): 286a tR = 16.4 min, 286b tR = 20.8 min.
Figure imgf000180_0002
3-(5-(4-CyclohexylthiazoI-2-yl)-6-ethyl-2-oxo-l,2,3,4-tetrahydropyrimidin-4- yl)benzonitrile (287)
1H NMR (400 MHz, CD3OD) δ 7.64 (d, J= 8.8 Hz, 2H), 7.56 (d, J= 7.6 Hz, IH), 7.45 (t, J= 7.8 Hz, IH), 6.89 (s, IH), 5.66 (s, IH), 2.65 (m, 3H), 1.93 (m, 2H), 1.79 (m, 2H), 1.71 (m, IH), 1.45-1.25 (m, 5H), 1.23 (t, J= 7.6 Hz, 3H); TLC i?/(CH2Cl2:Me0H 19:1) = 0.24. Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 25% /-PrOH in w-Hexanes, 6.5 mL/min): 287a tR = 19.2 min, 287b tR = 21.3 min.
Figure imgf000180_0003
288 5-(5-(4-Cyclohexylthiazol-2-yI)-6-ethyl-2-oxo-l,2,3,4-tetrahydropyrimidin-4-yl)-2- fluorobenzonitrile (288)
1H NMR (400 MHz, CD3OD) δ 7.70 (m, 2H), 7.29 (t, J= 9.4 Hz, IH), 6.92 (s, IH), 5.68 (s, IH), 2.66 (m, 3H), 1.97 (m, 2H), 1.82 (m, 2H), 1.73 (m, IH), 1.48-1.28 (m, 5H), 1.25 (t, J= 7.6 Hz, 3H); TLC ^7(CH2Cl2: MeOH 19:1) = 0.21.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 25% z-PrOH in «-Hexanes, 6.5 mL/min): 288a tR = 16.5 min, 288b tR = 22.1 min.
Figure imgf000181_0001
289 5-(4-CyclohexylthiazoI-2-yl)-6-ethyl-4-(4-fluorophenyl)-3,4-dihydropyrimidin-2(lH)-one
(289)
1H NMR (400 MHz, CD3OD) δ 7.31 (dd, J= 8.6 Hz, 5.4 Hz, 2H), 6.98 (t, J= 8.8 Hz, 2H), 6.86 (s, IH), 5.50 (s, IH), 2.63 (m, 3H), 1.96 (m, 2H), 1.79 (m, 2H), 1.71 (m, IH), 1.44-1.26 (m, 5H), 1.22 (t, J= 7.6 Hz, 3H); TLC i?/(CH2Cl2:Me0H 19:1) = 0.35 Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 10% i- PrOH in n-Hexanes, 1.0 mL/min): 289a tR = 8.8 min, 289b tR = 14.0 min.
Figure imgf000181_0002
290
5-(4-Cyclohexylthiazol-2-yl)-6-ethyl-4-(3-fluorophenyl)-3,4-dihydropyrimidin-2(ljH)-one (290)
1H NMR (400 MHz, CD3OD) δ 7.28 (q, J= 8.0 Hz, IH), 7.14 (d, J= 8.0 Hz, IH), 7.03 (d, J = 10.4 Hz, IH), 6.94 (dt, J= 8.2, 2.4 Hz, IH), 6.89 (s, IH), 5.56 (s, IH), 2.66 (m, 3H), 1.98 (m, 2H), 1.81 (m, 2H), 1.73 (d, J= 12.4 Hz, IH), 1.47-1.29 (m, 5H), 1.24 (t, J= 7.4 Hz, 3H); TLC i?/(CH2Cl2:Me0H 19:1) = 0.56. Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 25% i-PrOH in n-Hexanes, 6.5 mL/min): 290a tR = 13.3 min, 290b tR = 18.3 min.
Figure imgf000182_0001
291
4-(4-Chlorophenyl)-5-(4-cyclohexyIthiazol-2-yl)-6-ethyI-3,4-dihydropyrimidin-2(ljiϊ)-one (291)
1H NMR (400 MHz, CD3OD) δ 7.26 (m, 4H), 6.87 (s, IH), 5.51 (s, IH), 2.62 (m, 3H), 1.96 (m, 2H), 1.79 (m, 2H), 1.71 (m, IH), 1.44-1.33 (m, 4H), 1.27 (m, IH), 1.22 (t, J= 7.4 Hz, 3H); TLC i?/(CH2Cl2:Me0H 19:1) = 0.28.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 15% /-PrOH in ra-Hexanes, 6.5 mL/min): 291a ^ = 13.9 min, 291b tR = 21.8 min.
Figure imgf000182_0002
292
4-(3-Chlorophenyl)-5-(4-cyclohexylthiazol-2-yl)-6-ethyI-3,4-dihydropyrimidin-2(lH)-one
(292)
1H NMR (400 MHz, CD3OD) δ 7.33 (s, IH), 7.26-7.21 (m, 3H), 6.89 (s, IH), 5.56 (s, IH), 2.66 (m, 3H), 1.96 (m, 2H), 1.81 (m, 2H), 1.73 (d, J= 12.4 Hz, IH), 1.48-1.28 (m, 5H), 1.24 (t, J= 7.4 Hz, 3H); TLC i?/(CH2Cl2:Me0H 19:1) = 0.50.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 25% /-PrOH in rc-Hexanes, 6.5 mL/min): 292a tR = 14.2 min, 292b tR = 18.6 min.
Figure imgf000183_0001
4-(2-Chlorophenyl)-5-(4-cycIohexylthiazol-2-yl)-6-ethyl-3,4-dihydropyrimidin-2(lH)-one
(293)
1H NMR (400 MHz, CD3OD) δ 7.39 (m, IH), 7.33 (m, IH), 7.23-7.20 (m, 2H), 6.84 (s, IH), 5.98 (s, IH), 2.65 (q, J= 7.6 Hz, 2H), 2.64 (m, IH), 1.93 (m, 2H), 1.77 (m, 2H), 1.69 (m, IH), 1.40-1.32 (m, 5H), 1.26 (t, J= 7.6 Hz, 3H); TLC i?/(CH2Cl2:Me0H 19:1) = 0.38. Enantiomerically pure forms were obtained by cbiral HPLC (OD-H preparative column, 20% i-PrOH in n-Hexanes, 6.5 mL/min): 293a tR = 12 A min, 293b tR = 16.5 min.
Figure imgf000183_0002
4-(4-BromophenyI)-5-(4-cyclohexyIthiazol-2-yl)-6-ethyl-3,4-dihydropyrimidin-2(lH)-one (294)
1H NMR (400 MHz, CD3OD) δ 7.40 (d, J= 8.8 Hz, 2H), 7.22 (d, J= 8.4 Hz, 2H), 6.87 (s, IH), 5.50 (s, IH), 2.62 (m, 3H), 1.96 (m, 2H), 1.79 (m, 2H), 1.71 (m, IH), 1.44-1.34 (m, 4H), 1.27 (m, IH), 1.22 (t, J= 7.4 Hz, 3H); TLC ^/(CH2Cl2 :MeOH 19:1) = 0.25. Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 15% /-PrOH in rc-Hexanes, 6.5 mL/min): 294a tR = 14.9 min, 294b tR = 26.3 min.
Figure imgf000183_0003
295 4-(3-Bromophenyl)-5-(4-cyclohexyIthiazol-2-yI)-6-ethyl-3,4-dihydropyrimidin-2(lJHr)-one
(295)
1H NMR (400 MHz, CD3OD) δ 7.49 (t, J= 1.6 Hz, IH), 7.37 (d, J= 8.0 Hz, IH), 7.30 (d, J= 7.6 Hz, IH), 7.19 (t, J= 7.8 Hz, IH), 6.90 (s, IH), 5.56 (s, IH), 2.66 (m, 3H), 2.00 (m, 2H), 1.82 (m, 2H), 1.72 (m, IH), 1.49-1.29 (m, 5H), 1.24 (t, J= 7.6 Hz, 3H); TLC R1 (CH2Cl2:Me0H 19:1) = 0.33.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 15% z-PrOH in «-Hexanes, 6.5 mL/min): 295a tR = 24.3 min, 295b tR = 35.1 min.
Figure imgf000184_0001
296
5-(4-Cyclohexylthiazol-2-yl)-4-(3,5-difluorophenyl)-6-ethyl-3,4-dihydropyrimidin-2(lJfiT)- one (296)
1H NMR (400 MHz, CD3OD) δ 6.93 (s, IH), 6.91 (dd, J= 8.4, 2.0 Hz, 2H), 6.79 (tt, J= 9.0, 2.4 Hz, IH), 5.62 (s, IH), 2.66 (m, 2H), 1.97 (m, 2H), 1.81 (m, 2H), 1.73 (m, IH), 1.48-1.36 (m, H), 1.29 (m, IH), 1.25 (t, J= 7.6 Hz, 3H); TLC £/(CH2Cl2:Me0H 19:1) = 0.23. Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 20% z-PrOH in rc-Hexanes, 6.5 mL/min): 296a tR = 14.4 min, 296b tR = 20.1 min.
Figure imgf000184_0002
297
5-(4-CycIohexylthiazol-2-yl)-4-(3,5-dibromophenyl)-6-ethyl-3,4-dihydropyriinidin- 2(l#)-one (297)
1H NMR (400 MHz, CD3OD) δ 7.57 (d, J= 1.6 Hz, IH), 7.48 (d, J= 1.6 Hz, 2H), 6.93 (s, IH), 5.62 (s, IH), 2.66 (m, 3H), 2.01 (m, 2H), 1.82 (m, 2H), 1.74 (m, IH), 1.44 (m, 4H), 1.32 (m, IH), 1.26 (t, J= 7.4 Hz, 3H); TLC i?/(CH2Cl2:Me0H 19:1) = 0.23. Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 20% i-PrOH in n-Hexanes, 6.5 mL/min): 297a tR = 14.8 min, 297b tR = 17.7 min.
Figure imgf000185_0001
5-(4-Cyclohexylthiazol-2-yl)-6-ethyI-4-(4-(trifluoromethyl)phenyl)-3,4- dihydropyrimidin-2(liϊ)-one (298)
1H NMR (400 MHz, CD3OD) δ 7.54 (d, J= 8.0 Hz, 2H), 7.47 (d, J= 8.4 Hz, 2H), 6.86 (s, IH), 5.63 (s, IH), 2.64 (m, 3H), 1.94 (m, 2H), 1.78 (m, 2H), 1.69 (m, IH), 1.40-1.32 (m, 4H), 1.23 (m, IH), 1.21 (t, J = 7.4 Hz, 3H); TLC i?/(CH2Cl2:Me0H 19:1) = 0.31. Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 15% /-PrOH in rc-Hexanes, 6.5 mL/min): 298a tR = 14.6 min, 298b tR = 18.7 min.
Figure imgf000185_0002
299
4-(3,5-Bis(trifluoromethyl)phenyl)-5-(4-cyclohexylthiazol-2-yl)-6-ethyl-3,4- dihydropyrimidin-2(liϊ)-one (299)
1H NMR (400 MHz, CD3OD) δ 7.92 (s, 2H), 7.82 (s, IH), 6.92 (s, IH), 5.87 (s, IH), 2.67 (m, 3H), 1.94 (m, 2H), 1.80 (m, 2H), 1.73 (m, IH), 1.45-1.34 (m, 5H), 1.27 (t, J= 7.6 Hz, 3H); TLC i?/(CH2Cl2:Me0H 19:1) = 0.30.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 15% /-PrOH in rc-Hexanes, 6.5 mL/min): 299a tR = 12.2 min, 299b tR = 13.7 min.
Figure imgf000186_0001
5-(4-Cyclohexylthiazol-2-yl)-6-ethyl-4-(4-nitrophenyl)-3,4-dihydropyrimidin-2(lH)-one
(300)
1R NMR (400 MHz, DMSO-J6) δ 9.01 (s, IH), 8.15 (d, J= 8.4 Hz, 2H), 7.75 (s, IH), 7.52 (d, J= 8.8 Hz, 2H), 6.99 (s, IH), 5.54 (d, J= 3.6 Hz, IH), 2.66 (m, IH), 2.59 (m, 2H), 1.87 (m, 2H), 1.70 (m, 2H), 1.62 (m, IH), 1.30 (m, 5H), 1.16 (t, J= 7.4 Hz, 3H); TLC Rf (CH2Cl2:Me0H 19:1) = 0.35
Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 20% i- PrOH in rc-Hexanes, 1.0 mL/min): 300a tR = 8.0 min, 300b tR = 10.6 min.
Figure imgf000186_0002
4-(4-Aminophenyl)-5-(4-cyclohexylthiazol-2-yl)-6-ethyl-3,4-dihydropyrimidin-2(lH)-one
(301)
1H NMR (400 MHz, CD3OD) δ 7.04 (d, J= 8.4 Hz, 2H), 6.83 (s, IH), 6.61 (d, J= 8.8 Hz, 2H), 5.28 (s, IH), 2.65 (m, IH), 2.62 (q, J= 7.6 Hz, 2H), 1.96 (m, 2H), 1.79 (m, 2H), 1.71 (m, IH), 1.45-1.24 (m, 5H), 1.21 (t, J= 7.4 Hz, 3H); TLC .K7(CH2Cl2: MeOH 19:1) = 0.15. Enantiomerically pure forms were obtained by chiral HPLC (OD-H analytical column, 20% i- PrOH in rc-Hexanes, 1.0 mL/min): 301a tR = 19.7 min, 301b tR = 34.4 min.
Figure imgf000187_0001
5-(4-Cyclohexylthiazol-2-yl)-6-ethyl-4-(3-nitrophenyl)-3,4-dihydropyrimidin-2(lH)-one (302)
1H NMR (400 MHz, CD3OD) δ 8.21 (t, J= 2.0 Hz, IH), 8.08 (td, J= 8.4, 4.0 Hz, IH), 7.74 (d, J= 7.6 Hz, IH), 7.52 (t, J= 7.8 Hz, IH), 6.88 (s, IH), 5.76 (s, IH), 2.66 (q, J= 7.6 Hz, 2H), 2.64 (m, IH), 1.95 (m, 2H), 1.78 (m, 2H), 1.71 (d, J= 13.2 Hz, IH), 1.44-1.26 (m, 5H), 1.25 (t, J= 7.4 Hz, 3H); TLC i?/(CH2Cl2:Me0H 19:1) = 0.27.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 25% /-PrOH in n-Hexanes, 6.5 mL/min): 302a tR = 19.3 min, 302b tR = 23.8 min.
Figure imgf000187_0002
4-(3-AminophenyI)-5-(4-cyclohexylthiazol-2-yl)-6-ethyl-3,4-dihydropyrimidin-2(lH)-one
(303)
1H NMR (400 MHz, CD3OD) δ 6.98 (t, J= 7.6 Hz, IH), 6.85 (s, IH), 6.69 (s, IH), 6.62 (d, J = 7.6 Hz, IH), 6.57 (dd, J= 8.0 Hz, 1.2 Hz, IH), 5.31 (s, IH), 2.63 (m, 3H), 1.97 (m, 2H), 1.79 (m, 2H), 1.71 (m, IH), 1.41 (m, 4H), 1.25 (m, IH), 1.21 (t, J= 7.6 Hz, 3H); TLC R1 (CH2Cl2:Me0H 19:1) = 0.15.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 50% z-PrOH in rc-Hexanes, 6.5 mL/min): 303a tR = 14.5 min, 303b tR = 18.4 min.
Figure imgf000188_0001
5-(4-Cyclohexylthiazol-2-yl)-6-ethyl-4-(2-nitrophenyl)-3,4-dihydropyrimidin-2(lH)-one
(304)
1H NMR (400 MHz, CD3OD) δ 7.85 (d, J= 8.0 Hz, IH), 7.60 (m, 2H), 7.42 (m, IH), 6.79 (s, IH), 6.21 (s, IH), 2.72 (m, 2H), 2.51 (m, IH), 1.80-1.66 (m, 3H), 1.36-1.21 (m, 8H); TLC R1 (CH2Cl2MeOH 19:1) = 0.36.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 25% z-PrOH in rc-Hexanes, 6.5 niL/min): 304a tR = 17.3 min, 304b tR = 23.1 min.
Figure imgf000188_0002
(S)-4-(4-(BenzyIamino)phenyl)-5-(4-cyclohexylthiazol-2-yI)-6-ethyl-3,4- dihydropyrimidin-2(lH)-one (305a)
1H NMR (400 MHz, CD3OD) δ 7.55 (d, J= 8.4 Hz, 2H), 7.50-7.42 (m, 5H), 7.33 (d, J- 8.4 Hz, 2H), 7.08 (s, IH), 5.72 (s, IH), 4.62 (s, 2H), 2.75 (m, 3H), 2.07 (m, 2H), 1.91 (m, 2H), 1.84 (m, IH), 1.56-1.34 (m, 5H), 1.29 (t, J= 7.2 Hz, 3H); TLC i?/(CH2Cl2:Me0H 19:1) = 0.31.
Figure imgf000188_0003
Λr-(4-(5-(4-CycIohexylthiazoI-2-yl)-6-ethyl-2-oxo-l,2,3,4-tetrahydropyrimidin-4- yl)phenyl)acetamide (306)
1H NMR (400 MHz, CD3OD) δ 7.45 (d, J= 8.4 Hz, 2H), 7.26 (d, J= 8.4 Hz, 2H), 6.87 (s, IH), 5.46 (s, IH), 2.68 (m, IH), 2.65 (q, J= 7.2 Hz, 2H), 1.98 (m, 2H), 1.81 (m, 2H), 1.72 (m, IH), 1.47-1.29 (m, 5H), 1.24 (t, J= 7.4 Hz, 3H); TLC i?/(CH2Cl2:Me0H 9:1) = 0.38. Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 20% → 40% /-PrOH in n-Hexanes, 6.5 mL/min): 306a tR = 17.5 min, 306b tR = 60.0 min.
Figure imgf000189_0001
iV-(4-(5-(4-Cyclohexylthiazol-2-yI)-6-ethyl-2-oxo-l,2,3,4-tetrahydropyrimidin-4- yl)phenyl)benzamide (307)
1H NMR (400 MHz, CD3OD) δ 7.88 (d, J= 7.6 Hz, 2H), 7.60 (d, J= 8.4 Hz, 2H), 7.54 (t, J= 7.2 Hz, IH), 7.47 (t, J= 7.4 Hz, 2H), 7.31 (d, J= 8.4 Hz, 2H), 6.86 (s, IH), 5.49 (s, IH), 2.66 (m, IH), 2.65 (q, J= 7.6 Hz, 2H), 1.97 (m, 2H), 1.80 (m, 2H), 1.71 (m, IH), 1.46-1.35 (m, 4H), 1.27 (m, IH), 1.23 (t, J= 7.4 Hz, 3H); TLC 7J7(CH2Cl2: MeOH 9:1) = 0.56. Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 40% /-PrOH in H-Hexanes, 6.5 mL/min): 307a tR = 11.8 min, 307b /^ = 16.1 min.
Figure imgf000189_0002
5-(4-CyclohexylthiazoI-2-yI)-6-ethyl-4-(pyridin-3-yl)-3,4-dihydropyrimidin-2(lJΪ)-one
(308)
1H NMR (400 MHz, CD3OD) δ 8.50 (d, J= 2.4 Hz, IH), 8.39 (dd, J= 4.8, 1.2 Hz, IH), 7.82 (d, J= 8.0 Hz, IH), 7.37 (dd, J= 7.8, 5.0 Hz, IH), 6.90 (s, IH), 5.71 (s, IH), 2.68 (m, 3H), 1.97 (m, 2H), 1.80 (m, 2H), 1.73 (d, J= 12.0 Hz, IH), 1.45-1.28 (m, 5H), 1.26 (t, J= 7.6 Hz, 3H); TLC i?/(CH2Cl2:Me0H 19:1) = 0.04.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 25% z-PrOH in ra-Hexanes, 6.5 mL/min): 308a tR = 17.6 min, 308b tR = 23.0 min.
Figure imgf000190_0001
5-(4-Cyclohexylthiazol-2-yl)-6-ethyl-4-(pyridin-2-yl)-3,4-dihydropyrimidiii-2(ljH)-one (309)
1H NMR (400 MHz, CD3OD) δ 8.44 (d, J= 4.4 Hz, IH), 7.71 (dt, J= 8.6, 1.6 Hz, IH), 7.36 (d, J= 7.6 Hz, IH), 7.24 (t, J= 6.2 Hz, IH), 6.85 (s, IH), 5.59 (s, IH), 2.60 (m, 3H), 1.89 (m, 2H), 1.77 (m, 2H), 1.69 (m, IH), 1.39-1.31 (m, 4H), 1.26-1.18 (m, 4H); TLC R1 (CH2Cl2:Me0H 19:1) = 0.16.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 25% z-PrOH in «-Hexanes, 6.5 mL/min): 309a tR = 15.7 min, 309b tR = 19.6 min.
Figure imgf000190_0002
4-(5-(4-Cyclohexylthiazol-2-yl)-6-ethyl-2-oxo-l,2,3,4-tetrahydropyrimidin-4-yl)benzoic acid (310)
1U NMR (400 MHz, CD3OD) δ 7.90 (d, J= 8.0 Hz, 2H), 7.40 (d, J= 8.4 Hz, 2H), 6.87 (s, IH), 5.61 (s, IH), 2.65 (m, 3H), 1.97 (m, 2H), 1.79 (m, 2H), 1.71 (d, J= 12.4 Hz5 IH), 1.45- 1.34 (m, 4H), 1.27 (m, IH), 1.23 (t, J= 7.6 Hz, 3H); TLC i?/(CH2Cl2:Me0H 9:1) = 0.29.
Figure imgf000191_0001
Methyl 4-(5-(4-cyclohexylthiazol-2-yl)-6-ethyl-2-oxo-l,2,3,4-tetrahydropyrimidin-4- yl)benzoate (311)
1H NMR (400 MHz, CD3OD) δ 7.90 (d, J= 8.4 Hz, 2H), 7.41 (d, J= 8.4 Hz, 2H)5 6.86 (s, IH), 5.61 (s, IH), 3.85 (s, 3H), 2.63 (m, 3H), 1.96 (m, 2H), 1.78 (m, 2H), 1.71 (m, IH), 1.44- 1.33 (m, 4H), 1.29 (m, IH), 1.23 (t, J= 7.4 Hz, 3H); TLC i?/(CH2Cl2:Me0H 9:1) = 0.48. Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 25% /-PrOH in rø-Hexanes, 6.5 mL/min): 311a ΪR = 12.1 min, 311b tR = 17.4 min.
Figure imgf000191_0002
312
Benzyl 4-(5-(4-cyclohexylthiazol-2-yl)-6-ethyI-2-oxo-l,2,354-tetrahydropyrimidin-4- yl)benzoate (312)
1H NMR (400 MHz, CD3OD) δ 7.95 (d, J= 8.4 Hz, 2H), 7.44-7.24 (m, 7H), 6.88 (s, IH), 5.63 (s, IH), 5.32 (s, 2H), 2.64 (m, 3H), 1.97 (m, 2H), 1.79 (m, 2H), 1.72 (m, IH), 1.45-1.35 (m, 4H), 1.28 (m, IH), 1.24 (t, J= 7.4 Hz, 3H); TLC i?/(CH2Cl2:Me0H 9:1) = 0.47. Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 25% /-PrOH in n-Hexanes, 6.5 mL/min): 312a tR = 14.6 min, 312b tR = 18.5 min.
Figure imgf000192_0001
iy-Benzyl-4-(5-(4-cyclohexylthiazol-2-yl)-6-ethyl-2-oxo-l,2,354-tetrahydropyrimidin-4- yl)benzamide (313)
1H NMR (400 MHz, CD3OD) δ 7.75 (d, J = 8.4 Hz, 2H), 7.40 (d, J= 8.0 Hz, 2H), 7.28 (m, 4H), 7.21 (m, IH), 6.87 (s, IH), 5.60 (s, IH), 4.52 (s, 2H), 2.63 (m, 3H), 1.96 (m, 2H), 1.79 (m, 2H), 1.70 (m, IH), 1.44-1.33 (m, 4H), 1.26 (m, IH), 1.22 (t, J= 7.4 Hz, 3H); TLC Rf (CH2Cl2:Me0H 9:1) = 0.44.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 20% → 40% /-PrOH in n-Hexanes, 6.5 mL/min): 313a ^ = 51.1 min, 313b tR = 52.9 min.
Figure imgf000192_0002
314
4-(5-(4-Cyclohexylthiazol-2-yl)-6-ethyl-2-oxo-l,2,354-tetrahydropyrimidin-4-yl)-iV-(4- methoxybenzyl)benzamide (314)
1H NMR (400 MHz, CD3OD) δ 7.73 (d, J= 8.0 Hz, 2H), 7.39 (d, J= 8.4 Hz, 2H), 7.22 (d, J= 8.8 Hz, 2H), 6.86 (s, IH), 6.84 (d, J= 8.8 Hz, 2H), 5.60 (s, IH), 4.45 (s, 2H), 3.74 (s, 3H), 2.63 (m, 3H), 1.96 (m, 2H), 1.78 (m, 2H), 1.71 (m, IH), 1.44-1.33 (m, 4H), 1.26 (m, IH), 1.22 (t, J= 7.6 Hz, 3H); TLC i?/(CH2Cl2:Me0H 9:1) = 0.61.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 40% /-PrOH in «-Hexanes, 6.5 mL/min): 314a fø = 25.2 min, 314b tR = 35.6 min.
Figure imgf000193_0001
Methyl 4-((4-(5-(4-cyclohexylthiazol-2-yl)-6-ethyl-2-oxo-l,2,3,4-tetrahydropyrimidin-4- yl)benzamido)methy l)benzoate (315)
1H NMR (400 MHz, CD3OD) δ 7.95 (d, J= 8.4 Hz, 2H), 7.76 (d, J= 8.0 Hz, 2H), 7.41 (d, J= 8.0 Hz, 4H), 6.87 (s, IH), 5.61 (s, IH), 4.59 (s, 2H), 3.86 (s, 3H), 2.63 (m, 2H), 1.95 (m, 2H), 1.78 (m, 2H), 1.70 (m, IH), 1.44-1.34 (m, 4H), 1.26 (m, IH), 1.22 (t, J= 7.4 Hz, 3H); TLC Rf (CH2Cl2MeOH 9:1) = 0.50.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 40% z-PrOH in n-Hexanes, 6.5 niL/min): 315a fø = 27.6 min, 315b ΪR = 49.4 min.
Figure imgf000193_0002
iV-(CyclohexyImethyl)-4-(5-(4-cycIohexyIthiazoI-2-yl)-6-ethyl-2-oxo-l,2,3,4- tetrahydropyrimidin-4-yl)benzamide (316)
1H NMR (400 MHz, CD3OD) δ 7.69 (d, J= 8.4 Hz, 2H), 7.39 (d, J= 8.0 Hz, 2H), 6.87 (s, IH), 5.60 (s, IH), 3.16 (d, J= 7.2 Hz, 2H), 2.62 (m, 3H), 1.97 (m, 2H), 1.80-1.55 (m, 9H), 1.44-1.34(m, 4H), 1.26-1.16 (m, 7H), 1.94 (m, 2H); TLC ^/(CH2Cl2 :MeOH 9:1) = 0.54. Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 25% z-PrOH in n-Hexanes, 6.5 mL/min): 316a fø = 16.2 min, 316b fø = 23.6 min.
Figure imgf000194_0001
3-(5-(4-Cyclohexylthiazol-2-yl)-6-ethyl-2-oxo-l,2,3,4-tetrahydropyrimidin-4-yl)benzoic acid (317)
1U NMR (400 MHz, CD3OD) δ 8.00 (s, IH), 7.86 (d, J= 7.6 Hz, IH), 7.53 (d, J= 8.0 Hz, IH), 7.35 (t, J= 7.6 Hz, IH), 6.84 (s, IH), 5.61 (s, IH), 2.64 (q, J= 7.6 Hz, 3H), 1.96 (m, 2H), 1.78 (m, 2H), 1.70 (m, IH), 1.44-1.29 (m, 5H), 1.23 (t, J= 7.4 Hz, 3H); TLC R1 (CH2Cl2:Me0H 9:1) = 0.22.
Figure imgf000194_0002
Methyl 3-(5-(4-cyclohexylthiazol-2-yl)-6-ethyl-2-oxo-l,2,3?4-tetrahydropyrimidin-4- yl)benzoate (318)
1R NMR (400 MHz, CD3OD) δ 7.99 (s, IH), 7.86 (d, J= 7.6 Hz, IH), 7.56 (d, J= 7.6 Hz, IH), 7.38 (t, J= 7.8 Hz, IH), 6.85 (s, IH), 5.63 (s, IH), 3.85 (s, 3H), 2.65 (q, J= 7.6 Hz, 2H), 2.64 (m, IH), 1.98 (m, 2H), 1.79 (m, 2H), 1.71 (m, IH), 1.44-1.33 (m, 5H), 1.24 (t, J= 7.4 Hz, 3H); TLC i?/(CH2Cl2:Me0H 19:1) = 0.34.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 25% Z-PrOH in «-Hexanes, 6.5 mL/min): 318a tR = 15.3 min, 318b tR = 17.8 min.
Figure imgf000194_0003
iV-Benzyl-3-(5-(4-cycIohexylthiazoI-2-yl)-6-ethyl-2-oxo-l,2,3,4-tetrahydropyrimidiii-4- yl)benzamide (319)
1H NMR ^OO MHZ, CD3OD) δ 7.81 (t, J= 1.8 Hz, IH), 7.68 (td, J= 8.0, 1.4 Hz, IH), 7.48 (td, J= 7.6, 1.6 Hz, IH), 7.36 (t, J= 7.8 Hz, IH), 7.32-7.27 (m, 4H), 7.23 (m, IH), 6.85 (s, IH), 5.59 (s, IH), 4.53 (s, 2H), 2.64 (m, 3H), 1.93 (m, 2H), 1.76 (m, 2H), 1.69 (m, IH), 1.43- 1.27 (m, 5H), 1.22 (t, J= 7.6 Hz, 3H); TLC i?/(CH2Cl2:Me0H 9:1) = 0.50. Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 25% /-PrOH in n-Hexanes, 6.5 mL/min): 319a tR = 34.8 min, 319b tR = 39.9 min.
Figure imgf000195_0001
320
5-(4-CycIohexylthiazol-2-yl)-6-ethyl-4-(4-hydroxyphenyl)-3,4-dihydropyrimidine-2(lH)- thione (320)
1B. NMR (400 MHz, CD3OD) δ 7.12 (d, J= 8.8 Hz, 2H), 6.88 (s, IH), 6.67 (d, J= 8.4 Hz, 2H), 5.36 (s, IH), 2.69 (m, 3H), 1.97 (m, 2H), 1.80 (m, 2H), 1.71 (m, IH), 1.48-1.30 (m, 4H), 1.24 (m, IH), 1.22 (t, J= 7.4 Hz, 3H); TLC i?/(CH2Cl2:Me0H 9:1) = 0.54. Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 25% /-PrOH in n-Hexanes, 6.5 mL/min): 320a tR = 22.4 min, 320b tR = 25.7 min.
Figure imgf000195_0002
5-(4-Cyclohexyl-lJjr-imidazol-2-yl)-6-ethyl-4-(4-methoxyphenyl)-3,4-dib.ydropyrimidin- 2(lH)-one (321)
1H NMR (400 MHz, CD3OD) δ 7.08 (d, J= 8.4 Hz, 2H), 6.78 (d, J= 8.4 Hz, 2H), 6.59 (s, IH), 5.34 (s, IH), 3.72 (s, 3H), 2.45 (m, IH), 2.38 (m, IH), 2.13 (m, IH), 1.92 (m, 2H), 1.79- 1.76 (m, 3H), 1.36-1.26 (m, 5H), 1.07 (t, J= 7.6 Hz, 3H); LRMS (electrospray) m/z calculated for C22H28N4O2 (M+H)+ 381.48, found 381.27.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 25% /-PrOH in rc-Hexanes, 6.5 mL/min): 321a tR = 19.0 min, 321b tR = 24.0 min.
Figure imgf000196_0001
322
5-(4-Cyclohexyl-ljfir-imidazol-2-yl)-6-ethyl-4-(3-fluoro-4-hydroxyphenyl)-3,4- dihydropyrimidin-2(lJfiT)-one (322)
1H NMR (400 MHz, CD3OD) δ 6.83 (dd, J= 12.8, 2.0 Hz, IH), 6.79-6.75 (m, 2H), 6.62 (s, IH), 5.30 (s, IH), 2.50 (m, IH), 2.36 (m, IH), 2.11 (m, IH), 1.95 (m, 2H), 1.80-1.69 (m, 3H), 1.40-1.26 (m, 5H), 1.07 (t, J= 7.6 Hz, 3H); LRMS (electrospray) m/z calculated for C21H25FN4O2 (M+H)+ 385.45, found 385.35.
Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 5% i- PrOH and MeOH in «-Hexanes, 0.85 mL/min): 322a tR = 35.0 min, 322b tR = 42.0 min.
Figure imgf000196_0002
6-(6-(2-(Benzo[rf][l,3]dioxol-5-yl)ethyl)-5-(4-cyclohexylthiazoI-2-yl)-2-oxo-l,2,3,4- tetrahydropyrimidin-4-yl)-2H-benzo[Λ][l,4]oxazin-3(4H)-one (323)
1H NMR (400 MHz, CDCl3) δ 9.07 (brs, IH), 8.0 (brs, IH), 6.83-6.64 (m, 7H), 6.35 (brs, IH), 5.87 (s, 2H), 5.41 (s, IH), 4.48 (d, J= 4.4 Hz, 2H), 3.03-2.87 (m, 4H), 2.68 (m, IH), 2.02 (m, 2H), 1.79-1.70 (m, 3H), 1.37-1.20 (m, 5H) ; LRMS (electrospray) m/z calculated for C30H30N4O5S (M+H)+ 559.65, found 559.34. Enantiomerically pure forms were obtained by chiral HPLC (OD-H preparative column, 10- 25% r-PrOH in H-Hexanes, 0.85 mL/min): 323a tR = 39.0 min, 323b tR = 59.0 min.
Triazine scaffold analogs
General procedure for the synthesis of triazine subunit 1 analogs
Figure imgf000198_0001
To a solution of aryl ketone (5.87 mmol, 1.0 equiv) in anhydrous THF (10 mL) was added phenyltriniethylammonium tribromide (11.75 mmol, 2.0 equiv) in small portions over 10 min. A white precipitate forms and the solution becomes yellow over one hour. The suspension was filtered and rinsed with THF. The filtrate was concentrated in vacuo and then subjected to flash column chromatography to give desired dibromide A.
To a solution of the dibromide (1.0 equiv) in anhydrous THF (0.6 M ) under Ar was added neat morpholine (4.2 equiv) all at once at 25 0C. The resulting solution was slowly heated to 65 0C over 1 h and aged at this temperature for 24-96 h, at which a 97% conversion was typically obtained as determined by 1H NMR spectroscopy. After cooling to 25 0C, the suspension was filtered through a fritted funnel and the wet cake was washed with CHCl3. The combined filtrate was then concentrated to give the crude aminal intermediate B, which was used without further purification.
To a solution of crude aminal B in MeOH (0.6 M) under Argon was added all at once solid aminoguanidine bicarbonate (AGB, 1.0 equiv with respect to dibromide), followed by slow addition of neat AcOH (3.0 equiv) over 10-15 min at 25 0C. The resulting suspension was stirred at 25 °C for 2 h, at which time CO2 evolution ceased, and then slowly heated to reflux and aged for 24-48 h. After cooling to 25 0C, the resulting suspension was concentrated in vacuo. The residue was treated with H2O and small amount Of CH2Cl2 to precipitate aminotriazine, cooled to 0 0C, aged for 1 h, filtered through a fritted funnel and washed with cold MeOH:H2O (4:1). The collected solid was freeze dried in vacuo to give solely the 5- substituted-3 -aminotriazine.
General procedure for the preparation of substituted aryl methyl ketones
Figure imgf000198_0002
To a 0 0C solution of phenol derivatives (40.9 mmol, 1.0 equiv) and triflic anhydride (81.8 mmol, 2.0 equiv) in CH2Cl2 (40 mL) was added slowly pyridine (81.8 mmol, 2.0 equiv) and stirred at room temperature for 40 min. The reaction mixture was sequentially washed with brine (20 mL) and water (20 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via flash column chromatography on silica gel to give trifluoromethanesulfonates.
To a solution of above trifluoromethanesulfonate (7.95 mmol, 1.0 equiv) and triethylamine (15.9 mmol, 2.0 equiv) in DMF (22 mL) was added butyl vinyl ether (38.9 mmol, 5.0 equiv), l,3-bis(diphenylphosphinopropane) (0.22 mmol, 0.028 equiv), and palladium ( II ) acetate (0.20 mmol, 0.025 equiv) at room temperature. The reaction mixture was heated to 80 °C for 30 min and then cooled to 25 °C. The resulting mixture was treated with aqueous IN HCl (10 mL) and stirred for 30 min. The solution was extracted with CH2Cl2 (3 x 10 mL). The combined organic layers were washed with water (2 x 10 mL) and dried over Na2SO4. After filtration and concentration in vacuo, the residue was purified via flash column chromatography on silica gel to give aryl methyl ketones.
Figure imgf000199_0001
To a 0 °C solution of substituted aryl compound (24.97 mmol, 1.0 equiv) and TMEDA (34.96 mmol, 1.4 equiv) in THF (50 mL) was added slowly rø-BuLi (1.6 M in hexanes, 29.96 mmol, 1.2 equiv). The reaction mixture was warmed to 25 "C and stirred for 3 h. After cooled to 0 °C, the reaction was treated with DMF (49.94 mmol, 2.0 equiv) and stirred at room temperature for 30 min. The reaction was quenched by the addition of aqueous IN HCl and extracted with EtOAc (3 x). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified via flash column chromatography to give formylated products.
To a 0 0C solution of above formylated compounds (8.77 mmol, 1.0 equiv) in Et2O (29 mL) was added MeMgCl (2.97 M in THF, 13.15 mmol, 1.5 equiv). The reaction mixture was warmed to room temperature and further stirred for 4 h. The reaction was quenched by the addition of saturated aqueous NH4Cl and extracted with EtOAc (3 x). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified via flash column chromatography to give alcohol products.
To a solution of above alcohols (8.89 mmol, 1.0 equiv) in CH2Cl2 (10 mL) was added PCC (22.23 mmol, 2.5 equiv) and SiO2 (4.79 g) in CH2Cl2 (13 mL). The resulting suspension was stirred at 25 °C for 6 h. The reaction mixture was filtered through a pad of silica gel and then concentrated in vacuo. The residue was purified via flash column chromatography to give ketone compounds.
General procedure for the synthesis of nitrile substituted methyl ketones
Figure imgf000200_0001
To a 0 °C solution of hydroxy acetophenone derivatives (33.2 mmol, 1.0 equiv) in CH2Cl2 (110 mL) was added Et3N (43.3 mmol, 1.3 equiv) and stirred for 15 min. The reaction mixture was treated with Tf2O (43.3 mmol, 1.3 equiv) at 0 °C. The resulting solution was stirred at 25 0C for overnight. The reaction was quenched with H2O (20 mL). The reaction mixture was extracted with CH2Cl2 (3 x) and the combined organic layers were washed with brine and dried over MgSO4. After filtration and concentration in vacuo, the residue was purified via flash column chromatography on silica gel to give aryl triflates.
To a 0 0C solution of triflate compound (24.8 mmol, 1.0 equiv) and Zn(CN)2 (49.6 mmol, 2.0 equiv) in DMF (31 mL) was added Pd(PPh3)4 (0.744 mmol, 0.03 equiv). The suspension was stirred at 120 °C for 2 h. After cooling to 25 °C, the reaction mixture was quenched by the addition of saturated aqueous NaHCO3 (20 mL) and extracted with CH2Cl2 (3 x 30 mL) and dried over Na2SO4. After filtration and concentration in vacuo, the residue was purified via flash column chromatography on silica gel to give aryl nitriles.
General procedure for the conversion of methoxy to nitrile group
Figure imgf000201_0001
To a solution of starting material (0.74 mmol, 1.0 equiv) in dry CH2Cl2 (30 mL) was added dropwise BBr3 (7.4 mmol, 10 equiv) at 0 °C. The resulting solution was stirred at 25 °C for 15 h. The reaction was quenched by the addition of saturated aqueous NaHCO3 (10 mL) solution and extracted with CH2Cl2 (3 x 30 mL). The combined organic layers were dried over Na2SO4. After filtration and concentration in vacuo, the residue was purified via flash column chromatography on silica gel.
To a solution of hydroxy compound (0.41 mmol, 1.0 equiv) in pyridine (0.5 mL) was added slowly Tf2O (0.57 mmol, 1.4 equiv) at 0 0C. The resulting solution was stirred at 25 °C for 4 h, and then quenched with H2O (10 mL). The mixture was extracted with EtOAc (3 x 10 mL) and dried over Na2SO4. After filtration and concentration in vacuo, the residue was purified via flash column chromatography on silica gel.
To a solution of triflate compound (0.69 mmol, 1.0 equiv) and anhydrous Zn(CN)2 (2.75 mmol, 4.0 equiv) in DMF (7 mL) was added Pd(PPh3)4 (0.10 mmol, 0.15 equiv) at 25 °C. The suspension was stirred at 120 0C for 4 h under Ar. After cooled to 25 0C, the reaction mixture was quenched by the addition of saturated aqueous NaHCO3 (20 mL) and extracted with CH2Cl2 (3 x 30 mL) and dried over Na2SO4. After filtration and concentration in vacuo, the residue was purified via flash column chromatography on silica gel.
General procedure for the synthesis of biaryl subunit 1 analogs
Figure imgf000201_0002
X1 = Cl, Br, I, OTf X2 = Cl, , OH, NH2 To a solution of boronic acid (2.73 mmol, 1.2 equiv) and bromoaniline (2.27 mmol, 1.0 equiv) in toluene-H2O (5:2, v/v, 23 mL) was added Pd(PPh3)4 (0.060 mmol, 0.03 equiv), followed by sat. K2CO3 (16 mL) at 25 0C under Ar. The reaction mixture was heated to reflux (oil bath temp 120 0C) for overnight then cooled to ambient temperature. The solid was removed by filtration through a pad of celite, and the filtrate was poured into a separatory funnel. The layers were separated, and the aqueous layer was extracted with EtOAc (2 x 50 mL). The combined layers were dried over Na2SO4, filtered, concentrated in vacuo. The residue was purified via flash column chromatography on silica gel to give cross-coupled products.
Figure imgf000202_0001
To a solution of boronic acid (1.05 equiv), dichloropyrimidine (1.0 equiv), Pd2(dba)3 (0.02 equiv) and K3PO4 (3.0 equiv) in dioxane was added P(Z-Bu)3 (10wt% in hexanes, 0.04 equiv) at 25 ° C under Ar. The reaction mixture was stirred at 70 0C for overnight. After cooled to room temperature, the reaction was quenched by the addition of water and extracted with EtOAc (3 x). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified via flash column chromatography (SiO2, n- Hexanes-.EtOAc 9:1) to give Suzuki coupling products.
General procedure for the conversion of chloride to amino groups
Figure imgf000202_0002
A, , C = CH, N, or N=O Method A
1. PMB-NH21 NMP, 150 0C, 12 h 2. TFA Method B NH4OH, EtOH, 80 c C, 12 h
Method A p-Methoxy benzylamine (4.12 mmol, 10.0 equiv) and K2CO3 (2.47 mmol, 6.0 equiv) were added to a solution of biaryl chloride (0.41 mmol, 1.0 equiv) in NMP. The mixture was heated to 150 0C for overnight. After cooling to room temperature, the crude reaction mixture was extracted with EtOAc (3 x). The combined organic layers were washed with water (4 x), followed by brine (2 x) and then dried over Na2SO4. After filtration and concentration in vacuo, the residue was purified via flash column chromatography on silica gel to give PMB adducts.
A solution of above PMB compounds (1.141 mmol, 1.0 equiv) in TFA (8.5 mL, 0.1 equiv) was heated to 120 ° C for overnight. After cooled to room temperature, the crude reaction mixture was extracted with EtOAc (3 x). The combined organic layers were washed with saturated aqueous NaHCO3 (2 x) and dried over Na2SO4. After filtration and concentration in vacuo, the residue was purified via flash column chromatography on silica gel to give amino products.
Method B
A mixture of pyrimidine (2.510 mmol, 1.0 equiv), ethanol (8 mL) and NH4OH (28% in water, 25.1 mmol, 10 equiv) in a sealed tube was kept in an oil bath for 24 h at 80 0C. After cooled to 25 °C, the reaction mixture was concentrated under reduced pressure and then partitioned between CH2Cl2 (3 x) and water. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified via flash column chromatography on silica gel to give amino products.
General procedure for the conversion of chloride to propargylated amino groups
Figure imgf000203_0001
A = CH, N, or N=O
B = Me, CF3, Cl1 Br, CN
To a sealed tube was added pyrimidine (1.0 equiv), propargyl amine (3.0 equiv), and DMF (0.1 M). The reaction mixture was stirred for 3 h at 140 °C. After cooled to room temperature, the reaction was quenched by the addition of water and extracted with EtOAc (3 x). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified via flash column chromatography (SiO2, «-Hexanes: EtOAc 7:3).
To a solution of alkyne (1.0 equiv) and azide (1.2 equiv) in t-BuOH/H2O (1:1, 0.25 M) was added sodium ascorbate (0.1 equiv) and copper sulfate pentahydrate (0.01 equiv) and stirred for 2 h at 25 "C. The reaction was quenched by the addition of water and extracted with EtOAc (3 x). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was purified via flash column chromatography (SiO2, n- Hexanes:EtOAc 3:7).
Figure imgf000204_0001
324 5-Phenyl-l ,2,4-triazin-3-amine (324)
1H NMR (400 MHz, DMSOcfe) δ 9.22 (s, IH), 8.18-8.16 (m, 2H), 7.61-7.54 (m 3H), 7.24 (bs, 2H); 13C NMR (100 MHz, DMSO-^) δ 163.7, 155.5, 137.8, 134.7, 132.5, 129.7, 127.9; TLC ^7(CH2Cl2IMeOH 10:1) = 0.60.
Figure imgf000204_0002
2,2-Dibromo-l-(naphthalen-l-yl)ethanone (325)
1H NMR (400 MHz, CDCl3) δ 8.41 (d, J= 8.4 Hz, IH), 8.07 (d, J= 8.0 Hz, IH), 7.95-7.90 (m, 2H), 7.68-7.64 (m, IH), 7.60-7.57 (m, IH), 7.54-7.50 (m, IH), 6.83 (s, IH); 13C NMR (100 MHz, CDCl3) δ 188.6, 134.1, 133.9, 130.9, 130.4, 128.6, 127.5, 127.0, 125.4, 124.1, 42.3; TLC i?/(«-Hexanes:Et2O 2:1) = 0.49.
Figure imgf000204_0003
326 5-(6-Methoxynaphthalen-2-yl)-l,2,4-triazin-3-amine (326)
1H NMR (400 MHz, OMSO-d6) δ 9.30 (s, IH), 8.72 (s, IH), 8.19 (dd, J = 8.4, 1.6 Hz, IH), 7.96-7.93 (m, 2H), 7.39 (d, J= 2.0 Hz, IH), 7.23 (dd, J= 8.8, 2.4 Hz, IH), 7.18 (bs, 2H), 3.88 (s, 3H).
Figure imgf000205_0001
2,2-Dibromo-l-(4-tert-butylphenyl)ethanone
1H NMR (400 MHz, CDCl3) δ 8.01 (d, J= 8.4 Hz, 2H), 7.50 (d, J= 8.4 Hz, 2H), 6.67 (s, IH), 1.34 (s, 9H); 13C NMR (IOO MHz, CDCl3) δ 185.8, 158.8, 141.2, 129.9, 128.3, 126.2, 66.0, 40.1, 35.4, 32.1; TLC i?/(Hexanes:EtOAc 2:1) = 0.87.
Figure imgf000205_0002
5-(4-ferf-Butylphenyl)-l,2,4-triazin-3-amine (327)
1H NMR (400 MHz, OMSO-d6) δ 9.15 (s, IH), 8.07 (dd, J= 8.8, 4.0 Hz, 2H), 7.52 (dd, J= 5.4, 3.4 Hz, 2H), 7.16 (bs, 2H), 1.24 (s, 9H); 13C NMR (100 MHz, DMSO-^) δ 163.7, 155.5, 155.4, 137.7, 131.9, 127.8, 126.6, 35.4, 31.5; TLC Rf (CH2Cl2 :MeOH 10:1) = 0.40.
Figure imgf000205_0003
5-ø-TolyI-l ,2,4-triazin-3-amine (328)
1H NMR (400 MHz, OMSO-d6) δ 8.74 (s, IH), 7.47 (d, J= 7.2 Hz, IH), 7.40-7.37 (m, IH), 7.32-7.28 (m, 2H), 7.20 (bs, 2H), 2.38 (s, 3H); 13C NMR (100 MHz, DMSO-J15) δ 163.5, 159.3, 140.8, 137.0, 135.3, 131.8, 130.8, 130.1, 126.9, 20.7; TLC £/ (CH2Cl2: MeOH 10:1) = 0.40.
Figure imgf000205_0004
5-(Naphthalen-2-yl)-l,2,4-triazin-3-amine (329)
1U NMR (400 MHz, DMSO-J6) δ 9.35 (s, IH), 8.80 (s, IH), 8.23 (dd, J= 8.6, 1.4 Hz, IH), 8.06 (d, J= 13.8, 6.2 Hz, 2H) 7.99-7.97 (m, IH), 7.63-7.57 (m, 2H)5 7.25 (bs, 2H); TLC R1 (CH2Cl2:Me0H 10:1) = 0.73.
Figure imgf000206_0001
2,2-Dibromo-l-(4-chIorophenyl)ethanone
1H NMR (400 MHz, CDCl3) δ 8.05 (d, J= 8.4 Hz, 2H), 7.49 (d, J= 8.4 Hz, 2H), 6.60 (s, IH); 13C NMR (IOO MHz, CDCl3) δ 185.1, 141.3, 131.4, 129.5, 129.3, 39.5; TLC Rf(n- Hexanes:EtOAc 2:1) = 0.87.
Figure imgf000206_0002
5-(4-Chlorophenyl)-l,2,4-triazin-3-amine (330)
1H NMR (400 MHz, DMS(W6) δ 9.19 (s, IH), 8.14 (d, J= 8.4 Hz, 2H), 7.57 (d, J= 8.4 Hz, 2H), 7.25 (bs, 2H); 13C NMR (100 MHz, DMSO-J6) δ 163.7, 154.4, 137.6, 137.4, 133.5, 129.8, 129.7; TLC Rf (CH2Cl2MeOH 10:1) = 0.40.
Figure imgf000206_0003
2,2-Dibromo-l-(2,4-dimethylphenyl)ethanone
1H NMR (400 MHz, CDCl3) δ 7.62 (d, J= 8.4 Hz, IH), 7.14 (bs, IH), 7.09 (d, J= 8.0 Hz, IH), 6.69 (s, IH), 2.50 (s, 3H), 2.38 (s, 3H); TLC i?/(Hexanes:Et2O 5:1) = 0.61.
Figure imgf000206_0004
S-(2,4-DimethylphenyI)-l,2,4-triazin-3-amine (331)
1H NMR (400 MHz, DMSO-J6) δ 8.72 (s, IH), 7.39 (d, J= 8.0 Hz, IH), 7.15-7.10 (m, 4H), 2.36 (s, 3H), 2.29 (s, 3H); 13C NMR (100 MHz, DMSO-J6) δ 163.4, 159.2, 140.7, 140.5, 137.0, 132.6, 132.4, 130.2, 127.5, 21.5, 20.8; TLC Rf (CH2Cl2: MeOH 20:1) = 0.36.
2,2-Dibromo-l-(4-ethylphenyl)ethanone
1H NMR (400 MHz, CDCl3) δ 8.01 (d, J= 8.0 Hz, 2H), 7.33 (d, J= 8.0 Hz, 2H), 6.70 (s, IH), 2.74 (q, J= 7.6 Hz, 2H), 1.28 (t, J= 7.6 Hz, 3H); TLC i?/(«-Hexanes:Et2O 2:1) = 0.66.
Figure imgf000207_0002
5-(4-EthyIphenyl)-l,2,4-triazin-3-amine (332)
1H NMR (400 MHz, DMSO-^6) δ 9.16 (s, IH), 8.06 (d, J= 8.0 Hz, 2H), 7.36 (d, J= 8.0 Hz, 2H), 7.15 (bs, 2H), 2.64 (q, J= 7.6 Hz, 2H), 1.17 (t, J= 7.6 Hz, 3H); 13C NMR (100 MHz, DMSO-^6) δ 163.7, 155.5, 148.8, 137.7, 132.1, 129.2, 128.0, 28.8, 15.9; TLC R1 (CH2Cl2:Me0H 20:1) = 0.23.
Figure imgf000207_0003
2,2-Dibromo-l-(4-bromophenyl)ethanone
1H NMR (400 MHz, CDCl3) δ 7.99-7.96 (m, 2H), 7.67-7.65 (m, 2H), 6.59 (s, IH); TLC Rf(n- Hexanes:Et2O 2:1) = 0.69.
Figure imgf000207_0004
5-(4-BromophenyI)-l,2,4-triazin-3-amine (333)
1H NMR (400 MHz, DMSO-^5) δ 9.20 (s, IH), 8.09 (d, J= 8.4 Hz, 2H), 7.75 (d, J= 8.4 Hz, 2H), 7.25 (bs, 2H); TLC R1 (CH2Cl2: MeOH 20:1) = 0.27.
Figure imgf000207_0005
2,2-Dibromo-l-(2-(trifluoromethyl)phenyI)ethanone
1H NMR (400 MHz, CDCl3) δ 7.79-7.75 (m, IH), 7.72-7.68 (m, IH), 7.68-7.64 (m, 2H)5 6.45 (s, IH); TLC i?/(Hexanes:Et2O 2:1) = 0.45.
Figure imgf000208_0001
5-(2-(Trifluoromethyl)phenyl)-l,2,4-triazin-3-amine (334)
1U NMR (400 MHz, DMSO-J6) δ 8.66 (s, IH), 7.89 (d, J= 7.6 Hz, IH), 7.81-7.78 (m, IH), 7.75-7.71 (m, IH), 7.60 (d, J= 7.2 Hz, IH), 7.35 (bs, 2H); TLC ^(CH2Cl2=MeOH 20:1) = 0.31.
Figure imgf000208_0002
5-/j-Tolyl-l,2,4-triazin-3-amine (335)
1H NMR (400 MHz, DMSO-J6) δ 9.15 (s, IH), 8.04 (d, J= 7.2 Hz, 2H), 7.33 (d, J= 7.6 Hz,
2H), 7.15 (bs, 2H), 2.34 (s, 3H); 13C NMR (100 MHz, DMSO-J6) δ 163.7, 155.4, 142.7, 137.6,
131.8, 130.4, 127.9, 21.7.
Figure imgf000208_0003
l-(2-(Benzyloxy)phenyl)ethanone
1H NMR (400 MHz, CDCl3) δ 7.75-7.45 (m, IH), 7.44-7.33 (m, 6H), 7.02-6.98 (m, 2H), 5.14 (s, 2H), 2.59 (s, 3H); TLC #/(rc-Hexanes:EtOAc 3:1) = 0.37.
Figure imgf000208_0004
l-(2-(Benzyloxy)phenyl)-2,2-dibromoethanone
1H NMR (400 MHz, CDCl3) δ 7.86-7.83 (m, IH), 7.54-7.39 (m, 6H), 7.10-7.04 (m, 3H), 5.21 (s, 2H); TLC i?/(n-Hexanes:EtOAc 3:1) = 0.42.
Figure imgf000209_0001
5-(2-(Benzyloxy)phenyI)-l,2,4-triazin-3-amine
1H NMR (400 MHz, DMSO-J6) δ 9.02 (s, IH), 7.83 (s, IH), 7.50-7.28 (m, 6H), 7.11 (s, 4H), 5.22 (s, 2H).
Figure imgf000209_0002
2,2-Dibromo-l-(2-chlorophenyl)ethanone
1H NMR (400 MHz, CDCl3) δ 7.59 (dd, J= 7.2, 1.2 Hz, IH), 7.46-7.42 (m, 2H), 7.38-7.34 (m, IH), 6.74 (s, IH); 13C NMR (100 MHz, CDCl3) δ 189.0, 134.2, 133.2, 131.3, 131.1, 130.7, 127.4, 42.3; TLC i?/(rc-Hexanes:EtOAc 2:1) = 0.43.
Figure imgf000209_0003
5-(2-ChIorophenyl)-l,2,4-triazin-3-amine
1H NMR (400 MHz, DMSO-J6) δ 8.81 (s, IH), 7.59-7.58 (m, 2H), 7.54-7.47 (m, 2H), 7.35 (bs, 2H); 13C NMR (100 MHz, DMSO-J6) δ 163.7, 157.0, 140.8, 134.7, 132.5, 132.0, 131.8, 130.8, 128.4.
Figure imgf000209_0004
5-(3-MethoxyphenyI)-l,2,4-triazin-3-amine
1H NMR (400 MHz, OMSO-d6) δ 9.19 (s, IH), 7.71 (d, J= 8.0 Hz, IH), 7.66 (s, IH), 7.43 (t, J= 8.0 Hz, IH), 7.20 (bs, 2H), 7.12 (dd, J= 8.0, 2.4 Hz, IH), 3.80 (s, 3H); 13C NMR (100 MHz, OMSO-d6) δ 163.7, 160.4, 155.3, 137.9, 136.1, 130.9, 120.3, 118.4, 112.8, 56.0.
Figure imgf000210_0001
2,2-Dibromo-l-(2,5-dimethoxyphenyl)ethanone
1H NMR (400 MHz, CDCl3) δ 7.34 (d, J= 3.2 Hz, IH), 7.01 (s, IH), 7.07 (dd, J= 3.2, 0.8 Hz, IH), 6.91 (d, J= 9.2 Hz, IH), 3.88 (s, 3H), 3.78 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 187.7, 154.1, 153.0, 122.5, 115.7, 113.5, 56.7, 56.1, 44.8; TLC /?/(rc-Hexanes:EtOAc 5:1) = 0.49.
Figure imgf000210_0002
5-(2,5-Dimethoxyphenyl)-l,2,4-triazin-3-amine
1H NMR (400 MHz, DMSO-^5) δ 9.01 (s, IH), 7.39 (d, J= 2.8 Hz, IH), 7.13 (bs, 2H), 7.09- 7.08 (m, 2H), 3.80 (s, 3H), 3.72 (s, 3H); 13C NMR (100 MHz, OMSO-d6) δ 164.0, 155.3, 154.0, 152.8, 141.3, 124.3, 118.9, 115.6, 114.4, 56.9, 56.2.
Figure imgf000210_0003
2,2-Dibromo-l-(2,5-dimethylphenyl)ethanone
1H NMR (400 MHz, CDCl3) δ 7.44 (s, IH), 7.26 (dd, J= 5.4, 2.2 Hz, IH), 7.20 (d, J= 8.0 Hz, IH), 6.69 (s, IH), 2.47 (s, 3H), 2.37 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 188.9, 137.2, 135.6, 133.7, 132.4, 132.3, 128.6, 42.6, 21.1, 20.7; TLC i?/(«-Hexanes:EtOAc 5:1) = 0.70.
Figure imgf000210_0004
5-(2,5-DimethylphenyI)-l,2,4-triazin-3-amine 1H NMR (400 MHz, OMSO-Cl6) δ 8.72 (s, IH), 7.28 (s, IH), 7.20-7.18 (m, 4H), 2.32 (s, 3H), 2.28 (s, 3H); 13C NMR (IOO MHz, DMSO-J6) δ 163.5, 159.3, 140.8, 135.9, 135.1, 133.8, 131.8, 131.4, 130.5, 21.0, 20.2.
Figure imgf000211_0001
l-(2-EthyIphenyl)ethanone
1H NMR (400 MHz, CDCl3) δ 7.62 (dd, J= 8.0, 1.6 Hz, IH), 7.40 (dt, J= 7.2, 1.2 Hz, IH), 7.29-7.23 (m, 2H), 2.87 (q, J= 7.6 Hz, 2H), 2.58 (s, 3H), 1.22 (t, J= 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 202.3, 144.2, 137.9, 131.4, 130.4, 128.9, 125.6, 29.9, 27.0, 15.9; TLC R1 («-Hexanes:Et2O 5:1) = 0.51.
Figure imgf000211_0002
2,2-Dibromo-l-(2-ethylphenyl)ethanone
1H NMR (400 MHz, CDCl3) δ 7.63 (dd, J= 7.6 Hz, IH), 7.49 (dt, J= 7.6, 1.2 Hz, IH), 7.37 (d, J= 7.2 Hz, IH), 7.30-7.28 (m, IH), 6.66 (s, IH), 2.82 (q, J= 7.2 Hz, 2H), 1.27 (t, J= 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 189.0, 146.0, 132.7, 132.3, 130.7, 127.8, 125.7, 42.3, 27.0, 15.8; TLC i?/(«-Hexanes:Et2O 5:1) = 0.54.
Figure imgf000211_0003
5-(2-EthylphenyI)-l,2,4-triazin-3-amine
1H NMR (400 MHz, CDCl3) δ 8.68 (s, IH), 7.42-7.29 (m, 4H), 7.20 (bs, 2H), 2.71 (q, J= 7.6 Hz, 2H), 1.00 (t, J= 7.2 Hz, 3H); TLC R1 (CH2Cl2 :MeOH 20:1) = 0.31.
Figure imgf000211_0004
l-(2-Isopropylphenyl)ethanone 1H NMR (400 MHz, CDCl3) δ 7.48 (bd, J= 7.6 Hz, IH), 7.42-7.41 (m, 2H), 7.25-7.21 (m, IH), 3.51-3.41 (m, IH), 2.57 (s, 3H), 1.24 (d, J= 6.8 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ D203.7, 147.7, 138.9, 131.0, 127.6, 126.5, 125.4, 30.7, 29.2, 24.1; TLC Λ/(»-Hexanes:Et2O 5:1) = 0.53.
Figure imgf000212_0001
2,2-Dibromo-l-(2-isopropyIphenyl)ethanone
1H NMR (400 MHz, CDCl3) δ 7.53-7.44 (m, 3H), 7.28-7.23 (m, IH), 6.59 (s, IH), 3.20 (h, J = 6.8 Hz, IH), 1.28 (d, J= 6.4 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 189.9, 149.6, 133.0, 132.3, 127.0, 126.7, 125.5, 42.9, 30.2, 24.2; TLC i?/(n-Hexanes:Et2O 5:1) = 0.69.
Figure imgf000212_0002
5-(2-Isopropylphenyl)-l,2,4-triazin-3-amine
1H NMR (400 MHz, DMSO-J6) δ 8.59 (s, IH), 7.43 (bs, 2H), 7.26 (bs, 2H), 7.19 (bs, 2H), 4.02 (bs, IH), 1.10 (d, J= 6.8 Hz, 6H); TLC R1 (CH2Cl2 :MeOH 20:1) = 0.43.
Figure imgf000212_0003
2,2-Dibromo-l-(4-methoxyphenyl)ethanone
1H NMR (400 MHz, CDCl3) δ 8.06-8.04 (m, 2H), 6.96-6.94 (m, 2H), 6.64 (s, IH), 3.87 (s, 3H); TLC i?/(π-Hexanes:EtOAc 5:1) = 0.48.
Figure imgf000212_0004
5-(4-Methoxyphenyl)-l,2,4-triazin-3-amine
1H NMR (400 MHz, DMSO-^) δ 9.13 (s, IH), 8.12 (d, J- 7.6 Hz, 2H), 7.07 (s, 4H), 3.80 (s, 3H).
Figure imgf000213_0001
2,2-Dibromo-l-(2-methoxyphenyl)ethanone
1H NMR ^OO MHZ, CDCl3) 6 7.85 (dd, J= 7.6, 1.6 Hz, IH), 7.57-7.53 (m, IH), 7.10 (s, IH), 7.09-7.05 (m, IH), 7.00 (d, J= 8.4 Hz, IH), 3.97 (s, 3H); 13C NMR (100 MHz, CDCl3) 6 187.8, 158.2, 135.2, 132.6, 122.2, 121.4, 111.7, 56.0, 44.7; TLC 7?/(rc-Hexanes:Et2O 5:1) = 0.39.
Figure imgf000213_0002
5-(2-Methoxyphenyl)-l,2,4-triazin-3-amine
1H NMR (400 MHz, DMSO-J6) δ 9.00 (s, IH), 7.80 (dd, J = 7.6, 1.6 Hz, IH), 7.53-7.48 (m, IH), 7.17 (d, J = 8.4 Hz, IH), 7.11 (bs, 2H), 7.10-7.06 (m, IH), 3.86 (s, 3H); 13C NMR (100 MHz, DMSO-J6) δ 164.0, 158.5, 155.7, 141.4, 133.5, 131.2, 121.6, 112.9, 56.5; TLC Rf (CH2Cl2MeOH 20:1) = 0.22.
Figure imgf000213_0003
l-(4-(Benzyloxy)phenyl)ethanone
1H NMR (400 MHz, CDCl3) δ 7.94-7.92 (m, 2H), 7.44-7.33 (m, 5H), 7.02-6.99 (m, 2H), 5.12 (s, 2H), 2.54 (s, 3H); TLC i?/(«-Hexanes:EtOAc 5:1) = 0.45.
Figure imgf000213_0004
l-(4-(Benzyloxy)phenyI)-2,2-dibromoethanone
1H NMR (400 MHz, CDCl3) δ 8.05-8.03 (m, 2H), 7.39-7.34 (m, 5H), 7.03-7.00 (m, 2H), 6.63 (s, IH), 5.13 (s, 2H); TLC i?/(n-Hexanes:EtOAc 3:1) = 0.53.
Figure imgf000214_0001
5-(4-(Benzyloxy)phenyI)-l,2,4-triazin-3-amine
1H NMR (400 MHz, DMSO-J6) δ 9.13 (s, IH), 8.12 (d, J= 8.8 Hz, IH), 7.83 (d, J= 8.0 Hz, 2H), 7.39-7.29 (m, 6H), 7.18-7.07 (m, 2H), 5.21 (s, 2H).
Figure imgf000214_0002
2,2-Dibromo-l-/M-toIylethanone
1U NMR (400 MHz, CDCl3) δ 7.87-7.86 (m, 2H), 7.46-7.36 (m, 3H), 6.72 (s, IH), 2.44 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 186.4, 139.2, 135.5, 131.1, 130.3, 129.0, 127.0, 40.0, 21.6; TLC i?/(π-Hexanes:Et2O 10:1) = 0.54.
Figure imgf000214_0003
5-m-Tolyl-l,2,4-triazin-3-amine
1H NMR (400 MHz, DMSO-^6) δ 9.20 (s, IH), 8.00 (s, IH), 7.95 (d, J= 7.6 Hz, IH), 7.44- 7.37 (m, 2H), 7.23 (s, 2H); 13C NMR (100 MHz, DMSO-^6) δ 136.1, 154.9, 138.4, 137.2, 133.9, 132.4, 128.9, 127.7, 124.4, 21.0; TLC ^7(CH2Cl2 :MeOH 20:1) = 0.28.
Figure imgf000214_0004
2,2-Dibromo-l-(2-fluorophenyl)ethanone
1H NMR (400 MHz, CDCl3) δ 7.99 (t, J= 7.6 Hz, IH), 7.64-7.59 (m, IH), 7.31 (t, J= 7.8 Hz, IH), 7.23-7.15 (m, IH), 6.85 (d, J= 2.4 Hz, IH); 13C NMR (100 MHz, CDCl3) δ 184.5, 159.9, 136.3, 134.1, 125.4, 117.1, 116.9, 43.3; TLC i?/(«-Hexanes:Et2O 10:1) = 0.54.
Figure imgf000214_0005
5-(2-FIuorophenyI)-l,2,4-triazin-3-amine
1H NMR (400 MHz, DMSO-J6) δ 9.20 (s, IH), 8.00-7.97 (m, IH), 7.64-7.57 (m, IH), 7.46- 7.27 (m, 4H); 13C NMR (IOO MHz, DMSO-J6) δ 163.9, 159.9, 153.1, 140.3, 134.3, 131.2, 125.9, 123.0, 117.4; TLC ^y(CH2Cl2=MeOH 20:1) - 0.28.
Figure imgf000215_0001
2,2-Dibromo-l-(3-fluorophenyl)ethanone
1H NMR (400 MHz, CDCl3) δ 7.89 (d, J= 7.6 Hz, IH), 7.79 (dt, J= 8.8, 2.0 Hz IH), 7.50 (m, IH), 7.35 (td, J= 8.2, 2.8 Hz, IH), 6.63 (d, J= 1.2 Hz, IH); TLC i?/(«-Hexanes:EtOAc 4:1) = 0.90.
Figure imgf000215_0002
5-(3-Fluorophenyl)-l,2,4-triazin-3-amine
1H NMR (400 MHz, CDCl3) δ 9.10 (s, IH), 7.84 (s, 2H), 7.51 (m, IH), 7.26 (s, IH), 5.38 (bs, 2H); TLC i?/(CH2Cl2:Me0H 19:1) = 0.39.
Figure imgf000215_0003
2,2-Dibromo-l-(3-chlorophenyl)ethanone
1H NMR (400 MHz, CDCl3) δ 8.06 (s, IH), 7.98 (d, J= 7.6 Hz, IH), 7.61 (d, J= 8.4 Hz, IH), 7.46 (t, J= 8.0 Hz, IH), 6.61 (s, IH); 13C NMR (100 MHz, CDCl3) δ 185.0, 135.5, 134.6, 132.6, 130.4, 130.0, 128.0, 39.2; TLC i?y(n-Hexanes:Et2O 5:1) = 0.63.
Figure imgf000215_0004
5-(3-Chlorophenyl)-l,2,4-triazin-3-amine 1H NMR (400 MHz, DMSO-J6) δ 9.27 (s, IH), 8.21 (s, IH), 8.13 (d, J= 7.6 Hz, IH), 7.66- 7.63 (m, IH), 7.58 (t, J= 7.8 Hz, IH), 7.32 (s, 2H); 13C NMR (100 MHz, OMSO-d6) δ 163.0, 153.4, 137.2, 136.2, 134.0, 131.5, 131.0, 126.9, 125.9; TLC i?/(CH2Cl2:Me0H 20:1) = 0.29.
Figure imgf000216_0001
2,2-Dibromo-l-(3-(trifluoromethyl)phenyl)ethanone
1H NMR (400 MHz, CDCl3) δ 8.36 (s, IH), 8.32 (d, J= 7.6 Hz, IH), 7.90 (d, J= 7.6 Hz, IH), 7.67 (t, J= 8.0 Hz, IH), 6.62 (s, IH); 13C NMR (IOO MHz, CDCl3) δ 185.0, 133.1, 131.7, 130.98, 130.95, 129.8, 126.96, 126.93, 39.1; TLC i?/(«-Hexanes:Et2O 10:1) = 0.48.
Figure imgf000216_0002
5-(3-(Trifluoromethyl)phenyl)-l,2,4-triazin-3-amine
1H NMR (400 MHz, DMSO-J6) δ 9.36 (s, IH), 8.23 (d, J= 8.0 Hz, IH), 8.18 (s, IH), 7.97 (d, J= 8.0 Hz, IH), 7.77 (t, J= 8.0 Hz, IH), 7.38 (s, 2H); TLC ^(CH2Cl2MeOH 20:1) = 0.26.
Figure imgf000216_0003
l-(3-(Benzyloxy)phenyl)ethanone
1H NMR (400 MHz, CDCl3) δ 7.56 (m, 2H), 7.39 (m, 6H), 7.18 (m, IH), 5.11 (s, 2H), 2.59 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 197.9, 158.9, 138.5, 136.5, 129.6, 128.6, 128.1, 127.5, 121.3, 120.3, 113.5, 70.2, 26.7; TLC i?/(«-Hexanes:EtOAc 4:1) = 0.53.
Figure imgf000216_0004
l-(3-(Benzyloxy)phenyl)-2,2-dibromoethanone
1U NMR (400 MHz, CDCl3) δ 7.66 (m, 2H), 7.42 (m, 6H), 7.25 (m, IH), 6.67 (s, IH), 5.12 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 186.0, 159.3, 136.4, 132.3, 130.2, 128.9, 128.5, 122.4, 122.0, 115.4, 70.6, 39.8; TLC i?/(n-Hexanes:EtOAc 19:1) = 0.47.
Figure imgf000217_0001
5-(3-(BenzyIoxy)phenyl)-l,2,4-triazin-3-amine
1H NMR (400 MHz3 CDCl3) δ 9.08 (s, IH), 7.73 (s, IH), 7.65 (d, J= 7.0 Hz, IH), 7.42 (m, 6H), 7.17 (dd, J= 8.4, 1.6 Hz, IH), 5.40 (bs, 2H), 5.16 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 162.6, 159.4, 156.2, 138.8, 136.5, 135.3, 130.3, 128.7, 128.2, 127.5, 120.0, 118.9, 113.5, 70.3; TLC ^/(CH2Cl2MeOH 9:1) = 0.45.
Figure imgf000217_0002
l-(2,6-Dimethylphenyl)ethanol
1H NMR (400 MHz, CDCl3) δ 7.08-6.91 (m, 3H), 5.39-5.34 (m, IH), 2.43 (s, 6H), 1.52 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 140.5, 135.6, 129.4, 126.8, 67.6, 21.4, 20.6; TLC i?/(«-Hexanes:Et2O 2:1) = 0.49.
Figure imgf000217_0003
l-(2,6-DimethylphenyI)ethanone
1H NMR (400 MHz, CDCl3) δ 7.15 (t, J= 7.6 Hz, IH), 7.10 (d, J= 7.6 Hz, 2H), 2.47 (s, 3H), 2.25 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 208.4, 142.6, 132.2, 128.5, 127.7, 32.1, 19.1; TLC i?/(«-Hexanes:Et2O 2:1) = 0.59.
Figure imgf000217_0004
2,2-Dibromo-l-(2,6-dimethyIphenyl)ethanone
1U NMR (400 MHz, CDCl3) δ 7.26 (t, J= 1.6 Hz, IH), 7.08 (d, J= 7.6 Hz, 2H), 6.31 (s, IH), 2.35 (s, 6H); 13C NMR (IOO MHz, CDCl3) δ 192.8, 135.8, 135.0, 130.4, 128.2, 44.0, 20.2; TLC i?/(«-Hexanes:Et2O 5:1) = 0.61.
Figure imgf000218_0001
5-(2,6-Dimethylphenyl)-l,2,4-triazin-3-amine
1H NMR (400 MHz, CD3OD) δ 8.46 (s, IH), 7.23 (t, J= 7.6 Hz, IH), 7.11 (d, J= 7.6 Hz, 2H), 2.09 (s, 6H); 13C NMR (IOO MHz, MeOH-^) δ 163.5, 161.8, 141.1, 135.4, 135.0, 129.2, 127.8, 18.8; TLC i?/(CH2Cl2:Me0H 20:1) = 0.32.
Figure imgf000218_0002
2,2-Dibromo-l-(3-ethylphenyl)ethanone
1H NMR (400 MHz, CDCl3) δ 7.89 (d, J= 8.8 Hz, 2H), 7.48 (d, J= 7.6 Hz, IH), 7.42 (t, J= 7.4 Hz, IH), 6.73 (s, IH), 2.73 (q, J= 7.6 Hz, 2H), 1.28 (t, J= 7.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 186.2, 145.2, 134.2, 130.9, 129.1, 128.8, 127.0, 39.8, 28.7, 15.3; TLC Rf(n- Hexanes:EtOAc 19:1) = 0.54.
Figure imgf000218_0003
5-(3-Ethylphenyl)-l,2,4-triazin-3-amine
1H NMR (400 MHz, DMSO-^6) δ 9.18 (s, IH), 7.99 (s, IH), 7.94 (d, J= 7.2 Hz, IH), 7.41 (m, 2H), 7.18 (bs, 2H), 2.66 (q, J= 7.6 Hz, 2H), 1.19 (t, J= 7.6 Hz, 3H); 13C NMR (100 MHz, DMSO-dβ) δ 163.1, 155.0, 144.7, 137.2, 134.0, 131.3, 129.0, 126.5, 124.7, 28.1, 15.5; TLC Rf (CH2Cl2:Me0H 19:1) = 0.39.
Figure imgf000218_0004
5-(2,3-Dimethoxyphenyl)-l,2,4-triazin-3-amme
1H NMR (400 MHz, DMSO-^) δ 8.89 (s, IH), 7.30 (dd, J= 7.4, 1.4 Hz, IH), 7.23-7.17 (m, 5H), 3.84 (s, 3H), 3.73 (s, 3H); TLC i?/(«-Hexanes:EtOAc 1 :2) = 0.33.
Figure imgf000219_0001
l-(2,3-Dimethylphenyl)ethanoI
1H NMR (400 MHz, CDCl3) δ 7.36 (d, J= 7.6 Hz, IH), 7.12 (t, J= 7.6 Hz, IH ), 7.06 (d, J = 6.8 Hz, IH), 5.19-5.16 (m, IH), 2.27 (s, 3H), 2.22 (s, 3H), 1.68 (d, J= 3.2 Hz, IH), 1.45 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 143.9, 137.1, 133.1, 129.1, 126.0, 122.4, 67.4, 24.2, 20.8, 14.7; TLC i?/(«-Hexanes: EtOAc 5:1) = 0.43.
Figure imgf000219_0002
l-(2,3-Dimethylphenyl)ethanone
1K NMR (400 MHz, CDCl3) δ 7.39 (d, J= 7.6 Hz, IH), 7.25 (d, J= 6.4 Hz, IH ), 7.14 (t, J= 7.6 Hz, IH), 2.56 (s, 3H), 2.35 (s, 3H), 2.31 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 204.0, 140.1, 138.5, 135.5, 132.7, 125.9, 125.4, 30.6, 20.6, 16.7; TLC i?/(rc-Hexanes:EtOAc 5:1) = 0.58.
Figure imgf000219_0003
2,2-Dibromo-l-(2,3-dimethylphenyl)ethanone
1H NMR (400 MHz, CDCl3) δ 7.37 (d, J= 7.6 Hz, IH), 7.33 (d, J= 7.6 Hz, IH ), 7.17 (t, J= 7.8 Hz, IH), 6.61 (s, IH), 2.34 (s, 3H), 2.33 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 190.2, 139.0, 137.3, 134.4, 133.9, 125.5, 125.0, 43.2, 20.7, 16.8; TLC i?/(«-Hexanes:EtOAc 5:1) = 0.79.
Figure imgf000219_0004
5-(2,3-DimethylphenyI)-l,2,4-triazin-3-amine
1H NMR (400 MHz,
Figure imgf000219_0005
δ 8.65 (s, IH), 7.29 (d, J= 5.6 Hz, IH), 7.21-7.17 (m, 5H), 2.28 (s, 3H), 2.22 (s, 3H).
Figure imgf000220_0001
l-(2-Phenoxyphenyl)ethanone
1H NMR (400 MHz, CDCl3) δ 7.85 (dd, J= 7.8, 1.8 Hz, IH), 7.45-7.35 (m, 3H), 7.19-7.13 (m, 2H), 7.02 (d, J= 7.6 Hz, 2H), 6.91 (d, J= 8.0 Hz, IH), 2.65 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 199.2, 156.7, 156.6, 133.8, 130.73, 130.71, 130.2, 124.1, 123.7, 119.5, 119.1, 31.8; TLC _K/(/»-Hexanes:Et2O 10:1) = 0.34.
Figure imgf000220_0002
2,2-Dibromo-l-(2-phenoxyphenyl)ethanone
1H NMR (400 MHz, CDCl3) δ 7.94 (dd, J= 8.0, 2.0 Hz, IH), 7.18-7.41 (m, 3H), 7.27-7.23 (m, 2H), 7.18 (s, IH), 7.16-7.11 (m, 2H), 6.83 (d, J= 7.6 Hz, IH); 13C NMR (100 MHz, CDCl3) δ 187.4, 156.9, 155.0, 135.1, 132.9, 130.5, 125.4, 123.8, 123.6, 120.5, 117.6, 44.8; TLC Rf(n- Hexanes:Et2O 10:1) = 0.39.
Figure imgf000220_0003
5-(2-PhenoxyphenyI)-l,2,4-triazin-3-amine
1H NMR (400 MHz, DMSO-J6) δ 8.99 (s, IH), 7.94 (dd, J= 8.0, 1.6 Hz, IH), 7.57-7.53 (m, IH), 7.40-7.32 (m, 3H), 7.27 (br, 2H), 7.14 (t, J= 7.4 Hz, IH), 7.02 (m, 3H); 13C NMR (100 MHz, DMSO-^6) δ 163.4, 156.2, 154.7, 154.4, 140.1, 132.9, 131.1, 130.2, 126.3, 124.3, 119.5, 118.4; TLC i?/(CH2Cl2:Me0H 20:1) = 0.34.
Figure imgf000220_0004
2,2-Dibromo-l-(4-fluorophenyl)ethanone 1H NMR (400 MHz, CDCl3) δ 8.17-8.14 (m, 2H), 7.19 (t, J= 8.4 Hz, 2H), 6.62 (t, J - 2.0 Hz, IH); 13C NMR (I OO MHZ, CDCl3) δ 184.5, 167.6, 165.0, 132.7 (d, J= 38.4 Hz), 127.1, 116.2 (d, J= 89.2 Hz), 39.3; TLC i?/(«-Hexanes:Et2O 5:1) = 0.61.
Figure imgf000221_0001
5-(4-Fluorophenyl)-l,2,4-triazin-3-amine
1H NMR (400 MHz, DMSO-^) δ 9.20 (s, IH), 8.24-8.20 (m, 2H), 7.28 (t, J- 8.8 Hz, 2H), 7.22 (bs, 2H); 13C NMR (IOO MHz, DMS(Mj) δ 166.3, 163.6, 154.5, 137.6, 131.2 (d, J= 12.0 Hz), 130.5 (d, J= 36.0 Hz), 116.8 (d, J= 86.0 Hz); TLC R1 (CH2Cl2:Me0H 20:1) = 0.44.
Figure imgf000221_0002
l-(Biphenyl-4-yl)-2,2-dibromoethanone
1H NMR (400 MHz, CDCl3) δ 8.17 (dt, J= 8.8, 2.0 Hz, 2H), 7.74-7.71 (m, 2H), 7.65-7.62 (m, 2H), 7.51-7.46 (m, 2H), 7.45-7.40 (m, IH), 6.72 (s, IH); 13C NMR (100 MHz, CDCl3) δ 185.6, 147.2, 139.3, 130.3, 129.4, 129.1, 128.6, 127.5, 127.3, 39.7; TLC i?/(«-Hexanes:Et2O 5:1) = 0.61.
Figure imgf000221_0003
5-(Biphenyl-4-yl)-l,2,4-triazin-3-amine
1B. NMR (400 MHz, DMSO-fife) δ 9.24 (s, IH), 8.24 (m, 2H), 7.84 (m, 2H), 7.73 (m, 2H), 7.47 (m, 2H), 7.40 (m, IH), 7.21 (bs, 2H); TLC Rf (CH2Cl2 :MeOH 20:1) = 0.33.
Figure imgf000221_0004
l-(Biphenyl-3-yI)ethanone
1H NMR (400 MHz, CDCl3) δ 8.19 (t, J= 1.8 Hz, IH), 7.94 (d, J= 8.0 Hz, IH), 7.80 (d, J = 8.0 Hz, IH), 7.64-7.62 (m, 2H), 7.55 (t, J= 7.6 Hz, IH), 7.48 (t, J= 7.4 Hz, 2H), 7.41-7.37 (m, IH), 2.66 (s, 3H); 13C NMR (IOO MHz, CDCl3) δ 198.3, 141.9, 140.4, 137.8, 132.0, 129.2, 129.1, 128.0, 127.40, 127.39, 127.2, 27.0; TLC Λ/(«-Hexanes:Et2O 10:1) = 0.32.
Figure imgf000222_0001
l-(Biphenyl-3-yl)-2,2-dibromoethanone
1H NMR (400 MHz, CDCl3) δ 8.31 (t, J= 1.8 Hz, IH), 8.06 (d, J= 8.0 Hz, IH), 7.86 (d, J= 7.6 Hz, IH), 7.63-7.57 (m, 3H), 7.49 (t, J= 7.6 Hz, 2H), 7.44-7.40 (m, IH), 6.74 (s, IH); 13C NMR (100 MHz, CDCl3) δ 186.2, 142.4, 139.8, 133.3, 131.6, 129.6, 129.3, 128.7, 128.6, 128.3, 127.4, 39.9; TLC i?/(ra-Hexanes:Et2O 10:1) = 0.36.
Figure imgf000222_0002
5-(Biphenyl-3-yl)-l,2,4-triazin-3-amine
1H NMR (400 MHz, DMSO-J6) δ 9.32 (s, IH), 8.40 (s, IH), 8.14 (d, J= 8.0 Hz, IH), 7.86 (d, J= 7.6 Hz, IH), 7.73 (d, J= 7.6 Hz, IH), 7.63 (t, J= 8.0 Hz, IH), 7.48 (t, J= 7.2 Hz, 2H), 7.39 (t, J= 7.2 Hz, IH), 7.24 (bs, 2H); 13C NMR (IOO MHz, OMSO-d6) δ 163.8, 155.4, 141.7, 140.1, 138.0, 135.4, 130.8, 130.4, 129.7, 128.6, 127.6, 127.0, 126.2; TLC i?/(CH2Cl2:Me0H 20:1) = 0.37.
Figure imgf000222_0003
2,2-Dibromo-l-(2-bromophenyl)ethanone
1K NMR (400 MHz, CDCl3) δ 7.64 (d, J= 8.0 Hz, IH), 7.56 (d, J= 7.6 Hz, IH), 7.44-7.37 (m, 2H), 6.72 (s, IH); 13C NMR (IOO MHz, CDCl3) δ 189.6, 136.7, 133.7, 133.0, 131.0, 127.8, 119.3, 41.9; TLC i?/(«-Hexanes:Et2O 10:1) = 0.51.
Figure imgf000223_0001
5-(2-Bromophenyl)-l,2,4-triazin-3-amine
1H NMR (400 MHz, DMSOd6) δ 9.04 (s, IH), 7.79 (d, J= 8.0 Hz, IH), 7.59-7.53 (m, 2H), 7.49.7.45 (m; m), 7.38 (s, 2H); 13C NMR (100 MHz, DMSO-J6) δ 163.0, 157.7, 140.1, 136.1, 133.2, 131.8, 131.2, 128.1, 120.5; TLC /J7(CH2Cl2=MeOH 20:1) = 0.25.
Figure imgf000223_0002
l-(2-Cyclohexylphenyl)ethanone
1H NMR (400 MHz, CDCl3) δ 7.47 (d, J= 8.0 Hz, IH), 7.42-7.37 (m, 2H), 7.24-7.20 (m, IH), 3.06-3.01 (m, IH), 2.57 (s, 3H), 1.84-1.74 (m, 5H), 1.47-1.35 (m, 4H), 1.30-1.22 (m, IH); 13C NMR (100 MHz, CDCl3) δ 203.8, 146.6, 139.1, 130.9, 127.6, 127.1, 125.3, 40.0, 34.5, 30.8, 26.9, 26.2; TLC /?/(rc-Hexanes:Et2O 1:1) = 0.56.
Figure imgf000223_0003
2,2-Dibromo-l-(2-cyclohexylphenyl)ethanone
1H NMR (400 MHz, CDCl3) δ 7.51-7.44 (m, 3H), 7.27-7.23 (m, IH), 6.56 (s, IH), 2.79-2.73 (m, IH), 1.89-1.74 (m, 5H), 1.51-1.35 (m, 4H), 1.32-1.24 (m, IH); 13C NMR (IOO MHz, CDCl3) δ 190.1, 148.3, 133.3, 132.2, 127.7, 126.8, 125.5, 43.0, 40.9, 34.6, 26.7, 26.1; TLC Rf (rc-Hexanes:Et2O 5:1) = 0.65.
Figure imgf000223_0004
5-(2-CyclohexyIphenyl)-l,2,4-triazin-3-amine 1H NMR (400 MHz, DMSO-J6) δ 8.61 (s, IH), 7.43-7.42 (m, 2H), 7.32-7.26 (m, 2H), 7.21 (bs, 2H), 2.72 (X, J= 11.2 Hz, IH), 1.71-1.61 (m, 5H), 1.42-1.36 (m, 2H), 1.19-1.17 (m, 3H); 13C NMR (100 MHz, DMSO- J6) δ 163.4, 159.9, 146.3, 140.9, 134.9, 130.7, 129.9, 127.3, 126.5, 39.6, 34.5, 31.4, 27.0, 26.2; TLC R1 (CH2Cl2MeOH 20:1) = 0.44.
Figure imgf000224_0001
5-(Biphenyl-2-yl)-l,2,4-triazin-3-amine
1H NMR (400 MHz, DMSO-J6) δ 7.87 (s, IH), 7.70 (d, J= 8.0 Hz, IH), 7.65-7.55 (m, 3H), 7.50 (d, J= 7.6 Hz, IH), 7.40-7.75 (m, 2H), 7.23 (s, 2H), 7.20-7.17 (m, IH); TLC Rf(n- Hexanes:Et2O 1 :1 + 0.5% MeOH) = 0.45.
Figure imgf000224_0002
l-(2-Ethoxyphenyl)ethanone
1H NMR (400 MHz, CDCl3) δ 7.73-7.71 (m, IH), 7.44-7.39 (m, IH), 6.97-6.90 (m, 2H), 4.14- 4.09 (m, 2H), 1.46 (t, J= 7.2 Hz, 3H); TLC i?/(n-Hexanes:Et2O 10:1) = 0.18.
Figure imgf000224_0003
2,2-Dibromo-l-(2-ethoxyphenyl)ethanone
1H NMR (400 MHz, CDCl3) δ 7.82 (t, J= 5.6 Hz, IH), 7.50-7.49 (m, IH), 7.11 (d, J= 4.4 Hz, IH), 6.96-6.93 (m, IH), 4.19-4.14 (m, 2H), 1.54-1.50 (m, IH); TLC i?/(«-Hexanes:EtOAc 3:1) = 0.42.
Figure imgf000224_0004
5-(2-Ethoxyphenyl)-l,2,4-triazin-3-amine 1H NMR (400 MHz, OMSO-d6) δ 9.05 (s, IH), 7.81 (d, J= 7.6 Hz, IH), 7.47 (t, J= 7.6 Hz, IH), 7.15-7.04 (m, 4H), 4.15-4.10 (m, 2H), 1.34 (d, J= 6.8 Hz, 3H).
Figure imgf000225_0001
l-(2-Isopropoxyphenyl)ethanone
1H NMR (400 MHz, CDCl3) δ 7.71-7.68 (m, IH), 7.42-7.37(m, IH), 6.95-6.91 (m, 2H), 4.70- 4.64 (m, IH), 2.60 (s, 3H), 1.38 (t, J= 2.4 Hz, 6H); TLC ^/(rc-Hexanes: Et2O 10:1) = 0.16.
Figure imgf000225_0002
2,2-Dibromo-l-(2-isopropoxyphenyl)ethanone
1H NMR (400 MHz, CDCl3) δ 7.81 (dd, J= 7.8, 1.8 Hz, IH), 7.50 (m, IH), 7.12 (s, IH), 7.02 (dt, J= 7.6, 1.2 Hz, IH), 6.96 (d, J= 8.8 Hz, IH), 4.74 (m, IH), 1.45 (d, J= 6.4 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 188.6, 156.6, 134.9, 132.8, 123.2, 121.0, 113.4, 71.4, 44.4, 21.9; TLC i?/(n-Hexanes:EtOAc 9:1) = 0.50.
Figure imgf000225_0003
5-(2-Isopropoxyphenyl)-l,2,4-triazin-3-amine
1H NMR (400 MHz, DMSO-c/6) δ 9.03 (s, IH), 7.80 (dd, J= 7.8, 1.8 Hz, IH), 7.46 (m, IH), 7.16 (d, J= 8.4 Hz, IH), 7.10 (bs, 2H), 7.04 (t, J= 7.4 Hz, IH), 4.73 (m, IH), 1.28 (d, J= 6.4 Hz, 6H); TLC i?/(CH2Cl2:Me0H 19:1) = 0.39.
Figure imgf000225_0004
2,2-Dibromo-l-(2-(trifluoromethoxy)phenyI)ethanone 1H NMR (400 MHz, CDCl3) δ 7.83 (dd, J= 7.6, 1.6 Hz, IH), 7.65-7.61 (m, IH), 7.43 (t, J= 7.6 Hz, IH), 7.36 (d, J= 8.4 Hz, IH), 6.72 (s, IH); 13C NMR (100 MHz, CDCl3) δ 186.9, 162.3, 134.5, 132.2, 127.5, 127.3, 120.84, 120.83, 42.2; TLC Λ/(«-Hexanes:Et2O 10:1) = 0.48.
Figure imgf000226_0001
5-(2-(Trifluoromethoxy)phenyl)-l,2,4-triazin-3-amine
1H NMR (400 MHz, DMSO-J6) δ 8.85 (s, IH), 7.86 (dd, J= 7.6, 1.6 Hz, IH), 7.73-7.69 (m, IH), 7.62-7.55 (m, 2H), 7.39 (br, 2H); 13C NMR (100 MHz, DMSO-J6) δ 163.9, 154.7, 146.5, 140.3, 133.4, 132.2, 129.5, 129.0, 122.7, 119.3; TLC i?/(CH2Cl2:Me0H 20:1) = 0.30.
Figure imgf000226_0002
l-(2-(Difluoromethoxy)phenyl)ethanol
1H NMR (400 MHz, CDCl3) δ 7.56 (dd, J= 7.2, 1.6 Hz, IH), 7.30-7.22 (m, 2H), 7.08 (d, J= 7.6 Hz, IH), 6.55 (t, J= 74.0 Hz, IH), 5.24 (q, J= 6.4 Hz, IH), 1.95 (s, IH), 1.50 (d, J= 6.4 Hz, 3H); TLC i?/(«-Hexanes:Et2O 2:1) = 0.25.
Figure imgf000226_0003
l-(2-(Difluoromethoxy)phenyl)ethan<me
1H NMR (400 MHz, CDCl3) δ 7.76 (dd, J= 7.6, 1.2 Hz, IH), 7.54-7.50 (m, IH), 7.30 (t, J= 7.6 Hz, IH), 7.18 (d, J= 8.4 Hz, IH), 6.60 (t, J= 73.6 Hz, IH), 2.63 (s, 3H); TLC Rf(n- Hexanes:Et2O 2:1) = 0.42.
Figure imgf000227_0001
2,2-Dibromo-l-(2-(difluoromethoxy)phenyl)ethanone
1H NMR (400 MHz, CDCl3) δ 7.85 (dd, J= 7.6, 1.6 Hz, IH), 7.62-7.58 (m, IH), 7.37-7.33 (m, IH), 7.22 (d, J= 8.0 Hz, IH), 6.87 (s, IH), 6.62 (t, J= 72.8 Hz, IH); TLC Rf(n- Hexanes:Et2O 2:1) = 0.44.
Figure imgf000227_0002
5-(2-(Difluoromethoxy)phenyl)-l,2,4-triazin-3-amine
1H NMR (400 MHz, DMSO-d*) δ 8.86 (s, IH), 7.81 (d, J= 6.8 Hz, IH), 7.60 (t, J= 6.8 Hz, IH), 7.40 (t, J= 7.2 Hz, IH), 7.33 (d, J= 8.0 Hz, IH), 7.26 (bs, 2H), 7.26 (t, J= 73.6 Hz, IH); TLC i?/(CH2Cl2:Me0H 20:1) = 0.36.
Figure imgf000227_0003
2,3-Dihydrobenzofuran-7-carbaldehyde
1H NMR (400 MHz, CDCl3) δ 10.19 (s, IH), 7.58 (d, J= 8.0 Hz, IH), 7.40 (d, J= 7.2 Hz, IH), 6.93 (t, J= 7.6 Hz, IH), 4.73 (t, J= 8.8 Hz, 2H), 3.24 (t, J= 8.6 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 189.3, 162.4, 131.1, 129.7, 127.6, 120.8, 119.9, 72.9, 28.9; TLC Rf(n- Hexanes:EtOAc 5:1) = 0.43.
Figure imgf000227_0004
l-(2,3-Dihydrobenzofuran-7-yl)ethanol
1H NMR (400 MHz, CDCl3) δ 7.13-7.10 (m, 2H), 6.84 (t, J= 7.4 Hz, IH), 4.60 (t, J= 8.6 Hz, 2H), 3.21 (t, J= 8.8 Hz, 2H), 1.52 (d, J= 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 156.9, 127.6, 127.3, 124.7, 124.0, 120.8, 71.6, 67.2, 29.8, 23.3; TLC i?/(n-Hexanes:EtOAc 3:1) - 0.21.
Figure imgf000228_0001
l-(2,3-Dihydrobenzofuran-7-yl)ethanone
1H NMR (400 MHz, CDCl3) δ 7.68 (d, J= 8.4 Hz, IH), 7.34 (d, J= 6.8 Hz, IH), 6.88 (t, J= 7.6 Hz, IH), 4.69 (t, J= 8.8 Hz, 2H), 3.24 (t, J= 8.6 Hz, 2H), 2.61 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 197.3, 160.6, 129.7, 129.4, 128.3, 121.0, 120.5, 72.1, 31.1, 29.2; TLC Rf(n- Hexanes:Et2O 10:1) = 0.43.
Figure imgf000228_0002
2,2-Dibromo-l-(2,3-dihydrobenzofuran-7-yl)ethanone
1H NMR (400 MHz, CDCl3) δ 7.81 (d, J= 8.4 Hz, IH), 7.42 (d, J= 7.2 Hz, IH), 7.21 (s, IH), 6.95 (t, J= 7.6 Hz, IH), 4.76 (t, J= 8.8 Hz, 2H), 3.28 (t, J= 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 185.0, 159.8, 131.3, 130.1, 129.4, 121.6, 114.8, 72.9, 44.1, 29.1, 29.0; TLC Rf (n-Hexanes:Et2O 10:1) = 0.46.
Figure imgf000228_0003
5-(2,3-Dihydrobenzofuran-7-yl)-l,2,4-triazin-3-amine
1H NMR (400 MHz, DMSO-J6) δ 9.20 (s, IH), 7.91 (d, J= 8.0 Hz, IH), 7.40 (d, J= 7.2 Hz, IH), 7.15 (s, 2H), 6.97 (t, J= 7.6 Hz, IH), 4.69 (t, J= 8.8 Hz, 2H), 3.23 (t, J= 8.6 Hz, 2H); 13C NMR (100 MHz, DMSO-^6) δ 163.7, 159.7, 153.8, 134.0, 130.1, 129.3, 127.4, 121.6, 116.5, 72.8, 29.1; TLC i?/(CH2Cl2:Me0H 20:1) = 0.38.
Figure imgf000228_0004
5-(Chroman-8-yl)-l,2,4-triazin-3-amine 1H NMR (400 MHz, OMSO-d6) δ 8.98 (s, IH), 7.59 (d, J= 8.0 Hz, IH), 7.20 (d, J= 7.2 Hz, IH), 7.08 (bs, 2H), 6.93 (t, J= 7.4 Hz, IH), 4.23 (t, J= 4.8 Hz, 2H), 2.78 (t, J= 6.2 Hz, 2H), 1.93 (t, J= 5.0 Hz, 2H); TLC tf/(«-Hexanes:EtOAc 2:1) = 0.10.
Figure imgf000229_0001
Benzo[<f][l,3]dioxole-4-carbaldehyde
1H NMR (400 MHz, CDCl3) δ 10.09 (s, IH), 7.24 (d, J= 4.0 Hz, IH), 6.99 (d, J= 7.6 Hz, IH), 6.90 (t, J= 7.8 Hz, IH), 6.10 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 188.2, 149.4, 149.1, 122.0, 121.3, 119.6, 113.6, 102.7; TLC i?/(rc-Hexanes: EtOAc 5:1) = 0.43.
Figure imgf000229_0002
l-(Benzo[rf][l,3]dioxol-4-yl)ethanol
1U NMR (400 MHz, CDCl3) δ 6.82 (d, J= 7.6 Hz, IH), 6.73 (d, J= 7.6 Hz, IH), 6.66 (dd, J = 7.8, 1.0 Hz, IH), 5.82 (dd, J= 8.8, 1.2 Hz, 2H), 4.90-4.89 (m IH), 3.32 (bs, IH), 1.42 (d, J = 6.4 Hz, 3H); 13C NMR (IOO MHz, CDCl3) δ 147.3, 144.0, 127.7, 121.8, 118.9, 107.7, 101.0, 65.7, 23.5; TLC i?/(«-Hexanes:EtOAc 5:1) = 0.21.
Figure imgf000229_0003
l-(Benzo[rf][l,3]dioxol-4-yI)ethanoiie
1H NMR (400 MHz, CDCl3) δ 7.35 (d, J= 8.4 Hz, IH), 6.95 (d, J= 7.6 Hz, IH), 6.86 (t, J= 7.8 Hz, IH), 6.07 (s, 2H), 2.58 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 195.7, 148.8, 148.2, 121.6, 121.5, 120.5, 112.7, 101.8, 30.5; TLC i?/(«-Hexanes:EtOAc 5:1) = 0.27.
Figure imgf000229_0004
l-(Benzo[έ/][l,3]dioxol-4-yl)-2,2-dibromoethanone 1H NMR (400 MHz, CDCl3) δ 7.46 (dd, J= 8.2, 1.4 Hz, IH), 7.01 (d, J= 7.8, 1.4 Hz, IH), 6.93-6.89 (m, 2H), 6.10 (s, 2H); 13C NMR (IOO MHz, CDCl3) δ 183.5, 148.7, 147.7, 122.8, 122.6, 114.2, 114.1, 102.2, 62.1; TLC i?/(«-Hexanes:EtOAc 5:1) = 0.45.
Figure imgf000230_0001
5-(Benzo [d\ [1 ,3] dioxol-4-yl)-l ,2,4-triazin-3-amine
1H NMR (400 MHz, OMSO-d6) δ 9.08 (s, IH), 7.61 (d, J= 8.0 Hz, IH), 7.24 (bs, 2H), 7.09 (d, J= 7.6 Hz, IH), 6.98 (d, J= 8.0 Hz, IH), 6.17 (s, 2H); 13C NMR (100 MHz, DMSO-^6) δ 163.8, 152.6, 148.8, 147.5, 139.4, 122.9, 120.7, 116.7, 112.0, 102.5; TLC i?/ (CH2Cl2: MeOH 10:1) = 0.53.
Figure imgf000230_0002
2,3-Dihydrobenzo [b] [1 ,4] dioxine-5-carbaldehyde
1H NMR (400 MHz, CDCl3) δ 10.17 (s, IH), 7.18 (d, J= 7.6 Hz, IH), 6.90 (d, J= 8.0 Hz, IH), 6.70 (t, J= 7.8 Hz, IH), 4.19 (d, J= 2.4 Hz, 2H), 4.12 (d, J= 2.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 188.9, 146.6, 144.2, 125.1, 123.2, 120.9, 120.6, 64.7, 64.0; TLC Rf(n- Hexanes:EtOAc 5:1) = 0.39.
Figure imgf000230_0003
l-(2,3-Dihydrobenzo [b] [1 ,4] dioxin-5-yl)ethanol
1H NMR (400 MHz, CDCl3) δ 6.90 (d, J= 7.2, 1.6 Hz, IH), 6.83-6.75 (m, 2H), 5.05-5.03 (m, IH), 4.28-4.26 (m 2H), 4.24-4.22 (m, 2H), 2.47 (bs, IH), 1.40 (d, J= 3.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 143.6, 140.8, 134.2, 121.3, 118.3, 116.6, 66.2, 64.5, 64.3, 23.2; TLC Rf («-Hexanes:EtOAc 5:1) = 0.14.
Figure imgf000230_0004
l-(2,3-Dihydrobenzo[6][l,4]dioxm-5-yl)ethanone
1H NMR (400 MHz, CDCl3) δ 7.28 (dd, J= 7.6, 1.2 Hz, IH), 6.99 (d, J= 8.0, 1.2 Hz, IH), 6.84 (t, J= 7.8 Hz, IH), 4.35-4.33 (m, 2H), 4.29-4.27 (m, 2H), 2.58 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 199.1, 144.2, 143.8, 128.7, 122.5, 121.5, 121.0, 64.6, 64.0, 31.9; TLC Rf(n- Hexanes:EtOAc 5:1) = 0.24.
Figure imgf000231_0001
2,2-Dibromo-l-(2,3-dihydrobenzo[6][l,4]dioxin-5-yl)ethanone
1H NMR (400 MHz, CDCl3) δ 7.40 (d, J= 7.6 Hz, IH), 7.07-7.05 (m, 2H), 6.93-6.89 (m, IH), 4.38 (t, J= 2.0 Hz, 2H), 4.31 (t, J= 2.8 Hz, 2H); TLC Λ/C/j-HexanesiEtOAc 5:1) = 0.57.
Figure imgf000231_0002
5-(2,3-Dihydrobenzo [b] [1 ,4] dioxin-5-yl)-l ,2,4-triazin-3-amine
1H NMR (400 MHz, CDCl3) δ 9.22 (s, IH), 7.49 (dd, J= 7.0, 2.0 Hz, IH), 7.01 (dd, J= 8.0, 2.0 Hz, IH), 6.94 (t, J= 8.0 Hz, IH), 5.42 (bs, 2H), 4.35-4.29 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 163.0, 155.8, 144.2, 143.1, 142.7, 123.7, 123.0, 121.8, 120.7, 64.7, 64.1; TLC R1 (CH2Cl2:Me0H 10:1) = 0.40.
Figure imgf000231_0003
2,3-Dihydro-lH-mden-4-ol
1U NMR (400 MHz, CDCl3) δ 7.05 (t, J= 7.8 Hz, IH), 6.85 (d, J= 7.6 Hz, IH), 6.63 (d, J= 7.6 Hz, IH), 4.92 (bs, IH), 2.94 (t, J= 7.6 Hz, 2H), 2.87 (t, J= 7.4 Hz, 2H), 2.11 (m, 2H); 13C NMR (IOO MHz, CDCl3) δ 151.8, 146.7, 129.3, 127.7, 117.0, 112.5, 33.2, 28.7, 25.0; TLC R1 (n-Hexanes:EtOAc 4:1) = 0.50.
Figure imgf000231_0004
2,3-Dihydro-lHr-inden-4-yl trifluoromethanesulfonate
1H NMR (400 MHz, CDCl3) δ 7.20 (m, 2H), 7.02 (d, J= 7.2 Hz, IH), 3.00 (m, 4H), 2.12 (m, 2H); TLC i?/(R-Hexanes:EtOAc 4:1) = 0.76.
Figure imgf000232_0001
l-(2,3-Dihydro-lH-inden-4-yl)ethanone
1H NMR (400 MHz, CDCl3) δ 7.59 (d, J= 7.6 Hz, IH), 7.33 (d, J= 7.2 Hz, IH), 7.16 (m, IH), 3.18 (t, J= 7.4 Hz, 2H), 2.84 (t, J= 7.6 Hz, 2H), 2.51 (s, 3H), 2.00 (m, 2H); TLC Rf(n- Hexanes:EtOAc 7:3) = 0.67.
Figure imgf000232_0002
2,2-Dibromo-l-(2,3-dihydro-lH-inden-4-yl)ethanone
1H NMR (400 MHz, CDCl3) δ 7.68 (d, J= 7.6 Hz, IH), 7.43 (d, J= 7.6 Hz, IH), 7.22 (t, J= 7.4 Hz, IH), 6.72 (s, IH), 3.22 (t, J= 7.2 Hz, 2H), 2.91 (t, J= 7.4 Hz, 2H), 2.07 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 187.2, 148.2, 147.3, 130.2, 127.8, 127.3, 126.5, 41.3, 34.2, 32.7, 25.0; TLC i?/(rc-Hexanes:EtOAc 9:1) = 0.58.
Figure imgf000232_0003
5-(2,3-Dihydro-lH-inden-4-yl)-l,2,4-triazin-3-amine
1H NMR (400 MHz, DMSO-J6) δ 8.87 (s, IH), 7.59 (d, J= 7.6 Hz, IH), 7.38 (d, J= 7.2 Hz, IH), 7.26 (t, J= 7.6 Hz, IH), 7.08 (bs, 2H), 3.13 (t, J= 7.4 Hz, 2H), 2.86 (t, J= 7.4 Hz, 2H), 1.97 (m, 2H); 13C NMR (IOO MHz, DMSO-^6) δ 163.2, 157.9, 146.1, 144.0, 139.4, 131.3, 127.4, 127.2, 126.7, 33.3, 32.6, 25.4; TLC ^7(CH2Cl2MeOH 19:1) = 0.39.
Figure imgf000232_0004
5,6,7,8-Tetrahydronaphthalen-l-yl trifluoromethanesulfonate 1H NMR (400 MHz, CDCl3) 8 7.06 (m, 3H), 2.76 (q, J= 6.4 Hz, 4H), 1.78 (m, 4H); TLC Rf OHexanesiEtOAc 19:1) = 0.55.
Figure imgf000233_0001
l-(5,6,7,8-Tetrahydronaphthalen-l-yl)ethanone
1H NMR (400 MHz, CDCl3) δ 7.40 (dd, J= 7.2, 1.6 Hz, IH), 7.13 (m, 2H), 2.91 (m, 2H), 2.76 (m, 2H), 2.51 (s, 3H), 1.73 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 202.9, 138.6, 136.7, 132.5, 126.2, 125.0, 30.2, 30.1, 27.7, 23.1, 22.4; TLC i?/(rc-Hexanes: EtOAc 9:1) = 0.41.
Figure imgf000233_0002
2,2-Dibromo-l-(5,6,7,8-tetrahydronaphthaIen-l-yl)ethanone
1H NMR (400 MHz, CDCl3) δ 7.39 (d, J= 7.6 Hz, IH), 7.24 (m, IH), 7.15 (t, J= 7.6 Hz, IH), 6.62 (s, IH), 2.89 (bs, 2H), 2.81 (bs, 2H), 1.79 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 189.1, 139.3, 138.4, 133.8, 133.1, 132.1, 125.0, 42.8, 30.0, 27.3, 22.8, 22.3; TLC Rf(n- Hexanes:EtOAc 9:1) = 0.56.
Figure imgf000233_0003
5-(5,6,7,8-Tetrahydronaphthalen-l-yl)-l,2,4-triazin-3-amine
1U NMR (400 MHz, DMSO-J6) δ 8.66 (s, 1.0H), 7.19 (s, 3H), 7.17 (bs, 2H), 3.29 (s, 2H), 2.75 (m, 3H), 1.67 (m, 3H); 13C NMR (100 MHz, DMSO-^6) δ 163.1, 159.5, 140.7, 138.1, 135.5, 131.4, 127.2, 126.0, 29.7, 27.3, 23.0, 22.6; TLC i?/(CH2Cl2:Me0H 19:1) = 0.39.
Figure imgf000233_0004
4-Acetyl-3-methylphenyl trifluoromethanesulfonate
1H NMR (400 MHz, CDCl3) 8 7.74 (d, J= 8.4 Hz, IH), 7.18-7.13 (m, IH), 2.56 (s, 3H), 2.54 (s, 3H); TLC i?/(«-Hexanes:EtOAc 5:1) = 0.89.
Figure imgf000234_0001
4-Acetyl-3-methylbenzonitrile
1H NMR (400 MHz, CDCl3) δ 7.67 (d, J= 8.0 Hz, IH), 7.55-7.52 (m, 2H), 2.57 (s, 3H), 2.50 (s, 3H); TLC i?/(«-Hexanes:EtOAc 5:1) = 0.80.
Figure imgf000234_0002
4-(2,2-Dibromoacetyl)-3-methylbenzonitrile
1H NMR (400 MHz, CDCl3) δ 7.74 (d, J= 12.8 Hz, IH), 7.59-7.56 (m, 2H), 6.50 (s, IH), 2.48 (s, 3H); TLC i?/(«-Hexanes:Et2O 10:1) = 0.51.
Figure imgf000234_0003
4-(3-Amino-l,2,4-triazin-5-yl)-3-methylbenzonitrile
1H NMR (400 MHz, OMSO-d6) δ 8.78 (d, J= 2.0 Hz, IH), 7.83 (s, H), 7.78 (d, J= 8.0 Hz, IH), 7.64 (d, J= 8.0 Hz, IH), 7.31 (s, IH), 2.39 (s, 3H); TLC i?/(rc-Hexanes:EtOAc 1:1) = 0.53.
Figure imgf000234_0004
l-(4-Methoxy-2-(trifluoromethyI)phenyl)ethanone
1H NMR (400 MHz, CDCl3) δ 7.53 (d, J= 8.4 Hz, IH), 7.22 (d, J= 2.8 Hz, IH), 7.07-7.04
(m, IH), 3.88 (s, 3H), 2.56 (s, 3H); TLC i?/(«-Hexanes:EtOAc 5:1) = 0.25.
Figure imgf000234_0005
2,2-Dibromo-l-(4-methoxy-2-(trifluoromethyl)phenyl)ethanone 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J= 8.4 Hz, IH), 7.26-7.25 (m, IH), 7.10-7.07 (m, IH), 6.48 (s, IH), 3.90 (s, 3H); TLC i?/(rc-Hexanes:EtOAc 10:1) = 0.49.
Figure imgf000235_0001
5-(4-Methoxy-2-(trifluoromethyl)phenyl)-l,2,4-triazin-3-amine
1H NMR (400 MHz, DMSO-J6) δ 8.65 (s, IH), 7.60 (d, J= 9.6 Hz, IH), 7.38-7.36 (m, IH), 7.31 (s, 2H), 3.90 (s, 3H).
Figure imgf000235_0002
4-(3-Amino-l,2,4-triazin-5-yI)-3-(trifluoromethyl)phenol
1H NMR (400 MHz, CD3OD) δ 8.60 (s, IH), 7.47 (d, J= 8.8 Hz, IH), 7.20 (d, J= 2.4 Hz, IH), 7.12-7.09 (m, IH); TLC i?/(n-Hexanes:EtOAc 1 :1) = 0.11.
Figure imgf000235_0003
4-(3-Amino-l,2,4-triaziπ-5-yl)-3-(trifluoromethyl)phenyl trifluoromethane sulfonate
1H NMR (400 MHz, CD3OD) δ 8.69 (s, IH), 7.91 (s, IH), 7.84-7.82 (m, 2H); TLC Rf(n- Hexanes:EtOAc 1 :1) = 0.38.
Figure imgf000235_0004
4-(3-Amino-l,2,4-triazin-5-yI)-3-(trifluoromethyl)benzonitrile
1H NMR (400 MHz, CD3OD) δ 8.68 (s, IH), 8.29 (s, IH), 8.14 (d, J= 8.0 Hz, IH), 7.81-7.79 (m, IH); TLC i?/(rc-Hexanes:EtOAc 1:1) = 0.25.
Figure imgf000236_0001
4-Acetyl-3-chlorophenyl trifluoromethanesulfonate
1H NMR (400 MHz, CDCl3) δ 7.66 (d, J= 8.4 Hz, IH), 7.38 (d, J= 2.4 Hz, IH), 7.27 (dd, J= 8.6, 2.6 Hz, IH), 2.66 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 198.6, 150.4, 139.1, 133.0, 131.1, 123.7, 120.2, 117.0, 30.7; TLC /?/(«-Hexanes:EtO Ac 5:1) = 0.52.
Figure imgf000236_0002
4-Acetyl-3-chlorobenzonitrile
1H NMR (400 MHz, CDCl3) δ 7.70 (d, J= 1.2 Hz, IH), 7.60 (dd, J= 8.0, 1.2 Hz, IH), 7.57 (d, J= 8.0 Hz, IH), 2.63 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 199.0, 143.1, 133.8, 131.9, 130.5, 129.6, 116.6, 115.6, 30.6; TLC i?/(«-Hexanes:EtOAc 5:1) = 0.37.
Figure imgf000236_0003
3-Chloro-4-(2,2-dibromoacetyl)benzonitrile
1U NMR (400 MHz, CDCl3) δ 7.77 (d, J= 1.2 Hz, IH), 7.73 (d, J= 7.6 Hz, IH), 7.68 (dd, J= 8.0, 1.2 Hz, IH), 6.64 (s, 3H); 13C NMR (IOO MHz, CDCl3) δ 187.3, 138.3, 133.6, 131.9, 131.2, 130.6, 116.6, 116.3, 41.0; TLC i?/(n-Hexanes: EtO Ac 5:1) = 0.38.
Figure imgf000236_0004
4-(3-Amino-l,2,4-triazin-5-yl)-3-chlorobenzonitrile
1H NMR (400 MHz, OMSO-d6) δ 8.84 (s, IH)5 8.23 (d, J= 1.6 Hz, IH), 7.97 (dd, J= 7.8, 1.4 Hz, IH), 7.79 (d, J= 8.0 Hz, IH), 7.45 (bs, 2H); 13C NMR (100 MHz, DMSO-J15) δ 163.5, 155.5, 140.1, 139.0, 134.1, 132.6, 132.6, 131.9, 117.5, 114.7; TLC i?/(n-Hexanes:EtOAc 1 :1) = 0.23.
Figure imgf000237_0001
Biphenyl-3-amine
1H NMR (400 MHz, CDCl3) δ 7.56-7.51 (m, 2H), 7.49-7.29 (m, 2H), 7.28-7.19 (m, 2H), 6.98 (dd, J= 7.6, 0.8 Hz, IH), 6.89 (t, J= 1.8 Hz, IH), 6.66 (dd, J= 7.4, 1.8 Hz, IH), 3.65 (bs, 2H); 13C NMR (IOO MHZ, CDCl3) δ 146.9, 142.7, 141.6, 129.9, 128.8, 127.4, 127.3, 117.9, 114.3, 114.1; TLC i?/(«-Hexanes:EtOAc 5:1) = 0.27.
Figure imgf000237_0002
2'-Chlorobiphenyl-3-amine
1H NMR (400 MHz, CDCl3) δ 7.48-7.46 (m, IH), 7.36-7.21 (m, 4H), 6.86-6.84 (m, IH), 6.76- 6.75 (m, IH), 6.72-6.69 (m, IH), 3.69 (bs, 2H); 13C NMR (100 MHz, CDCl3) δ 146.4, 141.0, 140.8, 132.7, 131.5, 130.1, 129.2, 128.7, 127.0, 120.1, 116.5, 114.7; TLC Rf(n- Hexanes:EtOAc 5:1) = 0.31.
Figure imgf000237_0003
2'-(TrifluoromethyI)biphenyl-3-amine
1H NMR (400 MHz, CDCl3) δ 7.71 (d, J= 7.6 Hz, IH ), 7.52 (t, J= 7.4 Hz, IH), 7.43 (t, J= 7.6 Hz, IH), 7.32 (d, J= 7.6 Hz, IH), 7.17 (t, J= 7.8 Hz, IH), 6.72-6.69 (m, 2H), 6.64 (s, IH), 3.71 (bs, 2H); 13C NMR (IOO MHz, CDCl3) δ 145.9, 141.8, 141.2, 132.1, 131.4, 128.8, 128.4, 127.4, 126.3, 126.2, 126.1, 125.8, 123.0, 119.8, 16.1, 114.6; TLC i?/(«-Hexanes:EtOAc 5:1) = 0.23.
Figure imgf000237_0004
2 ' -Methylbipheny 1-3-amine 1H NMR (400 MHz, CDCl3) δ 7.26-7.18 (m, 5H), 6.73 (d, J= 7.6 Hz, IH ), 6.70-6.64 (m, 2H), 3.55 (bs, 2H), 2.29 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 146.3, 143.4, 142.4, 135.6, 130.4, 129.8, 129.2, 127.4, 125.9, 120.0, 116.2, 113.8, 20.7; TLC i?/(«-Hexanes:EtOAc 5:1) = 0.39.
Figure imgf000238_0001
2'-MethoxybiphenyI-3-amine
1H NMR (400 MHz, CDCl3) δ 7.33-7.29 (m, 2H), 7.24-7.18 (m, IH), 7.03-6.91 (m, 3H), 6.86 (d, J= 2.4 Hz, IH ), 6.67-6.65 (m, IH), 3.80 (s, 3H), 3.67 (bs, 2H); 13C NMR (100 MHz, CDCl3) δ 156.7, 146.3, 139.9, 131.1, 131.0, 129.1, 128.7, 120.9, 120.3, 116.7, 114.1, 111.5, 55.8; TLC i?/(n-Hexanes: EtOAc 5:1) = 0.10.
Figure imgf000238_0002
Biphenyl-3-ol
1H NMR (400 MHz, CDCl3) δ 7.57 (d, J= 7.2 Hz, 2H), 7.43 (t, J= 7.6 Hz, 2H), 7.36-7.29 (m, 2H), 7.17 (d, J= 7.6 Hz, IH), 7.07-7.06 (m, IH), 6.82 (dd, J= 8.0, 2.4 Hz, IH), 4.85 (s, IH); TLC i?/(«-Hexanes:Et2O 2:1) = 0.34.
Figure imgf000238_0003
2'-Methylbiphenyl-3-ol
1H NMR (400 MHz, CDCl3) δ 7.29-7.21 (m, 5H), 6.89 (d, J= 7.6 Hz, IH), 6.83-6.77 (m, 2H), 4.82 (s, IH); TLC tf/(rc-Hexanes:Et2O 2:1) = 0.42.
Figure imgf000238_0004
2'-Chlorobiphenyl-3-ol
1H NMR (400 MHz, CDCl3) δ 7.45-7.42 (m, IH), 7.30-7.22 (m, 4H), 7.00-6.98 (m, IH), 6.92- 6.91 (m, IH), 6.85 (ddd, J= 8.0, 2.4, 0.8 Hz, IH), 5.43 (bs, IH); 13C NMR (100 MHz, CDCl3) δ 155.0, 140.9, 140.0, 132.3, 131.2, 129.9, 129.3, 128.6, 126.8, 122.1, 116.5, 114.6; TLC Rf 0-Hexanes:Et2O 2:1) = 0.37.
Figure imgf000239_0001
2'-(TrifluoromethyI)biphenyI-3-ol
1U NMR (400 MHz, CDCl3) δ 7.70 (d, J= 7.6 Hz, IH), 7.48 (t, J= 6.8 Hz, IH), 7.41 (t, J= 7.6 Hz, IH), 7.27-7.20 (m, 2H), 6.89-6.82 (m, 3H), 6.01 (bs, IH); TLC i?/(rc-Hexanes:Et2O 2:1) = 0.36.
Figure imgf000239_0002
2'-MethoxybiphenyI-3-ol
1H NMR (400 MHz, CDCl3) δ 7.34-7.28 (m, 3H), 7.10-7.08 (m, IH), 7.04-6.97 (m, 3H), 6.80 (ddd, J= 8.0, 2.4, 0.4 Hz, IH), 4.80 (s, IH), 3.81 (s, 3H); TLC i?/(«-Hexanes:Et2O 2:1) = 0.26.
Figure imgf000239_0003
5-PhenyIpyridin-3-amine
1H NMR (400 MHz, CDCl3) δ 8.26 (d, J= 1.6 Hz, IH), 8.08 (d, J= 2.4 Hz, IH), 7.70-7.64 (m, IH), 7.56-7.52 (m, IH), 7.48-7.43 (m, 2H), 7.40-7.36 (m, IH), 7.16 (t, J= 2.2 Hz, IH), 3.77 (bs, 2H); TLC i?/(rc-Hexanes:EtOAc 1 :1 with 0.5% MeOH) = 0.20.
Figure imgf000239_0004
5-ø-TolyIpyridin-3-amine
1H NMR (400 MHz, CDCl3) δ 8.06 (d, J= 2.4 Hz, IH), 7.67 (d, J= 7.2 Hz, IH), 7.46 (d, J= 2.8 Hz, IH), 7.27-7.17 (m, 2H), 6.92 (t, J= 2.0 Hz, IH), 3.73 (bs, 2H), 2.25 (s, 3H); TLC Rf («-Hexanes: EtOAc 1 :1 with 0.5% MeOH) = 0.21.
Figure imgf000240_0001
5-(2-Chlorophenyl)pyridin-3-amine
1H NMR (400 MHz, CDCl3) δ 8.10 (d, J= 2.0 Hz, IH), 8.07 (s, IH), 7.69-7.64 (m, IH), 7.56- 7.52 (m, IH), 7.48-7.43 (m, IH), 7.32-7.29 (m, IH), 7.07 (s, IH), 3.77 (s, 2H); TLC Rf(n- Hexanes:EtOAc 1:1 with 0.5% MeOH) = 0.18.
Figure imgf000240_0002
5-(2-(Trifluoromethyl)phenyl)pyridin-3-amiiie
1H NMR (400 MHz, CDCl3) δ 8.12 (d, J= 2.4 Hz, IH), 7.98 (s, IH), 7.76 (d, J= 7.6 Hz, IH), 7.69-7.64 (m, IH), 7.60-7.44 (m, IH), 7.32 (d, J= 7.6 Hz, IH), 6.95 (s, IH), 3.75 (s, 2H); TLC i?/(«-Hexanes: EtOAc 1 :1 with 0.5% MeOH) = 0.14.
Figure imgf000240_0003
5-(2-Methoxyphenyl)pyridin-3-amine
1H NMR (400 MHz, CDCl3) δ 8.17 (d, J= 2.0 Hz, IH), 8.04 (d, J= 2.8 Hz, IH), 7.36-7.32 (m, IH), 7.29 (dd, J= 7.6, 1.6 Hz, IH), 7.16 (t, J= 2.2 Hz, IH), 7.05-7.01 (m, IH), 6.98 (d, J = 8.4 Hz, IH), 3.81 (s, 3H), 3.72 (s, 2H); TLC i?/(«-Hexanes:EtOAc 1:1 with 0.5% MeOH) = 0.16.
Figure imgf000240_0004
5-(2,6-Dimethylphenyl)pyridin-3-amine
1H NMR (400 MHz, CDCl3) δ 8.07 (d, J= 2.8 Hz, IH), 7.84 (d, J= 1.6 Hz, IH), 7.67-7.65 (m, IH), 7.17 -7.07 (m, 2H), 6.78 -6.77 (m, IH), 2.03 (s, IH); TLC i?/(«-Hexanes:EtOAc 1 :1) = 0.11.
Figure imgf000241_0001
4-(5-Aminopyridin-3-yl)-3-methylbenzonitrile
1U NMR (400 MHz, CDCl3) δ 8.12 (s, IH), 8.11 (s, IH), 7.50 (s, IH), 7.46 (d, J= 8.0 Hz, IH), 7.22 (d, J = 7.6 Hz, IH), 6.91 (s, IH), 4.50 (bs, 2H), 2.24 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 143.5, 143.4, 138.5, 137.3, 136.7, 136.0, 133.9, 130.5, 129.6, 121.2, 119.0, 111.4, 20.3; TLC i?/(«-Hexanes: EtOAc 1:2) = 0.34.
Figure imgf000241_0002
5-(2-Chloro-4-fluorophenyl)pyridin-3-amine
1H NMR (400 MHz, CDCl3) δ 8.09 (d, J= 2.4 Hz, IH), 8.01 (d, J= 1.2 Hz, IH), 7.67-7.62 (m, IH), 7.46 -7.42 (m, IH), 7.29-7.19 (m, 2H), 7.05 -7.00 (m, 2H), 3.75 (s, 2H); TLC Rf(n- Hexanes:EtOAc 3:1) = 0.10.
Figure imgf000241_0003
6-Phenylpyridin-2-amine
1H NMR (400 MHz, CDCl3) δ 7.93-7.89 (m, 2H), 7.51-7.33 (m, 4H), 7.09-7.05 (m, IH), 6.45- 6.41 (m, IH), 4.50 (bs, 2H); TLC i?/(n-Hexanes: EtOAc 5:1) = 0.16.
Figure imgf000241_0004
6-ø-Tolylpyridin-2-amine
1H NMR (400 MHz, CDCl3) δ 7.37 (t, J= 7.8 Hz, IH), 7.29 (d, J= 6.8 Hz, IH), 7.19-7.17 (m, 3H), 6.64 (d, J= 7.6 Hz, IH), 6.34 (d, J= 8.0 Hz, IH), 4.53 (bs, 2H), 2.29 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 158.7, 158.1, 141.0, 138.0, 135.8, 130.7, 129.5, 128.1, 125.9, 114.3, 106.7, 20.4; TLC i?/(n-Hexanes:EtOAc 2:1) - 0.29.
Figure imgf000242_0001
6-(2-ChIorophenyl)pyridin-2-amine
1H NMR (400 MHz, CDCl3) δ 7.93-7.89 (m, 2H), 7.51-7.41 (m, 3H), 7.32-7.24 (m, 2H), 6.90 (d, J= 7.2 Hz, IH), 6.45 (d, J= 8.0 Hz, IH), 4.61 (bs, 2H); 13C NMR (100 MHz, CDCl3) δ 158.4, 155.6, 139.8, 137.9, 132.4, 131.4, 130.2, 129.4, 127.0, 115.1, 107.6; TLC Rf(n- Hexanes:EtOAc 2:1) = 0.32.
Figure imgf000242_0002
6-(2-(Trifluoromethyl)phenyl)pyridin-2-amine
1H NMR (400 MHz, CDCl3) δ 7.71 (d, J= 8.0 Hz, IH), 7.54 (t, J= 7.4 Hz, IH), 7.46-7.41 (m, 3H), 6.72 (d, J= 7.2 Hz, IH), 6.45 (d, J= 8.4 Hz, IH), 4.56 (bs, 2H); 13C NMR (100 MHz, CDCl3) δ 158.0, 156.4, 140.5, 137.9, 131.7, 131.5, 128.5, 128.2, 126.5, 126.4, 125.7, 123.0, 114.3, 114.2, 107.7; TLC i?/(«-Hexanes:EtOAc 2:1) = 0.37.
Figure imgf000242_0003
6-(2-Methoxyphenyl)pyridin-2-amine
1H NMR (400 MHz, CDCl3) δ 7.68 (d, J= 7.2 Hz, IH), 7.42 (t, J= 7.6 Hz, IH), 7.31 (t, J= 7.2 Hz, IH), 7.12 (d, J= 7.2 Hz, IH), 7.03 (t, J= 7.2 Hz, IH), 6.95 (d, J= 8.0 Hz, IH), 6.38 (d, J= 8.4 Hz, IH), 4.57 (bs, 2H), 3.76 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 158.5, 157.2, 154.7, 137.7, 131.1, 129.8, 129.7, 121.1, 115.5, 111.7, 107.0, 55.8; TLC Rf (n- Hexanes:EtOAc 2:1) = 0.19.
Figure imgf000242_0004
4-ø-Tolylpyridin-2-amine
1H NMR (400 MHz, CDCl3) δ 8.06 (d, J= 5.6 Hz, IH), 7.27-7.13 (m, 4H), 6.57-6.56 (m, IH), 6.39 (s, IH), 4.77 (bs, 2H), 2.24 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 158.5, 151.4, 147.4, 139.6, 134.7, 130.2, 128.7, 127.8, 125.6, 114.8, 108.6, 20.0; TLC i?/(«-Hexanes:EtOAc 1:1) = 0.13.
Figure imgf000243_0001
4-(2-Chlorophenyl)pyridin-2-amine
1H NMR (400 MHz, CDCl3) δ 8.08 (d, J= 5.2 Hz, IH), 7.43 (m, IH), 7.26 (m, 3H), 6.68 (dd, J= 5.4, 1.4 Hz, IH), 6.52 (s, IH), 4.52 (bs, 2H); TLC i?/(rc-Hexanes:EtOAc 3:2) = 0.16.
Figure imgf000243_0002
4-(2-(Trifluoromethyl)phenyI)pyridin-2-amine
1H NMR (400 MHz, CDCl3) δ 8.06 (d, J= 5.2 Hz, IH), 7.73 (d, J= 8.0 Hz, IH), 7.56 (t, J= 7.4 Hz, IH), 7.48 (t, J= 7.6 Hz, IH), 7.28 (d, J= 7.6 Hz, IH), 6.61 (d, J= 5.2 Hz, IH), 6.45 (s, IH), 4.76 (bs, 2H); TLC #/(rc-Hexanes:EtOAc 1:1) = 0.20.
Figure imgf000243_0003
4-(2-Methoxyphenyl)pyridin-2-amine
1H NMR (400 MHz, CDCl3) δ 8.08 (d, J= 5.2 Hz, IH), 7.40 (dd, J= 7.67, 11.8 Hz, IH), 7.47-7.43 (m, IH), 7.37-7.33 (m, IH), 7.31-7.29 (m, IH), 6.82 (dd, J= 5.0, 1.0 Hz, IH), 6.67 (s, IH), 4.47 (bs, 2H), 3.81 (s, 3H); TLC i?/(rc-Hexanes:EtOAc 1 :1 with 0.5% MeOH) = 0.12.
Figure imgf000243_0004
4-(2-Aminopyridin-4-yl)benzonitriIe
1H NMR (400 MHz, CD3OD) δ 7.96 (d, J= 5.2 Hz, IH), 7.79 (m, 4H), 6.85 (dd, J= 5.4, 1.4 Hz, IH), 6.82 (s, IH); TLC i?/(rc-Hexanes:EtOAc 3:7) = 0.21.
Figure imgf000244_0001
4-(2-Aminopyridin-4-yl)-3-methylbenzonitrile
1H NMR (400 MHz, CD3OD) δ 7.96 (d, J= 5.2 Hz, IH), 7.66 (s, IH), 7.61 (dd, J= 8.0, 1.2 Hz, IH), 7.35 (d, J= 7.6 Hz, IH), 6.55 (dd, J= 5.4, 1.4 Hz, IH), 6.51 (s, IH), 2.31 (s, 3H); TLC i?/(«-Hexanes:EtOAc 1:1 with 0.5% MeOH) = 0.13.
Figure imgf000244_0002
4-(2-Chloro-4-fluorophenyl)pyridin-2-amine
1H NMR (400 MHz, CD3OD) δ 7.90 (d, J= 5.2 Hz, IH), 7.61 (m, IH), 7.34 (dd, J= 8.4, 6.0 Hz, IH), 7.29 (dd, J= 8.8, 2.8 Hz, IH), 7.12 (dt, J= 8.4, 2.8 Hz, IH), 6.59 (s, IH); TLC Rf(n- Hexanes:EtOAc 3:7) = 0.37.
Figure imgf000244_0003
2-Chloro-4-cyanophenyl trifluoromethanesulfonate
1H NMR (400 MHz, CDCl3) δ 7.84 (d, J= 2.0 Hz, IH), 7.67-7.65 (m, IH), 7.49 (d, J= 8.8 Hz, IH); TLC i?/(«-Hexanes: EtOAc 5:1) = 0.92.
Figure imgf000244_0004
3-Chloro-4-(2-chloropyridin-4-yl)benzonitrile
1H NMR (400 MHz, CDCl3) δ 8.48 (d, J= 5.2 Hz, IH), 7.79 (d, J= 2.0 Hz, IH), 7.65-7.63 (m, IH), 7.41 (d, J= 8.0 Hz, IH), 7.37 (s, IH), 7.27-7.25 (m, IH); TLC i?/(«-Hexanes:EtOAc 3:1) = 0.68.
Figure imgf000244_0005
3-ChIoro-4-(2-(4-methoxybenzylamino)pyridin-4-yl)benzonitrile
1H NMR (400 MHz, CDCl3) δ 8.18 (d, J= 4.8 Hz, IH), 7.73 (s, IH), 7.59-7.56 (m, IH), 7.38- 7.36 (m, IH), 7.27 (d, J= 7.6 Hz, 2H), 6.86 (d, J= 7.2 Hz, 2H), 6.59 (d, J= 5.2 Hz, IH), 6.35 (s, IH), 4.45 (d, J= 5.6 Hz, 2H), 3.78 (s, 3H); TLC i?/(«-Hexanes:EtOAc 3:1) = 0.08.
Figure imgf000245_0001
4-(2-Aminopyridin-4-yl)-3-chlorobenzonitrile
1H NMR (400 MHz, CDCl3) δ 8.17-8.15 (m, IH), 7.77 (d, J= 1.6 Hz, IH), 7.62-7.60 (m, IH), 7.42 (d, J= 8.0 Hz, IH), 6.68-6.66 (s, IH), 6.51 (t, J= 1.6 Hz, IH), 4.57 (s, 2H); TLC Rf (CH2Cl2MeOH 20:1) = 0.37.
Figure imgf000245_0002
4-(2-Chloropyridin-4-yl)-3-(trifluoromethyl)benzonitrile
1H NMR (400 MHz, CDCl3) δ 8.46 (d, J= 4.8 Hz, IH), 8.06 (s, IH), 7.91-7.88 (m, IH), 7.43 (d, J= 8.0 Hz, IH), 7.27 (s, IH), 7.16 (d, J= 4.8 Hz, IH); TLC i?/(«-Hexanes:EtOAc 5:1) = 0.48.
Figure imgf000245_0003
4-(2-(4-Methoxybenzylamino)pyridin-4-yl)-3-(trifluoromethyl)benzonitrile
1H NMR (400 MHz, CDCl3) δ 8.05 (d, J= 4.8 Hz, IH), 7.96 (s, IH), 7.78 (d, J= 8.0 Hz, IH), 7.38 (d, J= 7.6 Hz, IH), 7.22 (d, J= 8.4 Hz, 2H), 6.81 (d, J= 8.4 Hz, 2H), 6.47 (d, J= 4.8 Hz, IH), 6.25 (s, IH), 5.26 (t, J= 5.2 Hz, IH), 4.39 (d, J= 5.2 Hz, 2H), 3.73 (s, 3H); TLC Rf («-Hexanes:EtOAc 5:1) = 0.15.
Figure imgf000245_0004
4-(2-Aminopyridin-4-yl)-3-(trifluoromethyl)benzonitrile 1H NMR ^OO MHZ, CDCl3) 6 8.11-8.10 (m, IH), 8.01 (s, IH), 7.85-7.82 (m, IH), 7.42 (d, J= 8.0 Hz, IH), 6.38 (s, IH), 4.51 (s, 2H); TLC R1 (CH2Cl2 :MeOH 20:1) = 0.08.
Figure imgf000246_0001
4-(2,6-Dimethylphenyl)pyridin-2-amine
1H NMR (400 MHz, CDCl3) 6 8.12 (d, J= 5.2 Hz, IH), 7.18-7.14 (m, IH), 7.09 (d, J= 7.2 Hz, 2H), 6.47 (d, J= 5.2 Hz, IH), 6.31 (s, IH), 4.56 (s, 2H), 2.06 (s, 6H); TLC Rf(n- Hexanes:EtOAc 2:1) = 0.30.
Figure imgf000246_0002
4-(2-Chloropyridin-4-yl)-3,5-dimethylbenzonitrile
1H NMR (400 MHz, CDCl3) δ 8.47 (d, J= 5.2 Hz, IH), 7.39 (s, 2H), 7.13 (s, IH), 7.03 (dd, J = 5.2, 1.2 Hz, IH), 2.05 (s, 6H); TLC i?/(«-Hexanes:EtOAc 2:1) = 0.51.
Figure imgf000246_0003
4-(2-(4-MethoxybenzyIamino)pyridin-4-yl)-3,5-dimethylbenzonitrile
1H NMR (400 MHz, CDCl3) 6 8.15 (d, J= 4.8 Hz, IH), 7.33 (s, 2H), 7.26 (d, J= 8.4 Hz, 2H), 6.85 (d, J= 8.0 Hz3 2H), 6.32 (d, J= 4.8 Hz, IH), 6.08 (s, IH), 5.11 (bs, IH), 4.42 (d, J= 5.6 Hz, 2H), 3.78 (s, 3H), 2.02 (s, 6H); TLC i?/(«-Hexanes:EtOAc 2:1) = 0.17.
Figure imgf000246_0004
4-(2-Aminopyridin-4-yl)-3,5-dimethylbenzonitrile
1H NMR (400 MHz, CDCl3) 6 8.11 (d, J= 5.2 Hz, IH), 7.34 (s, 2H), 6.35 (dd, J= 5.0, 1.4 Hz, IH), 6.24 (s, IH), 4.79 (bs, 2H), 2.02 (s, 6H); TLC i?/(rc-Hexanes:EtOAc 1:2) = 0.26.
Figure imgf000247_0001
6-ø-Tolylpyrazin-2-amine
1R NMR (400 MHz, CDCl3) δ 8.00 (s, IH), 7.91 (s, IH), 7.35 (d, J= 6.8 Hz, IH ), 7.30-7.24 (m, 3H), 4.68 (bs, 2H), 2.36 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 153.8, 153.0, 137.4, 136.3, 134.4, 131.1, 130.3, 129.7, 129.0, 126.2, 20.5; TLC ^(rc-Hexanes: EtOAc 2:1) = 0.19.
Figure imgf000247_0002
6-(2-Chlorophenyl)pyrazin-2-amine
1U NMR (400 MHz, CDCl3) δ 8.20 (s, IH), 7.94 (s, IH), 7.51-7.49 (m, IH), 7.47-7.44 (m, IH), 7.34-7.31 (m, 2H), 4.74 (bs, 2H); 13C NMR (100 MHz, CDCl3) δ 154.0, 150.0, 136.6, 134.9, 132.6, 131.5, 131.0, 130.4, 130.2, 127.2; TLC i?/(«-Hexanes:EtOAc 2:1) = 0.13.
Figure imgf000247_0003
6-(2-(Trifluoromethyl)phenyl)pyrazin-2-amine
1H NMR (400 MHz, CDCl3) δ 7.99 (s, IH), 7.97 (s, IH), 7.75 (d, J= 7.6 Hz, IH), 7.60 (t, J= 7.2 Hz, IH), 7.52 (t, J= 7.2 Hz, IH), 7.45 (d, J= 6.8 Hz, IH), 4.71 (bs, 2H); TLC Rf(n- Hexanes:EtOAc 2:1) = 0.15.
Figure imgf000247_0004
6-(2-Methoxyphenyl)pyrazin-2-amine
1H NMR (400 MHz, CDCl3) δ 8.42 (s, IH), 7.84 (s, IH), 7.69 (dd, J= 7.6, 1.6 Hz, IH), 7.34- 7.31 (m, IH), 7.04-7.01 (m, IH), 6.95 (d, J= 8.4 Hz, IH ), 4.64 (bs, 2H), 3.82 (s, 3H); 13C NMR (IOO MHz, CDCl3) δ 157.4, 154.1, 149.0, 135.8, 131.1, 130.6, 130.6, 130.0, 126.4, 121.2, 111.6, 55.8; TLC i?/(π-Hexanes:EtOAc 2:1) = 0.13.
Figure imgf000248_0001
6-(2,6-DimethyIphenyl)pyrazin-2-amine
1H NMR (400 MHz, CDCl3) δ 7.91 (s, IH), 7.83 (s, IH), 7.18 (t, J= 7.6 Hz, IH), 7.09-7.07 (m, 2H), 4.71 (bs, 2H), 2.07 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 154.3, 152.7, 137.2, 136.4, 134.6, 132.3, 132.2, 130.4, 128.7, 127.9, 20.4; TLC i?/(«-Hexanes:EtOAc 2:1) = 0.37.
Figure imgf000248_0002
4-(6-Aminopyrazin-2-yl)-3-methylbenzonitriIe
1H NMR (400 MHz, DMSO-J6) δ 7.87 (s, IH), 7.81 (s, IH), 7.76 (s, IH), 7.70 (d, J= 8.0 Hz, IH), 7.52 (d, J= 7.6 Hz, IH), 6.54 (bs, 2H), 2.34 (s, 3H); 13C NMR (100 MHz, DMSO-J6) δ 155.8, 150.6, 142.9, 138.2, 134.7, 132.1, 131.6, 131.0, 130.3, 119.4, 111.6, 20.4; TLC Rf(n- Hexanes:EtOAc 1:2) = 0.53.
Figure imgf000248_0003
4-ø-Tolylpyrimidin-2-amine
1H NMR (400 MHz, DMSO-J6) δ 8.25 (d, J= 4.8 Hz, IH), 7.35-7.24 (m, 4H), 6.65-6.61 (m, 3H), 2.39 (s, 3H); 13C NMR (IOO MHz, DMSO-J6) δ 167.8, 164.1, 158.9, 139.2, 131.3, 129.6, 129.4, 126.4, 110.5, 20.7; TLC i?/(«-Hexanes:EtOAc 2:1) = 0.17.
Figure imgf000248_0004
2-Chloro-4-(2-chlorophenyl)pyrimidine
1H NMR (400 MHz, CDCl3) δ 8.68 (d, J= 5.2 Hz, IH), 7.71-7.69 (m, 2H), 7.49-7.47 (m, IH), 7.41-7.37 (m, 2H); TLC 7?/(«-Hexanes:EtOAc 5:1) = 0.72.
Figure imgf000249_0001
4-(2-Chlorophenyl)pyrimidin-2-amine
1H NMR (400 MHz, DMSO-J6) δ 8.31 (d, J= 4.8 Hz, IH), 7.56-7.53 (m, 2H), 7.48-7.42 (m, 2H), 6.79-6.76 (m, 3H), 5.75 (s, 2H); TLC #/(«-Hexanes:EtOAc 2:1) = 0.20.
Figure imgf000249_0002
2-Chloro-4-(2-(trifluoromethyl)phenyl)pyrimidine
1U NMR (400 MHz, CDCl3) δ 8.66 (d, J= 5.2 Hz, IH), 7.78 (d, J= 7.2 Hz, IH), 7.67-7.57 (m, 2H), 7.51 (d, J= 7.2 Hz, IH), 7.40 (d, J= 5.2 Hz, IH); TLC i?/(«-Hexanes:EtOAc 5:1) 0.75.
Figure imgf000249_0003
4-(2-(Trifluoromethyl)phenyl)pyrimidin-2-amine
1K NMR (400 MHz, CDCl3) δ 8.34 (d, J= 5.2 Hz, IH), 7.74 (d, J= 7.6 Hz, IH), 7.61 (t, J= 7.4 Hz, IH), 7.53 (t, J= 7.6 Hz, IH), 7.45 (d, J= 8.0 Hz, IH), 6.74 (d, J= 5.2 Hz, IH), 5.11 (s, 2H); TLC i?/(«-Hexanes: EtOAc 2:1) = 0.36.
Figure imgf000249_0004
4-(2-Methoxyphenyl)pyrimidin-2-amine
1H NMR (400 MHz, CDCl3) δ 8.27 (d, J= 5.6 Hz, IH), 7.81 (dd, J= 7.6, 1.6 Hz, IH), 7.25- 7.12 (m, 2H), 7.05 (d, J= 7.6 Hz, IH), 6.95 (d, J= 6.0 Hz, IH), 5.08 (bs, 2H), 3.85 (s, 3H); TLC i?/(«-Hexanes:EtOAc 1 :2) = 0.30.
Figure imgf000249_0005
4-(2,6-DimethyIphenyl)pyrimidin-2-amine
1H NMR (400 MHz, CDCl3) δ 8.30 (d, J= 5.2 Hz, IH), 6.79 (t, J= 7.6 Hz, IH), 7.06 (d, J= 7.2 Hz, 2H), 6.54 (d, J= 5.2 Hz, IH), 5.33 bs, 2H), 2.09 (s, 6H); ); 13C NMR (100 MHz, CDCl3) δ 169.4, 163.3, 158.5, 138.5, 135.2, 128.6, 127.9, 112.3, 20.1; TLC Rf(n- Hexanes:EtOAc 1 :1) = 0.25.
Figure imgf000250_0001
4-(2-Ammopyrimidin-4-yl)-3-methylbenzonitrile
1H NMR (400 MHz, OMSO-d6) δ 8.34 (d, J= 4.8 Hz, IH), 7.81 (s, IH), 7.75 (d, J= 8.0 Hz, IH), 7.57-7.54 (m, IH), 6.77 (s, 2H), 6.72 (d, J= 4.8 Hz, IH), 2.38 (s, 3H); TLC Rf(n- Hexanes:EtOAc 1 :1 with 0.5% MeOH) = 0.26.
Figure imgf000250_0002
4-(2-Chlorophenyl)-iV-(prop-2-ynyl)pyrimidiii-2-amine
1H NMR (400 MHz, CDCl3) δ 8.38 (d, J= 4.8 Hz, IH), 7.59 (t, J= 4.6 Hz, IH), 7.44 (m, IH), 7.33 (m, 2H), 6.96 (d, J= 4.8 Hz, IH), 5.72 (bs, IH), 4.22 (dd, J= 5.6, 2.4 Hz, 2H), 2.20 (t, J = 2.6 Hz, IH); TLC i?/(n-Hexanes:EtOAc 4:1) = 0.29.
Figure imgf000250_0003
N-(Prop-2-ynyl)-4-(2-(trifluoromethyI)phenyl)pyrimidin-2-amme
1H NMR (400 MHz, CDCl3) δ 8.39 (d, J= 5.2 Hz, IH), 7.77 (d, J= 7.6 Hz, IH), 7.62 (t, J= 7.4 Hz, IH), 7.55 (t, J= 7.6 Hz, IH), 7.49 (d, J= 7.6 Hz, IH), 6.75 (d, J= 5.2 Hz, IH), 5.35 (bs, IH), 4.27 (dd, J= 5.6, 2.4 Hz, 2H), 2.23 (t, J= 2.2 Hz, IH); TLC Λ//ι-Hexanes:EtOAc 4:1) = 0.24.
Figure imgf000250_0004
4-(2-Chloropyrimidin-4-yl)-3-methylbenzonitrile
1H NMR (400 MHz, CDCl3) δ 8.74 (d, J= 5.2 Hz, IH), 7.62 (d, J= 4.8 Hz, 2H), 7.56 (d, J = 8.4 Hz, IH), 7.39 (d, J= 4.8 Hz, IH), 2.48 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.4, 161.6, 160.3, 140.6, 138.1, 134.9, 130.6, 130.1, 119.7, 118.4, 114.0, 20.5; TLC Rf(n- Hexanes:EtOAc 5:1) = 0.18.
Figure imgf000251_0001
3-Methyl-4-(2-(prop-2-ynylamino)pyrimidin-4-yI)benzonitrile
1H NMR (400 MHz, CDCl3) δ 8.43 (d, J= 4.8 Hz, IH), 7.57 (m, 2H), 7.50 (d, J= 8.0 Hz, IH), 6.71 (d, J= 5.2 Hz, IH), 5.59 (bs, IH), 4.24 (m, 2H), 2.46 (s, 3H), 2.24 (s, IH); TLC Rf(n- Hexanes:EtOAc 2:1) = 0.31.
Figure imgf000251_0002
5-Methyl-4-phenylpyrimidin-2-amine
1H NMR (400 MHz, CDCl3) δ 8.16 (s, IH), 7.51-7.550 (m, 2H), 7.45-7.39 (m, 3H), 5.13 (bs, 2H), 2.15 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 166.4, 161.9, 160.1, 138.7, 132.3, 129.2, 128.7, 128.6, 128.5, 117.7, 16.2; TLC i?/(«-Hexanes:EtOAc 1:2) = 0.46.
Figure imgf000251_0003
5-Methyl-4-ø-toIyIpyrimidin-2-amine
1H NMR (400 MHz, CD3OD) δ 8.18 (s, IH), 7.28 (m, 3H), 7.11 (d, J= 7.6 Hz, IH), 2.11 (s, 3H), 1.87 (s, 3H); TLC i?/(«-Hexanes:EtOAc 1 :1) = 0.25.
Figure imgf000251_0004
4-(2-Chlorophenyl)-5-methylpyrimidin-2-amine 1H NMR (400 MHz, CDCl3) δ 8.18 (s, IH), 7.43 (dd, J= 5.8, 3.4 Hz, IH), 7.34-7.31 (m, 2H), 7.23 (dd, J= 6.0, 3.6 Hz, IH), 5.21 (bs, 2H), 1.94 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 165.4, 161.7, 159.5, 137.7, 132.2, 130.1, 129.9, 129.7, 127.2, 119.1, 14.8; TLC Rf(n- Hexanes:EtOAc 1 :2) = 0.39.
Figure imgf000252_0001
5-Methyl-4-(2-(trifluoromethyl)phenyl)pyrimidin-2-amine
1H NMR (400 MHz, CDCl3) δ 8.18 (s, IH), 7.74 (d, J= 8.0 Hz, IH), 7.59 (t, J= 7.6 Hz, IH), 7.52 (t, J= 8.0 Hz, IH), 7.24 (d, J= 7.6 Hz, IH), 5.09 (bs, 2H), 1.86 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 165.4, 161.7, 159.5, 137.7, 132.2, 130.1, 129.9, 129.7, 127.2, 119.1, 14.8; TLC i?/(«-Hexanes:EtOAc 1 :2) = 0.48.
Figure imgf000252_0002
4-(2-Methoxyphenyl)-5-methylpyrimidin-2-amine
1H NMR (400 MHz, CD3OD) δ 8.09 (s, IH), 7.42 (m, IH), 7.17 (dd, J= 7.6, 1.6 Hz, IH), 7.08 (d, J= 8.4 Hz, IH), 6.79 (t, J= 7.6 Hz, IH), 3.78 (s, 3H), 1.90 (s, 3H); TLC Rf(n- Hexanes:EtOAc 1:1) = 0.29.
Figure imgf000252_0003
4-(2-Amino-5-methyIpyrimidin-4-yl)benzonitrile
1H NMR (400 MHz, CD3OD) δ 8.20 (s, IH), 7.84 (d, J= 8.4 Hz, 2H), 7.73(d, J= 8.4 Hz, 2H), 2.14 (s, 3H); 13C NMR (IOO MHZ, CDCl3) δ 164.5, 160.2, 143.1, 132.0, 129.5, 128.8, 118.2, 116.9, 112.7, 14.5; TLC i?/(n-Hexanes: EtOAc 1:2) = 0.33.
Figure imgf000252_0004
4-(2-Amino-5-methylpyrimidin-4-yl)-3-methylbenzonitrile 1H NMR (400 MHz, CDCl3) δ 8.22 (s, IH), 7.56-7.53 (m, 2H), 7.23(d, J= 8.4 Hz, IH), 5.08 (bs, 2H), 2.16 (s, 3H), 1.88 (s, 3H); 13C NMR (IOO MHz, CDCl3) δ 166.0, 161.6, 160.1, 142.8, 137.0, 134.2, 129.9, 128.9, 118.8, 112.7, 19.3, 14.8; TLC i?/(rc-Hexanes:EtOAc 1 :2) = 0.32.
Figure imgf000253_0001
4-(2-Chloro-4-fluorophenyl)-5-methyIpyrimidin-2-amine
1U NMR (400 MHz, CDCl3) δ 8.16 (s, IH), 7.23-7.17 (m, 2H), 7.07-7.02 (m, IH), 5.73 (bs, 2H), 1.92 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 164.3, 161.3, 159.6, 133.9, 133.2, 131.1, 131.0, 118.7, 117.3, 114.5, 14.3; TLC i?/(«-Hexanes:EtOAc 2:1) = 0.17.
Figure imgf000253_0002
3-(2-Amino-5-methylpyrimidin-4-yl)benzonitrile
1H NMR (400 MHz, CD3OD) δ 8.20 (s, IH), 7.97 (s, IH), 7.88 (d, J= 8.0 Hz, IH), 7.82 (dd, J= 8.0, 1.2 Hz, IH), 7.66 (t, J= 7.6 Hz, IH), 2.16 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 164.1, 162.2, 160.2, 139.9, 133.1, 132.5, 132.2, 129.3, 118.1, 116.9, 112.5, 14.5; TLC Rf(n- Hexanes:EtOAc 1:2) = 0.24.
Figure imgf000253_0003
3-(2-Amino-5-methylpyrimidin-4-yl)-2-fluorobenzonitrile
1H NMR (400 MHz, OMSO-d6) δ 8.21 (s, IH), 8.03-7.99 (m, IH), 7.79-7.75 (m, IH), 7.51- 7.47 (m, IH), 6.56 (s, IH), 1.89 (s, 3H); TLC J?/(«-Hexanes:EtOAc 3:1) = 0.17.
Figure imgf000253_0004
3-(2-Amino-5-methylpyrimidin-4-yl)-4-fluorobenzonitrile 1H NMR (400 MHz, CD3OD) δ 8.21 (s, IH), 8.09-7.83 (m, 2H), 7.55-7.40 (m, IH), 1.99 (s, 3H); TLC i?/(n-Hexanes:EtOAc 3:1) = 0.22.
Figure imgf000254_0001
3-(2-Amino-5-methylpyrimidin-4-yl)-4-chlorobenzonitrile
1U NMR (400 MHz, CDCl3) δ 8.22 (s, IH), 7.63-7.55 (m, 3H), 5.21 (s, 2H), 1.93 (s, 3H); TLC i?/(«-Hexanes:EtOAc 1 :1) = 0.12.
Figure imgf000254_0002
2-(2-Amino-5-methylpyrimidin-4-yl)benzonitrile
1H NMR (400 MHz, CDCl3) δ 8.24 (s, IH), 7.84 (d, J= 7.6 Hz, IH), 7.75 (d, J= 8.0 Hz, IH), 7.50 (t, J= 8.2 Hz, IH), 7.37 (t, J= 7.4 Hz, IH), 5.58 (bs, 2H), 2.04 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 163.8, 162.2, 160.9, 142.5, 134.2, 133.8, 132.3, 129.1, 118.0, 112.3, 15.4; TLC J?/(n-Hexanes:EtOAc 1 :2) = 0.20.
Figure imgf000254_0003
2-Chloro-4-(4-cyano-2-methylphenyl)pyrimidine-5-carbonitrile
1R NMR (400 MHz, CDCl3) δ 9.00 (s, IH), 7.66-7.63 (m, 2H), 7.51 (d, J= 8.0 Hz, IH), 2.37 (s, 3H); TLC i?/(«-Hexanes:EtOAc 2:1) = 0.55.
Figure imgf000254_0004
2-Amino-4-(4-cyano-2-methylphenyl)pyrimidine-5-carbonitrile
1H NMR (400 MHz, CD3OD) δ 8.64 (s, IH), 7.72 (s, IH), 7.67 (d, J= 8.0 Hz, IH), 7.50 (d, J = 8.0 Hz, IH), 2.33 (s, 3H); TLC i?/(«-Hexanes:EtOAc 1:2) = 0.42.
Figure imgf000255_0001
4-(2-Chloro-5-(trifluoromethyl)pyrimidiii-4-yl)-3-methylbenzoiiitrile
1H NMR (400 MHz, CDCl3) δ 9.03 (s, IH), 7.63 (s, IH), 7.60 (d, J= 8.4 Hz, IH), 7.28 (d, J= 8.0 Hz, IH), 2.18 (s, 3H); TLC i?/(rc-Hexanes:EtOAc 9:1) = 0.30.
Figure imgf000255_0002
4-(2-Amino-5-(trifluoromethyl)pyrimidin-4-yl)-3-methylbenzonitrile
1H NMR (400 MHz, CDCl3) δ 8.66 (s, IH), 7.81 (s, IH), 7.74 (d, J= 8.0 Hz, IH), 7.65 (s, 2H), 7.39 (d, J= 7.6 Hz, IH), 2.10 (s, 3H); TLC i?/(rc-Hexanes:EtOAc 1 :1) = 0.42.
Figure imgf000255_0003
4-(2-Chloro-5-(trifluoromethyl)pyrimidin-4-yl)-3-methylbenzonitriIe
1H NMR (400 MHz, CDCl3) δ 9.00 (s, IH), 7.60-7.56 (m, 2H), 7.26 (d, J= 8.4 Hz, IH), 2.20 (s, 3H); TLC i?/(«-Hexanes: EtOAc 2:1) = 0.70.
Figure imgf000255_0004
4-(2-Amino-5-(trifluoromethyl)pyrimidin-4-yl)-3-methylbenzonitrile
1H NMR (400 MHz, CDCl3) δ 8.64 (s, IH), 7.56-7.54 (m, 2H), 7.25 (d, J= 8.4 Hz, IH), 5.49 (bs, 2H), 2.17 (s, 3H); TLC Rf(n-Uexams: EtOAc 1 :2) = 0.48.
Figure imgf000255_0005
4-(2,5-Dichloropyrimidin-4-yl)-3-methylbenzonitrile 1H NMR (400 MHz, CDCl3) δ 8.70 (s, IH), 7.59-7.57 (m, 2H), 7.35 (d, J= 8.0 Hz, IH), 2.23 (s, 3H); TLC fl/(rc-Hexanes:EtOAc 2:1) = 0.43.
Figure imgf000256_0001
4-(2-Amino-5-chloropyrimidin-4-yl)-3-methylbenzonitrile
1H NMR (400 MHz3 CDCl3) 5 8.71 (s, IH), 7.61-7.55 (m, 2H), 7.31 (d, J= 8.0 Hz, IH), 5.14 (bs, 2H), 2.24 (s, 3H); TLC i?/(CH2Cl2:Me0H 10:1) = 0.68.
General procedure for the synthesis of pyrazole subunit 2 analogs
Figure imgf000256_0002
A, B, C = CH, N or N=O
To a suspension of 1,3-diketones (12.33 mmol, 1.0 equiv) in EtOH 95% (12 mL) was added dropwise hydrazine monohydrate (15.41 mmol, 1.2 equiv). The reaction mixture was heated to reflux for 30 min, and then cooled to room temperature. The solution was concentrated under reduced pressure and then partitioned between EtOAc (3 x) and water. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via flash column chromatography on silica gel to give pyrazole compounds.
To a 0 °C solution of pyrazoles (1.90 mmol, 1.0 equiv) in anhydrous acetonitrile (10 mL) were added triethylamine (6.45 mmol, 3.4 equiv), DMAP (0.38 mmol, 0.2 equiv), and BoC2O (2.84 mmol, 1.5 equiv) successively. The reaction mixture was warmed to 25 °C and stirred for 1 h. The reaction mixture was partitioned between EtOAc (3 x) and brine. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via flash column chromatography to give Boc-protected pyrazole.
A mixture of Boc-protected pyrazole (0.77 mmol, 1.0 equiv), NBS (0.93 mmol, 1.2 equiv) and AIBN (0.154 mmol, 0.2 equiv) in ClCH2CH2Cl (6 mL) was heated at 90 °C for 2 h. After cooled to 25 0C, the reaction mixture was concentrated under reduced pressure. The resulting residue was directly purified by flash column chromatography on silica gel to give brominated products.
General procedure for the preparation of aryl methyl ketones
Figure imgf000257_0001
A solution of halide (or triflate) (1.0 equiv), Zn(CN)2 (3.0 equiv) , and Pd(PPh3)4 (0.04 equiv) in anhydrous DMF (0.8 M) was heated at 120 ° C for 2 h. After cooling, the reaction was quenched with saturated aqueous NaHCO3 solution and extracted with CH2Cl2 (3 x ) and dried over MgSO4. After filtration and concentration in vacuo, the residue was purified via flash column chromatography on silica gel to give nitrile compounds.
To a solution of aryl nitriles (36.0 mmol, 1.0 equiv) in THF/diethyl ether (20 mL/30 mL) at -78 0C was added MeMgI (3.0 M in diethyl ether) (108 mmol, 1.36 equiv) and stirred for 45 min at -78 0C. After removal of bath, extra THF (20 mL) was added and was stirred for 1 hr at 25 °C. The reaction mixture was treated with 2N HCl (aq) (50 mL) and was further stirred for 1-2 h at 25 °C. The reaction was quenched with saturated aqueous NaHCO3 solution and extracted with CH2Cl2 (3 x ) and dried over MgSO4. After filtration and concentration in vacuo, the residue was purified via flash column chromatography on silica gel to give corresponding aryl methyl ketone compounds.
General procedure for the preparation of Boc-protected pyrazoles
Figure imgf000258_0001
A, B, C = CH, N, or N= O
To a solution of aryl methyl ketones (6.9 mmol, 2.0 equiv) in dry toluene (10 ml) at 0 0C was added LiHMDS (1.0 M in THF, 2.0 equiv) (fast adding), 1 min later acetyl chloride (1.0 equiv) (fast adding) and was stirred at 25 °C for 1 min. The reaction mixture was then treated with AcOH (4 mL) and was stirred for 2 min at 25 0C. To the mixture was added THF (10 mL), EtOH (20 mL), and hydrazine monohydrate (6.7 mL, 41 equiv) successively. The resulting reaction mixture was heated at 90 ° C for 1 h. The reaction was quenched with IN NaOH solution and extracted with EtOAc (3 x ) and dried over MgSO4. After filtration and concentration in vacuo, the residue was subjected to the following step without further purification.
To the crude product above (1.0 equiv) was added CH3CN (0.3 M), Et3N (2.0 equiv), DMAP (0.2 equiv), and BoC2O (1.2 equiv) and was stirred at 25 °C for 1 h. The reaction was quenched by the addition of saturated aqueous NaHCO3 solution and extracted with CH2Cl2 (3 x ) and dried over MgSO4. After filtration and concentration in vacuo, the residue was purified via flash column chromatography on silica gel.
General procedure for the synthesis of PMB-protected pyrazole subunit 2.
Figure imgf000258_0002
To a solution of pyrazoles (2.30 mmol, 1.0 equiv) in DMF (15 mL) was added slowly NaH (60% in mineral oil, 2.54 mmol, 1.1 equiv), followed by l-(bromomethyl)-4-methoxybenzene (2.54 mmol, 1.1 equiv) at 25 °C. The suspension was stirred at room temperature for 15 h, and then quenched with a mixture of saturated aqueous NH4Cl (10 mL) and H2O (10 mL). The mixture was extracted with CH2Cl2 (3 x 20 mL) and dried over Na2SO4. After filtration and concentration in vacuo, the residue was purified via flash column chromatography on silica gel to give PMB-protected pyrazoles.
To a solution of PMB-protected pyrazoles (0.59 mmol, 1.0 equiv) in Et2O (3 mL) was added slowly LiAlH4 (0.77 mmol, 1.3 equiv) at 25 0C. The suspension was stirred at 25 0C for Ih, and then quenched by the addition of H2O (30 μL), 15% NaOH (30 μL), H2O (90 μL) successively. After stirred at 25 °C for 30 min, the suspension was filtered and rinsed thoroughly with 5% MeOHZCH2Cl2. The filtrate was concentrated in vacuo to give desired alcohols.
To a solution of above alcohols (0.62 mmol, 1.0 equiv) in CH2Cl2 (15 mL) was added PPh3 (1.23 mmol, 2.0 equiv) and CBr4 (1.23 mmol, 2.0 equiv) successively at 0 °C. The suspension was stirred at 25 °C for 30 min, and then quenched with a mixture of saturated aqueous NaHCO3 (10 mL) and H2O (10 mL). The mixture was extracted with CH2Cl2 (3 x 20 mL) and dried over Na2SO4. After filtration and concentration in vacuo, the residue was purified via flash column chromatography on silica gel to give bromide compounds
General procedure for the synthesis of triazole subunit 2.
Figure imgf000259_0001
A solution of sodium methoxide (16.53 mmol, 1.5 equiv) in anhydrous ethanol (12 mL) was added to a solution of acetamide hydrochloride (16.53 mmol, 1.5 equiv) in anhydrous EtOH (25 mL) at room temperature. The milky slurry was stirred at room temperature for 30 min and filtered. To the ethanol filtrate was added to benzohydrazide (11.02 mmol, 1.0 equiv) and the reaction mixture was stirred at room temperature for overnight. The resulting slurry was cooled to 0 °C, stirred for 2 h and the precipitated was collected by filtration, rinsed with cold anhydrous EtOH and dried in vacuo to afford acyl amidrazone. A slurry of acyl amidrazone (1.85 mmol, 1.0 equiv) in a mixture of xylene (3 mL) and 1-octanol (0.15 mL) was refluxed in an apparatus fitted with a Dean-Stark trap. After 45 min, a rapid evolution of water ensued and the starting material dissolved. The solution was allowed to cool to room temperature and was cooled to -5 °C and stirred for 30 min. The precipitated product was collected by filtration, washed with cold xylenes (4 x 15 mL) and dried in vacuo to give triazole products.
General procedure for the synthesis of triazole subunit 2 via click chemistry
Figure imgf000260_0001
Figure imgf000260_0002
To a solution of anilines (5.48 mmol, 1.0 equiv) in CH3CN (11 mL, 0.5 M) at 0 °C was added tert-butyl nitrite (8.24 mmol, 1.5 equiv). After dropwise addition of azidotrimethylsilane (6.62 mmol, 1.2 equiv), the mixture was stirred for 3 h at room temperature. The solution was concentrated under reduced pressure and then the resulting residue was directly purified via flash column chromatography (SiO2, «-Hexanes: EtOAc 19:1) to give aryl azides.
To a solution of aryl azides (1.68 mmol, 1.0 equiv) and propargyl alcohol (1.68 mmol, 1.0 equiv) in t-BuOH/H2O (1 :1, 7 mL, 0.25 M) was added sodium ascorbate (0.17 mmol, 0.1 equiv) and copper sulfate pentahydrate (0.02 mmol, 0.01 equiv) and stirred for 16 h at 25 0C. The reaction was quenched by the addition of water and extracted with CH2Cl2 (4 x). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was purified via flash column chromatography (SiO2, ra-Hexanes: EtOAc 3:7) to give a click adducts.
To a solution of above alcohols (0.25 mmol, 1.0 equiv) in CHCl3 (2.5 mL, 0.1 M) was added MnO2 (2.3 mmol, 8.0 equiv) and the reaction mixture was refluxed for 2.5 h at 90 0C. The reaction was cooled to room temperature and then filtered through a pad of celite. After concentrated in vacuo, the residue was purified via flash column chromatography (SiO2, n- Hexanes: EtOAc 9:1) to give aldehydes.
General procedure for the synthesis of THP-protected subunit 2
Figure imgf000261_0001
A, B, C = CH, N
Figure imgf000261_0002
To a solution of aryl ketones (8.25 mmol, 1.0 equiv) in toluene (17 mL) was added DMFDMA (10.73 mmol, 1.3 equiv). The reaction mixture was heated to 100 °C until complete by TLC (usually > 20 h) and concentrated in vacuo. The resulting residue was redissolved in EtOH (17 mL) and treated with hydrazine hydrate (9.91 mmol, 1.2 equiv) at room temperature. The reaction mixture was heated to 120 °C for 16 h and concentrated in vacuo. The residue was purified via flash column chromatography on silica gel to pyrazoles.
To a solution of pyrazoles (3.44 mmol, 1.0 equiv) and DHP (27.56 mmol, 8.0 equiv) in toluene/CH3CN (1/1 = 5.74 mL/5.74 mL) was added TFA (517 μmol, 15 mol%). The reaction mixture was heated to 80 0C until complete by TLC (usually > 24 h). The reaction was quenched with saturated aqueous NaHCO3 solution and extracted with EtOAc (3 x). The combined organic layers were washed with brine and dried over MgSO4. After filtration and concentration in vacuo, the residue was purified via flash column chromatography to give THP -protected pyrazoles.
To a -78 °C solution of THP-protected pyrazoles (1.06 mmol, 1.0 equiv) in THF (3.6 mL) was added H-BuLi (1.6 M in rø-hexanes, 1.27 mmol, 1.2 equiv). The reaction mixture was warmed to 0 "C and stirred for 10 min. The reaction mixture was treated with DMF (994 μmol, 1.2 equiv) at 0 °C. After 30 min at 0 0C, the reaction was stirred further 1.5 h at 25 °C. The reaction was quenched with saturated aqueous NH4Cl solution and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine (20 mL) and dried over MgSO4. After filtration and concentration in vacuo, the residue was purified via flash column chromatography to give formylated pyrazoles.
General scheme for the synthesis of subunit 2 furan derivatives.
Figure imgf000262_0001
To a -78 °C solution of 5-(furan-2-yl)-3-methyl-lH-pyrazole (1.82 g, 12.3 mmol, 1.0 equiv) and TMEDA (4.05 niL, 27.1 mmol, 2.2 equiv) in TΗF (18 mL) was H-BuLi (1.6 M in hexane, 16.9 mmol, 27.1 mmol, 2.2 equiv). The reaction mixture was slowly warmed to 0 °C for 30 min while stirring. After cooling to -78 "C, CO2 gas was bubbled and slowly warmed to room temperature. To the reaction mixture was added 4N HCl in dioxane (8 mL). The solution was evaporated to obtain a crude solid. The crude material was washed with Et2O and CH2Cl2 to give carboxylated compound which is used in the following step without further purification.
To a solution of carboxylated compound in MeOH (0.2 M, 60 mL) was added SOCl2 (3.6 mL, 49.2 mmol, 4.0 equiv) at room temperature. The reaction mixture was heated at 75 °C overnight. After removed the solvent under reduced pressure, the resulting residue was treated with saturated aqueous NaHCO3 solution and extracted with CH2Cl2 (3 x ). The combined organic layers were dried over MgSO4. After filteration and concentration in vacuo, the residue was purified via flash column chromatography on silica gel.
General procedure for the synthesis of subunit 2 indazole derivatives.
Figure imgf000262_0002
A, B, C = CH, N NBS, AIBN
1 ,2-dichloroethane
(or CCI4)
90 0C
Figure imgf000262_0003
To a solution of 2-fluoroacetophenone derivatives (14.48 mmol, 1.0 equiv) in ethylene glycol (10 mL) was added hydrazine monohydrate (15.06 mmol, 1.04 equiv) at 25 "C. After 2 h at 25 0C, the reaction was heated to 165 °C and stirred until complete by TLC. After cooled to 25 °C, the mixture was extracted with CH2Cl2 (3 x). The combined organic layers were washed with saturated aqueous NaHCO3 and dried over MgSO4. After filtration and concentration in vacuo, the residue was purified via flash column chromatography on silica gel to indazole analogs.
To a solution of above indazole analogs (6.05 mmol, 1.0 equiv) in anhydrous acetonitrile (30 mL) was added Et3N (20.52 mmol, 3.4 equiv) and DMAP (1.21 mmol, 0.2 equiv) successively at 25 °C. The resulting reaction mixture was stirred at 25 "C until complete by TLC (usually < 3 h) and was partitioned between EtOAc (2 x) and brine. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via flash column chromatography on silica gel to give Boc-protected indazoles.
A solution of above Boc-protected indazoles (2.69 mmol, 1.0 equiv), NBS (3.23 mmol, 1.2 equiv), and AIBN (0.54 mmol, 0.2 equiv) in 1 ,2-dichloroethane (21 mL, 0.13 M) was heated to 90 ° C and stirred until complete by TLC (usually < 3 h).The reaction mixture was concentrated under reduced pressure with silica gel and then directly purified via flash column chromatography on silica gel to give brominated products.
Figure imgf000263_0001
3-methyl-5-phenyI-l/7-pyrazole
1H NMR (400 MHz, CDCl3) δ 10.39 (bs, IH), 7.72-7.70 (m, 2H), 7.41-7.40 (m, 2H), 7.33- 7.26 (m, IH), 6.36 (s, IH), 2.33 (s, 3H); TLC i?/(n-Hexanes: EtOAc 2:1) = 0.14.
Figure imgf000263_0002
fer£J3utyI 3-methyl-5-phenyl-lH-pyrazole-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 7.87-7.85 (m, 2H), 7.42-7.33 (m, 3H), 6.46 (s, IH), 2.56 (s, 3H), 1.67 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 153.6, 149.1, 144.8, 132.3, 129.0, 128.7, 126.5, 107.6, 85.1, 28.2, 15.0; TLC i?/(«-Hexanes:EtOAc 2:1) = 0.68.
Figure imgf000264_0001
tert-Butyl 3-(bromomethyl)-5-phenyl-liϊ-pyrazole-l-carboxylate
1U NMR (400 MHz, CDCl3) δ 7.86-7.83 (m, 2H), 7.41-7.35 (m, 3H), 6.77 (s, IH), 4.77 (s, 2H), 1.69 (s, 9H); TLC i?/(n-Hexanes:Et2O 5:1) = 0.32.
Figure imgf000264_0002
3-(4-Methoxyphenyl)-5-methyl-lHr-pyrazole
1H NMR (400 MHz, CDCl3) δ 7.59 (s, 2H), 6.91 (d, J= 8.0 Hz, 2H), 6.28 (s, IH), 3.78 (s, 3H), 2.27 (s, 3H); TLC i?/(rc-Hexanes:EtOAc 3:1) = 0.12.
Figure imgf000264_0003
te/-/-ButyI 3-(4-methoxyphenyl)-5-methyl-liϊ-pyrazole-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 7.80-7.78 (m, 2H), 6.93-6.91 (m, 2H), 6.40 (s, IH), 3.83 (s, 3H), 2.54 (s, 3H), 1.66 (s, 9H); TLC i?/(«-Hexanes:EtOAc 3:1) = 0.62.
Figure imgf000264_0004
tert-Butyl 5-(bromomethyl)-3-(4-methoxyphenyl)-l/f-pyrazole-l-carboxyIate
1H NMR (400 MHz, CDCl3) δ 7.78 (d, J= 8.8 Hz, 2H), 6.91 (d, J= 8.8 Hz, 2H), 6.71 (s, IH), 4.76 (s, 2H), 3.82 (s, 3H), 1.69 (s, 9H); TLC i?/(«-Hexanes:EtOAc 5:1) = 0.52.
Figure imgf000264_0005
l-(3-MethoxyphenyI)butane-l,3-dione
1 1HH NNMMRR ((440000 MMHHzz,, CCDDCCll33)) δδ 77..4477--77..4444 (m, 2H), 7.38-7.34 (m, IH), 7.09-7.06 (m, IH), 6.11
(s, IH), 3.87 (s, 3H), 2.21 (s, 3H); TLC i?/(«-Hexanes:EtOAc 10:1) = 0.53.
Figure imgf000265_0001
3-(3-Methoxyphenyl)-5-methyl-liϊ-pyrazole
1H NMR (400 MHz, CDCl3) δ 7.28 (d, J= 5.2 Hz, 3H), 6.88-6.83 (m, IH), 6.35 (s, IH), 3.82 (s, 3H), 2.30 (s, 3H); TLC i?/(«-Hexanes:EtOAc 1 :1) = 0.12.
Figure imgf000265_0002
tert-Butyl 3-(3-methoxyphenyl)-5-methyl-lJHr-pyrazoIe-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 7.44-7.39 (m, 2H), 7.32-7.28 (m, IH), 6.91-6.88 (m, IH), 6.44 (s, IH), 3.86 (s, 3H), 2.55 (s, 3H), 1.67 (s, 9H); TLC i?/(ra-Hexanes: EtOAc 1:1) = 0.78.
Figure imgf000265_0003
tert-Butyl 5-(bromomethyl)-3-(3-methoxyphenyl)-l//-pyrazole-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 7.42-7.38 (m, 2H), 7.32-7.28 (m, IH), 6.92-6.89 (m, IH), 6.76 (s, IH), 4.76 (s, 2H), 3.84 (s, 3H), 1.69 (s, 9H); TLC i?/(«-Hexanes:EtOAc 3:1) = 0.52.
Figure imgf000265_0004
3-(Iodomethyl)-5-phenyIisoxazole
1H NMR (400 MHz, CDCl3) δ 7.75-7.73 (m, 2H), 7.46-7.41 (m, 3H), 6.54 (s, IH), 4.32 (s, 2H); 13C NMR (100 MHz, CDCl3) d 170.9, 162.7, 130.6, 129.2, 127.3, 126.0, 100.0, -10.2; TLC i?/(n-Hexanes:EtOAc 2:1) = 0.94.
Figure imgf000265_0005
l-(2-Methoxyphenyl)butane-l,3-dione 1H NMR (400 MHz, CDCl3) δ 7.85-7.83 (m, IH), 7.46-7.39 (m, IH), 7.03-6.93 (m, 2H), 6.40 (s, IH), 3.89 (s, 3H), 2.16 (s, 2H); TLC i?/(n-Hexanes:EtOAc 10:1) = 0.42.
Figure imgf000266_0001
3-(2-Methoxyphenyl)-5-methyl-l//-pyrazole
1H NMR (400 MHz, CDCl3) δ 7.64-7.61 (m, IH), 7.29-7.25 (m, IH), 7.03-6.98 (m, 2H), 6.41 (s, IH), 3.96 (s, 3H), 2.32 (s, 3H); TLC i?/(π-Hexanes:EtOAc 1:1) = 0.24.
Figure imgf000266_0002
te/-f-Butyl 3-(2-methoxyphenyl)-5-methyl-lH-pyrazole-l-carboxylate
1H NMR (400 MHz5 CDCl3) δ 8.01-7.99 (m, IH), 7.32-7.28 (m, IH), 7.01-6.92 (m, 2H), 6.65 (s, IH), 3.86 (s, 3H), 2.53 (s, 3H), 1.64 (s, 9H); TLC iJyC/i-HexanesiEtOAc 3:1) = 0.51.
Figure imgf000266_0003
tert-Butyl 5-(bromomethyl)-3-(2-methoxyphenyI)-lH-pyrazole-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 8.05-8.03 (m, 2H), 7.38-7.30 (m, IH), 7.02-6.93 (m, 3H), 4.78 (s5 2H), 3.88 (s, 3H), 1.69 (s, 9H); TLC i?/(«-Hexanes:EtOAc 5:1) = 0.62.
Figure imgf000266_0004
l-(4-(Difluoromethoxy)phenyl)ethanone
3-F2ClCCO2Na (5.15 g, 33.8 mmol, 2.3 equiv) was added to a solution Of Cs2CO3 (6.70 g, 20.6 mmol, 1.4 equiv), alcohol (2.0 g, 14.7 mmol, 1.0 equiv), DMF (0.25 m, 60 mL), and water (4.0 M, 3.6 mL). The solution was heated to 100 ° C for 2 h, cooled to room temperature, and poured into a solution OfNH4Cl (aq). The solution was extracted with EtOAc, and the organic layer was washed with brine and dried (MgSO4). The crude product was purified by silica chromatography eluting with a EtOAc/hexane (20%) which afforded 1.33 g (49%) of 1- (4-(difluoromethoxy)phenyl)ethanone: 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J= 8.8 Hz, 2H), 7.18 (d, J= 8.8 Hz, 2H), 6.60 (t, J= 73.0 Hz, IH), 2.60 (s, 3H); TLC i?/(«-Hexanes:EtOAc 5:1) = 0.43.
Figure imgf000267_0001
ter/-Butyl 3-(4-(difluoromethoxy)phenyl)-5-methyl-lJfiT-pyrazoIe-l-carboxyIate
1H NMR (400 MHz, CDCl3) δ 7.86 (d, J= 8.8 Hz, 2H), 7.14 (d, J= 8.4 Hz, 2H), 6.54 (t, J= 73.8 Hz, IH), 6.43 (s, IH), 2.56 (s, 3H), 1.67 (s, 9H); TLC i?/(«-Hexanes:EtOAc 5:1) = 0.66.
Figure imgf000267_0002
tert-Butyl 5-(bromomethyl)-3-(4-(difluoromethoxy)phenyl)-lJΪ-pyrazole-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 7.87 (d, J= 8.8 Hz, 2H), 7.16 (d, J= 8.4 Hz, 2H), 6.76 (s, IH), 6.55 (t, J= 73.6 Hz, IH), 4.78 (s, 2H), 1.71 (s, 9H); TLC i?/(«-Hexanes:EtOAc 5:1) = 0.66.
Figure imgf000267_0003
4-(3-Oxobutanoyl)benzonitrile
1 1HH NNMMRR ((440000 MMHHzz,, CCDDCCll33)) δδ 77..'95-7.92 (m, 2H), 7.73-7.71 (m, 2H), 6.17 (s, IH), 2.22 (s,
3H); TLC tf/(n-Hexanes:EtOAc 10:1) = 0.39.
Figure imgf000267_0004
4-(5-MethyI-l/7-pyrazol-3-yl)benzonitrile
1H NMR (400 MHz, CDCl3) δ 7.88 (d, J= 7.6 Hz, 2H), 7.70 (d, J= 8.4 Hz, 2H)5 6.50 (s, IH), 2.31 (s, 3H); TLC i?/(«-Hexanes: EtOAc 3:1) = 0.10.
Figure imgf000267_0005
ter/-Butyl 3-(4-cyanophenyl)-5-methyl-lH-pyrazole-l-carboxylate 1H NMR (400 MHz, CDCl3) δ 7.95-7.93 (m, 2H), 7.68-7.66 (m, 2H), 6.47 (s, IH), 2.56 (s, 3H), 1.66 (s, 9H); TLC tf/(rc-Hexanes:EtOAc 3:1) = 0.62.
Figure imgf000268_0001
tert-Butyl 5-(bromomethyl)-3-(4-cyanophenyl)-lH-pyrazole-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 7.95 (d, J= 8.4 Hz, 2H), 7.69 (d, J= 8.0 Hz, 2H), 6.81 (s, IH), 4.77 (s, 2H), 1.69 (s, 9H); TLC i?/(rc-Hexanes:EtOAc 3:1) = 0.62.
Figure imgf000268_0002
3-(3-Methyl-i//-pyrazol-5-yl)benzonitrile
LRMS (electrospray) m/z calculated for CnH9N3 (M+H)+ 184.08, found 184.19.
Figure imgf000268_0003
tert-Butyl 3-(3-cyanophenyl)-5-methyl-liϊ-pyrazole-l-carboxylate
LRMS (electrospray) m/z calculated for Cj6H17N3O2 (M+H)+ 284.13, found 284.34.
Figure imgf000268_0004
ter?-ButyI 5-(bromomethyI)-3-(3-cyanophenyl)-lH-pyrazole-l-carboxyIate
LRMS (electrospray) m/z calculated for C16H17BrN3O2 (M+H)+ 364.05, found 364.26.
Figure imgf000268_0005
3-(4-Bromophenyl)-5-methyl-ll/-pyrazole 1H NMR (400 MHz, CD3OD) δ 7.61 (d, J= 6.4 Hz, 2H), 7.50 (d, J= 8.0 Hz, 2H), 6.39 (s, IH), 2.29 (s, 3H); TLC i?/(«-Hexanes:EtOAc 10:1) = 0.13.
Figure imgf000269_0001
ter^Butyl 3-(4-bromophenyl)-5-methyl-lH-pyrazole-l-carboxyIate
1H NMR (400 MHz, CDCl3) δ 7.72-7.70 (m, 2H), 7.50 (d, J= 8.4 Hz, 2H), 6.41 (s, IH), 2.53 (s, 3H), 1.65 (s, 9H); TLC /?/(«-Hexanes:EtOAc 3:1) = 0.68.
Figure imgf000269_0002
tert-Butyl 5-(bromomethyl)-3-(4-bromophenyl)-lHr-pyrazole-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 7.72 (d, J= 7.2 Hz, 2H), 7.52 (d, J= 6.8 Hz, 2H), 6.74 (s, IH), 4.76 (s, 2H), 1.69 (s, 9H); TLC i?/(rc-Hexanes: EtOAc 5:1) = 0.65.
Figure imgf000269_0003
tert-Butyl 3-(2-chlorophenyl)-5-methyl-lH-pyrazoIe-l-carboxylate
1R NMR (400 MHz, CDCl3) δ 7.86 (m, IH), 7.42 (m, IH), 7.30 (m, 2H), 6.65 (s, IH), 2.58 (s, 3H), 1.67 (s, 9H); TLC i?/(n-Hexanes:EtOAc 5:1) = 0.56.
Figure imgf000269_0004
tert-Butyl 5-(bromomethyl)-3-(2-chlorophenyl)-lH-pyrazole-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 7.88 (m, IH), 7.43 (m, IH), 7.31 (m, 2H), 7.00 (s, IH), 4.81 (s, 2H), 1.71 (s, 9H); TLC #/(rc-Hexanes:EtOAc 5:1) = 0.56.
Figure imgf000269_0005
3-(3-chlorophenyl)-5-methyl-lH-pyrazole-l-carboxylate 1H NMR (400 MHz, CDCl3) δ 7.86 (s, IH), 7.73 (m, IH), 7.32 (m, 2H), 6.44 (s, IH), 2.56 (s, 3H), 1.68 (s, 9H); TLC i?/(«-Hexanes:EtOAc 5:1) = 0.61.
Figure imgf000270_0001
ter^-Butyl 5-(bromomethyl)-3-(3-chlorophenyl)-lJHr-pyrazole-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 7.87 (s, IH), 7.73 (m, IH), 7.35 (m, 2H), 6.78 (s, IH), 4.78 (s, 2H), 1.72 (s, 9H); TLC i?/(«-Hexanes:EtOAc 5:1) = 0.61.
Figure imgf000270_0002
3-(4-chlorophenyl)-5-methyI-lJϊ-pyrazole-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 7.78 (d, J= 8.8 Hz, 2H), 7.35 (d, J= 8.4 Hz, 2H), 6.41 (s, IH), 2.54 (s, 3H), 1.65 (s, 9H); TLC i?/(«-Hexanes:EtOAc 5:1) = 0.66.
Figure imgf000270_0003
tert- Butyl 5-(bromomethyl)-3-(4-chlorophenyI)-ll/-pyrazole-l-carboxyIate
1H NMR (400 MHz, CDCl3) δ 7.80 (d, J= 8.4 Hz, 2H), 7.39 (d, J= 8.8 Hz, 2H), 6.77 (s, IH), 4.78 (s, 2H), 1.71 (s, 9H); TLC i?/(«-Hexanes: EtOAc 5:1) = 0.66.
Figure imgf000270_0004
5-(4-Fluorophenyl)-3-methyl-ljHr-pyrazole
1H NMR (400 MHz, CDCl3) δ 12.42 (br, IH), 7.80 (dd, J= 5.2, 1.2 Hz, 2H), 7.08 (dd, J= 5.7, 1.2 Hz, 2H), 6.37 (s, IH), 2.54 (s, 3H)
Figure imgf000270_0005
fer^Butyl 3-(4-fluorophenyl)-5-methyI-l//-pyrazole-l-carboxylate 1H NMR (400 MHz, CDCl3) δ 7.80 (dd, J= 5.2, 1.3 Hz, 2H), 7.08 (dd, J= 5.7, 1.2 Hz, 2H), 6.38 (s, IH), 2.56 (s, 3H), 1.65 (s, 9H)
Figure imgf000271_0001
tert-Butyl 5-(bromomethyl)-3-(4-fluorophenyI)-lH-pyrazole-l-carboxyIate
1 1HH NNMMRR ((440000 MMHHzz,, CCDDCCll33)) δδ 77..8833 ((ddcd, J= 5.2, 1.3 Hz, 2H), 7.07 (dd, J= 5.7, 1.2 Hz, 2H), 6.72 (s, IH), 4.77 (s, 2H), 1.67 (s, 9H)
Figure imgf000271_0002
tert-Buty\ 3-(3-fluorophenyl)-5-methyl-lH-pyrazole-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 7.63-7.60 (m, 2H), 7.34-7.31 (m, IH), 7.04-7.00 (m, IH), 6.38 (s, IH), 2.51 (s, 3H), 1.66 (s, 9H)
Figure imgf000271_0003
tert-Butyl 5-(bromomethyl)-3-(3-fluorophenyl)-ljHr-pyrazole-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 7.61 (m, 2H), 7.38 (q, J= 6.0 Hz, IH), 7.07 (td, J= 8.4, 2.4 Hz, IH), 6.78 (s, IH), 4.79 (s, 2H), 1.71 (s, 9H); TLC i?/(n-Hexanes:EtOAc 5:1) = 0.66.
Figure imgf000271_0004
tert-Butyl 3-(2-fluorophenyl)-5-methyl-l//-pyrazole-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 8.13 (m, IH), 7.34 (m, IH), 7.19 (m, IH), 7.11 (m, IH), 6.61 (m, IH), 2.57 (s, 3H), 1.67 (s, 9H); TLC i?/(«-Hexanes:EtOAc 5:1) = 0.59.
Figure imgf000272_0001
tert-Butyl 5-(bromomethyl)-3-(2-fluorophenyl)-lJϊ-pyrazoIe-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 8.07 (dt, J- 7.8, 1.6 Hz, IH), 7.28 (m, IH), 7.15 (dt, J= 7.4, 0.8 Hz, IH), 7.07 (ddd, J = 11.2, 8.4, 1.2 Hz, IH), 6.88 (d, J= 3.6 Hz, IH), 4.74 (s, 2H), 1.66 (s, 9H); TLC tf/(n-Hexanes:EtOAc 5:1) = 0.59.
Figure imgf000272_0002
5-(2-Chloro-4-fluorophenyl)-3-methyl-liϊ-pyrazole
1H NMR (400 MHz, CDCl3) δ 7.84 (dd, J= 15.2, 2.4 Hz, IH), 7.15 (dd, J= 11.2, 6.0 Hz, IH), 7.02. (dd, J= 19.2, 5.2 Hz, IH), 6.57 (s, IH), 2.50 (s, 3H)
Figure imgf000272_0003
tert-Butyl 3-(2-Chloro-4-fluorophenyI)-5-methyl-l/J-pyrazole-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 7.82 (dd, J= 15.2, 2.4 Hz, IH), 7.14 (dd, J= 11.2 7.01 (dd, J= 19.2, 5.2 Hz, IH), 6.59 (s, IH), 2.55 (s, 3H), 1.51 (s, 9H)
Figure imgf000272_0004
tert-Butyl 5-(bromomethyl)-3-(2-chloro-4-fluorophenyI)-lH-pyrazoIe-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 7.85 (dd, J= 15.2, 2.4 Hz, IH), 7.16 (dd, J= 11.2, 6.0 Hz, IH), 7.02 (dd, J= 19.2, 5.2 Hz, IH), 6.94 (s, IH), 4.77 (s, 2H), 1.68 (s, 9H)
Figure imgf000272_0005
te/"f-Butyl 3-(3-bromo-4-fluoropb.enyl)-5-methyl-l£r-pyrazole-l-carboxylate 1H NMR (400 MHz, CDCl3) δ 8.01-7.99 (m, IH), 7.32-7.28 (m, IH), 7.01-6.92 (m, 2H), 6.65 (s, IH), 3.86 (s, 3H), 2.53 (s, 3H), 1.64 (s, 9H)
Figure imgf000273_0001
tert-Butyl 3-(3-bromo-4-fluorophenyI)-5-(bromomethyI)-lHr-pyrazole-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 8.09 (dd, J= 6.6, 1.8 Hz, IH), 7.77 (m, IH), 7.16 (t, J= 8.4 Hz, IH), 6.74 (s, IH), 4.77 (s, 2H), 1.71 (s, 9H)
Figure imgf000273_0002
te^-Butyl 3-(2,5-dichlorophenyl)-5-methyI-liϊ-pyrazole-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 7.90 (d, J= 2.8 Hz, IH), 7.37 (d, J= 8.4 Hz, IH), 7.27 (dd, J- 8.2, 3.0 Hz, IH), 6.68 (s, IH), 2.60 (s, 3H), 1.70 (s, 9H); TLC i?/(n-Hexanes:EtOAc 5:1) = 0.72.
Figure imgf000273_0003
tert-Butyl 5-(bromomethyl)-3-(2,5-dichlorophenyl)-lH-pyrazoIe-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 7.90 (d, J= 2.4 Hz, IH), 7.37 (d, J= 8.8 Hz, IH), 7.28 (dd, J- 8.4, 2.8 Hz, IH), 7.01 (s, IH), 4.80 (s, 2H), 1.72 (s, 9H); TLC i?/(«-Hexanes:EtOAc 5:1) = 0.72.
Figure imgf000273_0004
terf-Butyl 3-(2,4-dichlorophenyl)-5-methyI-lH-pyrazole-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 7.81 (d, J= 8.4 Hz, IH), 7.42 (d, J= 2.4 Hz, IH), 7.28-7.24 (m, IH), 6.62 (s, IH), 2.55 (s, 3H), 1.64 (s, 9H)
Figure imgf000274_0001
tert-Butyl 5-(bromomethyl)-3-(2,4-dichlorophenyl)-lijr-pyrazole-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 7.81 (d, J= 8.4 Hz, IH), 7.39 (d, J= 2.4 Hz, IH), 7.25 (dd, J= 8.4, 2.0 Hz, IH), 6.96 (s, IH), 4.76 (s, 2H), 1.67 (s, 9H)
Figure imgf000274_0002
tert-Butyl 3-(2-bromo-4-fluorophenyl)-5-methyl-l//-pyrazole-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 7.72 (dd, J= 9.0, 6.2 Hz, IH), 7.35 (dd, J= 8.4, 2.4 Hz, IH), 7.08-7.0 (m, IH), 6.57 (s, IH), 2.55 (s, 3H), 1.64 (s, 9H)
Figure imgf000274_0003
te^-ButyI 3-(2-bromo-4-fluorophenyl)-5-(bromomethyl)-lH-pyrazole-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 7.76-7.73 (m, IH), 7.35 (d, J= 8.0 Hz, IH), 7.06 (t, J= 7.8 Hz, IH), 6.94 (s, IH), 4.79 (s, 2H), 1.69 (s, 9H)
Figure imgf000274_0004
l-(2-Chloro-4-methoxyphenyl)ethanone
1 1HH NNMMRR ((440000 MMHHzz,, CCDDCCll33)) δδ 7.62 (d, J= 8.8 Hz, IH), 6.86 (s, IH), 6.77 (dd, J= 8.8, 2.4 Hz, IH), 3.78 (s, 3H), 2.57 (s, 3H)
Figure imgf000274_0005
tert-Butyl 3-(2-chloro-4-metb.oxyphenyl)-5-methyl-lJHr-pyrazole-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 7.78 (d, J= 8.4 Hz, IH), 6.93 (s, IH), 6.83 (d, J= 8.8 Hz, IH), 6.60 (s, IH), 3.81 (s, 3H), 1.64 (s, 9H)
Figure imgf000275_0001
tert-Butyl 5-(bromomethyl)-3-(2-chloro-4-methoxyphenyl)-lH-pyrazoIe-l-carboxyIate
1H NMR (400 MHz, CDCl3) δ 7.79 (d, J= 8.4 Hz, IH), 6.94-6.93 (m, 2H), 6.84 (d, J= 8.8, 2.4 Hz, IH), 4.77 (s, 2H), 3.80 (s, 3H), 1.68 (s, 9H)
Figure imgf000275_0002
te^-Butyl 3-(2-fluoro-4-methoxyphenyl)-5-methyl-lH-pyrazole-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 8.01 (t, J= 8.8 Hz, IH), 6.73 (dd, J= 8.8, 2.8 Hz, IH), 6.63 (dd, J= 13.0, 2.6 Hz, IH), 6.52 (d, J= 4.0 Hz, IH), 3.81 (s, 3H), 2.53 (s, 3H), 1.65 (s, 9H)
Figure imgf000275_0003
tert-Butyl 5-(bromomethyl)-3-(2-fluoro-4-methoxyphenyl)-lJΪ-pyrazole-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 8.02 (t, J= 8.8 Hz, IH), 6.85 (d, J= 3.6 Hz, IH), 6.75-6.62 (m, 2H), 4.76 (s, 2H), 3.82 (s, 3H), 1.69 (s, 9H)
Figure imgf000275_0004
tert-Butyl 3-(3-chloro-4-fluorophenyl)-5-methyl-lH-pyrazole-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 7.90 (dd, J= 7.2, 2.0 Hz, IH), 7.71-7.67 (m, IH), 7.14 (t, J- 8.6 Hz, IH), 6.38 (s, IH), 2.54 (s, 3H), 1.65 (s, 9H)
Figure imgf000275_0005
3-Methyl-5-(4-nitrophenyl)-l/7-pyrazole 1H NMR (400 MHz, CD3OD) δ 8.26 (d, J= 8.8 Hz, 2H), 7.97 (d, J= 8.0 Hz, 2H), 6.58 (s, IH), 2.35 (s, 3H); TLC i?/(rc-Hexanes:EtOAc 2:1) = 0.18.
Figure imgf000276_0001
tert-Butyl 5-(bromomethyl)-3-(3-chloro-4-fluorophenyl)-ljy-pyrazole-l-carboxyIate
1H NMR (400 MHz, CDCl3) δ 7.91 (dd, J= 6.8, 1.6 Hz, IH), 1.72-7.69 (m, IH), 7.16 (t, J- 8.4 Hz, IH), 6.72 (s, IH), 4.75 (s, 2H), 1.69 (s, 9H)
Figure imgf000276_0002
tert-ButyI 3-(4-fluoro-3-methoxyphenyl)-5-methyl-lJHr-pyrazole-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 7.54 (d, J= 8.4 Hz, IH), 7.27-7.25 (m, IH), 7.09-7.04 (m, IH), 6.40 (s, IH), 3.93 (s, 3H), 2.53 (s, 3H), 1.65 (s, 9H)
Figure imgf000276_0003
ter^-Butyl 5-(bromomethyl)-3-(4-fluoro-3-methoxyphenyl)-lH-pyrazole-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 7.53 (dd, J= 8.2, 1.8 Hz, IH), 7.29-7.25 (m,- IH), 7.08-7.03 (m, IH), 6.73 (s, IH), 4.74 (s, 2H), 3.90 (s, 3H), 1.68 (s, 9H)
Figure imgf000276_0004
tert-Butyl 5-methyl-3-(4-nitrophenyl)-lH-pyrazole-l-carboxyIate
1H NMR (400 MHz, CDCl3) δ 8.27 (d, J= 8.8 Hz, 2H), 8.03 (d, J= 8.8 Hz, 2H), 6.54 (s, IH), 2.59 (s, 3H), 1.69 (s, 9H); TLC i?/(«-Hexanes: EtOAc 5:1) = 0.43.
Figure imgf000277_0001
5-(bromomethyl)-3-(4-nitrophenyI)-lH-pyrazole-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 8.27 (d, J= 9.2 Hz, 2H), 8.02 (d, J= 8.8 Hz, 2H), 6.86 (s, IH), 4.78 (s, 2H), 1.71 (s, 9H); TLC i?/(«-Hexanes:EtOAc 5:1) = 0.43.
Figure imgf000277_0002
3-Methyl-5-(3-nitrophenyl)-lJBT-pyrazole
1H NMR (400 MHz, CDCl3) δ 9.89 (s, IH), 8.46 (s, IH), 8.14-8.08 (m, 2H), 7.64 (t, J= 8.0 Hz, IH), 6.44 (s, IH), 2.38 (s, 3H)
Figure imgf000277_0003
tert-Butyl 5-methyl-3-(3-nitrophenyl)-l/7-pyrazole-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 8.62 (s, IH), 8.22-8.16 (m, 2H), 7.56 (t, J= 8.0 Hz, IH), 6.52 (s, IH), 2.57 (s, 3H), 1.66 (s, 9H)
Figure imgf000277_0004
tert-Bntyϊ 5-(bromomethyI)-3-(3-nitrophenyI)-l/7-pyrazole-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 8.64 (s, IH), 8.22-8.19 (m, 2H), 7.58 (t, J= 8.0 Hz, IH), 6.88 (s, IH), 4.89 (s, 2H), 1.65 (s, 9H)
B
Figure imgf000277_0005
fert-Butyl 5-methyl-3-(2-nitrophenyl)-l//-pyrazoIe-l-carboxylate
1U NMR (400 MHz, CDCl3) δ 7.78 (d, J= 8.0 Hz, 2H), 7.58 (d, J= 7.6 Hz, IH), 7.47 (d, J= 7.8 Hz5 IH), 6.20 (s, IH), 2.53 (s, 3H), 1.64 (s, 9H)
Figure imgf000278_0001
5-(bromomethyl)-3-(2-nitrophenyl)-liϊ-pyrazole-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 7.84 (dd, J= 8.2, 1.0 Hz, IH), 7.78 (dd, J= 7.8, 1.4 Hz, IH), 7.64-7.59 (m, IH), 6.54 (s, IH), 4.75 (s, 2H), 1.68 (s, 9H)
Figure imgf000278_0002
tert-ButyI 3-(4-chloro-3-nitrophenyl)-5-methyl-lJΪ-pyrazole-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 8.32 (d,. J= 2.0 Hz, IH), 8.02 (dd, J= 8.4, 2.4 Hz, IH), 7.57 (d, J= 8.4 Hz, IH), 6.49 (s, IH), 2.58 (s, 3H). 1.68 (s, 9H); TLC i?/(n-Hexanes:EtOAc 5:1) = 0.43.
Figure imgf000278_0003
tert-Butyl 5-(bromomethyI)-3-(4-chloro-3-nitrophenyl)-lHr-pyrazole-l-carboxylate
1B. NMR (400 MHz, CDCl3) δ 8.34 (d, J= 2.0 Hz, IH), 8.03 (dd, J= 8.6, 1.8 Hz, IH), 7.60 (d, J= 8.4 Hz, IH), 6.83 (s, IH), 4.78 (s, 2H), 1.72 (s, 9H); TLC i?/(n-Hexanes:EtOAc 5:1) = 0.43.
Figure imgf000278_0004
terf-Butyl 3-(5-chIoropyridin-2-yl)-5-methyI-lH-pyrazole-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 8.53 (d, J= 2.0 Hz, IH), 8.08 (d, J= 8.8 Hz, IH), 7.70-7.67 (m, IH), 6.76 (s, IH), 2.55 (s, 3H), 1.63 (s, 9H); TLC #/(rc-Hexanes:EtOAc 1 :1) = 0.89.
Figure imgf000278_0005
tert-Butyl 5-(bromomethyl)-3-(5-chloropyridin-2-yl)-l//-pyrazole-l-carboxylate 1H NMR (400 MHz, CDCl3) δ 8.56 (t, J= 1.2 Hz, IH), 8.11 (d, J= 8.4 Hz, IH), 7.74-7.71 (m, IH), 7.11 (s, IH), 4.78 (s, 2H), 1.72 (s, 9H); TLC i?/(CH2Cl 100%) = 0.72.
Figure imgf000279_0001
ter/-Butyl 3-(4-methoxypyridin-2-yl)-5-methyl-ljHr-pyrazole-l-carboxylate
1U NMR (400 MHz, CDCl3) δ 8.41 (d, J= 6.0 Hz, IH), 7.67 (d, J= 2.4 Hz, IH), 6.81-6.78 (m, IH), 3.98 (s, 3H), 2.56 (s, 3H), 1.67 (s, 9H); TLC i?/(«-Hexanes:EtOAc 3:1) = 0.90.
Figure imgf000279_0002
5-(bromomethyl)-3-(4-methoxypyridiii-2-yl)-lH-pyrazole-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 8.45 (d, J= 6.0 Hz, IH), 7.69 (d, J= 2.4 Hz, IH), 7.17 (s, IH), 6.84-6.82 (m, IH), 4.78 (s, 2H), 3.91 (s, 3H), 1.72 (s, 9H); TLC i?/(CH2Cl 100%) = 0.41.
Figure imgf000279_0003
6-Methoxypicolinonitrile
1H NMR (400 MHz, CDCl3) δ 7.34 (dd, J= 11.4, 4.2 Hz, IH), 7.26 (d, J= 6.8 Hz, IH), 6.93 (d, J= 8.4 Hz, IH), 3.94 (s, 3H)
Figure imgf000279_0004
l-(6-Methoxypyridin-2-yl)ethanone
1 1HH NNMMRR ((440000 MMHHzz,, CCDDCCll33)) δδ 7.69-7.65 (m, IH), 7.62-7.60 (m, IH), 6.91 (dd, J= 8.2, 1.0 Hz, IH), 3.98 (s, 3H), 2.67 (s, 3H)
Figure imgf000279_0005
tert-Butyl 3-(6-methoxypyridin-2-yl)-5-methyI-ljBT-pyrazole-l-carboxylate 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J= 7.6 Hz, IH), 7.58 (t, J= 8.0 Hz, IH), 6.78 (s, IH), 6.68 (d, J= 8.0 Hz, IH), 3.94 (s, 3H), 2.55 (s, 3H), 1.66 (s, 9H)
Figure imgf000280_0001
te/"f-Butyl 5-(bromomethyl)-3-(6-methoxypyridin-2-yl)-lJH-pyrazole-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 7.73 (d, J= 7.2 Hz, IH), 7.61 (t, J= 7.6 Hz, IH), 7.10 (s, IH), 6.71 (d, J= 8.4 Hz, IH), 4.78 (s, 2H), 3.98 (s, 3H), 1.70 (s, 9H)
Figure imgf000280_0002
l-(4-Chloropyridin-2-yl)ethanone
1R NMR (400 MHz, CDCl3) δ 8.55 (d, J= 5.2 Hz, IH), 8.00 (d, J= 2.0 Hz, IH), 7.44 (dd, J= 5.2, 2.0 Hz, IH), 2.69 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 199.1. 155.0. 150.2. 145.7. 127.3. 122.4. 26.0; TLC i?/(ra-Hexanes:EtOAc 5:1) = 0.69.
Figure imgf000280_0003
te^-Butyl 3-(4-chloropyridin-2-yl)-5-methyl-lH-pyrazole-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 8.48 (d, J= 5.6 Hz, IH), 8.17 (d, J= 1.6 Hz, IH 6.78 (s, IH), 2.55 (s, 3H), 1.67 (s, 9H); TLC i?/(«-Hexanes:EtOAc 5:1) = 0.44.
Figure imgf000280_0004
tert-Butyl 5-(bromomethyl)-3-(4-chIoropyridin-2-yl)-lH-pyrazole-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 8.52 (d, J= 5.2 Hz, IH), 8.20 (d, J= 2.4 Hz, IH), 7.28 (dd, J = 5.4, 1.8 Hz, IH), 7.14 (s, IH), 4.79 (s, 2H), 1.73 (s, 9H); TLC i?/(«-Hexanes:EtOAc 5:1) = 0.44.
Figure imgf000281_0001
l-(6-Chloropyridin-2-yl)ethanone
1H NMR (400 MHz, CDCl3) δ 7.95 (d, J= 7.6 Hz, IH), 7.80 (t, J- 7.8 Hz, IH), 7.51 (d, J- 8.0 Hz, IH), 2.70 (s, 3H); TLC i?/(n-Hexanes:EtOAc 5:1) = 0.66.
Figure imgf000281_0002
tert-Butyl 3-(6-chloropyridin-2-yl)-5-methyI-lH-pyrazole-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 8.02 (d, J= 7.6 Hz, IH), 7.63 (t, J= 7.6 Hz, IH), 7.21 (d, J= 7.6 Hz, IH), 6.79 (s, IH), 2.50 (s, 3H), 1.62 (s, 9H); TLC i?/(«-Hexanes:EtOAc 5:1) = 0.53.
Figure imgf000281_0003
fert-Butyl 5-(bromomethyI)-3-(6-chloropyridin-2-yl)-lH-pyrazole-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 8.04 (d, J= 7.6 Hz, IH), 7.66 (t, J= 7.8 Hz, IH), 7.26 (d, J= 7.6 Hz, IH), 7.13 (s, IH), 4.72 (s, 2H), 1.67 (s, 9H); TLC i?/(n-Hexanes:EtOAc 5:1) = 0.53.
Figure imgf000281_0004
5-Methoxypicolinonitrile
1H NMR (400 MHz, CDCl3) δ 8.40 (d, J= 2.8 Hz, IH), 7.67 (d, J= 8.4 Hz, IH), 7.26 (dd, J- 8.6, 3.0 Hz, IH), 3.95 (s, 3H); TLC i?/(ra-Hexanes:EtOAc 5:1) = 0.23.
Figure imgf000281_0005
l-(5-Methoxypyridin-2-yl)ethanone
1H NMR (400 MHz, CDCl3) δ 8.33 (d, J= 2.8 Hz, IH), 8.06 (d, J= 8.8 Hz, IH), 7.27 (dd, J= 8.8, 3.2 Hz, IH), 3.94 (s, 3H), 2.69 (s, 3H); TLC i?/(rc-Hexanes:EtOAc 5:1) = 0.35.
Figure imgf000282_0001
terf-Butyl 3-(5-methoxypyridin-2-yl)-5-methyl-l//-pyrazole-l-carboxyIate
1H NMR (400 MHz, CDCl3) δ 8.30 (d, J= 2.8 Hz, IH), 8.09 (d, J= 9.2 Hz, IH), 8.24 (d, J= 2.8 Hz, IH), 6.75 (s, IH), 3.88 (s, 3H), 2.56 (s, 3H), 1.67 (s, 9H); TLC i?/(n-Hexanes:EtOAc 2:1) = 0.41.
Figure imgf000282_0002
tert-Butyl 5-(bromomethyl)-3-(5-methoxypyridin-2-yl)-lH-pyrazole-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 8.29 (d, J= 2.8 Hz, IH), 8.08 (d, J= 8.8 Hz, IH), 7.24 (dd, J- 7.8, 3.8 Hz, IH), 7.06 (s, IH), 4.76 (s, 2H), 3.87 (s, 3H), 1.69 (s, 9H); TLC Rf(n- Hexanes:EtOAc 2:1) = 0.42.
Figure imgf000282_0003
te^-butyl 3-(5-fluoropyridin-2-yl)-5-methyl-lJΪ-pyrazole-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 8.44 (d, J= 2.8 Hz, IH), 8.15 (dd, J= 8.8, 4.8 Hz, IH), 7.45- 7.40 (m, IH), 6.74 (s, IH), 2.55 (s, 3H), 1.66 (s, 9H)
Figure imgf000282_0004
fe/'i'-Butyl 5-(bromomethyl)-3-(5-fluoropyridin-2-yl)-lH-pyrazole-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 8.45 (d, J= 2.8 Hz, IH), 8.16 (dd, J= 9.0, 4.6 Hz, IH), 7.47- 7.42 (m, IH), 7.08 (s, IH), 4.76 (s, 2H), 1.70 (s, 9H)
Figure imgf000282_0005
3-Methyl-5-(4-(trifluoromethoxy)phenyl)-l£T-pyrazole 1H NMR (400 MHz, CDCl3) δ 11.17 (bs, IH), 7.69 (d, J= 8.4 Hz, 2H), 7.15 (d, J= 8.4 Hz, 2H), 6.27 (s, IH), 2.20 (s, 3H); TLC i?/(«-Hexanes: EtOAc 2:1) = 0.28.
Figure imgf000283_0001
tert-Butyl 5-methyl-3-(4-(trifluoromethoxy)phenyl)-lH-pyrazole-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 7.82-7.80 (m, 2H), 7.16 (d, J= 8.0 Hz, 2H), 6.34 (s, IH), 2.47 (s, 3H), 1.59 (s, 9H); TLC #/(rc-Hexanes:Et2O 2:1) = 0.57.
Figure imgf000283_0002
ter^-Butyl 5-(bromomethyl)-3-(4-(trifluoromethoxy)phenyl)-l£T-pyrazoIe-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 7.90-7.88 (m, 2H), 7.26 (d, J= 8.4 Hz, 2H), 6.77 (s, IH), 4.78 (s, 2H), 1.71 (s, 9H); TLC _fy(«-Hexanes:Et2O 2:1) = 0.57.
Figure imgf000283_0003
4-Acetyl-ΛyV-dimethylbenzenesulfonamide
1H NMR (400 MHz, CDCl3) δ 8.07 (d, J= 1.3 Hz, 2H), 7.86 (d, J= 1.6 Hz, 2H), 2.72 (s, 6H), 2.64 (s, 3H)
Figure imgf000283_0004
iV,iV-Dimethyl-4-(3-methyl-lJy-pyrazol-5-yl)benzenesulfonainide
1H NMR (400 MHz, DMSO-^) δ 12.82 (br, IH), 7.99 (d, J= 2.1 Hz, 2H), 7.74 (d, J= 2.1 Hz, 2H), 6.58 (s, IH), 2.61 (s, 6H), 2.27 (s, 3H)
Figure imgf000283_0005
ter^-Butyl 3-(4-(Λr,Λ'-dimethylsulfamoyl)phenyl)-5-methyl-lJΪ-pyrazole-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 7.99 (d, J= 8.43 Hz, 2H), 7.78 (d, J= 8.0 Hz, 2H), 6.49 (s, IH), 2.69 (s, 6H), 2.56 (s, 3H), 1.66 (s, 9H)
Figure imgf000284_0001
/e/-/-Butyl 5-(bromomethyl)-3-(4-(7V,N-(limethylsuIfamoyl)phenyl)-lJc/-pyrazole-l- carboxylate
1H NMR (400 MHz, CDCl3) δ 8.01 (d, J= 8.43 Hz, 2H), 7.80 (d, J= 8.0 Hz, 2H), 6.83 (s, IH), 4.78 (s, 2H), 2.69 (s, 6H), 1.70 (s, 9H)
Figure imgf000284_0002
Methyl l-(4-methoxybenzyl)-3-/?-tolyl-l/3T-pyrazole-5-carboxylate
1H NMR (400 MHz, CDCl3) δ 7.70-7.68 (m, 2H), 7.27-7.18 (m, 4H), 7.08 (s, IH), 6.87-6.79 (m, 3H), 5.70 (s, 2H)5 3.84 (s, 3H), 3.74 (s, 3H), 2.35 (s, 3H),; TLC i?/(Hexanes: EtOAc 5:1) = 0.68.
Figure imgf000284_0003
(l-(4-Methoxybenzyl)-3-p-tolyl-l£T-pyrazoI-5-yl)methanol
1H NMR (400 MHz, CD3OD) δ 7.63-7.61 (m, 2H), 7.24-7.10 (m, 4H), 6.86 (t, J= 8.8 Hz, 2H), 6.56 (s, IH), 5.34 (s, 2H), 4.41 (s, 2H), 3.75 (s, 3H), 2.32 (s, 3H); TLC Rf (Hexanes:EtOAc 1 :1) = 0.45.
Figure imgf000284_0004
5-(Bromomethyl)-l-(4-methoxybenzyl)-3-/7-tolyl-l/J-pyrazole
1H NMR (400 MHz, CD3OD) δ 7.64-7.62 (m, IH), 7.24-7.14 (m, 4H), 6.88-6.86 (m, 3H), 6.68 (s, IH), 5.37 (s, 2H), 4.51 (s, 2H), 3.74 (s, 3H), 2.32 (s, 3H),; TLC i?/(Hexanes:EtOAc 1 :1) = 0.89.
Figure imgf000285_0001
Methyl 4-(4-methoxyphenyl)-2,4-dioxobutanoate
1H NMR (400 MHz, CDCl3) δ 7.99 (d, J= 8.8 Hz, 2H), 7.04 (s, IH) 6.98 (d, J= 9.2 Hz, 2H), 3.94 (s, 3H), 3.90 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 190.4, 167.6, 164.4, 162.9, 130.3, 127.7, 114.2, 97.9, 55.6, 53.1; TLC i?/(n-Hexanes:EtOAc 2:1) = 0.24.
Figure imgf000285_0002
Methyl 3-(4-methoxyphenyl)-liϊ-pyrazole-5-carboxylate
1H NMR (400 MHz, CDCl3) δ 7.66 (d, J= 8.8 Hz, 2H), 7.03 (s, IH), 6.96 (d, J= 8.8 Hz, 2H), 3.94 (s, 3H), 3.85 (s, 3H); TLC i?/(«-Hexanes:EtOAc 2:1) = 0.24.
Figure imgf000285_0003
5-(4-methoxyphenyl)-l//-pyrazole-3-carboxylic acid
1H NMR (400 MHz, OMSO-d6) δ 7.72 (d, J= 8.8 Hz, 2H), 7.05 (s, IH), 6.96 (d, J= 9.2 Hz, 2H), 3.76 (s, 3H).
Figure imgf000285_0004
(3-(4-Methoxyphenyl)-llϊ-pyrazol-5-yl)methaϊiol
1H NMR (400 MHz, CD3OD) δ 7.57 (d, J= 8.4 Hz, 2H), 6.89 (d, J= 8.4 Hz, 2H), 6.45 (s, IH), 4.56 (s, 2H), 3.75 (s, 3H); TLC /Jy(CH2Cl2=MeOH 20:1) = 0.07.
Figure imgf000285_0005
3-(4-Methoxyphenyl)-lfir-pyrazole-5-carbaldehyde 1H NMR (400 MHz, OMSO-d6) δ 9.86 (s, IH), 7.74 (d, J- 8.8 Hz5 2H), 7.00 (d, J= 8.8 Hz, 2H), 3.76 (s, 3H); TLC Rf (CH2Cl2MeOH 20:1) = 0.28.
Figure imgf000286_0001
(3-(4-(Dimethylamino)phenyl)-liZ-pyrazol-5-yl)methaiiol
1H NMR (400 MHz, CD3OD) δ 7.52 (d, J= 8.4 Hz, 2H), 6.78 (d, J= 8.4 Hz, 2H), 6.46 (s, IH), 4.62 (s, 2H), 2.94 (s, 6H); TLC Rf (CH2Cl2MeOH 10:1) = 0.26.
Figure imgf000286_0002
3-(4-(Dimethylamino)phenyl)-lH-pyrazole-5-carbaldehyde
1U NMR (400 MHz, CD3OD) δ 9.86 (s, IH), 7.54-7.50 (m, 2H), 6.89 (bs, IH), 6.79-6.75 (m, 2H), 2.95 (s, 6H); TLC R1 (CH2Cl2MeOH 10:1) = 0.41.
Figure imgf000286_0003
1 -(Furan-2-y l)butane-l ,3-dione
1H NMR (400 MHz, CDCl3) δ 7.52 (t, J= 0.6 Hz, IH), 7.09 (d, J= 3.6 Hz5 IH)5 6.47 (dd, J- 3.6, 1.2 Hz5 IH)5 6.01 (s, IH), 2.05 (s, 3H); TLC #/(ra-Hexanes:EtOAc 2:1) = 0.70.
Figure imgf000286_0004
5-(Furan-2-yl)-3-methyl-lH-pyrazole
1H NMR (400 MHz, CDCl3) δ 10.08 (bs, IH), 7.41 (t, J= 1.0 Hz, IH), 6.58 (d, J= 3.2 Hz, IH)5 6.43 (dd, J= 3.2, 2.0 Hz, IH), 6.26 (s, IH)5 2.32 (s, 3H); TLC i?/(n-Hexanes:EtOAc 2:1) = 0.37.
Figure imgf000286_0005
ter/-Butyl 3-(furan-2-yl)-5-methyl-lH-pyrazole-l-carboxylate 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J= 1.6 Hz, IH), 6.80 (d, J= 3.2 Hz, IH), 6.44 (dd, J= 3.4, 1.8 Hz, IH), 6.36 (s, IH), 2.53 (s, 3H), 1.63 (s, 9H); TLC Λ/w-HexanesrEtOAc 2:1) = 0.65.
Figure imgf000287_0001
tert-Butyl S-CS-bromofuran-l-y^-S-φromomethy^-lJϊ-pyrazole-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 6.79 (d, J= 3.6 Hz, IH), 6.67 (s, IH), 6.38 (d, J= 4.0 Hz, IH), 4.72 (s, 2H), 1.65 (s, 9H); TLC i?/(«-Hexanes: EtOAc 5:1) = 0.33.
Figure imgf000287_0002
5-(3-Methyl-liϊ-pyrazol-5-yl)furan-2-carboxylic acid
1H NMR (400 MHz, CD3OD) δ 7.24 (d, J= 3.6 Hz, IH), 6.79 (d, J= 3.6 Hz, IH), 6.46 (s, IH), 2.33 (s, 3H).
Figure imgf000287_0003
Methyl 5-(3-methyl-lIZ-pyrazoI-5-yl)furan-2-carboxylate
1H NMR (400 MHz, CDCl3) δ 8.35 (bs, IH), 7.24 (d, J= 3.6 Hz, IH), 6.90 (m, IH), 6.49 (s, IH), 3.90 (s, 3H), 2.41 (s, 3H); TLC i?/(«-Hexanes:EtOAc 1 :1) = 0.33.
Figure imgf000287_0004
3-(5-(methoxycarbonyl)furan-2-yl)-5-methyl-l/f-pyrazole-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 7.22 (d, J= 3.6 Hz, IH), 6.96 (d, J= 3.6 Hz, IH), 6.55 (s, IH), 3.89 (s, 3H), 2.54 (s, 3H), 1.65 (s, 9H); TLC i?/(«-Hexanes:EtOAc 2:1) = 0.54.
Figure imgf000288_0001
te/"f-Butyl 5-(bromomethyI)-3-(5-(methoxycarbonyl)furan-2-yl)-lJϊ-pyrazole-l- carboxylate
1H NMR (400 MHz, CDCl3) δ 7.22 (d, J= 3.6 Hz, IH), 6.99 (d, J= 3.6 Hz, IH), 6.89 (s, IH), 4.74 (s, 2H), 3.89 (s, 3H), 1.69 (s, 9H); TLC /J/w-HexanesiEtOAc 2:1) = 0.54.
Figure imgf000288_0002
3-Methyl-5-(thiophen-2-yl)-l//-pyrazole
1H NMR (400 MHz, CDCl3) δ 7.26-7.21 (m, 3H), 7.02 (t, J= 4 Hz, IH), 6.25 (s, IH), 2.31 (s, 3H)
Figure imgf000288_0003
tert-Butyl 5-methyI-3-(thiophen-2-yl)-lf/-pyrazole-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 7.29-7.25 (m, 2H), 7.16 (t, J= 4 Hz, IH), 6.22 (s, IH), 2.38 (s, 3H), 1.52 (s, 9H)
Figure imgf000288_0004
tert-Butyl 4-bromo-5-(bromomethyl)-3-(5-bromothiophen-2-yl)-l/f-pyrazole-l- carboxylate
1H NMR (400 MHz, CDCl3) δ 7.56 (d, J= 4.0 Hz, IH), 7.04 (d, J= 4.0 Hz, IH), 4.79 (s, 2H), 1.67 (s, 9H)
Figure imgf000288_0005
l-(4-(Morpholine-4-carbonyl)phenyl)ethanone 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J= 8.4 Hz, 2H), 7.46 (d, J= 8.4 Hz, 2H), 3.75 (bs, 4H), 3.59 (bs, 2H), 3.37 (bs, 2H), 2.59 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 197.4, 169.5, 139.9, 138.2, 128.8, 127.5, 67.0, 43.0, 26.9; TLC i?/(CH2Cl2:Me0H 19:1) = 0.43.
Figure imgf000289_0001
Methyl 4-(4-(morpholine-4-carbonyl)phenyl)-2,4-dioxobutanoate
1H NMR (400 MHz, CDCl3) δ 8.00 (d, J= 7.6 Hz, 2H), 7.49 (d, J= 7.6 Hz, 2H), 7.03 (s, IH), 3.90 (s, 3H), 3.71 (bs, 4H), 3.59 (bs, 2H), 3.37 (bs, 2H); 13C NMR (100 MHz, CDCl3) δ 189.2, 170.2, 169.9, 162.3, 140.2, 135.8, 128.1, 127.5, 98.0, 66.7, 53.2, 29.6; TLC #/(CH2Cl2:Me0H 19:1) = 0.46.
Figure imgf000289_0002
Methyl 5-(4-(morpholine-4-carbonyI)phenyl)-lH-pyrazole-3-carboxylate
1H NMR (400 MHz, CD3OD) δ 7.85 (bs, 2H), 7.48 (d, J= 8.0 Hz, 2H), 7.19 (s, IH), 3.89 (s, 3H), 3.72 (bs, 6H), 3.47 (bs, 2H); TLC ^(CH2Cl2MeOH 19:1) = 0.35.
Figure imgf000289_0003
Methyl l-(4-methoxybenzyl)-3-(4-(morpholine-4-carbonyl)phenyl)-l/jT-pyrazole-5- carboxylate
1H NMR (400 MHz, CDCl3) δ 7.95 (d, J= 8.4 Hz, 2H), 7.53 (d, J= 8.0 Hz, 2H), 7.37 (d, J= 8.4 Hz, 2H), 7.35 (s, IH), 6.91 (d, J= 8.8 Hz, 2H), 5.81 (s, 2H), 3.96 (s, 3H), 3.90-3.51 (m, 1 IH); TLC i?/(rc-Hexanes:EtOAc 1 : 1) = 0.31.
Figure imgf000289_0004
(4-(5-(Hydroxymethyl)-l-(4-methoxybenzyl)-l//-pyrazol-3- yl)phenyl)(morpholino)methanone
1H NMR (400 MHz, DMSO-J6) δ 7.78 (d. J= 8.4 Hz, 2H), 7.38 (d, J= 8.4 Hz, 2H), 7.14 (d. J = 8.4 Hz, 2H), 6.84 (d, J= 8.8 Hz, 2H), 6.66 (s, IH), 5.40 (bs, IH), 5.26 (s, 2H), 4.45 (s, 2H), 3.67 (s, 3H), 3.52 (bs, 6H), 3.29 (bs, 2H); 13C NMR (100 MHz, DMSO-J6) δ 169.6, 159.3, 148.8, 145.1, 135.3, 134.8, 129.9, 129.4, 128.3, 125.4, 114.5, 103.5, 66.8, 55.7, 54.7, 53.8, 52.7; TLC i?/(«-Hexanes:EtOAc 3:7) = 0.39.
Figure imgf000290_0001
(4-(5-(Bromomethyl)-l-(4-methoxybenzyl)-lHr-pyrazol-3- yl)phenyl)(morpholino)methanone
1H NMR (400 MHz, CDCl3) δ 7.81 (d, J= 7.6 Hz, 2H), 7.53 (d, J= 7.6 Hz, 2H), 7.16 (d, J= 8.4 Hz, 2H), 6.84 (d, J= 8.8 Hz, 2H), 6.61 (s, IH), 5.40 (s, 2H), 4.31 (s, 2H), 3.76 (s, 3H), 3.74-3.42 (bs, 8H); TLC i?/(«-Hexanes:EtOAc 2:3) = 0.37.
Figure imgf000290_0002
tert-Butyl 3-methyl-ljHT-pyrazole-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 7.95 (d, J= 2.8 Hz, IH), 6.16 (d, J= 2.8 Hz, IH), 2.31 (s, 3H), 1.64 (s, 9H);TLC i?/(«-Hexanes: EtOAc 2:1) = 0.57.
Figure imgf000290_0003
tert-Bnty\ 3-(bromomethyl)-l/7-pyrazole-l-carboxyIate
1H NMR (400 MHz, CDCl3) δ 8.01 (d, J= 2.8 Hz, IH), 6.44 (d, J= 2.8 Hz, IH), 4.47 (s, 2H), 1.64 (s, 9H); TLC i?/(«-Hexanes: EtOAc 2:1) = 0.64.
Figure imgf000290_0004
5-Methyl-3-phenyl-l//-l,2,4-triazole as white solid: 1H NMR (400 MHz, CD3OD) δ 7.96-7.94 (m, 2H), 7.46-7.38 (m, 3H), 2.45 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 164.3, 161.3, 159.6, 133.9, 131.1, 131.0, 118.7, 117.3, 114.5, 14.3; TLC i?/(CH2Cl2:Me0H 10:1) = 0.46.
Figure imgf000291_0001
tert-Butyl 5-methyI-3-phenyl-lH-l,2,4-triazole-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 8.14-8.12 (m, 2H), 7.42-7.40 (m, 3H), 2.76 (s, 3H), 1.67 (s, 9H); TLC i?/(«-Hexanes: EtOAc 1 :2) = 0.83.
Figure imgf000291_0002
tert-Butyl 5-(bromomethyl)-3-phenyl-lH-l,2,4-triazoIe-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 8.15-8.13 (m, 2H), 7.42-7.41 (m, 3H), 4.81 (s, 2H), 1.70 (s, 9H); TLC Rf(n-Hexanes: EtOAc 2:1) = 0.58.
Figure imgf000291_0003
Azidobenzene
1H NMR (400 MHz, CDCl3) δ 7.34 (t, J= 8.0 Hz, 2H), 7.12 (t, J= 7.2 Hz, IH), 7.02 (d, J- 7.6 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 140.2, 130.0, 125.1, 119.2; TLC Rf(n- Hexanes:EtOAc 7:3) = 0.88.
Figure imgf000291_0004
(l-Phenyl-lH-l,2,3-triazoI-4-yl)methanol
1H NMR (400 MHz, CD3OD) δ 8.41 (s, IH), 7.82 (d, J= 8.0 Hz, 2H), 7.56 (t, J= 7.8 Hz, 2H), 7.47 (t, J= 7.0 Hz, IH), 4.74 (s, 2H); TLC i?/(rc-Hexanes:EtOAc 3:7) = 0.20.
Figure imgf000291_0005
1 -Phenyl- IiY-1, 2,3-triazole-4-carbaldehyde 1H NMR (400 MHz, CDCl3) δ 10.19 (s, IH), 8.52 (s, IH), 7.74 (d, J= 8.0 Hz, 2H), 7.49 (m, 3H); TLC i?/(«-Hexanes:EtOAc 3:7) = 0.84.
Figure imgf000292_0001
te^-Butyl 4-bromo-3-methyl-lH-pyrazole-l-carboxyIate
1H NMR (400 MHz, CDCl3) δ 7.98 (s, IH), 7.27 (s, 3H), 2.32 (s, 3H), 1.60 (s, 9H); TLC (Rf 0?-Hexanes:EtOAc 3:1) = 0.68.
Figure imgf000292_0002
fer^Butyl 3-methyl-4-phenyl-lH-pyrazole-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 8.06 (s, IH), 7.39-7.30 (m, 4H), 2.41 (s, 3H), 1.63 (s, 9H); TLC i?/(«-Hexanes:EtOAc 5:1) = 0.42.
Figure imgf000292_0003
tert-Butyl 3-(bromomethyl)-4-phenyl-lJϊ-pyrazole-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 8.08 (s, IH), 7.53-7.51 (m, 2H), 7.50-7.41 (m, 2H), 7.40-7.35 (m, IH), 4.46 (s, 2H), 1.65 (s, 9H); TLC i?/(«-Hexanes:EtOAc 5:1) = 0.52.
Figure imgf000292_0004
5-Pheny 1- lH-py razole
1H NMR (400 MHz, CDCl3) δ 7.77-7.74 (m, 2H), 7.62 (d, J= 2.4 Hz, IH), 7.44-7.31 (m, 3H), 6.62 (d, J= 2.0 Hz, IH); TLC i?/(«-Hexanes:EtOAc 2:1) = 0.22.
Figure imgf000293_0001
3-Pheny 1- 1 -(tetrahy dro-2/f-py ran-2-yl)- 1 H-py razole
1H NMR (400 MHz, CDCl3) δ 7.84-7.81 (m, 2H), 7.64 (d, J= 2.4 Hz, IH), 7.40-7.36 (m, 2H), 7.31-7.27 (m, IH), 6.61 (d, J= 2.4 Hz, IH), 5.44 (dd, J= 9.4, 3.0 Hz, IH), 4.12-4.08 (m, IH), 3.76-3.70 (m, IH), 2.43-2.04 (m, 3H), 1.78-1.52 (m, 3H); TLC ^(n-Hexanes^tOAc 2:1) = 0.57.
Figure imgf000293_0002
3-Phenyl-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazoIe-5-carbaldehyde
1H NMR (400 MHz, CDCl3) δ 9.99 (s, IH), 7.85 (d, J= 7.6 Hz, 2H), 7.42 (t, J= 7.8 Hz, 2H), 7.36-7.33 (m, IH), 7.22 (s, IH), 6.15 (dd, J= 9.6, 2.8 Hz, IH), 4.09-4.04 (m, IH), 3.80-3.74 (m, IH), 2.57-2.48 (m, IH), 2.18-2.04 (m, 2H), 1.81-1.52 (m, 3H); TLC i?/(«-Hexanes:EtOAc 2:1) = 0.59.
Figure imgf000293_0003
5-(4-Methoxy phenyl)- lH-py razole
1H NMR (400 MHz, CD3OD) δ 7.64 (s, 3H), 6.96-6.93 (m, 2H), 6.53 (s, IH), 3.79 (s, 3H); TLC i?/(CH2Cl2:Me0H 10:1) = 0.47.
Figure imgf000293_0004
3-(4-Methoxyphenyl)-l-(tetrahydro-2//-pyran-2-yl)-li/-pyrazole
1H NMR (400 MHz, CDCl3) δ 7.74-7.71 (m, 2H), 7.58 (d, J= 2.4 Hz, IH), 6.91-6.88 (m, 2H), 6.51 (d, J= 2.4 Hz, IH), 5.41-5.37 (m, IH), 4.11-4.05 (m, IH), 3.84 (s, 3H), 3.80-3.67 (m, IH), 2.16-2.02 (m, 2H), 1.71-1.51 (m, 3H); TLC i?/(«-Hexanes:EtOAc 3:1) = 0.82.
Figure imgf000294_0001
3-(4-Methoxyphenyl)-l-(tetrahydro-2/T-pyraπ-2-yl)-lH-pyrazole-5-carbaldehyde
1H NMR (400 MHz, CDCl3) δ 9.95 (s, IH), 7.76-7.73 (m, 2H), 7.12 (s, IH), 6.93-6.09 (m, 2H), 4.12-4.03 (m, IH), 3.84 (s, 3H), 2.50-2.00 (m, 2H), 1.75-1.50(m, 3H); TLC Rf(n- Hexanes:EtOAc 1:1) = 0.88.
Figure imgf000294_0002
4-(lH-Pyrazol-5-yl)pyridine
1H NMR (400 MHz, CDCl3) δ 8.66 (d, J= 4.8 Hz, 2H), 7.71 (d, J= 5.2 Hz, 2H), 7.68 (d, J = 2.4 Hz, IH), 6.75 (d, J= 2.4 Hz3 IH); TLC i?/(CH2Cl2:Me0H 20:1) = 0.23.
Figure imgf000294_0003
4-(l-(Tetrahydro-2H-pyran-2-yl)-ljHr-pyrazol-3-yl)pyridine
1H NMR (400 MHz, CDCl3) δ 8.62 (m, 2H), 7.70 (d, J= 5.2 Hz, 2H), 7.68 (d, J= 2.4 Hz, IH), 6.70 (d, J= 2.4 Hz, IH), 5.45 (dd, J= 9.2, 2.8 Hz, IH), 4.11-4.08 (m, IH), 3.77-3.70 (m, IH), 2.21-2.04 (m, 3H), 1.75-1.61 (m, 3H); TLC ^7(CH2Cl2MeOH 20:1) = 0.45.
Figure imgf000294_0004
3-(Pyridin-4-yl)-l-(tetrahydro-2H-pyran-2-yI)-liϊ-pyrazole-5-carbaldehyde
1H NMR (400 MHz, CDCl3) δ 10.01 (s, IH), 8.66 (d, J= 6.0 Hz, 2H), 7.72 (d, J= 6.0 Hz, 2H), 7.31 (s, IH), 6.15 (dd, J= 9.4, 2.6 Hz, IH), 4.08-4.04 (m, IH), 3.80-3.74 (m, IH), 2.54- 2.45 (m, IH), 2.17-2.14 (m, IH), 2.09-2.04 (m, IH), 1.82-1.62 (m, 3H); TLC Rf (CH2Cl2:Et0Ac 2:1) = 0.17.
Figure imgf000294_0005
3-(l/7-PyrazoI-5-yl)pyridine
1H NMR (400 MHz, CDCl3) δ 9.05 (s, IH), 8.58 (dd, J= 4.8, 1.6 Hz, IH), 8.10 (d, J= 6.8 Hz, IH), 7.67 (d, J= 2.4 Hz, IH), 7.35 (dd, J= 8.0, 4.8 Hz, IH), 6.70 (d, J= 2.4 Hz, IH); TLC ^(CH2Cl2=MeOH 20:1) = 0.22.
Figure imgf000295_0001
3-(l-(Tetrahydro-2//-pyran-2-yl)-l/7-pyrazoI-3-yl)pyridiiie
1H NMR (400 MHz, CDCl3) δ 9.03 (s, IH), 8.53 (d, J= 3.6 Hz, IH), 8.13 (d, J= 8.0 Hz, IH), 7.67 (d, J= 2.8 Hz, IH), 7.32-7.29 (m, IH), 6.65 (d, J= 2.4 Hz, IH), 5.44 (dd, J= 9.6, 2.8 Hz, IH), 4.12-4.09 (m, IH), 3.77-3.71 (m, IH), 2.24-2.04 (m, 3H), 1.79-1.57 (m, 3H); TLC R1 (CH2Cl2:Et0Ac 2:1) = 0.23.
Figure imgf000295_0002
3-(Pyridin-3-yl)-l-(tetrahydro-2H-pyran-2-yI)-lH-pyrazoIe-5-carbaldehyde
1H NMR (400 MHz, CDCl3) δ 10.01 (s, IH), 9.07 (s, IH), 8.59 (d, J= 4.8 Hz, IH), 8.16 (d, J = 8.0 Hz, IH), 7.35 (dd, J= 8.0, 4.8 Hz, IH), 7.28 (s, IH), 6.16 (dd, J= 9.8, 2.6 Hz, IH), 4.08 (d, J= 10.0 Hz, IH), 3.81-3.75 (m, IH), 2.56-2.46 (m, IH), 2.15-2.05 (m, 2H), 1.82-1.60 (m, 3H); TLC i?/(CH2Cl2:Et0Ac 20:1) = 0.45.
Figure imgf000295_0003
(£)-3-(Dimethylamino)-l-(pyridin-2-yl)prop-2-en-l-one
1HNMR (400 MHz, CDCl3) δ 8.60-8.58 (m, IH), 8.11 (d, J= 6.8 Hz, IH), 7.87 (d, J= 12.4 Hz, IH), 7.89-7.74 (m, IH), 7.34-7.30 (m, IH), 6.42 (d, J= 12.4 Hz, IH), 3.13 (d, J= 12.4 Hz, 3H), 2.97 (d, J= 12.0 Hz, 3H); TLC i?/(«-Hexanes:EtOAc 1:1) = 0.01.
Figure imgf000295_0004
2-(l//-Pyrazol-5-yl)pyridine 1H NMR (400 MHz, CD3OD) δ 8.54 (d, J= 3.2 Hz, IH), 7.96 (s, IH), 7.86-7.82 (m, IH), 7.70 (s, IH), 7.33-7.30 (m, IH), 6.89 (s, IH); TLC ^7(CH2Cl2MeOH 10:1) - 0.69.
Figure imgf000296_0001
2-(l-(Tetrahydro-2/y-pyran-2-yl)-l//-pyrazol-3-yl)pyridine
1H NMR (400 MHz, CDCl3) δ 8.60-8.58 (m, IH), 7.97 (d, J= 4.0 Hz, IH), 7.69-7.64 (m, 2H), 7.17-7.14 (m, IH), 6.92 (d, J= 2.4 Hz, IH), 5.45-5.42 (m, IH), 4.10-4.05 (m, IH), 3.73-3.66 (m, IH), 2.16-2.01 (m, 3H), 1.77-1.57 (m, 4H); TLC i?/(CH2Cl2:Me0H 20:1) = 0.48.
Figure imgf000296_0002
3-(Pyridin-2-yl)-l-(tetrahydro-2JET-pyran-2-yl)-lJϊ-pyrazole-5-carbaldehyde
1H NMR (400 MHz, CDCl3) δ 9.95 (s, IH), 8.60 (d, J= 4.8 Hz, IH), 8.05 (d, J= 8.0 Hz, IH), 7.73-7.69 (m, 2H), 7.57 (s, IH), 7.24-7.20 (m, IH), 6.18-6.15 (m, IH), 4.07-4.04 (m, IH), 3.78-3.72 (m, IH), 2.54-2.44 (m, IH), 2.14-2.00 (m, 2H), 1.78-1.58 (m, 3H); TLC Rf(n- Hexanes:EtOAc 1:1) = 0.57.
Figure imgf000296_0003
3-Methyl-lH-indazole
1H NMR (400 MHz, CDCl3) δ 7.68 (t, J- 4.0 Hz, IH), 7.43 (t, J= 4.0 Hz, IH), 7.36 (t, J= 7.4 Hz, IH), 7.13 (t, J= 4.0 Hz, IH), 6.63 (s, 3H); 13C NMR (100 MHz, CDCl3) d 143.5, 141.3, 126.9, 122.9, 120.4, 120.3, 109.9, 12.2; TLC Λ/(/i-Hexanes:EtOAc 2:1) = 0.45.
Figure imgf000296_0004
tert-Butyl 3-methyl-lH-indazole-l-carboxylate 1H NMR (400 MHz, CDCl3) δ 7.61 (dd, J= 8.0, 2.0 Hz, IH), 7.38 (dt, J= 7.6, 2.0 Hz, IH), 7.27 (dt, J= 8.0, 1.2 Hz, IH), 7.18 (dd, J= 8.0, 1.2 Hz, IH), 2.19 (s, 3H), 1.51 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 155.3, 151.6, 148.5, 132.3, 129.8, 129.4, 126.0, 123.1, 83.3, 27.6, 17.8; TLC i?/(ra-Hexanes:EtOAc 5:1) = 0.28.
Figure imgf000297_0001
terf-Butyl 3-(bromomethyl)-lH-indazole-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 8.11 (d, J= 8.8 Hz, IH), 7.83 (d, J= 6.8 Hz, IH), 7.53 (t, J= 7.8 Hz, IH ), 7.35 (t, J- 7.6 Hz, IH), 4.77 (s, 2H), 1.71 (s, 9H); 13C NMR (100 MHz, CDCl3) d 149.2, 148.2, 140.1, 128.6, 125.8, 123.1, 120.1, 114.5, 84.0, 28.1, 12.1; TLC Rf(n- Hexanes:EtOAc 5:1) = 0.46.
Figure imgf000297_0002
6-Methoxy-3-methyl-ljH-indazole
1H NMR (400 MHz, CDCl3) δ 7.50 (d, J= 8.8 Hz, IH), 6.79-6.77 (m, 2H), 3.84 (s, 3H), 2.53 (s, 3H); 13C NMR (IOO MHZ, CDCl3) δ 160.0, 142.6, 121.2, 117.8, 112.3, 99.6, 91.0, 55.7, 12.1; TLC i?/(«-Hexanes:EtOAc 2:1) = 0.14.
Figure imgf000297_0003
fer^ButyI 3-(bromomethyl)-6-methoxy-l//-indazoIe-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 7.68 (d, J= 8.8 Hz, IH), 7.60 (s, IH), 6.96 (d, J= 8.8 Hz, IH), 4.71 (s, 2H), 3.89 (s, 3H), 1.70 (s, 9H); 13C NMR (100 MHz, CDCl5) δ 160.0, 142.6, 121.2, 117.8, 112.3, 99.6, 91.0, 55.7, 12.0; TLC i?/(«-Hexanes:EtOAc 2:1) = 0.75.
Figure imgf000297_0004
5-Nitro-2-fluoroacetophenone 1H NMR (400 MHz, CDCl3) δ 8.80 (dd, J= 6.0, 3.0 Hz, IH), 8.40 (dd, J= 10.0, 3.0 Hz, IH), 7.45 (dd, J= 10.0, 8.0 Hz, IH), 2.75 (s, 3H)
Figure imgf000298_0001
3-Methyl-5-nitro-l//-indazoIe
1U NMR (400 MHz, CDCl3) δ 10.04 (s, IH), 8.67 (s, IH), 8.27 (d, J= 6.8 Hz, IH), 7.47 (d, J = 7.2 Hz, IH), 2.64 (s, 3H)
Figure imgf000298_0002
fert-Butyl 3-methyl-5-nitro-liϊ-indazole-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 8.59 (s, IH), 8.37 (d, J= 6.8 Hz, IH), 8.22 (d, J= 7.2 Hz, IH), 2.65 (s, 3H), 1.67 (s, 9H)
Figure imgf000298_0003
tert-Butyl 3-(bromomethyl)-5-nitro-l/J-indazole-l-carboxyIate
1H NMR (400 MHz, CDCl3) δ 8.78 (s, IH), 8.42 (d, J= 6.8 Hz, IH), 8.27 (d, J= 7.2 Hz, IH), 4.78 (s, 2H), 1.72 (s, 9H)
Figure imgf000298_0004
tert-Butyl 3-(bromomethyl)-l/jT-pyrazolo [3,4-6] pyridine- 1-carboxy late
1H NMR (400 MHz, CDCl3) δ 8.72 (dd, J= 4.8, 1.6 Hz, IH), 8.18 (dd, J= 8.0, 1.6 Hz, IH), 7.29 (dd, J= 8.0, 4.8 Hz, IH), 4.72 (s, 2H), 1.69 (s, 9H); TLC i?/(«-Hexanes:EtOAc 1 :1) = 0.45.
Figure imgf000299_0001
tert-Butyl 3-(bromomethyl)-ljB-pyrazoIo [3,4-c] pyridine-1-carboxylate
1H NMR (400 MHz, CDCl3) δ 9.53 (s, IH), 8.57 (d, J= 5.2 Hz, IH), 7.77 (dd, J= 5.2, 1.2 Hz, IH), 4.79 (s, 2H), 1.75 (s, 9H); TLC i?/(«-Hexanes:EtOAc 1:1) = 0.64.
Figure imgf000299_0002
te^-Butyl S-^romomethy^-o-fluoro-lH-pyrazoloP^-^pyridine-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 8.26 (dd, J= 8.0, 8.0 Hz, IH), 6.97 (dd, J= 8.0, 1.0 Hz, IH), 4.72 (s, 2H), 1.71 (s, 9H); TLC i?/(n-Hexanes:EtOAc 2:1) = 0.56.
Figure imgf000299_0003
2-(BromomethyI)benzo[rf]thiazole
1H NMR (400 MHz, CDCl3) δ 7.99 (d, J= 8.0 Hz, IH), 7.84 (d, J= 7.8 Hz, IH), 7.46 (t, J= 4.4 Hz ,1H), 7.36 (t, J= 4.5 Hz, IH), 4.78 (s, 2H)
Figure imgf000299_0004
ter/-Butyl 2-methyl-lH-benzo[</]imidazole-l-carboxyIate
1H NMR (400 MHz, CDCl3) δ 7.91-7.89 (m, IH), 7.66-7.63 (m, IH), 7.30-7.28 (m, 2H), 2.82 (s, 3H), 1.71 (s, 9H); TLC i?/(«-Hexanes:EtOAc 3:1) = 0.79.
Figure imgf000299_0005
fø/if-Butyl 2-(bromomethyl)-lH-benzo[rf]imidazole-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 7.97-7.94 (m, IH), 7.72-7.70 (m, IH), 7.39-7.31 (m, 2H), 4.93 (s, 2H), 1.73 (s, 9H); TLC £/(rc-Hexanes:EtOAc 3:1) = 0.89.
Figure imgf000300_0001
fø^-Butyl 3-methylpyridin-2-ylcarbamate
1H NMR (400 MHz, CDCl3) δ 8.25 (d, J= 4.0 Hz, IH), 7.50 (d, J= 7.2 Hz, IH), 7.03-7.00 (m, IH), 6.78 (s, IH), 2.28 (s, 3H), 1.51 (s, 9H)
Figure imgf000300_0002
tert-Butyl 3-ethylpyridin-2-ylcarbamate
1H NMR (400 MHz, CDCl3) δ 8.21 (d, J= 5.2 Hz, IH), 7.52 (d, J= 7.6 Hz, IH), 7.05-7.00 (m, IH), 6.72 (s, IH), 2.68-2.62 (m, 2H), , 1.51 (s, 9H), 1.35-1.23 (m, 3H)
Figure imgf000300_0003
3-Methyl-lH-py rrolo [2,3-Z>] pyridine
1H NMR (400 MHz, CDCl3) δ 8.38-8.35 (m, IH), 7.94-7.92 (m, IH), 7.17 (s, IH), 7.13-7.08 (m, IH), 2.36 (s, 3H) ); TLC i?/(«-Hexanes:EtOAc 1 :1) = 0.87.
Figure imgf000300_0004
tert-Butyl 3-methyl-lH-pyrrolo[2,3-^]pyridine-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 8.49-8.46 (m, IH), 7.86-7.83 (m, IH), 7.36 (d, J= 0.8 Hz, IH), 7.17-7.14 (m, IH), 7.23 (s, 3H), 1.65 (s, 9H); TLC i?/(n-Hexanes:EtOAc 3:1) = 0.65.
Figure imgf000300_0005
l//-Pyrrolo[2,3-Λ]pyridine-5-carbaldehyde 1H NMR (400 MHz, CDCl3) δ 10.91 (s, IH), 8.87 (d, J= 1.2 Hz, IH), 8.48 (d, J= 1.6 Hz, IH), 7.49 (s, IH), 6.69 (d, J= 2.4 Hz, IH); TLC i?/(«-Hexanes:EtOAc 3:1) = 0.36.
Figure imgf000301_0001
2-Methy 1-7-nitro- 1 iϊ-benzo [d] imidazole
1H NMR (400 MHz, CDCl3) δ 8.10 (d, J= 8.4 Hz, IH), 7.99 (d, J= 7.6 Hz, IH), 7.32 (t, J= 8.0 Hz, IH), 2.72 (s, 3H); TLC #/(rc-Hexanes:EtOAc 1 :1) = 0.35.
Figure imgf000301_0002
te/-/-Butyl 2-methyl-7-nitro-lH-benzo[</]imidazole-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 8.30-8.28 (m, IH), 8.14-8.12 (m, IH), 7.41 (t, J= 8.4 Hz, IH), 2.93 (s, 3H), 1.73 (s, 9H); TLC i?/(«-Hexanes:EtOAc 1 :1) = 0.89.
Figure imgf000301_0003
tert-Bntyl 2-(bromomethyl)-7-nitro-lH-benzo[</|iinidazole-l-carboxylate
1H NMR (400 MHz, CDCl3) δ 8.16 (d, J= 8.0 Hz, IH), 7.94 (d, J= 8.4 Hz, IH), 7.29 (t, J= 8.2 Hz, IH), 4.73 (s, 2H), 1.56 (s, 9H); TLC i?/(rc-Hexanes:EtOAc 1 :1) = 0.63.
Figure imgf000301_0004
2-Methyl-3/jT-imidazo [4,5-6] pyridine
1H NMR (400 MHz, CDCl3) δ 8.32 (d, J= 4.0 Hz, IH), 8.01 (d, J= 7.2 Hz, IH), 7.26-7.21 (m, IH), 2.74 (s, 3H); TLC i?/(«-Hexanes:EtOAc 1 :1) = 0.72.
Figure imgf000301_0005
tert-Butyl 2-methyI-3iϊ-imidazo [4,5-6] py ridine-3-carboxylate 1H NMR (400 MHz, CDCl3) δ 8.42 (t, J= 2.2 Hz, IH), 7.91-7.88 (m, IH), 7.26-7.21 (m, IH), 2.74 (s, 3H), 1.69 (s, 9H); TLC i?/(n-Hexanes:EtOAc 1 :1) = 0.89.
Figure imgf000302_0001
tert-Butyl 2-(bromomethyl)-3JΪ-imidazo [4,5-6] pyridine-3-carboxyIate
1H NMR (400 MHz, CDCl3) δ 8.54-8.53 (m, IH), 8.01-7.99 (m, IH), 7.33-7.29 (m, IH), 4.89 (s, 2H), 1.74 (s, 9H); TLC i?/(«-Hexanes:EtOAc 1 :1) = 0.92.
Figure imgf000302_0002
2-(Bromomethyl)benzo[rf]oxazole
1H NMR (400 MHz, CDCl3) δ 7.71 (d, J= 8.4 Hz, IH), 7.53 (d, J= 7.6 Hz, IH), 7.59-7.32 (m, 2H), 4.57 (s, 2H)
Figure imgf000302_0003
2-Methyl-4-nitrobenzo [d\ oxazole
1H NMR (400 MHz, CDCl3) δ 8.16 (d, J= 8.0 Hz, IH), 7,80 (d, J= 8.0 Hz, IH), 7.43 (t, J= 8.4 Hz, IH), 2.76 (s, 3H)
Figure imgf000302_0004
2-(Bromomethyl)-4-nitrobenzo[</j oxazole
1H NMR (400 MHz, CDCl3) δ 8.16 (dd, J= 8.4, 0.8 Hz, IH), 7.86 (dd, J= 8.2, 0.6 Hz, IH), 7.51 (t, J= 8.2 Hz, IH), 4.64 (s, 2H)
Figure imgf000302_0005
2-Methyloxazolo [4,5-6] pyridine 1U NMR (400 MHz, CDCl3) δ 8.53 (dd, J= 5.0, 1.4 Hz, IH), 7.77 (d, J= 8.2, 1.4 Hz, IH), 7.28-7.24 (m, IH), 2.72 (s, 3H)
Figure imgf000303_0001
2-(Bromomethyl)oxazolo [4,5-6] pyridine
1U NMR (400 MHz, CDCl3) δ 8.60-8.56 (m, IH), 7.84 (t, J= 7.2 Hz, IH), 7.34-7.28 (m, IH), 4.78 (s, 2H)
General procedure for coupling subunit 1 and 2.
Figure imgf000303_0002
To a 0 °C solution of subunit 1 (0.41 mmol, 1.0 equiv) in THF (1 niL) was added dropwise n- BuLi (1.6 M in THF, 0.38 mmol, 1.1 equiv). The reaction mixture was stirred at 0 "C for 1 h. After stirring at 25 0C for 10 min, the reaction mixture was cooled to 0 °C, and then a solution of subunit 2 (0.41 mmol, 1.2 equiv) in THF (1 mL) was added via cannula. After 1 h at 0 "C, the reaction was quenched by the addition of saturated aqueous NH4Cl (10 mL). The mixture was extracted with CH2Cl2 (3 x 20 mL) and dried over Na2SO4. After filtration and concentration in vacuo, the residue was purified by flash column chromatography on silica gel to give coupled adducts.
Figure imgf000303_0003
A, B, C = CH, N, or N=O
To a solution of Boc-protected compound (0.19 mmol, 1.0 equiv) in 4N HCl in dioxane (3.93 mmol, 2.0 equiv) was stirred at 25 °C for 2 h, and then quenched with aqueous saturated K2CO3 (10 mL) and H2O (10 mL). The mixture was extracted with CH2Cl2 (3 x 10 mL) and dried over Na2SO4. After filtration and concentration in vacuo, the residue was purified by flash column chromatography on silica gel.
Figure imgf000304_0001
A, B, C = CH, N, or N=O
To a solution of PMB-protected compound (0.045 mmol, 1.0 equiv) in TFA (4 mL) was stirred at 120 °C for 30 min, and then quenched with aqueous IN NaOH (5 ml) and H2O (5 mL). The mixture was extracted with CH2Cl2 (3 x 10 mL) and dried over Na2SO4. After filtration and concentration in vacuo, the residue was purified via flash column chromatography on silica gel.
General procedure for C-N bond formation via reductive animation
Figure imgf000304_0002
Subunit 1 subunit 2 A, B, C = CH, N, or N=O
A solution of subunit 1 (0.295 mmol, 1.0 equiv) and subunit 2 aldehyde (0.324 mmol, 1.1 equiv) in MeOH (6 mL) was stirred for 1 h at 25 °C and then treated with AcOH (4.130 mmol, 14 equiv). The reaction was stirred for 15 min at 25 °C, after which NaCNBH3 (0.590 mmol, 2 equiv) was added in several small portions. After stirred at 25 0C under Ar overnight, the reaction mixture was filtered and the filtrate was concentrated in vacuo with silica gel. The residue was purified via flash column chromatography to give desired reductive animation products.
Figure imgf000304_0003
Subunit 1
Figure imgf000304_0004
A solution of subunit 1 (293 μmol, 1.0 equiv) and subunit 2 (352 μmol, 1.2 equiv) in THF (1.0 mL) was added molecular sieve and AcOH (586 μmol, 2.0 equiv) at 25 0C. After stirred for 5 h at 25 °C, the reaction mixture was treated with NaBH(OAc)3 (586 μmol, 2.0 equiv) at 25 °C. After stirred at 25 °C for 16 h, the reaction was quenched with saturated aqueous NaHCO3 solution and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (20 mL) and dried over MgSO4. After filtration and concentration in vacuo, the residue was purified via preparative TLC to THP -protected reductive animation products.
A solution of above THP-protected compounds (71 μmol, 1.0 equiv) in 1 mL of HCl/MeOH (stock solutions were prepared by adding 10 mL AcCl to 100 mL MeOH over 5 min with ice- cooling) was stirred at 25 ° C for 3 h. The reaction mixture was quenched with saturated aqueous K2CO3 solution and extracted with EtOAc (2 x 15 mL). The organic layers were washed with brine (30 mL) and dried over MgSO4. After filtration and concentration in vacuo, the residue was purified via preparative HPLC to give corresponding deprotected products.
General procedure for coupling via C-Q bond formation
Figure imgf000305_0001
subunit 1 subunit 2 A, B, C = CH, N, or N=O
To a solution of subunit 1 (0.33 mmol, 1.1 equiv) and Cs2CO3 (0.36 mmol, 1.2 equiv) in DMF (450 μL, 0.7 M) was added Boc-protected bromopyrazole subunit 2 (0.30 mmol, 1.0 equiv). The reaction mixture was heated at 90 0C for 1 h. After cooled to 25 °C, the reaction mixture was concentrated to remove DMF and then partitioned with EtOAc/H2O. The organic layer was washed with brine and dried over Na2SO4. After filtration and concentration in vacuo, the resulting residue was purified via flash column chromatography on silica gel to give coupled products.
Figure imgf000305_0002
To a 0 0C solution of THP-protected pyrazole subunit 2 (0.193 rnrnol, 2.0 equiv) in DMF (1.4 mL) was added slowly NaH (0.115 mmol, 1.2 equiv). The reaction mixture was heated at 60 °C for 30 min and then treated with subunit 1 (0.095 mmol, 1.0 equiv) at 25 0C. The resulting solution was stirred at 100 °C for 12 h. After cooled to 25 °C, the reaction was quenched with saturated aqueous NaHCO3 (10 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via flash column chromatography on silica gel to give coupled products.
To a solution of THP-protected coupled compound (0.067 mmol, 1.0 equiv) in 130 μL of HCl/MeOH (stock solutions were prepared by adding 10 mL AcCl to 100 mL MeOH over 5 min with ice-cooling) was stirred at 25 0C for 5 h. The reaction mixture was quenched with a mixture of saturated aqueous NaHCO3 (10 mL) and H2O (10 mL). The mixture was extracted with CH2Cl2 (3 x 10 mL) and dried over Na2SO4. After filtration and concentration in vacuo, the residue was purified via flash column chromatography on silica gel to give deprotected products.
General procedure for amide coupling between subunit 1 and subunit 2
Figure imgf000306_0001
To a solution of carboxylic acid (0.27 mmol, 1.0 equiv) in DMF (1 mL) was added 1,1'- carbonyldiimidazole (0.29 mmol, 1.1 equiv) at 25 °C. The reaction mixture was heated for 3 h at 60 °C and then treated with a solution of biarylamine (0.29 mmol, 1.1 equiv) in DMF (1 mL). The reaction was kept at 60 0C for overnight. After cooled to 25 °C, the mixture was concentrated under reduced pressure and directly purified via flash column chromatography on silica gel to give amide products.
General procedure for the conversion of fluoride to amino group
Figure imgf000306_0002
To an oven-dried sealed tube charged with fluoro compounds (0.259 mmol, 1.0 equiv) and PMBNH2 (3.88 mmol, 15.0 equiv) was added NMP (2.0 mL) under Ar. The reaction mixture was heated to 95 °C for 12 h. After cooled to 25 °C, the reaction mixture was quenched by the addition H2O (10 mL) and extracted with EtOAc (3 x 20 mL) and dried over Na2SO4. After filtration and concentration in vacuo, the residue was purified via flash column chromatography on silica gel.
To a solution of above compounds (1.67 mmol, 1.0 equiv) in TFA (3.0 mL) was heated in a sealed tube at 120 ° C for 2 h. After cooled to 25 °C, the reaction mixture was quenched by the addition of saturated aqueous NaHCO3 (20 mL) and H2O (5 mL). The mixture was extracted with EtOAc (3 x 10 mL) and dried over Na2SO4. After filtration and concentration in vacuo, the residue was purified via flash column chromatography on silica gel to give amine products.
General procedure for the conversion of fluoride to alkoxy & ketone group
Figure imgf000307_0001
To a solution of starting material (0.05 mmol, 1.0 equiv) in MeOH (0.3 mL) was added sodium methoxide (0.05 mL, 0.22 mmol, 4.0 eq, 25% in methanol) at 25 °C, and the mixture was stirred at 90 °C. After 3 h at 90 °C, the reaction mixture was treated with additional sodium methoxide (0.05 mL, 0.22 mmol, 4.0 eq, 25% in methanol). The reaction mixture was stirred at 63 °C for 15 h, and then quenched with H2O (10 mL)and extracted with CH2Cl (3 x 10 mL). The combined organic layers were dried over Na2SO4. After filtration and concentration in vacuo, the residue was purified via flash column chromatography on silica gel. To a solution of starting material (0.02 mmol, 1.0 equiv) in dry CH2Cl (2 niL) was added dropwise BBr3 (0.2 mmol, 10 equiv) at 0 °C. The resulting solution was stirred at 25 "C for 15 h, and then quenched with saturated aqueous NaHCO3 (10 mL) solution and extracted with CH2Cl (3 x 10 mL). The combined organic layers were dried over Na2SO4. After filtration and concentration in vacuo, the residue was purified via flash column chromatography on silica gel.
General procedure for the demethylation & Mitsunobu reaction
Figure imgf000308_0001
To a 0 °C solution of starting material (1.09 mmol, 1.0 equiv) in CH2Cl2 (50 mL) was added slowly BBr3 (10.87 mmol, 10.0 equiv) under Ar. The resulting solution was stirred at 0 0C until complete by TLC (usually < 4 h). The reaction was quenched by the addition of saturated aqueous NaHCO3 (10 mL) and extracted with CH2Cl2 (3 x 20 mL) and dried over Na2SO4. After filtration and concentration in vacuo, the residue was purified via flash column chromatography on silica gel to give demethylated products.
To a 0 0C solution of the above demethylated compounds (0.08 mmol, 1.0 equiv) and alcohol (0.24 mmol, 3.0 equiv) in CH2Cl2 (2.0 mL) was added PPh3 (0.624 mmol, 8.0 equiv) and DIAD (0.32 mmol, 4.0 equiv) successively. The resulting suspension was stirred at 25 "C for 12 h, and then quenched by the addition of H2O (10 mL) and extracted with CH2Cl2 (3 x 10 mL) and dried over Na2SO4. After filtration and concentration in vacuo, the residue was purified via flash column chromatography on silica gel to give ether products.
General procedure for the conversion of bromide to nitrile and hvdrodehalogenation
Figure imgf000309_0001
To a suspension of bromo compounds (0.112 mmol, 1.0 equiv) and sodium acetate (0.224 mmol, 2.0 equiv) in MeOH (5 niL) was added 10% Pd/C (6 mg) at 25 "C. The resulting reaction mixture was stirred under 1 tam of hydrogen at 25 "C for overnight. The mixture was filtered through a pad of celite and concentrated in vacuo. The residue was purified via flash column chromatography on silica gel to give hydrodehalogenated products.
To a suspension of bromo compounds (0.118 mmol, 1.0 equiv) and zinc cyanide (preactived, 0.591 mmol, 5.0 equiv) in anhydrous DMF (400 μL) was added Pd(PPh3)4(0.018 mmol, 15 mol%) under Ar at 25 °C. The resulting suspension was heated at 120 °C and stirred until complete by TLC (usually 2 h). After cooled to 25 0C, the reaction was quenched by the addition of saturated aqueous NaHCO3 and extracted with EtOAc (3 x ). The combined organic layers were washed with brine and dried over MgSO4. After filtration and concentration in vacuo, the residue was purified via flash column chromatography on silica gel to give nitrile products.
General procedure for the conversion of ester to amide analogs
Figure imgf000309_0002
To a solution of acid (0.075 mmol, 1.0 equiv), BOP (0.11 mmol, 1.5 equiv), and Et3N (0.23 mmol, 3 equiv) in DMF (0.5 mL) was added amines (0.15 mmol, 2 equiv) at 25 °C. The reaction mixture was stirred overnight at room temperature. The reaction was quenched with saturated aqueous NH4Cl solution and extracted with CH2Cl2 (3 x ). The combined organic layers were dried over MgSO4; filtered and concentrated in vacuo. The resulting residue was purified via flash column chromatography on silica gel.
General procedure for the coupling between subunitl & 2 via click chemistry
Figure imgf000310_0001
A, B, C = CH, N, or N=O
Azide (0.100 mmol, 1.2 equiv) and alkyne (0.082 mmol, 1.0 equiv) were suspended in a 1:1 mixture of water and tert-butyl alcohol (300 μL, 0.25 M). Sodium ascorbate (8.1 μmol, 81 μL of freshly prepared 0.1 M solution in water, 0.1 equiv) was added, followed by copper sulfate pentahydrate (0.2 mg, 0.81 μmol, in 50 μL of water). The heterogeneous mixture was stirred at 25 °C for 2 h and TLC analysis indicated complete consumption of the reactants. The reaction mixture was diluted with water and extracted with EtOAc (3 x). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified via flash column chromatography on silica gel to give click adducts.
Figure imgf000310_0002
336 5-Phenyl-7V-((5-phenyl-lH-pyrazol-3-yl)methyl)-l,2,4-triazin-3-amine (336)
1U NMR (400 MHz, OMSO-d6) δ 9.27 (d, J= 12 Hz, IH), 8.12 (d, J= 6.8 Hz, 2H), 7.73-7.67 (m, 2H), 7.56 (d, J= 7.2 Hz, 3H), 7.36-7.25 (m, 3H), 6.59 (s, IH), 4.66 (d, J= 21.6 Hz, 2H); TLC i?/(«-Hexanes:EtOAc 1:1) = 0.42.
Figure imgf000310_0003
5-(Naphthalen-l-yl)-iV-((5-phenyl-lJHr-pyrazoI-3-yl)inethyl)-l,2,4-triaziii-3-amine (337)
1H NMR (400 MHz, DMSO-^5) δ 8.96 (s, IH), 8.24 (s, IH), 8.10 (d, J= 8.0 Hz, IH), 8.01 (d, J= 7.6 Hz, IH), 7.80-7.61 (m, 5H), 7.54-7.27 (m, 4H), 6.61 (s, IH), 4.68 (s, 2H); TLC Rf(n- Hexanes:EtOAc 1:1) = 0.40; LRMS (electrospray) m/z calculated for C23H19N6 (M+H)+ 379.17, found 379.14.
Figure imgf000311_0001
5-(2,4-Dimethylphenyl)-iV-((5-phenyl-ljEir-pyrazol-3-yl)methyl)-l,2,4-triazin-3-amine
(338)
1H NMR (400 MHz, DMSO-^6) δ 13.02 (bs, 0.5H), 12.7 (bs, 0.5H), 8.81 (s, IH), 8.16 (bs, IH), 7.69 (d, J= 13.6 Hz, 2H), 7.44 (d, J= 7.6 Hz, IH), 7.36 (s, 2H), 7.25 (s, IH), 7.13 (s, IH), 6.55 (s, IH), 4.61 (s, 2H), 2.35 (s, 3H), 2.30 (s, 3H); TLC i?/(n-Hexanes:EtOAc 3:7) = 0.53.
Figure imgf000311_0002
iV-((5-Phenyl-lH-pyrazol-3-yl)methyl)-5-o-tolyl-l,2,4-triaziii-3-amine (339)
1H NMR (400 MHz, DMSO-^) δ 13.03 (s, 0.5H), 12.76 (s, 0.5H), 8.83 (d, J= 10.4 Hz, IH), 8.24 (bs, IH), 7.69 (d, J= 16.8 Hz, 2H), 7.51 (d, J= 6.8 Hz, IH), 7.48-7.25 (m, 6H), 6.54 (d, J= 16.8 Hz, IH), 4.62 (s, 2H), 2.42 (s, 3H); TLC ^/(CH2Cl2: MeOH 9:1) = 0.45.
5-(6-Methoxynaphthalen-2-yl)-Λ'-((5-phenyl-liϊ-pyrazol-3-yl)methyl)-l,2,4-triazin-3- amine (340)
1H NMR (400 MHz, CDCl3) δ 11.12 (bs, IH) 9.62 (s, IH), 8.71 (s, IH), 8.28 (dd, J= 8.6, 1.8 Hz, IH), 7.96 (dd, J= 8.6, 5.8 Hz, 2H), 7.84 (bs, 2H), 7.46 (t, J= 7.4 Hz, 2H), 7.38-7.26 (m, 4H), 6.73 (s, IH), 5.36 (d, J= 5.6 Hz, 2H), 4.04 (s, 3H); TLC ^/(CH2Cl2: MeOH 9:1) = 0.56. (m, 4H), 6.73 (s, IH), 5.36 (d, J= 5.6 Hz, 2H), 4.04 (s, 3H); TLC R/ (CH2Cl2 :MeOH 9:1) = 0.56.
Figure imgf000312_0001
5-(4-ChlorophenyI)-iV-((5-phenyl-lH-pyrazol-3-yl)methyl)-l,2,4-triazin-3-ainine (341)
1H NMR (400 MHz, CDCl3) δ 9.02 (s, IH), 8.01 (d, J= 8.0 Hz, 2H), 7.63 (d, J= 7.6 Hz, 2H) , 7.55 (d, J= 7.2 Hz, 2H), 7.45 (t, J= 7.8 Hz, 2H), 7.37 ( t, J= 7.4 Hz, IH), 6.54 (s, IH), 4.83 (d, J= 4.8 Hz, 2H); TLC .fy(Hexanes:EtOAc 1 :2) = 0.22; LRMS (electrospray) m/z calculated for C19H16ClN6 (M+H)+ 363.11, found 363.09.
Figure imgf000312_0002
5-(4-Bromophenyl)-Λ/-((5-phenyl-lH-pyrazol-3-yl)methyl)-l,2,4-triazin-3-amine (342)
1U NMR (400 MHz, DMSOd6) δ 12.96 (bs, IH), 9.30 (s, IH), 8.28 (bs, IH), 8.17 (d, J= 8.0 Hz, 2H), 7.77 (d, J= 8.4 Hz, 2H), 7.71 (d, J= 7.6 Hz, 2H), 7.37 (t, J= 7.0Hz, 2H), 7.27 (m, IH), 6.60 (s, IH), 4.66 (s, 2H); TLC ^(w-HexanesiEtOAc 3:7) = 0.37.
Figure imgf000312_0003
5-(4-ter^-ButylphenyI)-iV-((5-phenyl-lH-pyrazol-3-yl)methyl)-l,2,4-triazin[-3-amine (343)
1H NMR (400 MHz, CDCl3) δ 9.01 (s, IH), 7.99 (d, J= 7.6 Hz, 2H), 7.66 (d, J= 7.6 Hz, 2H), 7.49 (d, J= 7.6 Hz, 2H), 7.34 (t, J= 7.2 Hz, 2H), 7.27 (d, J= 7.6 Hz, IH), 6.54 (s, IH), 4.84 (d, J= 5.2 Hz, 2H), 1.33 (s,9H); TLC i?/(Hexanes:EtOAc 1:2) = 0.27; LRMS (electrospray) m/z calculated for C23H25N6 (MH-H)+ 385.21, found 385.19.
Figure imgf000312_0004
1H NMR (400 MHz, CDCl3) δ 11.12 (bs, IH) 9.57 (s, IH), 8.69 (s,lH), 8.23 (dd, J= 8.4, 1.6 Hz, IH), 7.99 (dd, J= 11.4, 8.2 Hz, 2H), 7.90 (d, J= 7.6 Hz, IH), 7.75 (bs, IH), 7.60 (m, 2H), 7.37 (t, J= 7.8 Hz, 2H), 7.28 (t, J= 7.2 Hz, IH), 6.64 (s, IH), 5.29 (d, J= 3.6 Hz, 2H); TLC i?/(CH2Cl2:Me0H 9:1) = 0.52.
Figure imgf000313_0001
5-(4-Ethylphenyl)-Λr-((5-phenyl-lJHr-pyrazol-3-yl)methyI)-l,2,4-triazin-3-amine (345)
1H NMR(400MHz, DMSO-J6) δ 13.00 (bs, 0.5H), 12.81 (bs, 0.5H), 9.23 (s, IH), 8.12 (d, J = 8.0 Hz, 3H), 7.69 (d, J= 6.8 Hz, 2H), 7.36 (dd, J= 12.8, 8.0 Hz, 4H), 7.25 (d, J- 6.4Hz, IH), 6.57 (s, IH), 4.64 (s, 2H), 2.65 (q, J= 8.0 Hz, 2H), 1.18 (t, J= 7.8 Hz, 3H); TLC Rf(n- Hexanes:EtOAc 3:7) = 0.36.
Figure imgf000313_0002
iV-((5-Phenyl-liϊ-pyrazol-3-yl)methyl)-5-p-tolyl-l,2,4-triaziii-3-amiiie (346)
1H NMR (400 MHz, DMSO-<4) δ 9.22 (d, J= 13.6 Hz, IH), 8.09 (d, J= 8.0 Hz, 2H), 7.71- 7.63 (m, 2H), 7.36-6.56 (m, 5H), 6.56 (s, IH), 4.65 (d, J= 21.2 Hz, 2H), 2.35 (s, 3H); LRMS (electrospray) m/z calculated for C20H19N6 (M+H)+ 343.17, found 343.16.
Figure imgf000313_0003
iV-((5-Phenyl-lH-pyrazol-3-yl)methyl)-5-(2-(trifluoromethyl)phenyl)-l,2,4-triazin-3- amine (347)
1H NMR (400 MHz, DMSO-c/δ) δ 8.75 (s, IH), 7.90 (d, J= 7.6 Hz, IH), 7.82-7.63 (m, 5H), 7.36-7.25 (m, 3H), 6.53 (s, IH), 4.60 (s, 3H); LRMS (electrospray) m/z calculated for C20Hi6F3N6 (M+H)+ 397.14, found 397.16.
Figure imgf000314_0001
5-(2-FluorophenyI)-J/V-((5-phenyl-lHr-pyrazol-3-yl)inethyl)-l,2,4-triazin-3-ainine (348)
1U NMR (400 MHz, DMSO-J6) δ 13.05 (s, 0.5H), 12.82 (s, 0.5H), 9.03 (s, IH), 8.07 (s, IH), 7.73-7.62 (m, 3H), 7.44-7.28 (m, 5H), 6.62 (s, IH), 4.67 (s, 2H); TLC i?/(CH2Cl2:Me0H 20:1) = 0.21.
Figure imgf000314_0002
349
5-(2-(Benzyloxy)phenyl)-iV-((5-phenyI-lH-pyrazoI-3-yl)methyl)-l,2,4-triaziii-3-amine (349)
1H NMR (400 MHz, OMSO-d6) δ 9.09 (s, IH), 7.87 (s, IH), 7.68 (d, J= 6.8 Hz, 2H), 7.52- 7.26 (m, 9H), 7.09 (t, J= 7.6Hz, IH), 6.56 (s, IH), 5.23 (s, 2H), 4.60 (s, 2H).
Figure imgf000314_0003
5-(Naphthalen-l-yl)-Λ'-((5-/7-tolyl-lH-pyrazol-3-yl)methyI)-l,2,4-triazin-3-amine (350)
1H NMR (400 MHz, CDCl3) δ 8.89 (s, IH), 8.21 (d, J =7.6 Hz, IH), 7.98-7.89 (m, 2H), 7.68- 7.45 (m, 6H), 7.10 (d, J=7.2 Hz, 3H), 4.82 (s, 2H), 2.31 (s, 3H); TLC i?/(«-Hexanes:EtOAc 1 :1) = 0.23.
Figure imgf000314_0004
5-(2-EthylphenyI)-iV-((5-pheiiyI-liϊ-pyrazoI-3-yI)methyl)-l,2,4-triaziii-3-amiiie (351)
1H NMR (400 MHz, OMSO-d6) δ 8.77 (s, IH), 7.66 (d, J= 7.6 Hz, 2H), 7.45-7.30 (m, 7H), 6.55 (s, IH), 4.83 (d, J= 5.2 Hz, 2H), 2.81-2.78 (m, 2H), 1.20-1.17 (m, 3H).
Figure imgf000315_0001
7V-((5-(4-Methoxyphenyl)-liϊ-pyrazol-3-yl)methyI)-5-(iiaphthalen-l-yl)-l,2,4-triazin-3- amine (352)
1H NMR (400 MHz, CDCl3) δ 8.86 (s, IH), 8.20 (d, J= 8.4 Hz, IH), 7.96 (d, J= 8.0 Hz, IH), 7.90-7.88 (m, IH), 7.66 (d, J= 7.2 Hz, IH), 7.53-7.43 (m, 5H), 6.78 (d, J= 8.8 Hz, 2H), 6.42 (s, IH), 4.80 (s, 2H), 3.75 (s, 3H).
Figure imgf000315_0002
5-(3-(Benzyloxy)phenyl)-Λr-((5-phenyl-lJϊ-pyrazol-3-yl)methyI)-l,2,4-triazin-3-amine
(353)
1H NMR (400 MHz, DMSOd6) δ 13.04 (bs, 0.5H), 12.82 (bs, 0.5H), 9.28 (s, IH), 8.25 (bs, IH), 7.83-7.69 (m, 4H), 7.49-7.22 (m, 10H), 6.66 (s, IH), 5.18 (s, 2H), 4.66 (bs, 2H); TLC R1 (CH2Cl2:Me0H 9:1) = 0.64.
Figure imgf000315_0003
5-(Naphthalen-l-yl)-iV-((5-o-tolyl-lHr-pyrazoI-3-yI)methyl)-l,2,4-triazin-3-amine (354)
1H NMR (400 MHz, CDCl3) δ 8.92 (s, IH), 8.25 (d, J= 7.2 Hz, IH), 7.99 (d, J= 8.0 Hz, IH), 7.92 (d, J= 8.0 Hz, IH), 7.70 (d, J= 6.8 Hz, IH), 7.57-7.49 (m, 3H), 7.36 (d, J= 7.2 Hz, IH), 7.26-7.18 (m, 3H), 6.42 (s, IH), 4.89 (bs, 2H), 2.04 (s, 3H); TLC #/(«-Hexanes:EtOAc 2:1) = 0.50; LRMS (electrospray) m/z calculated for C24H21N6 (M+H)+ 393.18, found 393.35.
Figure imgf000315_0004
5-(2-Chlorophenyl)-7V-((5-phenyl-liϊ-pyrazol-3-yl)methyl)-l,2,4-triazin-3-amine (355) 1H NMR (400 MHz, OMSO-d6) δ 8.90 (s, IH), 7.70-7.60 (m, 4H), 7.56-7.49 (m, 2H), 7.47- 7.34 (m, 2H), 121-126 (m, IH), 6.57 (s, IH), 4.62 (bs, 2H); LRMS (electrospray) m/z calculated for C19Hi6ClN6 (M+H)+ 363.11, found 363.16.
Figure imgf000316_0001
5-(Naphthalen-l-yl)-N-((5-phenylisoxazol-3-yl)methyl)-l,2,4-triazin-3-amine (356)
1H NMR (400 MHz, CDCl3) δ 8.97 (s, IH), 8.22 (d, J= 8.4 Hz, IH), 8.00 (d, J= 8.0 Hz, IH), 7.92 (d, J= 7.6 Hz, IH), 7.75-7.70 (m, 2H), 7.59-7.50 (m, 4H), 7.44-7.24 (m, 3H), 6.58 (s, IH), 4.93 (bs, 2H); TLC i?/(rc-Hexanes:EtOAc 2:1) = 0.64; LRMS (electrospray) m/z calculated for C23Hi8N5O (M+H)+ 380.15, found 380.16
Figure imgf000316_0002
5-(2,5-Dimethoxyphenyl)-N-((5-phenyl-liϊ-pyrazol-3-yl)methyl)-l,2,4-triazin-3-ainine
(357)
1H NMR (400 MHz, CD3OD) δ 9.16 (s, IH), 7.71-7.56 (m, 3H), 7.37-7.29 (m, 3H), 7.10-7.05 (m, 2H), 6.61 (s, IH), 4.73 (bs, 2H), 3.88 (s, 3H), 3.72 (s, 3H); LRMS (electrospray) m/z calculated for C21H21N6O2 (M+H)+ 389.17, found 389.20.
Figure imgf000316_0003
5-(2-Methoxyphenyl)-N-((5-phenyl-lJHr-pyrazol-3-yl)methyl)-l,2,4-triazin-3-amine (358)
1H NMR (400 MHz, DMSO-J6) δ 9.08 (s, IH), 7.88-7.86 (m, IH), 7.69-7.68 (m, 2H), 7.51 (t, J= 7.8 Hz, IH), 7.37-7.33 (m, 2H), 7.27-7.25 (m, IH), 7.18 (d, J= 8.4 Hz, IH), 7.08 (t, J= 7.6 Hz, IH), 6.57 (s, IH), 4.61 (bs, 2H), 3.87 (s, 3H); LRMS (electrospray) m/z calculated for C20H19N6O (M+H)+ 359.16, found 359.28.
Figure imgf000317_0001
5-(2,5-Dimethylphenyl)-7V-((5-phenyl-liϊ-pyrazol-3-yl)methyI)-l,2,4-triazin-3-amiiie
(359)
1H NMR (400 MHz, DMSO-J6) δ 8.81 (s, IH), 7.70-7.69 (m, 2H), 7.38-7.32 (m, 3H), 7.27- 7.24 (m, IH), 7.20-7.15 (m, 2H), 6.56 (s, IH), 4.59 (bs, 2H), 2.28 (s, 3H), 2. 24 (s, 3H); LRMS (electrospray) m/z calculated for C21H21N6 (M+H)+ 357.18, found 357.10.
Figure imgf000317_0002
N-((5-Phenyl-lJϊ-pyrazol-3-yl)methyl)-5-(3-(trifluoromethyl)phenyl)-l,2,4-triaziii-3- amine (360)
1H NMR (400 MHz, DMSO-J6) δ 13.06 (s, 0.5H), 12.81 (s, 0.5H), 9.43 (s, IH), 8.59 (s, 2H), 7.98 (d, J= 7.6 Hz, IH), 7.82 (t, J= 7.8 Hz, IH), 7.71 (m, 2H), 7.38 (m, 2H), 7.28 (m, IH), 6.62 (s, IH), 4.69 (s, 2H); TLC i?/(CH2Cl2:Me0H 20:1) = 0.23.
Figure imgf000317_0003
5-(2-Isopropylphenyl)-N-((5-phenyl-lH-pyrazoI-3-yl)methyl)-l,2,4-triazin-3-amine (361)
1H NMR (400 MHz, DMSO-J6) δ 13.05 (s, 0.5H), 12.78 (s, 0.5H), 8.76 (s, IH), 7.72 (s, 2H), 7.49 (d, J= 4.0 Hz, 2H), 7.39-7.29 (m, 5H), 6.56 (s, IH), 4.62 (s, IH), 3.25-3.19 (m, IH), 1.10 (m, 6H); TLC i?/(CH2Cl2:Me0H 20:1) == 0.23.
Figure imgf000317_0004
5-(3-Methoxyphenyl)-iV-((5-phenyl-lf-r-pyrazol-3-yl)methyl)-l,2,4-triaziii-3-amine (362) 1U NMR (400 MHz, OMSO-d6) δ 9.27 (s, IH), 7.77 (d, J= 8.0 Hz, lH),7.70-7.68 (m, 3H), 7.45 (t, J= 7.8 Hz, IH), 7.37-7.33 (m, 2H), 7.26-7.25 (m, IH), 7.14 (d, J= 8.0 Hz, IH ), 6.58 (s, IH), 4.63 (bs, 2H). 3.80 (s, 3H); LRMS (electrospray) m/z calculated for C20H19N6O (M+H)+ 359.16, found 359.21.
Figure imgf000318_0001
iV-((5-Phenyl-lH-pyrazol-3-yl)methyl)-5-ι«-tolyl-l,2,4-triaziii-3-amine (363)
1H NMR (400 MHz, DMSO-J6) δ 13.05 (s, 0.5H), 12.82 (s, 0.5H), 9.27 (s, IH), 8.04 (s, IH), 8.01 (d, J= 7.2 Hz, IH), 7.72 (m, 2H), 7.47-7.38 (m, 5H), 7.28 (m, IH), 6.62 (s, IH), 4.68 (s, 2H), 2.35 (s, 3H); TLC i?/(CH2Cl2:Me0H 20:1) = 0.22.
Figure imgf000318_0002
5-(3-Chlorophenyl)-Λr-((5-phenyl-lH-pyrazol-3-yl)methyl)-l,2,4-triazin-3-amine (364)
1H NMR (400 MHz, DMSO-J6) δ 13.06 (s, 0.5H), 12.83 (s, 0.5H), 9.34 (s, IH), 8.26 (s, IH), 8.19 (d, J= 7.6 Hz, IH), 7.72-7.58 (m, 4H), 7.38-7.28 (m, 3H), 6.62 (s, IH), 4.68 (s, 2H); TLC 22/-(CH2Cl2MeOH 20:1) = 0.25.
Figure imgf000318_0003
5-(2-Chlorophenyl)-7V-((5-(4-methoxyphenyl)-lH-pyrazol-3-yl)methyl)-l,2,4-triazin-3- amine (365)
1H NMR (400 MHz, CDCl3) δ 9.02 (s, IH), 7.62 (d, J= 7.6 Hz, IH), 7.55 (d, J= 8.8 Hz, 2H), 7.50 (d, J= 8.0 Hz, IH), 7.45-7.37 (m, 2H), 6.92 (d, J= 7.2 Hz, 2H), 6.47 (s, IH), 4.80 (bs, 2H), 3.81 (s, 3H); LRMS (electrospray) m/z calculated for C20H18ClN6O (M+H)+ 393.12, found 393.14.
Figure imgf000319_0001
5-(2-BromophenyI)-7V-((5-phenyl-ljEr-pyrazol-3-yl)methyl)-l,2,4-triazin-3-amine (366)
1H NMR (400 MHz, DMSO-J6) δ 13.01 (s, 0.5H), 12.81 (s, 0.5H), 8.82 (s, IH), 7.74 (d, J= 8.0 Hz, IH), 7.67-7.65 (m, 2H), 7.56-7.54 (m, IH), 7.50 (t, J= 7.4 Hz, IH), 7.45-7.40 (m, IH), 7.37-7.33 (m, 2H), 7.24 (t, J= 7.2 Hz, IH), 6.55 (s, IH), 4.60 (s, 2H); TLC R1 (CH2Cl2:Me0H 20:1) = 0.38.
Figure imgf000319_0002
5-(2,6-DimethyIphenyl)-N-((5-phenyl-lH-pyrazoI-3-yl)methyl)-l,2,4-triazin-3-amine
(367)
1H NMR (400 MHz, DMSO-J6) δ 12.92 (s, IH), 8.60 (s, IH), 7.69 (d, J= 7.2 Hz, 2H), 7.39 (t, J= 7.6 Hz, 2H), 7.30-7.23 (m, 2H), 7.13 (d, J= 7.6 Hz, 2H), 6.54 (s, IH), 4.60 (s, 2H), 2.01 (s, 6H) ; TLC ^(CH2Cl2MeOH 20:1) = 0.24.
Figure imgf000319_0003
5-(2-Methoxyphenyl)-iV-((5-(4-methoxyphenyl)-ljyr-pyrazol-3-yl)methyl)-l,2,4-triazin-3- amine (368)
1H NMR (400 MHz, DMSO-J6) δ 12.88 (s, 0.5H), 12.71 (s, 0.5H), 9.68 (s, IH), 8.02 (dd, J = 7.8, 1.8 Hz), IH), 7.61 (m, 3H), 7.27 (d, J = 8.4 Hz, IH), 7.16 (t, J = 7.4 Hz, IH), 6.95 (bs, 2H), 6.44 (s, IH), 5.15 (s, 2H), 3.95 (s, 3H), 3.76 (s, 3H); TLC /J7(CH2Cl2 :MeOH 9:1) = 0.43.
Figure imgf000319_0004
iV-((5-(4-Methoxyphenyl)-lJHr-pyrazol-3-yl)methyl)-5-(2-(trifluoromethyl)phenyl)-l,2,4- triazin-3-amine (369) 1H NMR (400 MHz, DMSO-J6) δ 13.48 (s, 0.5H), 12.84 (s, 0.5H), 8.76 (s, IH), 7.92 (d, J = 7.6 Hz, IH), 7.84-7.75 (m, 2H), 7.66-7.60 (m, 3H), 6.95 (d, J = 8.8 Hz, 2H), 6.44 (s, IH), 4.60 (s, 2H), 3.75 (s, 3H) ; TLC i?/(CH2Cl2:Me0H 20:1) = 0.28.
Figure imgf000320_0001
5-(3-Ethylphenyl)-7V-((5-phenyl-lH-pyrazol-3-yI)methyl)-l,2,4-triazin-3-amine (370)
1H NMR (400 MHz, DMSO-^6) δ 12.99 (bs, 0.5H), 12.81 (bs, 0.5H), 9.25 (s, IH), 8.22 (bs, IH), 8.03 (s, IH), 8.00 (d, J= 7.2 Hz, IH), 7.69 (d, J= 6.8 Hz, 2H), 7.43 (m, 2H), 7.35 (t, J = 7.4 Hz, 2H), 7.25 (t, J= 6.8 Hz5 IH), 6.58 (s, IH), 4.64 (s, 2H), 2.66 (q, J= 7.6 Hz, 2H), 1.19 (t, J= 7.6 Hz, 3H); TLC i?/(CH2Cl2:Me0H 19:1) = 0.26.
Figure imgf000320_0002
4-(3-((5-(Naphthalen-l-yI)-l,2,4-triazin-3-ylamino)methyl)-lH-pyrazol-5-yl)benzamide
(371)
1H NMR (400 MHz, CD3OD) δ 8.92 (s, IH), 8.32 (s, IH), 8.08 (d, J= 7.2 Hz, IH), 7.95-7.76 (m, 6H), 7.58 (s, IH), 7.47-7.27 (m, 2H), 6.78 (s, IH); TLC i?/(«-Hexanes: EtOAc 1:1) = 0.09; LC/MS (EI) m/z calcd for C24H20N7O (M+H)+ 422.45, found 422.11
Figure imgf000320_0003
4-(3-((5-(Naphthalen-l-yl)-l,2,4-triazin-3-ylamino)methyl)-liϊ-pyrazol-5-yl)benzoic acid
(372)
1H NMR (400 MHz, CD3OD) δ 8.84 (s, IH), 8.19 (s, IH), 8.01 (d, J= 6.8 Hz, 3H), 8.91 (d, J
= 6.4 Hz, IH), 7.79-7.74 (m, 3H), 7.56-7.48 (m, 3H), 6.71 (s, IH), 4.55 (s, 2H); TLC Rf
(CH2Cl2MeOH 10:1) = 0.21; LC/MS (EI) m/z calcd for C24H19N6O2 (M+H)+ 423.44, found
423.13
Figure imgf000321_0001
N-((5-(4-Bromophenyl)-lH-pyrazol-3-yI)methyl)-5-(naphthaIen-l-yl)-l,2,4-triazin-3- amine (373)
1H NMR (400 MHz DMSO-fifc) δ 8.93 (s, IH), 8.20 (s, 2H), 8.08 (d, J= 8.0 Hz, IH), 7.99 (d, J= 8.0 Hz, IH), 7.78-7.54 (m, 6H), 6.62 (s, IH), 4.62 (s, 2H); TLC i?/(n-Hexanes:EtOAc 1:1) = 0.03.
Figure imgf000321_0002
5-(Biphenyl-2-yl)-7V-((5-phenyl-ljHr-pyrazol-3-yl)methyl)-l,2,4-triazin-3-amine (374) 1H NMR (400 MHz, DMSO-J6) δ 13.00 (s, 0.5H), 12.75 (s, 0.5H), 7.99 (s, IH), 7.71-7.69 (m, 3H), 7.60 (t, J= 7.6 Hz, IH), 7.53 (t, J= 7.4 Hz, IH), 7.46 (d, J= 7.6 Hz, IH), 7.38-7.26 (m, 6H), 6.52 (s, IH), 4.48 (s, 2H); TLC i?/(CH2Cl2:Me0H 20:1) = 0.34.
Figure imgf000321_0003
5-(2,3-Dimethylphenyl)-Λr-((5-phenyl-lH-pyrazol-3-yl)methyl)-l,2,4-triazin-3-amine
(375)
1R NMR (400 MHz, OMSO-d6) δ 8.73 (s, IH), 7.69 (d, J= 6.4 Hz, 2H), 7.38-7.17 (m, 6H),
6.56 (s, IH), 4.59 (bs, 2H), 2.33 (s, 3H), 2.18 (s, 3H); TLC .Sy(CH2Cl2=MeOH 10:1) = 0.49.
Figure imgf000321_0004
4-(3-((5-(Naphthalen-l-yl)-l,2,4-triazin-3-ylamino)methyl)-lΛT-pyrazol-5-yl)benzonitrile
(376) 1H NMR (400 MHz, DMSO-J6) δ 8.94 (s, IH), 8.09 (s, IH), 8.07-8.00 (m, IH), 7.98-7.92 (m, 4H), 7.81-7.76 (m, 3H), 7.63-7.59 (m, IH), 7.52 (s, IH), 6.76 (s, IH), 4.65 (s, 2H); TLC Rf{n- Hexanes:EtOAc 1:1) = 0.05; LC/MS (EI) m/z calcd for C24H18N7 (M+H)+ 404.44, found 404.09.
Figure imgf000322_0001
377 5-(2-Phenoxyphenyl)-iV-((5-phenyl-lH;-pyrazol-3-yl)methyl)-l,2,4-triaziii-3-amine (377)
1H NMR (400 MHz, DMSO-J6) δ 13.06 (s, 0.5H), 12.79 (s, 0.5H), 9.06 (s, IH), 8.00 (d, J = 6.0 Hz, IH), 7.72 (s, 2H), 7.57 (t, J= 7.0 Hz, IH), 7.40-7.33 (m, 6H), 7.29 (br, 2H), 7.14 (t, J = 7.4 Hz, IH), 7.06-7.00 (m, 3H), 6.58 (s, IH), 4.62 (s, 2H) ; TLC 22/(CH2Cl2MeOH 20:1) = 0.33.
Figure imgf000322_0002
5-(2,3-Dimethoxyphenyl)-iV-((5-phenyl-lH-pyrazol-3-yl)methyl)-l,2,4-triaziii-3-amine
(378)
1H NMR (400 MHz, CDCl3) δ 8.96 (s, IH), 7.69 (d, J= 7.6 Hz, 2H), 7.38-7.34 (m, 3H), 7.27- 7.17 (m, 3H), 6.57 (s, IH), 4.61 (bs, 2H), 3.80 (s, 3H), 3.70 (s, 3H); TLC 2?/(CH2Cl2:Me0H 10:1) = 0.53.
Figure imgf000322_0003
379 iV-((5-(3-Methoxyphenyl)-lH-pyrazol-3-yI)methyl)-5-(naphthalen-l-yl)-l,2,4-triazin-3- amine (379)
1H NMR (400 MHz, CDCl3) δ 8.86 (s, IH), 8.19 (d, J= 8.4 Hz, IH), 7.95 (d, J= 8.4 Hz, IH), 7.89 ( t, J= 7.6 Hz, IH), 7.65 (d, J= 6.8 Hz, IH), 7.52-7.43 (m, 3H), 7.24-7.18 (m, 3H), 6.82- 6.79 (m, IH), 6.49 (s, IH), 4.79 (s, 2H), 3.76 (s, 3H); TLC i?/(rc-Hexanes:EtOAc 1 :1) = 0.12.
Figure imgf000323_0001
5-(Biphenyl-4-yl)-iV-((5-phenyl-lJfir-pyrazoI-3-yl)methyl)-l,2,4-triazin-3-amine (380)
1H NMR (400 MHz, DMSO-J6) δ 13.06 (s, 0.5H), 12.84 (s, 0.5H), 9.35 (s, IH), 8.33 (d, J= 8.4 Hz, 2H), 7.88 (d, J= 8.0 Hz, 2H), 7.78-7.72 (m, 4H), 7.51 (t, J= 7.6 Hz, 2H), 7.44-7.37 (m, 3H), 7.29-7.27 (m, IH), 6.63 (s, IH), 4.70 (s, 2H); TLC ^/(CH2Cl2 :MeOH 20:1) = 0.31.
Figure imgf000323_0002
5-(4-FIuorophenyl)-N-((5-phenyl-lH-pyrazoI-3-yl)methyl)-l,2,4-triazin-3-amine (381)
1H NMR (400 MHz, DMSO-J6) δ 9.26 (s, IH), 8.29-8.25 (m, 2H), 7.78-7.68 (m, 2H), 7.40- 7.35 (m, 4H), 7.30-7.34 (m, IH), 6.57 (s, IH), 4.64 (bs, 2H).
Figure imgf000323_0003
iV-((5-(2-Methoxyphenyl)-lH-pyrazol-3-yl)methyl)-5-(naphthalen-l-yl)-l,2,4-triaziii-3- amine (382)
1H NMR (400 MHz, CDCl3) δ 8.89 (s, IH), 8.26 (d, J= 7.6 Hz, IH), 7.97 (d, J= 8.4 Hz, IH), 7.90 ( t, J= 7.2 Hz, IH), 7.70 (d, J= 6.8 Hz, IH), 7.61-7.48 (m, 4H), 7.29-7.24 (m, IH), 7.01- 6.96 (m, 2H), 6.64 (s, IH), 4.86 (s, 2H), 3.93 (s, 3H); TLC i?/(«-Hexanes:EtOAc 1 :1) = 0.13.
Figure imgf000323_0004
5-(Biphenyl-3-yl)-Λ'-((5-phenyl-lH-pyrazol-3-yI)methyl)-l,2,4-triaziii-3-amme (383)
1H NMR (400 MHz, DMSO-J6) δ 13.03 (s, 0.5H), 12.84 (s, 0.5H), 9.42 (s, IH), 8.46 (s, IH), 8.21 (d, J= 7.6 Hz, IH), 7.90 (d, J= 8.0 Hz, IH), 7.77-7.64 (m, 5H), 7.49 (t, J= 7.4 Hz, 2H), 7.43-7.36 (m, 3H), 7.27 (m, IH), 6.63 (s, IH), 4.69 (s, 2H); TLC i?/(CH2Cl2:Me0H 20:1) : 0.34.
Figure imgf000324_0001
5-(2-Cyclohexylphenyl)-iV-((5-phenyl-ljHr-pyrazol-3-yl)methyl)-l,2,4-triazin-3-amine
(384)
1H NMR (400 MHz, OMSO-d6) δ 8.70 (s, IH), 7.61 (d, J= 6.8 Hz, 2H), 7.44 (s, IH), 7.35- 7.25 (m, 5H), 6.53 (s, IH), 4.84 (s, 2H), 2.84 (s, IH), 2.03-1.68 (m, 5H), 1.47 (d, J= 10.0 Hz, 2H), 1.24 (s, 3H); TLC i?/(rc-Hexanes:EtOAc 5:1) = 0.49.
Figure imgf000324_0002
5-o-tolyl-N-((3-p-tolyI-lH-pyrazol-5-yl)methyl)-l,2,4-triazin-3-amine (385)
1H NMR (400 MHz, CDCl3) δ 8.73 (s, IH), 7.51-7.45 (m,3H), 7.37-7.24 (m, 3H), 7.13 (d, J =7.6 Hz, 2H), 4.80 (s, 2H), 2.44 (s, 3H), 2.32 (s, 3H); TLC i?/(Hexanes: EtOAc 1:1) = 0.19.
Figure imgf000324_0003
7V-((5-PhenyI-lH-pyrazol-3-yI)methyI)-5-(3-(trifluoromethoxy)phenyI)-l,2,4-triaziii-3- amine (386)
1H NMR (400 MHz, OMSO-d6) δ 9.32 (s, IH), 8.23 (d, J= 7.6 Hz, IH), 7.14 (s, IH), 7.70- 7.60 (m, 2H), 7.57 (d, J= 8.4 Hz, 2H), 7.34 (s, 2H), 7.24 (s, IH), 6.57 (s, IH), 4.64 (s, 2H); TLC i?/(n-Hexanes:EtOAc 5:1) = 0.25.
Figure imgf000324_0004
387 5-(3-FIuorophenyl)-iV-((5-phenyl-lH-pyrazol-3-yl)methyl)-l,2,4-triazin-3-amine (387)
1H NMR (400 MHz, DMSO-J6) δ 13.04 (bs, 0.5H), 12.79 (bs, 0.5H), 9.30 (s, IH), 8.30 (bs, IH), 8.06 (d, J= 7.6 Hz, IH), 8.01 (d, J= 10.0 Hz, IH), 7.69 (bs, 2H), 7.59 (q, J= 8.0 Hz, IH), 7.42 (dt, J= 8.4, 2.0 Hz, IH), 7.35 (bs, 2H), 7.25 (bs, IH), 6.58 (s, IH), 4.65 (bs, 2H); TLC i?/(CH2Cl2:Me0H 19:1) = 0.18.
Figure imgf000325_0001
5-(4-(Benzyloxy)phenyl)-7V-((5-phenyl-lH-pyrazol-3-yI)methyl)-l,2,4-triazin-3-amine
(388)
1H NMR (400 MHz, DMSO-^) δ 9.21 (s, IH), 8.19 (d, J= 8.8 Hz, 3H), 7.68 (s, 2H), 7.45- 7.31 (m, 8H), 7.16 (d, J= 8.8 Hz, IH), 6.57 (s, IH), 5.19 (s, 2H), 4.63 (s, 2H).
Figure imgf000325_0002
5-(4-Methoxyphenyl)-7V-((5-phenyl-li7-pyrazol-3-yl)methyl)-l,2,4-triazin-3-ainine (389)
1H NMR (400 MHz, OMSO-d6) δ 9.20 (s, IH), 8.18 (d, J= 9.2 Hz, 2H), 7.68 (s, 2H), 7.34 (s, 2H), 7.24 (s, IH), 7.07 (d, J= 8.8 Hz, 2H), 6.57 (s, IH), 4.62 (s, 2H), 3.81 (s, 3H).
Figure imgf000325_0003
7V-((5-Phenyl-lH-pyrazol-3-yl)methyl)biphenyl-3-amine (390)
1H NMR (400 MHz, CD3OD) δ 7.67 (d, J= 7.2 Hz, 2H ), 7.53-7.50 (m, 2H), 7.38-7.33 (m, 4H), 7.29-7.23 (m, 2H), 7.16 (t, J= 7.8 Hz, IH), 6.93-6.92 (m, IH), 6.87-6.85 (m, IH), 6.69- 6.66 (m, IH), 6.59 (s, IH), 4.39 (s, 2H); TLC i?/(«-Hexanes: EtOAc 2:1) = 0.21.
Figure imgf000325_0004
2'-Methyl-iV-((5-phenyl-lH-pyrazol-3-yl)methyl)biphenyl-3-ainine (391)
1H NMR (400 MHz, CD3OD) δ 7.66 (d, J= 7.6 Hz, 2H), 7.36 (t, J= 7.4 Hz, 2H), 7.28 (t, J= 7.2 Hz, IH), 7.16-7.11 (m, 5H), 6.67 (d, J= 8.0 Hz, IH), 6.59-6.53 (m, 3H), 4.36 (s, 2H), 2.14 (s, 3H); TLC i?/(«-Hexanes: EtOAc 2:1) = 0.34; LRMS (electrospray) m/z calculated for C23H22N3 (M+H)+ 340.18, found 340.17.
Figure imgf000326_0001
J/V-((5-PhenyI-l/-r-pyrazoI-3-yl)methyl)-2'-(trifluoromethyl)biphenyl-3-amine (392)
1H NMR (400 MHz, CD3OD) δ 7.70-7.66 (m, 3H), 7.55 (t, J= 7.4 Hz, IH), 7.46 (t, J= 7.4 Hz, IH), 7.39-7.35 (m, 2H), 7.31-7.29 (m, 2H), 7.13 (t, J= 7.8 Hz, IH), 6.72 (d, J= 8.0 Hz, IH), 6.62 (s, IH), 6.57-6.55 (m, 2H), 4.35 (s, 2H); TLC i?/(«-Hexanes: EtOAc 2:1) = 0.36; LRMS (electrospray) m/z calculated for C23Hi9F3N3 (M+H)+ 394.15, found 394.09.
Figure imgf000326_0002
2'-Methoxy-Λr-((5-phenyl-lH-pyrazol-3-yl)methyl)biphenyl-3-amine (393)
1H NMR (400 MHz, CD3OD) δ 7.64 (d, J= 8.0 Hz, 2H), 7.33 (t, J= 7.6 Hz, 2H), 7.26-7.18 (m, 3H), 7.10 (t, J= 7.8 Hz, IH), 6.94-6.88 (m, 2H), 6.81 (s, IH), 6.73 (d, J= 7.2 Hz, IH), 6.64-6.61 (m, IH), 6.54 (s, IH), 4.32 (s, 2H), 3.63 (s, 3H); TLC i?/(«-Hexanes: EtOAc 2:1) = 0.29; LRMS (electrospray) m/z calculated for C23H22N3O (M+H)+ 356.18, found 356.15.
Figure imgf000326_0003
2'-Chloro-7V-((5-phenyl-ljfir-pyrazoI-3-yI)inethyl)biphenyl-3-amiiie (394)
1H NMR (400 MHz, CD3OD) δ 7.63 (d, J= 8.4 Hz, 2H), 7.37-7.31 (m, 3H), 7.26-7.18 (m, 4H), 7.12 (d, J= 7.0 Hz, IH), 6.68-6.65 (m, 2H), 6.60 (dd, J= 6.0, 1.2 Hz, IH), 6.54 (s, IH), 4.32 (s, 2H); TLC i?/(n-Hexanes: EtOAc 2:1) = 0.32; LRMS (electrospray) m/z calculated for C22H19ClN3 (M+H)+ 360.13, found 360.03.
Figure imgf000327_0001
395 4-(3-((5-(Naphthalen-l-yl)-l,2,4-triazin-3-ylamino)methyl)-lZ-r-pyrazol-5-yl)phenol (395)
1U NMR (400 MHz, CD3OD) δ 8.86 (s, IH), 8.22 (bs, IH), 8.04 (d, J= 8.0 Hz5 IH), 7.94 (d, J= 8.4 Hz, IH), 7.76 (d, J= 7.2 Hz, IH), 7.59 (t, J= 7.2 Hz, IH), 7.51 (m, 3H), 7.45 (bs, IH), 6.80 (d, J= 8.4 Hz, 2H), 6.50 (s, IH), 5.06 (s, 2H); TLC i?/(CH2Cl2:Me0H 9:1) = 0.47.
Figure imgf000327_0002
3-(3-((5-(Naphthalen-l-yl)-l,2,4-triazin-3-ylamiiio)methyl)-lZr-pyrazol-5-yl)phenoI (396)
1H NMR (400 MHz, CD3OD) δ 8.86 (s, IH), 8.20 (bs, IH), 8.03 (d, J= 8.0 Hz, IH), 7.93 (d, J= 8.4 Hz, IH), 7.76 (d, J= 6.8 Hz, IH), 7.58 (t, J= 7.8 Hz, IH), 7.50 (t, J= 7.2 Hz, IH), 7.43 (bs, IH), 7.18 (m, 3H), 6.74 (dd, J= 9.0, 2.2 Hz, IH), 6.57 (s, IH), 4.90 (s, 2H); TLC R1 (CH2Cl2MeOH 9:1) = 0.46.
Figure imgf000327_0003
2-(3-((5-(NaphthaIen-l-yl)-l,2,4-triazin-3-ylamino)methyl)-liϊ-pyrazol-5-yI)phenol (397)
1U NMR (400 MHz, CD3OD) δ 8.87 (s, IH), 8.18 (bs, IH), 8.03 (d, J= 8.4 Hz, IH), 7.93 (d, J= 8.0 Hz, IH), 7.76 (d, J= 6.4 Hz, IH), 7.58 (t, J= 7.8 Hz, 2H), 7.49 (m, IH), 7.42 (bs, 2H), 7.14 (m, IH), 6.87 (m, 2H), 6.71 (s, IH), 5.18 (s, 2H); TLC i?/(CH2Cl2:Me0H 9:1) = 0.67.
Figure imgf000327_0004
2-(3-((5-Phenyl-lH-pyrazol-3-yl)methylamino)-l,2,4-triazin-5-yI)phenol (398) 1H NMR (400 MHz, CD3OD) δ 9.27 (s, IH), 8.03 (dd, J= 8.0, 1.6 Hz, IH), 7.68 (d, J= 7.6 Hz, 2H), 7.40 (m, 3H), 7.29 (t, J= 7.4 Hz, IH), 6.97 (t, J= 8.8 Hz, 2H), 6.64 (s, IH), 5.18 (s, 2H); TLC i?/(CH2Cl2:Me0H 9:1) = 0.63.
Figure imgf000328_0001
5-(4-Fluorophenyl)-Λr-((5-phenyl-lJΪ-pyrazol-3-yl)methyl)-l,2,4-triazin-3-amine (399)
1H NMR (400 MHz, DMSO-cfe) δ 9.26 (s, IH), 8.29-8.25 (m, 2H), 7.78-7.68 (m, 2H), 7.40- 7.35 (m, 4H), 7.30-7.34 (m, IH), 6.57 (s, IH), 4.64 (bs, 2H).
Figure imgf000328_0002
5-(Biphenyl-4-yl)-7V-((5-phenyl-lHr-pyrazol-3-yl)methyl)-l,2,4-triaziii-3-amine (400)
1U NMR (400 MHz, DMSO-J6) δ 13.06 (s, 0.5H), 12.84 (s, 0.5H), 9.35 (s, IH), 8.33 (d, J= 8.4 Hz, 2H), 7.88 (d, J= 8.0 Hz, 2H), 7.78-7.72 (m, 4H), 7.51 (t, J= 7.6 Hz, 2H), 7.44-7.37 (m, 3H), 7.29-7.27 (m, IH), 6.63 (s, IH), 4.70 (s, 2H); TLC i?/(CH2Cl2:Me0H 20:1) = 0.31.
Figure imgf000328_0003
5-(BiphenyI-3-yl)-7V-((5-phenyl-ljHr-pyrazol-3-yl)methyl)-l,2,4-triazin-3-amine (401)
1H NMR (400 MHz, DMSO-^6) δ 13.03 (s, 0.5H), 12.84 (s, 0.5H), 9.42 (s, IH), 8.46 (s, IH), 8.21 (d, J= 7.6 Hz, IH), 7.90 (d, J= 8.0 Hz, IH), 7.77-7.64 (m, 5H), 7.49 (t, J= 7.4 Hz, 2H), 7.43-7.36 (m, 3H), 7.27 (m, IH), 6.63 (s, IH), 4.69 (s, 2H); TLC ^/(CH2Cl2 :MeOH 20:1) = 0.34.
Figure imgf000328_0004
N-((lHr-pyrazol-3-yl)methyl)-5-(naphthaIen-l-yI)-l,2,4-triazin-3-amine (402)
1H NMR (400 MHz, CD3OD) δ 8.86 (s, IH), 8.24-8.23 (m, IH), 8.05 (d, J= 8.0 Hz, IH), 7.96 (d, J= 7.6 Hz, IH), 7.77 (d, J= 7.2 Hz, IH), 7.66-7.50 (m, 4H), 6.32 (bs, IH), 4.74 (s, 2H); TLC i?/(CH2Cl2:Me0H 10:1) = 0.55.
Figure imgf000329_0001
403
7V-((lHr-pyrazol-3-yl)methyI)-5-(2-chIorophenyl)-l,2,4-triazin-3-amine (403)
1H NMR (400 MHz, CD3OD) δ 8.90 (s, IH), 7.68 (d, J= 6.0 Hz, IH), 7.58-7.47 (m, 4H), 6.31 (bs, IH), 4.74 (s, 2H); TLC i?/(n-Hexanes:EtOAc 1:2) = 0.10.
Figure imgf000329_0002
(4-(3-((5-(2-Chlorophenyl)-l,2,4-triazin-3-ylamino)methyl)-ll/-pyrazoϊ-5- yl)phenyl)(morpholino)methanone (404)
1H NMR (400 MHz, CDCl3) δ 9.00 (s, IH), 7.64 (d, J= 8.4 Hz, 2H), 7.53 (dd, J= 7.6, 1.6 Hz, IH), 7.48 (d, J= 8.0 Hz, IH), 7.40 (td, J- 7.6, 1.6 Hz, IH), 7.34 (m, 3H), 6.50 (bs, IH), 5.05 (bs, 2H), 3.69 (bs, 6H), 3.46 (bs, 2H); TLC i?/(CH2Cl2:Me0H 19:1) = 0.17.
Figure imgf000329_0003
405
5-(2-Ethoxyphenyl)-7V-((5-phenyl-lH-pyrazol-3-yl)methyl)-l,2,4-triazin-3-amiiie (405)
1H NMR (400 MHz, CD3OD) δ 9.71 (s, IH), 8.09 (dd, J= 8.0, 1.6 Hz, IH), 7.62 (bs, 2H), 7.50 (m, IH), 7.35 (t, J= 7.6 Hz, IH), 7.26 (t, J= 7.2 Hz, IH), 7.12 (d, J= 8.4 Hz, IH), 7.06 (t, J= 7.6 Hz, IH), 6.57 (s, IH), 5.23 (s, 2H), 4.19 (q, J= 6.8 Hz, 2H), 1.45 (t, J= 7.0 Hz, 3H); TLC £/(CH2Cl2:Me0H 19:1) = 0.22.
Figure imgf000330_0001
406
5-(2-Isopropoxyphenyl)-N-((5-phenyl-lH-pyrazol-3-yl)methyl)-l,2,4-triazin-3-amine (406)
1H NMR (400 MHz, CD3OD) δ 9.72 (s, IH), 8.08 (dd, J= 7.8, 1.8 Hz, IH), 7.62 (bs, 2H), 7.53 (m, IH), 7.36 (t, J= 6.8 Hz, 2H), 7.29 (m, IH), 7.18 (d, J= 8.4 Hz, IH), 7.07 (t, J= 7.6 Hz, IH), 6.57 (s, IH), 4.77 (m, IH), 1.38 (d, J= 6.0 Hz, 6H); TLC i?/(CH2Cl2:Me0H 9:1) = 0.29.
Figure imgf000330_0002
7V-((lH-pyrazol-3-yl)methyl)-5-(2-(trifluoromethyl)phenyl)-l,2,4-triazin-3-amine (407)
1H NMR (400 MHz, CD3OD) δ 8.41 (s, IH), 7.61 (d, J= 6.8 Hz, IH), 7.53-7.45 (m, 2H), 7.34 (d, J= 7.2 Hz, IH), 7.28-7.27 (m, IH), 6.01 (bs, IH), 4.44 (s, 2H); TLC T^(CH2Cl2: MeOH 5:1) = 0.53.
Figure imgf000330_0003
N-((5-Phenyl-lJy-pyrazol-3-yl)methyl)-5-(2-(trifluoromethoxy)phenyl)-l,2,4-triazin-3- amine (408)
1H NMR (400 MHz, DMSO-^6) δ 13.07 (s, 0.5H), 12.82 (s, 0.5H), 8.93 (s, IH), 7.92 (s, J= 7.2 Hz, IH), 7.74-7.67 (m, 3H), 7.62-7.53 (m, 2H), 7.39 (m, 2H), 7.29 (m, IH), 6.60 (s, IH), 4.66 (s, 2H) ; TLC i?/(CH2Cl2:Me0H 20:1) = 0.31.
Figure imgf000330_0004
409 5-(2-(Difluoromethoxy)phenyl)-iV-((5-phenyl-lJir-pyrazol-3-yl)methyl)-l,2,4-triazin-3- amine (409)
1H NMR (400 MHz, DMSO-^) δ 8.94 (s, IH), 7.87 (d, J= 7.6 Hz, IH ), 7.70-7.60 (m, 3H), 7.46-7.25 (m, 6H), 6.57 (s, IH), 4.62 (bs, 2H); TLC i?/(CH2Cl2:Me0H 10:1) = 0.51.
Figure imgf000331_0001
5-(2,3-Dihydrobenzofuran-7-yl)-iV-((5-phenyl-lH-pyrazol-3-yl)methyl)-l,2,4-triaziii-3- amine (410)
1H NMR (400 MHz, DMSO-J6) δ 13.01 (s, 0.5H), 12.87 (s, 0.5H), 9.23 (s, IH), 7.95 (d, J= 8.0 Hz, IH), 7.66 (d, J= 7.2 Hz, 2H), 7.41 (d, J= 7.2 Hz, IH), 7.36 (t, J= 7.6 Hz, 2H), 7.28- 7.25 (m, IH), 6.98 (t, J= 7.6 Hz, IH), 6.57 (s, IH), 4.68 (t, J= 8.8 Hz, 2H), 4.63 (s, 2H), 3.21 (t, J= 8.8 Hz, 2H) ; TLC i?/(CH2Cl2:Me0H 20:1) = 0.30.
Figure imgf000331_0002
411
5-(Chroman-8-yl)-iV-((5-phenyI-lHr-pyrazol-3-yI)methyI)-l,2,4-triazin-3-amine (411)
1H NMR (400 MHz, DMSO-^6) δ 9.05 (s, IH), 7.67-7.66 (m, 3H), 7.34-7.32 (m, 2H), 7.25- 7.20 (m, 2H), 6.92 (t, J= 7.6 Hz, IH), 6.54 (s, IH)5 4.59 (bs, 2H), 4.23 (t, J= 5.2 Hz, 2H)5 2.78 (t, J= 6.2 Hz, 2H), 1.95-1.90 (m, 2H); TLC i?/(CH2Cl2:Me0H 10:1) = 0.39; LRMS (electrospray) m/z calculated for C22H2 !N60(M+H)+ 385.18, found 385.12.
Figure imgf000331_0003
5-(2,3-Dihydro-lHr-inden-4-yl)-Λ^-((5-phenyl-lJ5r-pyrazol-3-yl)methyl)-l,2,4-triazin-3- amine (412)
1H NMR (400 MHz, CD3OD) δ 8.87 (s, IH), 7.64 (m, 3H), 7.35 (m, 3H), 7.25 (m, 2H), 6.58 (s, IH)5 4.73 (s, 2H), 3.13 (m, 2H), 2.89 (t, J= 7.4 Hz, 2H)5 1.99 (t, J= 7.4 Hz, 2H), 1.26 (m, 2H); TLC i?/(«-Hexanes:EtOAc 1 :1) = 0.19.
Figure imgf000332_0001
iV-CCS-Phenyl-lH-pyrazol-S-yOmethyO-S-CSjό^^-tetrahydronaphthalen-l-yl)-!^^- triazin-3-amine (413)
1H NMR (400 MHz, CD3OD) δ 8.63 (s, IH), 7.66 (d, J= 7.6 Hz, 2H)5 7.36 (t, J= 7.4 Hz, 2H), 7.28 (t, J= 7.2 Hz, IH), 7.19 (m, 3H), 6.57 (s, IH), 4.69 (s, 2H), 2.78 (t, J= 6.4 Hz, 2H), 2.68 (bs, IH), 1.72 (m, 2H), 1.61 (bs, 2H), 1.28 (m, 2H); TLC i?/(rc-Hexanes:EtOAc 1 :1) = 0.20.
Figure imgf000332_0002
414
5-(Benzo[<^[l,3]dioxol-4-yl)-N-((5-phenyl-lJSr-pyrazol-3-yl)methyI)-l,2,4-triazin-3-amme (414)
1H NMR (400 MHz, DMSO-^) δ 9.13 (s, IH), 7.80-7.60 (m, 3H), 7.35-7.30 (m, 2H), 7.29- 7.24 (m, IH), 7.10 (d, J= 7.2 Hz, IH), 6.99 (t, J= 7.8 Hz, IH), 6.57 (s, IH), 6.19 (s, 2H), 4.62 (bs, 2H); TLC £/ (CH2Cl2: MeOH 10:1) = 0.42.
Figure imgf000332_0003
5-(2,3-Dihydrobenzo[A][l,4]dioxin-5-yl)-iV-((5-phenyl-lJHr-pyrazol-3-yI)methyl)-l,2,4- triazin-3-amine (415)
1H NMR (400 MHz, DMSO-^) δ 9.07 (s, IH), 7.68-7.66 (m, 2H), 7.41-7.25 (m, 4H), 7.02 (dd, J= 8.0, 1.6 Hz, IH), 6.94 (t, J= 7.8 Hz, IH), 6.56 (s, IH), 4.60 (bs, 2H), 4.34 (t, J= 2.2 Hz, 2H), 4.29 (t, J= 2.4 Hz, 2H); TLC ^/(CH2Cl2: MeOH 10:1) = 0.56.
Figure imgf000332_0004
416 7V-((5-(4-Methoxyphenyl)-lΛT-pyrazol-3-yl)methyl)-iV-methyl-5-(2- (trifluoromethyl)phenyl)-l,2,4-triazin-3-amine (416)
1K NMR (400 MHz, CDCl3) δ 8.74 (s, IH), 7.78 (d, J= 7.6 Hz, IH), 7.65-7.57 (m, 4H), 7.44 (d, J= 7.6 Hz, IH), 6.85 (d, J= 8.8 Hz, 2H), 6.42 (s, IH), 4.74 (s, 2H), 3.84 (s, 3H), 3.76 (s, 3H); TLC ^(CH2Cl2MeOH 20:1) = 0.30.
Figure imgf000333_0001
3-Methyl-4-(3-((5-phenyl-liϊ-pyrazol-3-yl)methylainino)-l,2,4-triaziii-5-yI)benzonitrile
(417)
1H NMR (400 MHz, CDCl3) δ 8.72 (s, IH), 7.61 (d, J= 7.2 Hz, 2H), 7.57-7.52 (m, 3H), 7.38- 7.28 (m, 3H), 6.52 (s, IH), 4.81 (s, 2H), 2.45 (s, 3H); TLC Rf (CH2Cl2 :MeOH 10:1) = 0.33; LRMS (electrospray) m/z calculated for C2IHnN7 (M+H+) 367.41, found 367.94.
Figure imgf000333_0002
3-((Biphenyl-3-yloxy)methyl)-5-phenyl-lJfiT-pyrazole (418)
1K NMR (400 MHz, CDCl5) δ 7.65 (d, J= 8.0 Hz, 2H), 7.55 (d, J= 8.4 Hz, 2H ), 7.43-7.18 (m, 9H), 6.94 (t, J= 4.6 Hz, IH ), 6.63 (s, IH), 5.13 (s, 2H); TLC i?/(o-Hexanes:EtOAc 2:1) = 0.40; LRMS (electrospray) m/z calculated for C22H19N2O (M+H)+ 327.15, found 327.12.
Figure imgf000333_0003
3-((2'-Methylbiphenyl-3-yloxy)methyl)-5-phenyl-lH-pyrazole (419)
1H NMR (400 MHz, CDCl3) δ 7.64 (d, J= 7.6 Hz, 2H), 7.38-7.21 (m, 8H), 6.95-6.93 (m, 3H), 6.62 (s, IH), 5.11 (s, 2H), 2.24 (s, 3H); TLC i?/(n-Hexanes:EtOAc 2:1) = 0.37; LRMS (electrospray) m/z calculated for C23H21N2O (M+H)+ 341.17, found 341.06.
Figure imgf000334_0001
3-((2'-Chlorobiphenyl-3-yIoxy)methyl)-5-phenyl-lH-pyrazole (420)
1H NMR (400 MHz, CDCl3) δ 7.78 (d, J= 7.6 Hz, 2H), 7.58 (t, J= 4.4 Hz, IH), 7.48-7.37 (m, 7H), 7.17-7.14 (m, 2H), 7.07 (dd, J= 8.2, 2.2 Hz, IH ), 6.74 (s, IH), 5.19 (s, 2H); TLC R1 (rc-Hexanes:EtOAc 2:1) = 0.43; LRMS (electrospray) m/z calculated for C22H18ClN2O (M+H)+ 361.11, found 361.05.
Figure imgf000334_0002
5-Phenyl-3-((2'-(trifluoromethyl)biphenyl-3-yloxy)methyl)-lH-pyrazole (421)
1R NMR (400 MHz, CDCl3) δ 7.70 (d, J= 8.8 Hz, IH), 7.62 (d, J= 7.2 Hz, 2H), 7.52-7.22 (m, 7H), 7.01 (d, J= 7.2 Hz, IH), 6.95-6.91 (m, 2H), 6.61 (s, IH), 5.14 (s, 2H); TLC Rf(n- Hexanes: EtOAc 2:1) = 0.47; LRMS (electrospray) m/z calculated for C23H18F3N2O (M+H)+ 395.14, found 395.11.
Figure imgf000334_0003
3-((2'-Methoxybiphenyl-3-yloxy)methyl)-5-phenyl-l//-pyrazole (422)
1H NMR (400 MHz, CDCl3) δ 7.66 (dd, J= 5.2, 3.2 Hz, 2H), 7.40 (t, J= 7.2 Hz, 2H), 7.35- 7.28 (m, 4H)5 7.20-7.19 (m, IH), 7.14-7.12 (m, IH), 7.03-6.95 (m, 3H), 6.64 (s, IH), 5.18 (s, 2H), 3.79 (s, 3H); TLC i?/(«-Hexanes: EtOAc 2:1) = 0.47; LRMS (electrospray) m/z calculated for C23H21N2O2 (M+H)+ 357.16, found 357.10.
Figure imgf000334_0004
423
4-(2-Chlorophenyl)-2-((5-phenyl-l//-pyrazol-3-yl)methoxy)pyrimidine (423) 1H NMR (400 MHz, CDCl3) δ 8.60 (d, J= 5.2 Hz, IH), 7.71-7.69 (m, IH), 7.66-7.64 (m, IH), 7.49.7.46 (m, IH), 7.39-7.29 (m, 7H), 6.68 (s, IH), 5.56 (s, 2H); TLC ^(CH2Cl2MeOH 10:1) = 0.48.
Figure imgf000335_0001
424 2-((5-Phenyl-lHr-pyrazol-3-yl)methoxy)-4-(2-(trifluoromethyl)phenyI)pyrimidine (424)
1H NMR (400 MHz, CDCl3) δ 8.60 (d, J= 5.2 Hz, IH), 7.78 (d, J= 7.2 Hz, IH), 7.70-7.68 (m, 2H), 7.62-7.57 (m, 2H), 7.49 (d, J= 7.2 Hz, IH), 7.38-7.34 (m, 2H), 7.30-7.28 (m, IH), 7.12 (d, J= 4.8 Hz, IH), 6.67 (s, IH), 5.55 (s, 2H); TLC Rf (CH2Cl2 :MeOH 10:1) = 0.50.
Figure imgf000335_0002
425 iV-(2'-Methylbiphenyl-3-yl)-5-phenyl-lH-pyrazoIe-3-carboxamide (425)
1H NMR (400 MHz, CD3OD) δ 7.71-7.68 (m, 4H), 7.47-7.35 (m, 4H), 7.26-7.15 (m, 4H), 7.07 (d, J= 8.0 Hz, IH), 2.22 (s, 3H); TLC tf/(rc-Hexanes:EtOAc 2:1) = 0.53.
Figure imgf000335_0003
426 iV-(2'-Chlorobiphenyl-3-yl)-5-phenyl-lJBT-pyrazole-3-carboxamide (426)
1H NMR (400 MHz, CDCl3) δ 8.75 (bs, IH), 7.78-7.73 (m, 2H), 7.60-7.58 (m, 2H), 7.50-7.31 (m, 5H), 7.30-7.11 (m, IH ), 6.98 (s, IH); TLC i?/(«-Hexanes:EtOAc 2:1) = 0.40.
Figure imgf000335_0004
427 iV-(5-(2-Chloropb.enyl)pyridin-3-yI)-5-phenyl-lH-pyrazole-3-carboxamide (427) 1H NMR (400 MHz, DMSO-J6) δ 9.06 (d, J= 1.6 Hz, IH), 8.37 (s, 2H), 7.85 (d, J= 7.2 Hz, 2H), 7.65-7.63 (m, IH), 7.54-7.47 (m, 5H), 7.39 (t, J= 7.4 Hz, IH), 7.30 (s, IH); TLC Rf(n- Hexanes:EtOAc 1 :1) = 0.34.
Figure imgf000336_0001
428 5-Phenyl-iV-(5-(2-(trifluoromethyl)phenyl)pyridin-3-yl)-ljHr-pyrazole-3-carboxamide
(428)
1H NMR (400 MHz, CD3OD) δ 9.01 (d, J= 2.4 Hz, IH), 8.33 (s, IH), 8.25 (s, IH), 7.86 (d, J = 7.6 Hz, IH), 7.74 (t, J= 7.2 Hz, 3H), 7.65 (t, J=7.6 Hz, IH), 7.47 (t, J= 7.2 Hz, 3H), 7.39 (t, J= 7.2 Hz, IH), 7.18 (s, IH); TLC i?/(rc-Hexanes:EtOAc 1 :1) = 0.67.
Figure imgf000336_0002
5-(2-Chlorophenyl)-iV-((4-phenyl-lJιy-pyrazol-3-yI)methyI)-l,2,4-triaziii-3-amine (429)
1H NMR (400 MHz, CDCl3) δ 8.98 (s, IH), 7.65 (s, IH), 7.56-7 '.47 (m, IH), 7.44-7.25 (m, 8H), 4.92 (d, J= 5.2 Hz, 2H); TLC i?/(n-Hexanes: EtOAc 1:1) = 0.11; LRMS (electrospray) m/z calculated for C19H15ClN6 (M+H+) 362.82, found 363.09.
Figure imgf000336_0003
430
4-(2-Chlorophenyl)-iV-((l-phenyl-lJϊ-l,2,3-triazol-4-yl)methyl)pyridiii-2-amine (430)
1H NMR (400 MHz, CD3OD) δ 8.37 (s, IH), 8.02 (dd, J= 5.0, 1.4 Hz, IH), 7.78 (d, J= 7.6 Hz, 2H), 7.53 (t, J= 7.8 Hz, 2H), 7.45 (m, 2H), 7.33 (m, 3H), 6.63 (dd, J= 5.2, 1.2 Hz, 2H), 4.69 (s, 2H); TLC i?/(CH2Cl2:Me0H 19:1) = 0.20.
Figure imgf000337_0001
4-(2-Chlorophenyl)-N-((l-phenyl-lH-l,2,3-triazol-4-yI)methyI)pyrimidin-2-amine (431)
1U NMR (400 MHz, CD3OD) δ 8.33 (d, J= 4.8 Hz, 2H), 7.74 (d, J= 8.0 Hz, 2H), 7.50 (t, J= 7.8 Hz, 3H), 7.44 (m, 2H), 7.36 (m, 2H), 6.88 (d, J= 5.2 Hz, IH), 4.75 (s, 2H); TLC Rf(n- Hexanes:EtOAc 3:7) = 0.45.
Figure imgf000337_0002
iV-((l-PhenyHH-l,2,3-triazol-4-yl)methyl)-4-(2-(trifluoromethyl)phenyl)pyrimidiii-2- amine (432)
1H NMR (400 MHz, CDCl3) δ 8.36 (d, J- 4.8 Hz, IH), 8.31 (bs, IH), 7.78 (t, J= 8.6 Hz, 3H), 7.69 (t, J= 7.0 Hz, IH), 7.62 (t, J= 7.6 Hz, IH), 7.57-7.45 (m, 5H), 6.74 (d, J= 4.8 Hz, IH), 4.90 (s, 2H); TLC i?/(π-Hexanes:EtOAc 3:7) = 0.43.
Figure imgf000337_0003
433
5-(2-ChlorophenyI)-7V-((5-phenyl-lH-l,2,4-triazol-3-yl)methyI)-l,2,4-triazin-3-amine
(433)
1H NMR (400 MHz, CD3OD) δ 8.95 (s, IH), 7.98-7.96 (m, 2H), 7.63-7.45 (m, 7H), 4.88 (s, 2H); TLC i?/(CH2Cl2:Me0H 10:1) = 0.23; LRMS (electrospray) m/z calculated for C18H15C1N7(M+H)+ 364.11, found 363.90.
Figure imgf000337_0004
5-PhenyI-Λ'-((5-phenyl-lH-pyrazol-3-yl)methyl)pyridin-3-amine (434) 1H NMR (400 MHz, CD3OD) δ 8.02 (d, J= 1.6 Hz, IH), 7.98 (d, J= 2.8 Hz, IH), 7.69 (d, J= 7.2 Hz, 2H), 7.57-7.54 (m, 2H), 7.45-7.35 (m, 5H), 7.34-7.28 (m, 2H), 6.63 (s, IH), 4.46 (s, 2H); TLC i?/(CH2Cl2:Me0H 20:1) = 0.13.
Figure imgf000338_0001
5-Phenyl-7V-((5-phenyl-lH-pyrazol-3-yl)methyl)pyridin-3-amine hydrochloride (435)
1H NMR (400 MHz, CD3OD) δ 8.35 (s, IH), 8.15 (d, J= 2.4 Hz, IH), 8.04 (t, J= 2.2 Hz, IH), 7.77 (dd, J= 7.8, 1.8 Hz, 2H), 7.73 (dd, J= 7.8, 1.4 Hz, 2H), 7.60-7.46 (m, 6H), 6.99 (s, IH), 4.75 (s, 2H).
Figure imgf000338_0002
436 7V-((5-Phenyl-l//-pyrazol-3-yI)methyl)-5-o-tolylpyridm-3-amine (436)
1U NMR (400 MHz, CD3OD) δ 7.99 (d, J= 2.4 Hz, IH), 7.70 (m, 3H), 7.40 (t, J= 7.2 Hz, 2H), 7.33-7.31 (m, IH), 7.25-7.19 (m, 3H), 7.15 (d, J= 7.2 Hz, IH), 7.00 (s, IH), 6.61 (s, IH), 4.43 (s, 2H), 2.15 (s, 3H); TLC i?/(CH2Cl2:Me0H 20:1) = 0.28.
Figure imgf000338_0003
N-((5-Phenyl-liy-pyrazoI-3-yl)methyl)-5-ø-tolyIpyridin-3-ainine hydrochloride (437) 1U NMR (400 MHz, CD3OD) δ 8.17 (d, J= 2.4 Hz, IH), 8.05 (s, IH), 7.77-7.73 (m, 3H), 7.52-7.44 (m, 3H), 7.41-7.27 (m, 4H), 6.91 (s, IH), 4.68 (s, 2H), 2.24 (s, 3H).
Figure imgf000338_0004
5-(2-Chlorophenyl)-7V-((5-phenyl-lH-pyrazol-3-yl)methyl)pyridin-3-amine (438) 1H NMR (400 MHz, CD3OD) δ 8.02, (s, IH), 7.80 (s, IH), 7.68 (d, J= 6.8 Hz, 2H), 7.48 (t, J = 3.8 Hz, IH), 7.41-7.29 (m, 6H), 7.13 (s, IH), 6.61 (s, IH), 4.43 (s, 2H); TLC R1 (CH2Cl2:Me0H 20:1) = 0.31.
Figure imgf000339_0001
5-(2-Chlorophenyl)-iV-((5-phenyl-lH-pyrazol-3-yl)methyl)pyridin-3-amine hydrochloride (439)
1H NMR (400 MHz, CD3OD) δ 8.23 (d, J= 2.8 Hz, IH), 8.18 (s, IH), 7.87 (t, J= 2.0 Hz, IH), 7.78-7.76 (m, 2H), 7.60-7.58 (m, IH), 7.54-7.47 (m, 6H), 6.97 (s, IH), 4.72 (s, 2H).
Figure imgf000339_0002
iV-((5-Phenyl-lH-pyrazol-3-yl)methyl)-5-(2-(trifluoromethyl)phenyl)pyridin-3-ainine (440)
1H NMR (400 MHz, CD3OD) δ 8.04 (d, J= 2.0 Hz, IH), 7.78 (d, J= 7.6 Hz, IH), 7.71-7.63 (m, 4H), 7.57 (t, J= 7.6 Hz, IH), 7.41-7.30 (m, 4H), 7.03 (s, IH), 6.60 (s, IH), 4.41 (s, 2H); TLC J^(CH2Cl2=MeOH 20:1) = 0.26.
Figure imgf000339_0003
441 iV-((5-Phenyl-lH-pyrazol-3-yl)methyl)-5-(2-(trifluoromethyl)phenyl)pyridin-3-amine hydrochloride (441)
1H NMR (400 MHz, CD3OD) δ 8.31 (d, J= 2.4 Hz, IH), 8.11 (s, IH), 7.88 (d, J= 7.6 Hz, IH), 7.79-7.76 (m, 4H), 7.72 (t, J= 7.4 Hz, IH), 7.56-7.49 (m, 4H), 7.01 (s, IH), 4.75 (s, 2H).
Figure imgf000340_0001
5-(2-Methoxyphenyl)-iV-((5-phenyl-liϊ-pyrazol-3-yI)methyl)pyridiii-3-amine (442)
1H NMR (400 MHz, CD3OD) δ 7.93 (d, J= 2.4 Hz, IH), 7.89 (s, IH), 7.69 (bs, 2H), 7.41- 7.31 (m, 4H), 7.27-7.22 (m, 2H), 7.04 (d, J= 8.4 Hz, IH), 7.00 (t, J= 7.4 Hz, IH), 6.62 (s, IH), 4.42 (s, 2H), 3.73 (s, 3H); TLC i?/(CH2Cl2:Me0H 20:1) = 0.26.
Figure imgf000340_0002
5-(2-Methoxyphenyl)-Λ'-((5-phenyl-lH-pyrazoI-3-yl)methyl)pyridin-3-amine hydrochloride (443)
1H NMR (400 MHz, CD3OD) δ 8.17 (s, IH), 8.09 (d, J= 2.8 Hz, IH), 7.95 (t, J= 2.0 Hz, IH), 7.80-7.77 (m, 2H), 1.55-1 Al (m, 4H), 7.43 (dd, J= 7.6, 1.6 Hz, IH), 7.17 (d, J= 8.4 Hz, IH), 7.11 (t, J= 7.6 Hz, IH), 7.00 (s, IH), 4.72 (s, 2H), 3.82 (s, 3H).
Figure imgf000340_0003
3-Methyl-4-(5-((3-phenyl-l-(tetrahydro-2iy-pyran-2-yl)-l//-pyrazol-5- yl)methylamino)pyridin-3-yl)benzonitrile
1H NMR (400 MHz, CDCl3) δ 8.13 (s,lH), 7.91 (s, IH), 7.75 (d, J= 7.2 Hz, 2H), 7.53 (s, IH), 7.50 (d, J= 8.0 Hz, IH), 7.35 (t, J= 7.6 Hz, 2H), 7.29-7.25 (m, 2H), 6.82 (s, IH), 6.54 (s, IH), 5.43 (dd, J= 9.2, 2.8 Hz, IH), 4.51 (dd, J= 14.8, 6.0 Hz, IH), 4.42 (dd, J= 14.6, 4.6 Hz, IH), 3.99-3.97 (m, IH), 3.66-3.60 (m, IH), 2.55-2.47 (m, IH), 2.24 (s, 3H), 2.17-2.14 (m, IH), 2.09-2.02 (m, IH), 1.73-1.60 (m, 3H); TLC i?/(CH2Cl2:Me0H 20:1) = 0.43.
Figure imgf000340_0004
3-Methyl-4-(5-((5-phenyl-lH-pyrazol-3-yl)methylamino)pyridin-3-yl)benzoiiitrile (444)
1H NMR (400 MHz, CDCl3) δ 8.11 (s, IH), 7.84 (s, IH), 7.58 (d, J= 7.2 Hz, 2H), 7.48 (s, IH), 7.45 (d, J= 8.0 Hz, IH), 7.37-7.28 (m, 3H), 7.20 (d, J= 8.0 Hz, IH), 6.82 (s, IH), 6.48 (s, IH), 4.39 (s, 2H), 2.17 (s, 3H); TLC i?/(CH2Cl2:Me0H 20:1) = 0.20.
Figure imgf000341_0001
3-(4-Cyano-2-methylphenyl)-5-((5-phenyl-liy-pyrazol-3-yl)methylamino)pyridine 1- oxide (445)
1H NMR (400 MHz, CD3OD) δ 9.26 (t, J= 1.6 Hz, IH), 7.70-7.68 (m, 3H), 7.64-7.61 (m, 2H), 7.43-7.38 (m, 3H), 7.35-7.31 (m, IH), 6.88 (s, IH), 6.63 (s, IH), 4.43 (s, 2H), 2.25 (s, 3H); TLC i?/(CH2Cl2:Me0H 20:1) = 0.43.
Figure imgf000341_0002
5-(2,6-Dimethylphenyl)-iV-((5-phenyl-lJΪ-pyrazol-3-yl)inethyl)pyridin-3-amiiie (446)
1H NMR (400 MHz, CDCl3) δ 8.09 (s, IH), 7.78 (s, IH), 7.59 (d, J= 4.4 Hz, 2H), 7.36-7.30 (m, 3H), 7.14-7.12 (m, IH), 7.07 (s, 2H), 6.75 (s, IH), 6.48 (s, 2H), 4.38 (s, 2H), 1.98 (s, 3H); TLC i?/(CH2Cl2:Me0H 10:1) = 0.53.
Figure imgf000341_0003
5-(2-ChIoro-4-fluorophenyl)-N-((5-phenyl-ljBr-pyrazol-3-yl)methyl)pyridin-3-amine
(447)
1H NMR (400 MHz, CDCl3) δ 8.07 (d, J= 2.4 Hz, IH), 7.95 (s, IH), 7.58 (d, J= 7.6 Hz, 2H), 7.38 -7.28 (m, 3H), 7.22-7.15 (m, 2H), 7.00-6.95 (m, 2H), 6.49 (s, IH), 4.39 (s, 2H); TLC Rf (CH2Cl2:Me0H 10:1) = 0.21.
Figure imgf000342_0001
6-Phenyl-Λr-((5-phenyl-ljHr-pyrazol-3-yl)methyl)pyridin-2-amine (448)
1H NMR (400 MHz, CDCl3) δ 7.98 (d, J= 7.6 Hz, 2H), 7.63 (d, J= 8.0 Hz, 2H), 7.45-7.24 (m, 7H), 7.06 (d, J= 7.2 Hz, IH), 6.47 (s, IH), 6.33 (d, J= 8.0 Hz, IH), 4.60 (bs, 2H); TLC i?/(«-Hexanes:EtOAc 2:1) = 0.27.
Figure imgf000342_0002
N-((5-Phenyl-lH-pyrazol-3-yl)methyI)-6-o-tolyIpyridin-2-amine (449)
1H NMR (400 MHz, CDCl3) δ 7.65 (d, J= 8.0 Hz, 2H), 7.49-7.42 (m, 2H), 7.37-7.34 (m, 2H), 7.29-7.24 (m, 4H), 6.74 (d, J= 7.2 Hz, IH ), 6.45 (s, IH), 6.40 (d, J= 8.4, IH ), 4.56 (d, J= 5.2, 2H), 2.40 (s, 3H); TLC i?/(«-Hexanes:EtOAc 2:1) = 0.22.
Figure imgf000342_0003
450 6-(2-ChlorophenyI)-N-((5-phenyl-lH-pyrazol-3-yl)methyl)pyridin-2-amine (450)
1H NMR (400 MHz, CDCl3) δ 7.68-7.65 (m, 2H), 7.55 (dd, J= 7.2, 2.0 Hz, IH), 7.50-7.44 (m, 2H), 7.35-7.27 (m, 5H), 6.92 (d, J= 7.6 Hz, IH), 6.45-6.43 (m, 2H), 4.58 (d, J= 5.6 Hz, 2H); TLC i?/(«-Hexanes:EtOAc 2:1) = 0.10.
Figure imgf000342_0004
J/V-((5-Phenyl-lH-pyrazol-3-yl)methyl)-6-(2-(trifluoromethyl)phenyl)pyridin-2-amine (451)
1H NMR (400 MHz, CDCl3) δ 7.72 (t, J= 8.0 Hz, IH), 7.62-7.60 (m, IH), 7.54 (t, J= 7.4, IH), 7.48-7.42 (m, 5H), 7.33 (t, J= 7.4 Hz, IH ), 7.28-7.24 (m, IH), 6.71 (d, J= 7.2 Hz, IH), 6.49-6.40 (m, 2H), 4.50 (s, 2H); TLC i?/(«-Hexanes: EtOAc 2:1) = 0.14.
Figure imgf000343_0001
6-(2-Methoxyphenyl)-N-((5-phenyM/7-pyrazoI-3-yl)methyl)pyridin-2-amine (452)
1H NMR (400 MHz, CDCl3) δ 7.70 (d, J= 7.6 Hz, 2H), 7.55 (d, J= 7.6, IH), 7.45 (t, J= 7.8 Hz, lH),7.37-7.34 (m, 3H), 7.29-7.25 (m, IH), 7.04-7.01 (m, 2H), 6.95 (d, J= 7.2, IH), 6.46 (s, IH), 6.38 (d, J= 8.4 Hz, IH), 4.55 (s, 2H), 3.96 (s, 3H); TLC i?/(«-Hexanes:EtOAc 2:1) = 0.14.
Figure imgf000343_0002
7V-((5-Phenyl-liϊ-pyrazol-3-yl)methyl)-4-o-toIylpyridin-2-amine (453)
Yellow oil: 1H NMR (400 MHz, CD3OD) δ 7.99 (d, J= 4.0 Hz, IH), 7.70-7.67 (m, 2H), 7.37- 7.35 (m, 2H), 7.30-7.29 (m, 1H),7.23-7.13 (m, 4H), 6.58 (s, IH), 6.54 (d, J= 5.2 Hz, IH), 6.50 (s, IH), 4.55 (s, 2H), 2.20 (s, 3H); TLC i?/(«-Hexanes:EtOAc 1 :2) = 0.21.
Figure imgf000343_0003
454 4-(2-Chlorophenyl)-7V-((5-phenyl-lH-pyrazol-3-yl)methyl)pyridin-2-amine (454)
1H NMR (400 MHz, DMSO-J6) δ 12.92 (bs, 0.5H), 12.73 (bs, 0.5H), 8.06 (d, J= 6.0 Hz, IH), 7.89 (d, J= 8.4 Hz, 2H), 7.78 (d, J= 8.4 Hz, 2H), 7.67 (d, J= 7.2 Hz, 2H), 7.33 (t, J= 6.4 Hz, 2H), 7.22 (m, IH), 6.99 (bs, IH), 6.81 (s, 2H), 6.53 (s, IH), 4.47 (s, 2H); TLC R1 (CH2Cl2MeOH 19:1) = 0.14.
Figure imgf000343_0004
455
4-(2-Chlorophenyl)-iV-((5-(4-(dimethylamino)phenyl)-lJϊ-pyrazol-3-yl)methyl)pyridin-2- amine (455) 1H NMR (400 MHz, CD3OD) δ 8.01 (d, J= 5.2 Hz, IH), 7.50 (d, J= 8.8 Hz, 2H), 6.79 (t, J= 3.4 Hz, IH), 7.33 (dd, J= 8.6, 4.6 Hz, 3H), 6.75 (d, J= 8.8 Hz, 2H), 6.62 (d, J= 6.8 Hz, 2H), 6.42 (s, IH), 4.52 (s, 2H), 2.93 (s, 6H); TLC ^(CH2Cl2MeOH 19:1) = 0.24.
Figure imgf000344_0001
7V-((5-Phenyl-l/-r-pyrazol-3-yI)methyl)-4-(2-(trifluoromethyl)pheiiyl)pyridin-2-amine (456)
1H NMR (400 MHz, CDCl3) δ 8.18 (d, J= 5.6 Hz, IH), 7.75-7.71 (m, 3H), 7.56 (t, J= 7.2 Hz, IH), 7.49 (t, J= 7.6 Hz5 IH), 7.40 (t, J= 7.6 Hz, 2H), 7.33-7.27 (m, 2H), 6.63 (d, J= 5.2 Hz, IH), 6.50 (s, IH), 6.43 (s, IH)5 4.61 (d, J= 5.6 Hz5 2H); TLC #/(CH2Cl2:Me0H 20:1) = 0.39.
Figure imgf000344_0002
457
4-(2-Methoxyphenyl)-7V-((5-phenyl-lH-pyrazol-3-yI)methyI)pyridin-2-amine (457) White solid: 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J= 5.2 Hz, IH), 7.71 (d, J= 8.0 Hz, 2H), 7.39-7.26 (m, 5H), 7.00 (t, J= 7.4 Hz, IH), 6.95 (d, J= 8.4 Hz, IH)5 6.63 (s, IH), 6.48 (s, IH), 4.59 (s, 2H), 3.77 (s, 3H); TLC 7?/(«-Hexanes:EtOAc 1 :1) = 0.08.
Figure imgf000344_0003
4-(2-ChIoro-4-fluorophenyl)-Λr-((5-phenyl-lHf-pyrazol-3-yl)inethyl)pyridiii-2-amine
(458)
1H NMR (400 MHz5 CD3OD) δ 8.01 (d, J= 5.2 Hz, IH), 7.66 (d, J= 6.8 Hz, 2H)5 7.36 (m, 3H), 7.29 (dd, J= 8.6, 2.6 Hz, 2H), 7.12 (dt, J= 8.2, 2.0 Hz, IH), 6.59 (m, 3H), 4.55 (s, 2H); TLC i?/(CH2Cl2:Me0H 19:1) = 0.25.
Figure imgf000345_0001
4-(2,6-Dimethylphenyl)-7V-((5-phenyl-lH-pyrazol-3-yl)methyl)pyridin-2-amine (459)
1H NMR (400 MHz, CDCl3) δ 8.22 (d, J= 5.2 Hz, IH), 7.72 (d, J= 8.0 Hz, 2H), 7.40 (t, J= 7.4 Hz, 2H), 7.34-7.31 (m, IH), 7.18-7.07 (m, 3H), 6.50 (s, IH), 6.48 (d, J= 5.2 Hz, IH), 6.28 (s, IH), 4.61 (d, J= 4.4 Hz, 2H), 2.05 (s, 6H); TLC ^7(CH2Cl2-MeOH 20:1) = 0.34.
Figure imgf000345_0002
460 3-Methyl-4-(2-((5-phenyl-lHr-pyrazol-3-yl)methylamino)pyridin-4-yl)benzonitrile (460)
1H NMR (400 MHz5 CDCl3) δ 8.21 (d, J= 5.2 Hz, IH), 7.70 (d, J= 1.6 Hz, 2H), 7.54 (s, IH), 7.51 (d, J= 8.0 Hz, IH), 7.40 (t, J= 7.4 Hz, 2H), 7.33 (d, J= 7.2 Hz, IH)5 7.25 (d, J= 9.2 Hz, IH), 6.55 (dd, J= 6.4, 2.4 Hz, IH), 6.51 (s, IH)5 6.35 (s, IH), 4.62 (d, J= 4.8 Hz, 2H), 2.26 (s, 3H); TLC ^7(CH2Cl2 :MeOH 20:1) = 0.28.
Figure imgf000345_0003
4-(4-Cyano-2-methyIphenyI)-2-((5-phenyl-lJHr-pyrazol-3-yl)methylamino)pyridine 1- oxide (461)
1H NMR (400 MHz, CD3OD) δ 8.19 (d, J= 6.8 Hz, IH), 7.67-7.65 (m, 3H)5 7.59 (t, J= 8.8 Hz, 1), 7.47-7.31 (m, 4H)5 6.90 (d, J= 2.4 Hz5 IH), 6.71 (dd, J= 6.8, 2.0 Hz, IH), 6.62 (s, IH), 4.64 (s5 2H)5 2.20 (s, 3); TLC i?/(CH2Cl2:Me0H 10:1) = 0.30.
Figure imgf000345_0004
3,5-Dimethyl-4-(2-((5-phenyl-lH-pyrazol-3-yI)methylamino)pyridiii-4-yl)benzonitrile (462) 1H NMR (400 MHz, CDCl3) δ 8.22 (d, J= 5.2 Hz, IH), 7.67 (d, J= 7.6 Hz, 2H), 7.39-7.34 (m, 5H), 6.47 (s, IH), 6.37 (d, J= 5.2 Hz, IH), 5.54 (s, IH), 4.59 (d, J= 5.6 Hz, 2H), 2.14 (s, 6H).
Figure imgf000346_0001
3-Chloro-4-(2-((5-phenyHjBT-pyrazol-3-yI)methylamino)pyridin-4-yl)benzonitrile (463)
1H NMR (400 MHz, CDCl3) δ 8.21 (d, J= 5.2 Hz, IH), 7.31 (s, IH), 7.67 (d, J= 7.6 Hz, 2H), 7.56 (d, J= 8.0 Hz, IH), 7.39-7.36 (m, 3H), 7.35-7.24 (m, IH), 6.64 (d, J= 5.2 Hz, IH), 6.48 (s, IH), 6.44 (s, IH), 5.32 (s, IH), 4.61 (d, J= 5.6 Hz, IH); TLC Rf (CH2Cl2: MeOH 20:1) = 0.57; LRMS (electrospray) m/z calculated for C22H16ClN5 (M+H+) 385.85, found 385.93.
Figure imgf000346_0002
4-(2-((5-Phenyl-ljHr-pyrazol-3-yl)methylamino)pyridin-4-yl)-3- (trifluoromethyl)benzonitrile (464)
1H NMR (400 MHz, CDCl3) δ 8.17 (d, J= 5.2 Hz, IH), 7.99 (d, J= 1.2 Hz, IH), 7.81-7.78 (m, IH), 7.65 (d, J= 7.2 Hz, 2H), 7.38-7.30 (m, 3H), 7.29-7.27 (m, IH), 6.54 (d, J= 5.2 Hz, IH), 6.47 (s, IH), 6.34 (s, IH), 5.45 (s, IH), 4.58 (d, J= 5.6 Hz, IH); TLC /Jy(CH2Cl2JMeOH 10:1) = 0.68.
Figure imgf000346_0003
4-(2-Chlorophenyl)-Λr-((3-(pyridin-4-yl)-l-(tetrahydro-2JHr-pyran-2-yl)-lH-pyrazol-5- yl)methyI)pyridin-2-amine
1H NMR (400 MHz, CDCl3) δ 8.58 (s, 2H), 8.17 (d, J= 5.2 Hz, IH), 7.66 (d, J= 4.8 Hz, 2H), 7.45-7.42 (m, IH), 7.31-7.25 (m, 3H), 6.70 (dd, J= 5.2, 1.2 Hz, IH), 6.66 (s, IH), 6.49 (s, IH), 5.50 (dd, J= 9.6, 2.8 Hz, IH), 4.80 (dd, J= 15.6, 6.0 Hz, IH), 4.65 (dd, J= 15.4, 5.0 Hz, IH), 4.02-3.99 (m, IH), 3.64-3.58 (m, IH), 2.57-2.48 (m, IH), 2.15-2.02 (m, 2H), 1.73-1.57 (m, 3H); TLC i?/(CH2Cl2:Me0H 20:1) = 0.70.
Figure imgf000347_0001
465 4-(2-Chlorophenyl)-iV-((5-(pyridin-4-yl)-lH-pyrazol-3-yl)methyl)pyridiii-2-amine (465)
1H NMR (400 MHz, CDCl3) δ 8.62 (d, J= 6.4 Hz, 2H), 8.23 (d, J= 5.2 Hz, IH), 7.66 (d, J= 6.0 Hz, 2H), 7.49-7.44 (m, IH), 7.34-7.27 (m, 3H), 6.77 (d, J= 5.6 Hz, IH), 6.58 (s, IH), 6.53 (s, IH), 4.64 (s, 2H); TLC i?/(CH2Cl2:Me0H 20:1) = 0.16.
Figure imgf000347_0002
4-(3-((4-(4-Cyano-2-methylphenyl)pyridin-2-ylamino)methyl)-liϊ-pyrazol-5-yl)pyridine 1-oxide (466)
1H NMR (400 MHz, CD3OD) δ 8.31 (d, J= 6.8 Hz, 2H), 8.08 (d, J= 5.6 Hz, IH), 7.90 (d, J= 6.4 Hz, 2H), 7.66 (s, IH), 7.60 (d, J= 8.0 Hz, IH), 7.35 (d, J= 7.6, IH), 6.78 (s, IH), 6.58 (d, J= 5.2 Hz, IH), 6.51 (s, IH), 4.64 (s, 2H), 2.28 (s, 3H); TLC ^(CH2Cl2MeOH 10:1) = 0.21.
Figure imgf000347_0003
3-Methyl-4-(2-((5-(pyridm-3-yl)-lH-pyrazoI-3-yl)methylamino)pyridin-4-yl)benzonitrile
(467)
1H NMR (400 MHz, CD3OD) δ 8.92 (s, IH), 8.47 (d, J= 3.6 Hz, IH), 8.17 (s, IH), 8.08 (d, J = 5.2 Hz, IH), 7.66 (s, IH), 7.61 (d, J= 8.0 Hz, IH), 7.48 (t, J= 6.2 Hz, IH), 7.36 (d, J= 8.0 Hz, IH), 6.72 (s, IH), 6.57 (d, J= 5.2 Hz, IH), 6.52 (s, IH), 4.63 (s, 2H), 2.28 (s, 3H); TLC i?/(CH2Cl2:Me0H 20:1) = 0.15.
Figure imgf000347_0004
4-(2-ChlorophenyI)-iV-((3-(pyridm-3-yl)-l-(tetrahydro-2H-pyran-2-yI)-lH-pyrazol-5- yl)methyl)pyridin-2-amine
1H NMR (400 MHz, CDCl3) δ 9.00 (s, IH), 8.52 (d, J= 4.0 Hz, IH), 8.13-8.08 (m, 2H), 7.47- 7.43 (m, IH), 7.33-7.22 (m, 4H), 6.72 (dd, J= 5.2, 1.2 Hz, IH), 6.63 (s, IH), 6.54 (s, IH), 5.50 (dd, J= 9.6, 2.8 Hz, IH), 4.76 (d, J= 15.6 Hz, IH), 4.65 (d, J= 15.6 Hz, IH), 4.03-3.99 (m, IH), 3.67-3.61 (m, IH), 2.58-2.48 (m, IH), 2.15-2.03 (m, 2H), 1.77-1.59 (m, 3H); TLC Rf (CH2Cl2MeOH 20:1) = 0.30.
Figure imgf000348_0001
468 4-(2-Chlorophenyl)-iV-((5-(pyridiii-3-yl)-lH-pyrazol-3-yl)methyl)pyridin-2-ainine (468)
1H NMR (400 MHz, CDCl3) δ 8.99 (s, IH), 8.55 (d, J= 4.4 Hz, IH), 8.18 (d, J= 5.2 Hz, IH), 8.07 (d, J= 7.6 Hz, IH), 7.48-7.46 (m, IH), 7.34-7.26 (m, 4H), 6.78 (d, J= 5.6 Hz, IH), 6.01 (s, IH), 6.56 (s, IH), 4.66 (s, 2H); TLC i?/(CH2Cl2:Me0H 20:1) = 0.16.
Figure imgf000348_0002
4-(2-Chlorophenyl)-Λr-((5-(pyridin-2-yl)-lH-pyrazol-3-yl)methyl)pyridin-2-amine (469)
1H NMR (400 MHz, CD3OD) δ 8.51 (d, J= 3.6 Hz, IH), 8.02 (d, J= 5.6 Hz, IH), 7.91 (d, J= 5.2 Hz, IH), 7.82 (t, J= 7.0 Hz, IH), 7.47 (m, IH), 7.37-7.28 (m, 4H), 6.81 (s, IH), 6.63 (m, 2H), 4.60 (s, 2H); TLC i?/(CH2Cl2:Me0H 9:1) = 0.37.
Figure imgf000348_0003
3-Methyl-4-(2-((3-(pyridin-4-yl)-l-(tetrahydro-2Hr-pyran-2-yl)-lJHr-pyrazol-5- yl)methylamino)pyridin-4-yl)benzonitrile
1H NMR (400 MHz, CDCl3) δ 8.57 (d, J= 5.6 Hz, 2H), 8.18 (d, J= 5.2 Hz, IH), 7.65 (d, J = 6 Hz, 2H), 7.53 (s, IH), 7.50 (d, J= 8.0 Hz, IH), 7.25-7.23 (m, IH), 6.66 (s, IH), 6.55 (d, J = 5.6 Hz, IH), 6.31 (s, IH), 5.52 (dd, J= 9.2, 2.8 Hz, IH), 4.83 (dd, J= 15.2, 6.4 Hz, IH), 4.65 (dd, J= 15.4, 5.0 Hz, IH), 4.00-3.97 (m, IH), 3.65-3.59 (m, IH), 2.56-2.48 (m, IH), 2.25 (s, 3H), 2.16-2.04 (m, 2H), 1.71-1.61 (m, 3H); TLC i?/(CH2Cl2:Me0H 20:1) = 0.32.
Figure imgf000349_0001
3-Methyl-4-(2-((5-(pyridin-4-yl)-lH-pyrazoI-3-yl)methylamino)pyridin-4-yl)benzonitrile
(470)
1H NMR (400 MHz, CD3OD) δ 8.53 (s, 2H), 8.08 (d, J= 5.3 Hz, IH), 7.78 (s, 2H), 7.66 (s, IH), 7.35 (d, J= 8.0 Hz, IH), 6.80 (s, IH), 6.57 (d, J= 5.2 Hz, IH), 6.52 (s, IH), 4.64 (s, 2H), 2.28 (s, 3H); TLC
Figure imgf000349_0002
20:1) = 0.11.
Figure imgf000349_0003
3-MethyI-4-(2-((5-(pyridin-4-yl)-lH-pyrazoI-3-yl)methyIamino)pyridin-4-yl)benzonitrile hydrochloride (471)
1H NMR (400 MHz, CD3OD) δ 8.79 (d, J= 6.8 Hz, 2H), 8.43 (d, J= 6.8 Hz, 2H), 8.01 (d, J= 6.4 Hz, IH), 7.73 (s, IH), 7.68 (d, J= 8.4 Hz, IH), 7.46 (d, J= 7.6 Hz, IH), 7.26 (s, IH), 7.10 (s, IH), 7.00 (d, J= 6.4 Hz, IH), 4.84 (s, 2H), 2.32 (s, 3H).
Figure imgf000349_0004
3-Methyl-4-(2-((5-(pyridin-3-yl)-lH-pyrazol-3-yl)methylamino)pyridin-4-yl)benzonitrile hydrochloride (472)
1H NMR (400 MHz, CD3OD) δ 9.26 (s, IH), 8.95 (d, J= 8.4 Hz, IH), 8.78 (d, J= 5.2 Hz, IH), 8.11 (dd, J= 8.2, 5.8 Hz, IH), 8.02 (d, J= 6.4 Hz, IH), 7.76 (s, IH), 7.71 (d, J= 8.0 Hz, IH), 7.48 (d, J= 8.0 Hz, IH), 7.11 (s, IH), 7.08 (s, IH), 7.03 (dd, J= 6.8, 1.6 Hz, IH), 4.83 (s, 2H), 2.35 (s, 3H).
Figure imgf000350_0001
3-Methyl-4-(2-((5-(pyridin-2-yl)-lH-pyrazol-3-yl)methylamino)pyridin-4-yI)benzonitrile
(473)
1H NMR (400 MHz, CDCl3 with 20% CD3OD) δ 8.49 (d, J= 4.8 Hz, 2H), 8.04 (d, J= 5.6 Hz, 2H), 7.73-7.70 (m, IH), 7.49-7.31 (m, 2H), 7.22-7.19 (m, 2H), 6.72 (s, IH), 6.47 (d, J= 5.6 Hz, IH), 4.53 (s, 2H), 2.20 (s, 3H); TLC R1 (CH2Cl2: MeOH 20:1) = 0.56.
Figure imgf000350_0002
474
3-Methyl-4-(2-((5-(pyridin-2-yl)-ljHr-pyrazol-3-yl)methyIamino)pyridin-4-yl)benzonitrile hydrochloride (474)
1H NMR (400 MHz, CDCl3 with 20% CD3OD) δ 8.69 (d, J= 5.6 Hz, IH), 8.56-8.52 (m, IH), 8.37 (d, J= 8.0 Hz, IH), 8.03 (d, J= 6.4 Hz, IH), 7.88 (d, J= 7.2 Hz, IH), 7.75 (m, IH), 7.69 (d, J= 8.0 Hz, IH), 7.46 (d, J= 8.0 Hz, IH), 7.22 (s, IH), 7.10 (m, 2H), 7.04-7.02 (s, IH), 2.33 (s, 3H).
Figure imgf000350_0003
3-Chloro-4-(2-((5-(pyridin-4-yl)-l.fir-pyrazol-3-yl)methylamino)pyridin-4-yl)benzonitrile
(475)
1H NMR (400 MHz, CDCl3) δ 8.96 (dd, J= 4.6, 1.8 Hz, 2H), 8.10 (d, J= 5.6 Hz, IH), 7.74
(d, J= 1.6 Hz, IH), 7.67 (m, 2H), 7.59 (dd, J= 8.0, 1.6 Hz, IH), 7.37 (d, J= 8.0 Hz, IH),
6.66 (dd, J= 5.8, 1.4 Hz, IH), 6.65 (s, IH), 6.57 (s, IH); TLC ^7(CH2Cl2MeOH 10:1) =
0.30.
Figure imgf000350_0004
3-Chloro-4-(2-((5-(pyridin-3-yl)-lH-pyrazol-3-yl)methylamino)pyridin-4-yl)benzonitrile
(476)
1U NMR (400 MHz, CDCl3) δ 8.96 (s, IH), 8.53 (s, IH), 8.14 (d, J= 5.6 Hz, IH), 8.08 (d, J= 8.0 Hz, IH), 7.75 (s, IH), 7.61 (d, J= 8.0 Hz, IH), 7.39 (d, J= 7.6 Hz, IH), 7.35 (m, IH), 6.71 (d, J= 5.6 Hz, IH), 6.67 (s, IH), 6.57 (s, IH), 4.70 (s, IH); TLC ^/(CH2Cl2 :MeOH 10:1) = 0.30.
Figure imgf000351_0001
3-Chloro-4-(2-((5-(pyridin-2-yl)-lH-pyrazol-3-yl)methylamino)pyridin-4-yl)benzonitrile
(477)
1U NMR (400 MHz, CDCl3) δ 8.60 (d, J= 4.0 Hz, IH), 8.16 (d, J= 5.6 Hz, IH), 7.75 (s, IH), 7.73 (d, J= 7.6 Hz, IH), 7.67 (d, J= 7.6 Hz, IH), 7.60 (d, J= 8.0 Hz, IH), 7.40 (d, J= 8.0 Hz, IH), 7.23 (m, IH), 6.75 (s, IH), 6.67 (d, J= 5.6 Hz, IH), 6.63 (s, IH)5 4.65 (s, IH); TLC i?/(CH2Cl2:Me0H 10:1) == 0.30.
Figure imgf000351_0002
4-(2-((5-(Pyridin-4-yl)-lJΪ-pyrazoI-3-yl)methylamino)pyridin-4-yl)-3- (trifluoromethyl)benzonitrile (478)
1H NMR (400 MHz, CDCl3) δ 8.60 (d, J= 4.8 Hz, 2H), 8.21 (d, J= 5.2 Hz, IH), 8.04 (s, IH), 7.87 (d, J= 7.6 Hz, IH), 7.73 (d, J= 5.2 Hz, 2H), 7.43 ( d, J= 8.0 Hz, IH), 6.63 (d, J= 5.6 Hz, IH), 6.61 (s, IH), 6.48 (s, IH), 4.67 (s, 2H); TLC i?/(CH2Cl2:Me0H 10:1) = 0.30.
Figure imgf000351_0003
4-(2-((5-(Pyridin-3-yl)-l/7-pyrazoI-3-yl)methylamino)pyridin-4-yl)-3- (trifluoromethyl)benzonitrile (479) 1H NMR (400 MHz, CDCl3) δ 8.98 (s, IH), 8.54 (d, J= 4.4 Hz, IH), 8.15 (d, J= 5.6 Hz, IH), 8.10 (d, J= 7.6 Hz, IH), 8.04 (s, IH), 7.87 (d, J= 8.0 Hz, IH), 7.43 (d, J= 8.0 Hz, IH), 7.37 (dd, J= 7.4, 5.0 Hz, IH), 6.62 (d, J= 5.2 Hz, IH), 6.57 (s, IH), 6.55 (s, IH); 4.68 (s, IH); TLC i?/(CH2Cl2:Me0H 10:1) = 0.30.
Figure imgf000352_0001
4-(2-((5-(Pyridin-2-yl)-ljHr-pyrazol-3-yl)methylamino)pyridin-4-yl)-3- (trifluoromethyl)benzonitrile (480)
1H NMR (400 MHz, CDCl3) δ 8.57 (d, J= 4.0 Hz, IH), 8.08 (d, J= 5.2 Hz, IH), 8.02 (s, IH), 7.85 (d, J= 6.4 Hz, IH), 7.74 (m, IH), 7.65 (d, J= 7.6 Hz, IH), 7.42 (d, J= 7.6 Hz, IH), 7.23 (m, IH), 6.75 (s, IH), 6.58 (m, 2H), 4.64 (s, 2H); TLC i?/(CH2Cl2:Me0H 10:1) = 0.34.
Figure imgf000352_0002
481 iV-((5-PhenyI-lJΪ-pyrazol-3-yl)methyl)-6-o-tolylpyrazin-2-amine (481)
1H NMR (400 MHz, CD3OD) δ 7.93 (s, IH), 7.73 (s, IH), 7.66 (d, J= 7.6 Hz, 2H), 7.40-7.27 (m, 7H), 6.59 (s, IH), 4.53 (s, 2H), 2.30 (s, 3H); TLC i?/(n-Hexanes:EtOAc 1 :2) = 0.24.
Figure imgf000352_0003
482 6-(2-Chlorophenyl)-Λ'-((5-phenyl-lH-pyrazol-3-yl)methyl)pyrazin-2-amine (482)
1H NMR (400 MHz, CD3OD) δ 7.93 (s, IH), 7.92 (s, IH), 7.68-7.66 (m, 2H), 7.54-7.52 (m, IH), 7.50-7.47 (m, IH), 7.38-7.36 (m, 5H), 6.59 (s, IH), 4.62 (s, 2H); TLC Rf(n- Hexanes:EtOAc 2:1) = 0.18; LRMS (electrospray) m/z calculated for C2OH17C1N5(M+H)+ 362.12, found 361.79.
Figure imgf000353_0001
iV-((S-Phenyl-lH-pyrazol-3-yl)methyl) 6-(2-(Trifluoromethyl)phenyl)-pyrazin-2-amme
(483)
1H NMR (400 MHz, DMSO-J6) δ 8.01 (s, IH), 7.82 (d, J= 8.0 Hz, IH ), 7.76 (s, IH), 7.73- 7.61 (m, 4H), 7.54 (d, J= 7.6 Hz, IH ), 7.36 (t, J= 7.2 Hz, 2H ), 121-125 (m, IH), 6.54 (s, IH), 4.44 (s, 2H); TLC i?/(«-Hexanes:EtOAc 1:2) = 0.24.
Figure imgf000353_0002
484 6-(2-Methoxyphenyl)-N-((5-phenyl-lH-pyrazol-3-yI)methyl)pyrazin-2-amine (484)
1H NMR (400 MHz, CD3OD) δ 8.22 (s, IH), 7.79-7.65 (m, 2H), 7.64 (d, J= 7.2 Hz, 2H), 7.34-7.22 (m, 4H), 7.02-6.95 (m, 2H), 6.55 (s, IH), 4.61 (s, 2H), 3.80 (s, 3H); TLC Rf (CH2Cl2:Me0H 10:1) = 0.47; LRMS (electrospray) m/z calculated for C21H19N5O(M+H)+ 358.17, found 358.06.
Figure imgf000353_0003
6-(2,6-Dimethylphenyl)-iV-((5-phenyl-ljlϊ-pyrazoI-3-yl)methyl)pyrazin-2-amine (485)
1H NMR (400 MHz, CD3OD) δ 7.90 (s, IH), 7.64-7.61 (m, 2H), 7.55 (s, IH), 7.37-7.29 (m, 3H), 7.17-7.13 (m, IH), 7.07-7.04 (m, 2H), 6.53 (s, IH), 4.56 (s, 2H), 2.06 (s, 6H); LRMS (electrospray) m/z calculated for C22H22N5(M+H)+ 356.19, found 356.02.
Figure imgf000353_0004
3-Methyl-4-(6-((5-phenyl-lH-pyrazol-3-yl)methylamino)pyrazin-2-yl)benzonitriIe (486) 1H NMR (400 MHz, CD3OD) δ 7.95 (s, IH), 7.80 (s, IH), 7.66-7.65 (m, 2H), 7.61-7.58 (m, 2H), 7.53-7.51 (m, IH), 7.37 (t, J= 7.6 Hz, 2H), 7.31-7.29 (m, IH), 6.55 (s, IH), 4.61 (s, 2H), 2.31 (s, 3H); TLC ^7(CH2Cl2MeOH 10:1) = 0.38.
Figure imgf000354_0001
7V-((5-Phenyl-lH-pyrazol-3-yl)methyl)-4-o-tolylpyrimidin-2-amine (487)
1B. NMR (400 MHz, CDCl3) δ 8.73 (d, J= 5.2 Hz, IH), 7.80 (d, J= 6.8 Hz, 2H), 7.42-7.22 (m, 7H), 7.16 (d, J= 5.2 Hz, IH), 6.63 (s, IH), 5.51 (s, 2H), 2.34 (s, 3H), 1.66 (s, 9H), 1.47 (s, 9H); TLC i?/(«-Hexanes:EtOAc 1:2) = 0.19.
Figure imgf000354_0002
488 4-(2-Chlorophenyl)-Λr-((5-phenyl-ljHr-pyrazol-3-yl)methyl)pyrimidin-2-amine (488)
1H NMR (400 MHz, CD3OD) δ 8.12 (d, J= 5.2 Hz, IH), 7.45-7.44 (m, 2H), 7.32-7.30 (m, IH), 7.26-7.24 (m, IH), 7.19-7.12 (m, 4H), 7.08-7.05 (m, IH), 6.68 (d, J= 4.8 Hz, IH), 6.34 (s, IH), 4.43 (s, 2H); TLC i?/(«-Hexanes:EtOAc 1 :2) = 0.28; LRMS (electrospray) m/z calculated for C2OH17C1N5(M+H)+ 362.12, found 362.00.
Figure imgf000354_0003
J/V-((5-Phenyl-lH-pyrazol-3-yl)methyl)-4-(2-(trifluoromethyl)phenyl)pyrimidin-2-amine (489)
1H NMR (400 MHz, CD3OD) δ 8.33 (d, J= 5.2 Hz, IH), 7.78 (d, J= 7.6 Hz, IH), 7.66-7.58 (m, 4H), 7.48 (d, J= 7.2 Hz, IH), 7.35-7.34 (m, 2H), 7.29-7.27 (m, IH), 6.71 (d, J= 5.2 Hz, IH), 6.53 (s, IH), 4.64 (s, 2H); TLC i?/(CH2Cl2:Me0H 10:1) = 0.33.
Figure imgf000355_0001
490 4-(2-MethoxyphenyI)-7V-((5-phenyl-llf-pyrazol-3-yl)methyl)pyrimidin-2-aiiiine (490)
1H NMR (400 MHz, CD3OD) δ 8.25 (d, J= 5.2 Hz, IH), 7.82-7.80 (m, IH), 7.70-7.68 (m, 2H), 7.43-7.36 (m, 3H), 7.29-7.27 (m, IH), 7.19 (d, J= 5.2 Hz, IH), 7.09 (d, J= 8.4 Hz, IH), 7.01 (t, J= 7.6 Hz, IH), 6.57 (s, IH), 4.67 (s, 2H), 3.85 (s, 3H); TLC ^(CH2Cl2MeOH 10:1) = 0.33.
Figure imgf000355_0002
4-(2,6-Dimethylphenyl)-N-((5-phenyl-lH-pyrazol-3-yl)methyl)pyrimidin-2-amine (491)
1H NMR (400 MHz5 CD3OD) δ 8.09 (d, J= 4.8 Hz, IH), 7.39 (m, 2H), 7.09 (m, 2H), 7.01 (m, IH), 6.79 (t, J= 7.6 Hz, IH), 6.79 (m, 2H), 6.28 (d, J= 5.2 Hz, IH), 6.26 (s, IH), 4.35 (s, 2H), 1.76 (s, 6H); TLC ^/(CH2Cl2MeOH 19:1) = 0.29.
Figure imgf000355_0003
3-Methyl-4-(2-((5-phenyI-lJΪ-pyrazol-3-yl)methylainino)pyriinidiii-4-yI)benzonitrile (492)
1H NMR (400 MHz, CDCl3) δ 8.45 (d, J= 4.8 Hz, IH), 7.63 (d, J= 7.6 Hz, 2H), 7.55 (d, J= 4.8 Hz, 2H)5 7.50 (d, J= 8.4 Hz, IH)5 7.39 (t5 J= 7.8 Hz, IH), 7.33 (d, J= 8.0 Hz, IH), 6.71 (d, J= 7.8 Hz, IH), 6.50 (s, IH)5 4.70 (d5 J= 6.4 Hz5 2H), 2.43 (s, 3H); TLC Rf(n- Hexanes:EtOAc 1 :1 with 0.5% MeOH) = 0.10.
Figure imgf000355_0004
5-Methyl-4-phenyl-7V-((5-phenyl-lH-pyrazol-3-yl)methyI)pyrimidm-2-amme (493) 1H NMR (400 MHz, CD3OD) δ 8.22 (s, IH), 7.69-7.67 (m, 2H), 7.57-7.56 (m, 2H), 7.46-7.40 (m, 3H), 7.38-7.28 (m, 3H), 6.57(s, IH), 4.57 (s, 2H), 2.17 (s, 3H); TLC i?/(CH2Cl2:Me0H 10:1) = 0.25; LRMS (electrospray) m/z calculated for C21H20N5(M+H)+ 342.17, found 342.08.
Figure imgf000356_0001
494 5-Methyl-Λ^-((5-phenyl-lH-pyrazoI-3-yl)methyl)-4-o-tolylpyrimidin-2-amine (494)
1H NMR (400 MHz, CD3OD) δ 8.23 (s, IH), 7.66 (d, J= 6.8 Hz, 2H), 7.39-7.22 (m, 5H), 7.11 (d, J= 8.0 Hz, 2H), 6.53 (s, IH), 4.60 (s, 2H), 2.11 (s, 3H), 1.87 (s, 3H); TLC Rf(n- Hexanes:EtOAc 3:7) = 0.33.
Figure imgf000356_0002
4-(2-Chlorophenyl)-5-methyl-ΛL((5-phenyl-lH-pyrazol-3-yl)methyl)pyrimidin-2-amine (495)
1H NMR (400 MHz, CD3OD) δ 8.22 (s, IH), 7.66 (d, J= 7.6 Hz, 2H), 7.49 (t, J= 4.6 Hz, IH), 7.42-7.34 (m, 5H), 7.30-7.25 (m, IH), 6.55 (s, IH), 4.60 (s, 2H), 1.90 (s, 3H); TLC Rf (CH2Cl2:Me0H 10:1) = 0.50.
Figure imgf000356_0003
496
5-Methyl-7V-((5-phenyl-lJE-r-pyrazol-3-yl)methyl)-4-(2- (trifluoromethyl)phenyl)pyrimidin-2-amine (496)
1H NMR (400 MHz, CD3OD) δ 8.24 (s, IH), 7.81(d, J= 8.0 Hz, IH), 7.70-7.61 (m, 4H), 7.39-7.29 (m, 4H), 6.53 (s, IH), 4.60 (s, 2H), 1.87 (s, 3H); TLC i?/(CH2Cl2:Me0H 10:1) = 0.36.
Figure imgf000357_0001
497
4-(2-Methoxyphenyl)-5-methyl-iV-((5-phenyl-lJϊ-pyrazol-3-yl)methyl)pyriiiiidiii-2-anime
(497)
1H NMR (400 MHz, CD3OD) δ 8.15 (s, IH), 7.68 (d, J= 6.0 Hz, 2H), 7.44-7.26 (m, 4H), 7.18 (dd, J= 7.6, 1.6 Hz, IH), 7.08 (d, J= 8.8 Hz, IH), 7.03 (t, J= 7.4 Hz, IH), 6.55 (s, IH), 4.60 (s, 2H), 3.78 (s, 3H), 1.92 (s, 3H); TLC i?/(«-Hexanes:EtOAc 3:7) = 0.29.
Figure imgf000357_0002
4-(5-Methyl-2-((5-phenyl-ljHr-pyrazol-3-yl)methyIamino)pyrimidin-4-yl)benzoiiitrile (498)
1H NMR (400 MHz, CD3OD) δ 8.26 (s, IH), 7.82 (d, J= 8.4 Hz, 2H), 7.76 (d, J= 8.4 Hz, 2H), 7.70-7.60 (m, 2H), 7.40-7.22 (m, 3H), 6.55(s, IH), 4.64 (s, 2H), 2.17 (s, 3H); TLC Rf (CH2Cl2MeOH 10:1) = 0.30.
Figure imgf000357_0003
3-Methyl-4-(5-methyl-2-((5-phenyl-lH-pyrazol-3-yl)methyIamino)pyrimidin-4- yl)benzonitrile (499)
1H NMR (400 MHz, CD3OD) δ 8.28 (s, IH), 7.70-7.60 (m, 4H), 7.38-7.32 (m, 4H), 6.52 (s, IH), 4.60 (s, 2H), 2.12 (s, 3H), 1.88 (s, 3H); TLC i?/(CH2Cl2:Me0H 10:1) = 0.35.
Figure imgf000357_0004
500 2-(5-Methyl-2-((5-phenyl-lH-pyrazol-3-yl)methylamino)pyrimidin-4-yl)benzonitrile
(500) 1H NMR (400 MHz, CD3OD) δ 8.17 (s, IH), 7.72-7.70 (m, 2H), 7.57-7.49 (m, 2H), 7.37-7.30 (m, 5H), 6.56 (s, IH), 4.62 (s, 2H), 2.00 (s, 3H).
Figure imgf000358_0001
3-(5-Methyl-2-((5-phenyl-lJH-pyrazol-3-yl)methylamino)pyrimidin-4-yl)benzoiiitrile (501)
1H NMR (400 MHz, CD3OD) δ 8.25 (s, IH), 7.96 (s, IH), 7.89 (d, J= 8.4 Hz, IH), 7.80 (d, J = 8.0 Hz, IH), 7.66-7.62 (m, 3H), 7.38-7.36 (m, 2H), 7.31-7.29 (m, IH), 6.56 (s, IH), 4.64 (s, 2H), 2.18 (s, 3H);TLC ^/(CH2Cl2 :MeOH 10:1) = 0.68; LRMS (electrospray) m/z calculated for C22H19N6(M+H)+ 367.17, found 366.89.
Figure imgf000358_0002
4-(2-Chloro-4-fluorophenyl)-5-methyI-N-((5-phenyl-lH-pyrazol-3-yl)methyl)pyrimidiii- 2-amine (502)
1H NMR (400 MHz, CD3OD) δ 8.25 (s, IH), 7.78-7.62 (m, 2H), 7.49-7.22 (m, 5H), 7.19 (t, J = 8.6 Hz, IH), 6.55 (s, IH), 4.61 (s, 2H), 1.94 (s, 3H); TLC ^(CH2Cl2MeOH 10:1) = 0.34.
Figure imgf000358_0003
4-Chloro-3-(5-methyl-2-((5-phenyl-liϊ-pyrazol-3-yl)methyIamino)pyriinidiii-4- yl)benzonitrile (503)
1H NMR (400 MHz, CDCl3) δ 8.28 (s, IH), 7.65-7.57 (m, 2H), 7.56 (d, J= 3.2 Hz, 2H), 7.38- 7.27 (m, 2H), 7.24 (s, IH), 6.47 (s, IH), 5.93 (s, IH), 4.63 (d, J= 5.2 Hz, 2H), 1.95 (s, 3H); TLC i?/(CH2Cl2:Me0H 10:1) = 0.28; LRMS (electrospray) m/z calculated for C22H17ClN6 (M+H+) 400.86, found 400.96.
Figure imgf000359_0001
4-Fluoro-3-(5-methyl-2-((5-phenyl-lH-pyrazoI-3-yI)methylamino)pyrimidin-4- yl)benzonitrile (504)
1H NMR (400 MHz, CDCl3) δ 8.23 (s, IH), 7.72-7.61 (m, 2H), 7.60 (d, J= 7.2 Hz, 2H), 7.35- 7.31 (m, 2H), 7.28-7.24 (m, 2H), 6.46 (s, IH), 6.32 (s, IH), 4.63 (d, J= 6.0 Hz, 2H), 1.99 (s, 3H); TLC i?/(CH2Cl2:Me0H 10:1) = 0.33; LRMS (electrospray) m/z calculated for C22H17FN6 (M+H+) 384.41, found 384.98.
Figure imgf000359_0002
2-Fluoro-3-(5-methyl-2-((5-phenyl-lJfir-pyrazol-3-yI)methylamino)pyrimidin-4- yl)benzonitrile (505)
1H NMR (400 MHz, CDCl3) δ 7.94 (s, IH), 7.35-7.26 (m, 4H), 7.04-6.91 (m, 4H), 6.13 (s, IH), 5.81 (s, IH), 4.31 (d, J= 6.0 Hz, 2H), 1.70 (s, 3H); TLC ^7(CH2Cl2: MeOH 10:1) = 0.33; LRMS (electrospray) m/z calculated for C22H17FN6 (M+H+) 384.41, found 384.98.
Figure imgf000359_0003
4-(4-Cyano-2-methylphenyl)-2-((5-phenyl-liϊ-pyrazol-3-yl)methylamino)pyrimidine-5- carbonitrile (506)
1H NMR (400 MHz, CDCl3) δ 8.75 (s, 0.9H), 8.66 (s, IH), 7.71-7.65 (m, 8H), 7.52-7.50 (m, 2H), 7.38-7.30 (m, 6H), 6.58 (s, IH), 6.51 (s, IH), 4.72 (s, 2H), 4.64 (s, 2H), 2.34 (s, 3H), 2.22 (s, 3H); LRMS (electrospray) m/z calculated for C23H19N7(M+H)+ 392.16, found 392.04.
Figure imgf000359_0004
3-MethyI-4-(2-((5-phenyl-lJfir-pyrazoI-3-yl)methyIamino)-5-(trifluoromethyI)pyrimidin- 4-yl)benzonitrile (507)
1H NMR (400 MHz, CDCl3) δ 8.69 (s, IH), 8.57 (s, IH), 7.42-7.29 (m, 16H), 6.50 (s, IH), 6.39 (s, IH), 4.74 (s, 2H), 4.64 (s, 2H), 2.12 (s, 6H); TLC i?/(«-Hexanes:EtOAc 1 :2) = 0.37; LRMS (electrospray) m/z calculated for C23H19F3N6(M+H)+ 435.15, found 435.00.
Figure imgf000360_0001
508
N-((lH-indazol-3-yl)methyl)-5-(2-chlorophenyl)-l,2,4-triazin-3-amine (508)
1H NMR (400 MHz, DMSO-έfc) δ 8.91 (s, IH), 7.84-7.81 (m, IH), 7.65-7.63 (m, 2H), 7.60- 7.55 (m, IH), 7.53-7.48 (m, 2H), 7.32 (t, J= 7.4 Hz, IH), 7.08-7.05 (m, IH), 4.96 (bs, 2H); TLC i?/(CH2Cl2:Me0H 10:1) = 0.37; LRMS (electrospray) m/z calculated for Ci7Hi4ClN6(M+H)+ 337.10, found 336.98.
Figure imgf000360_0002
5-(2-Chlorophenyl)-7V-((6-methoxy-l/r-indazol-3-yl)methyl)-l,2,4-triazin-3-amine (509)
1H NMR (400 MHz, CD3OD) δ 8.88 (s, IH), 7.66-7.62 (m, 2H), 7.56-7.42 (m, 3H), 6.88 (s, IH), 6.71 (d, J= 7.6 Hz, IH), 4.99 (s, 2H), 3.83 (s, 3H); TLC i?/(CH2Cl2:Me0H 10:1)= 0.33.
Figure imgf000360_0003
510 iV-((lH-Pyrazolo[3,4-6]pyridin-3-yl)methyl)-5-(2-chlorophenyl)-l,2,4-triazin-3-amine
(510)
1H NMR (400 MHz, CD3OD) δ 8.87 (s, IH), 8.45 (dd, J= 4.4, 1.2 Hz, IH), 8.29 (d, J= 7.6 Hz, IH), 7.60 (d, J= 7.2 Hz, IH), 7.54-7.40 (m, 3H), 7.12 (dd, J= 8.0, 4.4 Hz, IH), 5.03 (s, 2H); TLC i?/(CH2Cl2:Me0H 19:1) = 0.27.
Figure imgf000361_0001
4-(3-((l iϊ-Pyrazolo [3,4-6] py ridin-3-yl)methylamino)-l ,2,4-triazin-5-yl)-3- methylbenzonitrile (511)
1H NMR (400 MHz, CDCl3) δ 8.74 (s, IH), 8.60 (t, J= 3.2 Hz, IH), 7.59-7.57 (m, 2H), 7.51 (d, J= 8.4 Hz, IH), 5.12 (s, IH), 2.41 (s, 3H); TLC R/ (CH2Cl2MeOH 10:1) = 0.25; LRMS (electrospray) m/z calculated for C18H14N8 (MH-H+) 342.36, found 342.94.
Figure imgf000361_0002
4-(2-((lH-Pyrazolo[3,4-6]pyridin-3-yl)methylamino)pyridin-4-yl)-3-methylbenzonitrile
(512)
1H NMR (400 MHz, OMSO-d6) δ 13.36 (s, IH), 8.46 (dd, J= 4.8, 1.6 Hz, IH), 8.25 (dd, J= 8.0, 1.6 Hz, IH), 8.07 (dd, J= 4.8, 1.2 Hz, IH), 7.78 (s, IH), 7.70 (dd, J= 8.0, 1.2 Hz, IH), 7.34 (d, J= 8.0 Hz, IH), 7.22 (m, IH), 7.12 (dd, J= 8.0, 4.4 Hz, IH), 6.49 (d, J= 1.6 Hz, IH), 6.48 (s, IH), 4.80 (s, 2H), 2.20 (s, 3H); TLC i?/(CH2Cl2:Me0H 19:1) = 0.16.
Figure imgf000361_0003
7V-((lH-pyrazolo[3,4-c]pyridin-3-yI)methyl)-5-(2-chlorophenyl)-l,2,4-triazin-3-amine
(513)
1H NMR (400 MHz, CD3OD) δ 8.92 (d, J= 0.8 Hz, IH), 8.88 (s, IH), 8.11 (d, J= 6.0 Hz, IH), 7.84 (d, J= 5.2 Hz, IH), 7.60 (d, J= 7.6 Hz, IH), 7.57-7.49 (m, 2H), 7.43 (m, IH), 5.08 (s, 2H); TLC i?/(CH2Cl2:Me0H 9:1) = 0.12.
Figure imgf000361_0004
4-(2-((lH-Pyrazolo[3,4-b]pyridin-3-yl)methylamino)pyridin-4-yl)-3-chlorobenzoiiitrile
(514)
1H NMR (400 MHz, CD3OD) δ 8.45 (dd, J= 4.6, 1.0 Hz, IH), 8.28 (d, J= 8.0 Hz, IH), 8.08 (d, J= 5.2 Hz, IH), 7.90 (d, J = 1.6 Hz, IH), 7.72 (dd, J= 7.8, 1.0 Hz, IH), 7.50 (d, J= 8.0 Hz, IH), 7.14 (dd, J= 8.0 Hz, 4.8 Hz, IH), 6.62 (s, 2H), 4.88 (s, 2H); TLC i?/(CH2Cl2:Me0H 19:l) = 0.16.
Figure imgf000362_0001
4-(2-((lJBT-Pyrazolo[3,4-6]pyridin-3-yl)methylamiiio)pyridin-4-yl)-3- (trifluoromethyl)benzonitrile (515)
1H NMR (400 MHz, CD3OD) δ 8.45 (d, J= 4.4 Hz, IH), 8.25 (d, J= 8.0 Hz, IH), 8.16 (s, IH), 8.05 (d, J= 5.2 Hz, IH), 8.00 (d, J= 8.0 Hz, IH), 7.52 (d, J= 8.0 Hz, IH), 7.13 (dd, J= 8.0, 4.8 Hz, IH), 6.53 (d, J= 5.2 Hz, 2H), 4.88 (s, 2H); TLC ^y(CH2Cl2=MeOH 19:1) = 0.25.
Figure imgf000362_0002
4-(2-((lH-pyrazolo[3,4-6]pyridin-3-yl)methylamino)-5-methyIpyrimidin-4-yl)-3- methylbenzonitrile (516)
1H NMR (400 MHz, CD3OD) δ 8.44 (d, J= 4.4 Hz, IH), 8.26 (s, IH), 8.21 (d, J= 7.2 Hz, IH), 7.65 (s, IH), 7.62 (d, J= 8.0 Hz, IH), 7.29 (d, J= 8.0 Hz, IH), 7.06 (dd, J= 7.8, 4.6 Hz, IH), 4.89 (s, 2H), 2.03 (s, 3H), 1.86 (s, 3H); TLC ^7(CH2Cl2: MeOH 19:1) = 0.13.
Figure imgf000362_0003
4-(2-((lH-Pyrazolo[3,4-A]pyridin-3-yl)methylamino)-5-chloropyrimidin-4-yl)-3- methylbenzonitrile (517) 1H NMR (400 MHz, CD3OD) δ 8.42 (d, J= 4.4 Hz, IH), 8.37 (s, IH), 8.21-8.19 (m, 2H), 7.64 (s, IH), 7.60 (d, J= 8.0 Hz, IH), 7.32 (d, J= 7.6 Hz, IH), 7.06 (s, IH), 4.87 (s, 2H), 2.18 (s, 3H); LRMS (electrospray) m/z calculated for C19Hi4ClFN7 (M+H)+ 376.11, found 375.87.
Figure imgf000363_0001
4-(2-((lJEr-Pyrazolo[3,4-6]pyridin-3-yl)methylamino)-5-(trifluoromethyl)pyrimidin-4-yl)- 3-methylbenzonitrile (518)
TLC i?/(CH2Cl2:Me0H 9:1) = 0.56; LRMS (electrospray) m/z calculated for C20H15F3N7 (M+H)+ 410.13, found 409.87.
Figure imgf000363_0002
5-(2-Chlorophenyl)-N-((6-fluoro-lH-pyrazolo[3,4-6]pyridin-3-yl)methyl)-l,2,4-triazin-3- amine (519)
1H NMR (400 MHz, CD3OD) δ 8.88 (s, IH), 8.36 (bs, IH), 7.61 (d, J= 7.2 Hz, IH), 7.54 (dd, J= 8.0, 1.6 Hz, IH), 7.49 (dt, J= 7.6, 2.0 Hz, IH), 7.44 (dt, J= 7.4, 1.6 Hz, IH), 6.76 (d, J= 8.4 Hz, IH), 5.00 (s, 2H); TLC #/(«-Hexanes:EtOAc 1:1) = 0.27.
Figure imgf000363_0003
3-((5-(2-Chlorophenyl)-l,2,4-triazin-3-ylamino)methyl)-Λr-(4-methoxybenzyl)-lH- py razolo [3,4-ό] py ridin-6-amine (520)
1H NMR (400 MHz, DMSO-^) δ 12.45 (s, IH), 8.86 (s, IH), 8.39 (bs, IH), 7.67 (m, IH), 7.60 (m, 2H), 7.55 (dt, J= 10.8, 1.6 Hz, IH), 7.49 (t, J= 10.0 Hz, IH), 7.30 (t, J= 5.6 Hz, IH), 7.20 (t, J= 8.6 Hz, 2H), 6.82 (m, 2H), 6.29 (d, J= 8.0 Hz, IH), 4.73 (bs, 2H), 4.41 (d, J = 5.6 Hz, IH), 3.67 (s, 3H); TLC i?/(CH2Cl2:Me0H 19:1) = 0.14.
Figure imgf000364_0001
3-((5-(2-Chlorophenyl)-l,2,4-triazin-3-ylamino)methyl)-lHr-pyrazolo[3,4-ό]pyridin-6- amine (521)
1H NMR (400 MHz, DMSO-J6) δ 12.35 (s, IH), 8.87 (s, IH), 8.30 (bs, IH), 7.68 (bs, IH), 7.60 (m, 2H), 7.53 (dt, J= 7.6, 1.6 Hz, IH), 7.47 (dt, J= 7.4, 1.6 Hz, IH), 6.20 (bs, 3H), 4.73 (bs, 2H); TLC ^/(CH2Cl2 :MeOH 9:1) = 0.59.
Figure imgf000364_0002
4-(3-((6-Fluoro-lH-pyrazolo[3,4-A]pyridin-3-yI)methyIamino)-l,2,4-triazin-5-yI)-3- methylbenzonitrile (522)
1H NMR (400 MHz, DMSO-J6) δ 13.47 (s, IH), 8.85 (s, IH), 8.67 (bs, IH), 8.39 (s, IH), 7.82 (s, IH), 7.77 (d, J= 8.0 Hz, IH), 7.66 (d, J= 7.6 Hz, IH), 6.88 (d, J= 8.8 Hz, IH), 4.87 (bs, 2H), 2.29 (bs, 3H); TLC #/(CH2Cl2:Me0H 9:1) = 0.40.
Figure imgf000364_0003
4-(3-((6-AnIiIiO-IH-PyFaZoIo [3,4-6] py ridin-3-yI)methylamino)-l ,2,4-triazin-5-yl)-3- methylbenzonitrile (523)
1H NMR (400 MHz, DMSO-J6) δ 12.34 (s, IH), 8.83 (s, IH), 8.35 (bs, IH), 7.82 (s, IH), 7.78 (d, J= 8.0 Hz, IH), 7.68 (bs, IH), 7.67 (d, J= 8.0 Hz, IH), 6.19 (s, 3H), 4.70 (bs, 2H), 2.33 (bs, 3H); TLC i?/(CH2Cl2:Me0H 9:1) = 0.39.
Figure imgf000364_0004
4-(2-((6-Fluoro-lHr-pyrazolo[3,4-6]pyridin-3-yl)methylamino)pyridin-4-yl)-3- methylbenzonitrile (524)
1H NMR (400 MHz, CDCl3 with 20% CD3OD) δ 8.16 (t, J= 8.0 Hz, IH), 7.98 (d, J= 4.8 Hz, IH), 7.41 (s, IH), 7.38 (d, J= 8.0 Hz, IH), 7.12 (d, J= 7.6 Hz, IH), 6.63 (d, J= 8.4 Hz, IH), 6.40-6.39 (m, IH), 6.30 (s, IH), 4.72 (s, 2H), 2.04 (s, 3H); TLC i?/(CH2Cl2:Me0H 20:1) = 0.47; LRMS (electrospray) m/z calculated for C20Hi5FN6 (M+H+) 358.37, found 359.01.
Figure imgf000365_0001
4-(2-((6-Amino-li/-pyrazoIo[3,4-ό]pyridin-3-yI)methylamino)pyridin-4-yl)-3- methylbenzonitrile (525)
1H NMR (400 MHz, OMSO-d6) δ 8.06 (d, J= 6.0 Hz, IH), 7.77 (s, IH), 7.70 (d, J= 8.4 Hz, 2H), 7.33 (d, J= 8.0 Hz, IH), 7.05 (t, J= 6.0 Hz, IH), 6.47-6.46 (m, 2H), 6.23 (d, J= 8.8 Hz, IH), 6.19 (s, IH), 4.60 (d, J= 5.6 Hz, 2H), 2.20 (s, 3H); TLC Rf (CH2Cl2MeOH 20:1) = 0.38; LRMS (electrospray) m/z calculated for C20H17N7 (M+H+) 355.40, found 355.88.
Figure imgf000365_0002
3-Chloro-4-(2-((6-fluoro-lHr-pyrazoIo[3,4-6]pyridin-3-yl)methylamino)pyridin-4- yl)benzonitrile (526)
1H NMR (400 MHz, CDCl3) δ 8.24-8.20 (m, IH), 7.73 (t, J= 1.6 Hz, IH), 7.59-7.56 (m, IH), 7.37 (d, J= 8.0 Hz, IH), 6.77-6.75 (m, IH), 6.64-6.62 (m, IH), 6.49 (s, IH), 5.26 (s, IH), 4.92 (d, J= 5.6 Hz, 2H); TLC R1 (CH2Cl2: MeOH 10:1) = 0.47; LRMS (electrospray) m/z calculated for C19H12ClFN6 (M+H+) 378.79, found 378.86.
Figure imgf000365_0003
4-(2-((6-Amino-l//-pyrazolo[3,4-ό]pyridin-3-yl)methylamino)pyridin-4-yl)-3- chlorobenzonitrile (527) 1U NMR (400 MHz, DMSO-J6) δ 8.13 (d, J= 1.6 Hz, IH), 8.07 (d, J= 5.2 Hz, IH), 7.87- 7.85 (m, IH), 7.69 (d, J= 8.8 Hz, IH), 7.53 (d, J= 7.6 Hz, IH), 7.12 (t, J= 5.2 Hz, IH), 6.53 (s, IH), 6.51-6.49 (m, IH), 6.21 (d, J= 8.8 Hz, 2H), 6.17 (s, 2H), 4.60 (d, J= 6.0 Hz, 2H); TLC Rf (CH2Cl2 :MeOH 5:1) = 0.91; LRMS (electrospray) m/z calculated for C19H14ClN7 (M+H+) 375.81, found 375.87.
Figure imgf000366_0001
4-(2-((6-Fluoro-lJϊ-pyrazolo[3,4-6]pyridin-3-yI)methylainino)pyridiii-4-yl)-3- (trifluoromethyl)benzonitrile (528)
1U NMR (400 MHz, CDCl3) δ 8.16 (t, J= 7.2 Hz, IH), 8.01 (s, IH), 7.84 (d, J= 8.4 Hz, IH), 7.42 (d, J= 8.0 Hz, IH), 6.77 (d, J= 8.4 Hz, IH), 6.56 (d, J= 5.6 Hz, IH), 6.40 (s, IH), 5.28 (d, J= 1.6 Hz, IH), 4.92 (d, J= 5.2 Hz, 2H); TLC Rf (CH2Cl2: MeOH 20:1) = 0.47; LRMS (electrospray) m/z calculated for C20Hj2F4N6 (M+H+) 412.34, found 412.99.
Figure imgf000366_0002
4-(2-((6-Amino-Hr-pyrazolo[3,4-6]pyridin-3-yl)methylamino)pyridin-4-yl)-3- (trifluoromethyl)benzonitrile (529)
1H NMR (400 MHz, CD3OD) δ 8.11 (s, IH), 8.06-8.04 (m, IH), 8.02-8.00 (m, IH), 7.78 (d, J = 8.8 Hz, IH), 7.54 (d, J= 8.0 Hz, IH), 6.54 (s, IH), 6.53 (s, IH), 4.72 (s, 2H); TLC Rf (CH2Cl2:Me0H 10:1) = 0.52; LRMS (electrospray) m/z calculated for C20H14F3N7 (MH-H+) 409.37, found 410.25.
Figure imgf000366_0003
4-(5-ChIoro-2-((6-fluoro-l//-pyrazolo[3,4-ό]pyridin-3-yl)methylamino)pyrimidin-4-yl)-3- methylbenzonitrile (530) 1H NMR (400 MHz, CDCl3) δ 8.39 (s, IH)5 8.13 (bs, IH), 7.58-7.56 (m, 2H), 7.31 (d, J= 8.0 Hz, IH), 6.74-6.73 (bs, IH), 4.94 (s, 2H), 2.21 (s, 3H); TLC i?/(CH2Cl2:Me0H 10:1) = 0.31; LRMS (electrospray) m/z calculated for Ci9H14ClFN7(M+H)+ 394.10, found 393.89.
Figure imgf000367_0001
4-(2-((6-Amino-lH-pyrazolo[3,4-o]pyridin-3-yl)methylamino)-5-chloropyriinidiii-4-yl)-3- methylbenzonitrile (531)
1H NMR (400 MHz, OMSO-d6) δ 12.36 (s, IH), 8.47 (bs, IH), 8.10-8.05 (m, 0.4H), 8.04-8.01 (m, 1.4H), 7.84-7.74 (m, 3.4H), 7.46-7.42 (m, IH), 7.30-7.28 (m, 0.7H), 6.23 (s, 3H), 4.64- 4.62 (m, 2H), 2.14-2.08 (m, 3.4H); LRMS (electrospray) m/z calculated for Ci9H16ClN8(MH-H)+ 391.12, found 390.90.
Figure imgf000367_0002
4-(2-((6-Fluoro-l/f-pyrazolo[3,4-6]pyridin-3-yl)methylamino)-5- (trifluoromethyl)pyrimidin-4-yl)-3-methyIbenzonitrile (532)
TLC i?/(CH2Cl2:Me0H 19:1) = 0.35; LRMS (electrospray) m/z calculated for C20H14F4N7 (M+H)+ 428.12, found 427.82.
Figure imgf000367_0003
4-(2-((6-Amino-lH-pyrazolo[3,4-ό]pyridin-3-yl)methylamino)-5- (trifluoromethyl)pyrimidin-4-yl)-3-methylbenzonitrile (533)
TLC i?/(CH2Cl2:Me0H 9:1) = 0.48; LRMS (electrospray) m/z calculated for C20H16F3N8 (M+H)+ 425.15, found 424.96.
Figure imgf000368_0001
4-(2-((5-(4-Methoxyphenyl)-li7-pyrazol-3-yl)methylamino)pyridin-4-yl)-3- methylbenzonitrile (534)
1H NMR (400 MHz, CDCl3) δ 8.19 (d, J= 4.8 Hz, IH), 7.59 (d, J= 8.0 Hz, 2H), 7.52-7.48 (m, H), 7.24 (s, IH), 6.93-6.91 (m, IH), 6.53 (d, J= 5.2 Hz, IH), 6.40 (s, IH), 6.32 (s, IH), 5.06 (s, IH), 4.59 (d, J= 6.0 Hz, IH), 3.82 (s, IH), 2.14 (s, IH); TLC R1 (CH2Cl2: MeOH 20:1) = 0.63.
Figure imgf000368_0002
4-(2-((5-(4-Hydroxyphenyl)-lH-pyrazol-3-yl)methylamino)pyridin-4-yl)-3- methylbenzonitrile (535)
1H NMR (400 MHz, CD3OD) δ 8.01 (d, J= 5.2 Hz, IH), 7.55 (s, IH), 7.51-7.49 (m, IH), 7.46 (d, J= 8.8 Hz, 2H), 7.25 (d, J= 7.6 Hz, IH), 6.79-6.77 (m, 2H), 6.48-6.45 (m, 2H), 6.41 (s, IH), 4.51 (s, 2H), 2.19 (s, 3H); TLC i?/(CH2Cl2:Me0H 20:1) = 0.43.
Figure imgf000368_0003
3-Methyl-4-(2-((5-(4-(2-morpholinoethoxy)phenyl)-l/7-pyrazol-3- yl)methyIamino)pyridin-4-yl)benzonitrile (536)
1H NMR (400 MHz, CDCl3) δ 8.16 (d, J= 5.2 Hz, IH), 7.57 (d, J= 8.4 Hz, 2H), 7.50 (s, IH), 7.47 (d, J= 8.0 Hz, IH), 7.22 (t, J= 7.6 Hz, IH), 6.90 (d, J= 8.8 Hz, 2H), 6.52-6.50 (m, IH), 6.39 (s, IH), 6.31 (s, IH), 5.36 (s, IH), 4.57 (d, J= 6.0 Hz, 2H), 4.11 (t, J= 6.0 Hz, 2H), 3.71 (t, J= 4.8 Hz, 4H), 2.79 (t, J= 6.0 Hz, 2H), 2.56 (t, J= 4.8 Hz, 4H), 2.22 (s, 3H); TLC Rf (CH2Cl2:Me0H 20:1) = 0.43; LRMS (electrospray) m/z calculated for C29H30N6O2 (M+H+) 494.59, found 495.05.
Figure imgf000369_0001
(R)-3-Methyl-4-(2-((5-(4-(morpholin-2-ylmethoxy)phenyl)-lH-pyrazol-3- yl)methylamino)pyridin-4-yl)benzonitrile (537)
1H NMR (400 MHz, CD3OD) δ 8.02 (d, J= 5.2 Hz, IH), 7.55 (d, J= 8.8 Hz, 3H), 7.53-7.51 (m, IH), 7.27 (d, J= 8.0 Hz, IH), 6.92-6.90 (m, 2H), 6.50-6.48 (m, IH), 6.46 (d, J= 2.8 Hz, 2H), 4.83 (s, 3H), 4.53 (s, 2H), 3.96-3.90 (m, 2H), 3.89-3.79 (m, 2H), 3.66-3.60 (m, IH), 3.32 (s, 2H), 2.95-2.92 (m, IH), 2.79-2.68 (m, IH), 2.12 (s, 3H); TLC Rf (CH2Cl2 :MeOH 5:1) = 0.11; LRMS (electrospray) m/z calculated for C28H28N6O2 (M+H+) 480.56, found 481.12.
Figure imgf000369_0002
4-(2-((5-(5-Bromofuran-2-yl)-lH-pyrazol-3-yl)methylamino)pyridin-4-yl)-3- methylbenzonitrile (538)
1H NMR (400 MHz, CDCl3) δ 8.20 (d, J= 5.2 Hz, IH), 7.51-7.48 (m, 2H), 7.22 (d, J= 8.4 Hz, IH), 6.56-6.53 (m, 2H), 6.38 (s, IH), 6.34 (d, J= 3.6 Hz, IH), 6.31 (s, IH), 4.57 (d, J= 5.6 Hz, 2H), 2.23 (s, 3H); TLC i?/(rc-Hexanes: EtOAc 1:2) = 0.27.
Figure imgf000369_0003
4-(2-((5-(Furan-2-yl)-l/r-pyrazol-3-yl)methylammo)pyridin-4-yl)-3-methylbenzonitrile
(539)
1H NMR (400 MHz, CD3OD) δ 8.03 (d, J= 3.6 Hz, IH), 7.62 (s, IH), 7.57 (d, J= 8.0 Hz, IH), 7.49 (s, IH), 7.32 (d, J= 8.0 Hz, IH), 6.64 (s, IH), 6.53 (d, J= 4.4 Hz, IH), 6.47-6.44 (m, 3H), 4.55 (sm, 2H), 2.24 (s, 3H); TLC i?/(«-Hexanes:EtOAc 1:2) = 0.25; LRMS (electrospray) m/z calculated for C21Hi8N5O (M+H)+ 356.15, found 356.01.
Figure imgf000370_0001
5-(3-((4-(4-Cyano-2-methylphenyl)pyridin-2-ylamino)methyl)-li|y-pyrazol-5-yl)furaii-2- carbonitrile (540)
1H NMR (400 MHz, CDCl3) δ 8.19 (d, J= 5.2 Hz, IH), 7.52-7.49 (m, 2H), 7.23 (d, J= 7.2 Hz, IH), 6.56-6.54 (m, 2H), 6.39 (s, IH), 6.34 (d, J= 3.2 Hz, IH), 6.32 (s, 1H),4.57 (d, J= 5.6 Hz, 2H), 2.24 (s, 3H); TLC i?/(rc-Hexanes:EtOAc 1 :2) = 0.19; LRMS (electrospray) m/z calculated for C22HπN6O(M+H)+ 381.15, found 381.02.
Figure imgf000370_0002
4-(2-((5-(4-CyanophenyI)-2H-pyrazol-3-yl)methylamino)pyridiii-4-yl)-3- methylbenzonitrile (541)
1H NMR (400 MHz, CDCl3) δ 8.23 (d, J= 5.2 Hz, IH), 7.86 (d, J= 8.4 Hz, 2H), 7.67 (d, J= 8.4 Hz, 2H), 7.54-7.51 (m, 2H), 7.24 (d, J= 8.0 Hz, IH), 6.60 (dd, J= 5.4, 1.4 Hz, IH), 6.54 (s, IH), 6.35 (s, IH), 5.12 (br, IH), 4.63(d, J= 6.0 Hz, 2H), 2.27 (s, 3H); LRMS (electrospray) m/z calculated for C24H18N6 (M+H)+ 391.16, found 391.41.
Figure imgf000370_0003
4-(2-((5-(3-Cyanophenyl)-i]ϊ-pyrazol-3-yI)methylamino)pyridin-4-yI)-3- methylbenzonitrile (542)
1H NMR (400 MHz, CDCl3) δ 8.24 (d, J= 5.2 Hz, IH), 8.04-7.99 (m, 2H), 7.58-7.49 (m, 4H), 7.24 (s, IH), 6.60 (dd, J= 5.2, 1.6 Hz, IH), 6.51 (s, IH), 6.35 (s, IH), 5.09 (br, IH), 4.64 (d, J = 5.6 Hz, 2H), 2.27 (s, 3H); LRMS (electrospray) m/z calculated for C24H18N6 (M+H)+ 391.16, found 391.47.
Figure imgf000371_0001
4-(2-((5-(3-Bromo-4-fluorophenyl)-iH-pyrazol-3-yl)methylamino)pyridin-4-yl)-3- methylbenzonitrile (543)
1H NMR (400 MHz, CDCl3) δ 8.20 (d, J= 5.2 Hz, IH), 7.93 (dd, J= 6.4, 2.0 Hz, IH), 7.65 (m, IH), 7.53 (s, IH), 7.50 (d, J= 8.0 Hz, IH), 7.24 (X, J= 8.2 Hz, IH), 7.11 (X, J= 8.4 Hz, IH), 6.57 (dd, J= 5.2, 0.8 Hz, IH), 6.43 (s, IH), 6.33 (s, IH), 4.60 (d, J= 6.0 Hz, IH), 2.25 (s, IH)
Figure imgf000371_0002
4-(3-((lH-Pyrazolo[3,4-&]pyridin-3-yl)methylamino)-l,2,4-triazin-5-yl)-3- (trifluoromethyl)benzonitrile (544)
1H NMR (400 MHz, CD3OD) δ 8.72 (s, IH), 8.46-8.45 (m, IH), 8.27 (s, IH), 8.19-8.10 (s, IH), 7.76 (d, J= 8.0 Hz, IH), 7.11 (s, IH), 5.02 (s, 2H); TLC i?/(rc-Hexanes:EtOAc 1:1) = 0.11.
Figure imgf000371_0003
4-(3-((6-fluoro-ljHr-pyrazoIo[3,4-b]pyridin-3-yl)methylamino)-l,2,4-triazin-5-yl)-3- (trifluoromethyl)benzonitrile (545)
1H NMR (400 MHz, CDCl3) δ 8.79 (s, IH), 8.18-8.12 (m, IH), 8.27 (s, IH), 7.98 (d, J= 6.4 Hz, IH), 7.68-7.65 (m, IH), 6.79-6.73 (m, 2H), 5.11 (s, 2H); TLC i?/(n-Hexanes:EtOAc 1 :2) = 0.32.
Figure imgf000371_0004
4-(3-((6-Amino-lH-pyrazolo[3,4-b]pyridin-3-yl)methylamino)-l,2,4-triazin-5-yl)-3- (trifluoromethyl)benzonitrile (546)
1H NMR (400 MHz, DMSO-J6) δ 8.85 (s, IH), 8.85 (s, IH), 8.33 (d, J= 8.0 Hz, IH), 7.90 (d, J= 8.0 Hz, IH), 6.23 (s, 2H), 4.82 (s, 2H); TLC i?/(CH2Cl2:Me0H 20:1) = 0.10
Figure imgf000372_0001
4-(3-((5-(4-Methoxyphenyl)-lH-pyrazol-3-yl)methylamino)-l,2,4-triazin-5-yl)-3- methylbenzonitrile (547)
1H NMR (400 MHz, CD3OD) δ 8.77 (s, IH), 7.70 (s, IH), 7.68 (d, J= 0.8 Hz, 2H), 7.60 (s, 2H), 6.95 (d, J= 8.4 Hz, 2H), 6.50 (s, IH), 4.73 (s, 2H), 3.80 (s, 3H), 2.43 (s, 3H); TLC R1 (CH2Cl2:Me0H 20:1) = 0.40.
Figure imgf000372_0002
4-(3-((5-(4-Hydroxyphenyl)-lfl-pyrazoI-3-yl)methylamino)-l,2,4-triaziii-5-yl)-3- methylbenzonitrile (548)
1H NMR (400 MHz, CD3OD) δ 8.76 (s, IH), 7.69 (s, IH), 7.66 (d, J= 0.8 Hz, 2H), 7.49 (d, J = 8.8 Hz, 2H), 6.81-6.79 (m, 2H), 6.46 (s, IH), 4.70 (s, 2H), 2.43 (s, 3H); TLC Rf (CH2Cl2:Me0H 10:1) = 0.38
Figure imgf000372_0003
549
3-Metb.yl-4-(3-((5-(4-(2-morpholinoethoxy)phenyl)-lJET-pyrazol-3-yl)methylamino)-l,2,4- triazin-5-yl)benzonitrile (549) 1H NMR (400 MHz, CD3OD) δ 8.76 (s, IH), 7.68 (s, IH), 7.66 (s, 2H), 7.59 (s, 2H), 6.96 (d, J= 8.4 Hz, 2H), 6.50 (s, IH), 4.79 (s, 2H), 4.17-4.14 (m, 2H), 3.79-3.65 (m, 4H), 2.81-2.79 (m, 2H), 2.60-2.57 (m, 4H), 2.42 (s, 3H); TLC ^/(CH2Cl2 :MeOH 15:1) = 0.37.
Figure imgf000373_0001
(S)-3-Methyl-4-(3-((5-(4-(morpholin-2-ylmethoxy)phenyI)-liϊ-pyrazoI-3- y I)methylamino)-1 ,2,4-triazin-5-yl)benzonitrile (550)
1H NMR (400 MHz, CD3OD) δ 8.77 (s, IH), 7.70-7.58 (m, 4H), 6.96 (d, J= 8.4 Hz, 2H), 6.50 (s, IH), 4.78 (s, 2H), 4.01-3.94 (m, IH), 3.92-3.81 (m, IH), 3.67-3.61 (m, IH), 3.05-2.96 (m, 2H), 2.83-2.43 (m, 4H); TLC i?/(CH2Cl2:Me0H 5:1) = 0.21.
Figure imgf000373_0002
4-(3-((5-(Pyridin-2-yI)-ljHr-pyrazol-3-yl)methyIamino)-l,2,4-triazin-5-yl)-3- (trifluoromethyl)benzonitrile (551)
1H NMR (400 MHz, CDCl3) δ 8.76 (s, IH), 8.59 (d, J= 4.4 Hz, IH), 8.11 (s, 2H), 7.98 (d, J= 8.0 Hz, IH), 7.76-7.67 (m, 3H), 7.62-7.60 (m, 2H), 6.71 (s, IH), 4.82 (s, 2H); TLC R1 (CH2Cl2:Me0H 10:1) = 0.47.
Figure imgf000373_0003
4-(2-((l/7-PyrazoIo[3,4-A]pyridin-3-yl)methyIamino)pyrimidiii-4-yl)-3- methylbenzonitrile (552)
1H NMR (400 MHz, CDCl3) δ 8.57-8.55 (m, IH), 8.46 (d, J- 5.2 Hz, IH), 8.14 (d, J= 7.6 Hz, IH), 7.55-7.54 (m, 2H), 7.49-7.47 (m, IH), 7.10-7.07 (m, IH), 6.68 (d, J= 5.2 Hz, IH), 5.06 (d, J= 5.6 Hz, 2H), 2.39 (s, 3H); TLC i?/(CH2Cl2:Me0H 20:1) = 0.22.
Figure imgf000374_0001
4-(2-((6-Fluoro-lf/-pyrazolo[3,4-ό]pyridin-3-yl)methylamino)pyrimidiii-4-yl)-3- methylbenzonitrile (553)
1H NMR (400 MHz, CDCl3) δ 8.39 (d, J= 5.2 Hz, IH), 8.32-8.28 (m, IH), 7.62-7.59 (m, 2H), 7.50 (d, J= 8.0 Hz, IH), 6.75 (d, J- 5.2 Hz, IH), 4.92 (s, 2H), 2.34 (s, 3H); TLC Rf (CH2Cl2:Me0H 20:1) = 0.52.
Figure imgf000374_0002
4-(2-((6-Amino-l//φyrazolo[3,4-ό]pyridin-3-yl)methylamino)pyrimidin-4-yl)-3- methylbenzonitrile (554)
1H NMR (400 MHz, DMSO-^) δ 8.41 (d, J- 4.8 Hz, IH), 7.78-7.68 (m, 3H), 7.56 (d, J= 8.0 Hz, IH), 6.76-6.75 ( m, IH), 6.18 (s, IH), 4.66 (d, J= 4.8 Hz, 2H), 2.31 (s, 3H); TLC Rf (CH2Cl2:Me0H 20:1) = 0.26.
Figure imgf000374_0003
3-Methyl-4-(2-((5-(pyridin-2-yl)-lH-pyrazol-3-yl)methylamino)pyrimidin-4- yl)benzonitrile (555)
1H NMR (400 MHz, CDCl3) δ 8.59 (s, IH), 8.45 (d, J= 5.2 Hz, IH), 7.83-7.70 (m, 2H), 7.68- 7.48 (m, 3H), 7.21-7.19 (m, IH), 6.70 (d, J= 4.8 Hz, IH), 6.66 (d, J= 4.8 Hz, IH), 4.73 (d, J = 5.6 Hz, 2H), 2.46 (s, 3H).
Figure imgf000374_0004
4-(2-((4-Bromo-5-(pyridin-2-yl)-l/-r-pyrazol-3-yl)methylamino)pyridiii-4-yl)-3- methylbenzonitrile (556) 1H NMR (400 MHz, CDCl3) δ 8.62 (d, J= 3.2 Hz, IH), 8.21 (d, J= 5.6 Hz, IH), 7.78 (t, J= 4.0 Hz, 2H), 7.52-7.51 (m, 2H), 7.31-7.26 (m, 2H), 6.53 (d, J= 5.2 Hz, IH), 6.45 (s, 2H), 4.62 (d, J= 5.6 Hz, 2H), 2.29 (s, 3H); TLC i?/(CH2Cl2:Me0H 10:1) = 0.69; LRMS (electrospray) m/z calculated for C22H17BrN6 (M+H)+ 445.31, found 445.28.
Figure imgf000375_0001
4-(2-((l//-Benzo [d\ imidazol-2-yl)methylamino)pyridin-4-yl)-3-methyIbenzonitrile (557) 1H NMR (400 MHz, CDCl3) δ 8.23 (d, J= 4.8 Hz, IH), 7.81 (s, IH), 7.77 (d, J= 8.0 Hz, IH), 7.55 (s, 2H), 7.24-7.20 (m, 2H), 6.63 (d, J= 5.2 Hz, IH), 6.41 (s, IH), 4.82 (s, 2H), 2.27 (s, 3H); TLC ^7(CH2Cl2IMeOH 20:1) = 0.46.
Figure imgf000375_0002
4-(2-((lH-Pyrrolo[2,3-^]pyridin-3-yl)methylamino)pyridin-4-yl)-3-methylbenzonitrile
(558)
1H NMR (400 MHz, CDCl3) δ 8.31 (d, J= 4.0 Hz, IH), 8.20 (d, J= 5.2 Hz, IH), 8.01-7.99 (m, IH), 7.53 (d, J= 4.4 Hz, IH), 7.50 (s, IH), 7.32 (s, IH), 7.25-7.08 (m, IH), 6.54- 6.52 (m, IH), 6.31 (s, IH), 4.69 (d, J= 5.2 Hz, 2H), 2.25 (s, 3H); TLC i?/(CH2Cl2:Me0H 20:1) = 0.43
Figure imgf000375_0003
4-(2-((5-(4-FIuorophenyl)-l//-pyrazol-3-yl)methylamino)pyridin-4-yl)-3- methylbenzonitrile (559)
1H NMR (400 MHz, CDCl3) δ 8.21 (d, J= 5.2 Hz, IH), 7.70-7.67 (m, 2H), 7.54-7.50 (m, 2H), 7.24 (d, J= 8.0 Hz, IH), 7.10-7.06 (m, IH), 6.57-6.56 (m, IH), 6.44 (s, IH), 6.33 (s, IH), 4.61 (d, J= 6.0 Hz, 2H), 2.26 (s, 3H); TLC i?/(CH2Cl2:Me0H 20:1) = 0.19.
Figure imgf000376_0001
560
4-(2-((5-(4-Fluorophenyl)-lH-pyrazol-3-yl)methylamino)pyridin-4-yI)-3,5- dimethylbenzonitrile (560)
1U NMR (400 MHz, CDCl3) δ 8.23 (d, J= 5.2 Hz, IH), 7.69-7.65 (m, 2H), 7.35 (d, J= 4.8 Hz, 2H), 7.09-7.04 (m, 2H), 6.42 (s, IH), 6.40-6.38 (m, IH), 6.18 (s, IH), 4.59 (d, J= 5.6 Hz, 2H), 2.04 (s, 3H); TLC i?/(CH2Cl2:Me0H 20:1) = 0.45.
Figure imgf000376_0002
4-(2-((lH-Pyrrolo[2,3-^]pyi*idin-5-yl)methylamino)pyridin-4-yl)-3-methylbenzoiiitrile (561)
1H NMR (400 MHz, CDCl3) δ 8.31 (s, IH), 8.19 (d, J= 4.8 Hz, IH), 7.96 (d, J= 1.6 Hz, IH), 7.51 (d, J= 2.0 Hz, IH), 7.49 (s, IH), 7.34 (t, J= 3.0 Hz, IH), 7.24 (s, IH), 6.53-6.52 (m, IH), 6.47-6.46 (m, IH), 6.28 (s, IH), 4.63 (d, J= 6.0 Hz, 2H), 2.28 (s, 3H); TLC Rf(n- Hexanes:EtOAc 1:1) = 0.52.
Figure imgf000376_0003
3-Methyl-4-(2-((7-nitro-lH-indol-3-yI)methylamino)pyridiii-4-yl)benzonitrile (562)
1H NMR (400 MHz, CDCl3) δ 8.18 (d, J= 4.4 Hz, IH), 8.03 (d, J= 7.6 Hz, IH), 7.52 (s, IH), 7.50 (d, J= 7.6 Hz, IH), 7.39 (d, J= 2.4 Hz, IH), 7.24-7.19 (m, 2H), 6.54-6.53 (m, IH), 6.31 (s, IH), 4.74 (d, J= 5.2 Hz, 2H), 2.01 (s, 3H); TLC i?/(«-Hexanes: EtOAc 2:1) = 0.79.
Figure imgf000376_0004
4-(2-((7-Amino-l/-r-indol-3-yl)methylamino)pyridin-4-yl)-3-methylbenzonitrile (563) 1H NMR (400 MHz, CD3OD) δ 8.02 (d, J= 4.8 Hz, IH), 7.62 (s, IH), 7.58-7.55 (m, IH), 7.32 (d, J= 7.6 Hz, IH), 7.19 (s, IH), 7.08-7.02 (m, 2H), 6.86-6.80 (m, IH), 6.53-6.48 (m, IH), 4.60 (s, 2H), 2.02 (s, 3H); TLC i?/(«-Hexanes:EtOAc 1:1) = 0.23.
Figure imgf000377_0001
4-(2-((5-(2-MethoxyphenyI)-l/f-pyrazol-3-yl)methylamino)pyridin-4-yl)-3- methylbenzonitrile (564)
1H NMR (400 MHz, CDCl3) δ 8.16 (d, J= 5.2 Hz, IH), 7.63-7.61 (m, IH), 7.50-7.47 (m, 2H), 7.31-7.23 (m, 2H), 7.03-6.99 (m, 2H), 6.60 (s, IH), 6.49-6.48 (m, IH), 6.34 (s, IH), 4.59 (d, J = 5.2 Hz, 2H), 3.90 (s, 3H), 2.23 (s, 3H); TLC i?/(CH2Cl2:Me0H 10:1) = 0.55.
Figure imgf000377_0002
4-(2-((5-(3-Methoxyphenyl)-lH-pyrazol-3-yl)methylamino)pyridin-4-yl)-3- methylbenzonitrile (565)
1H NMR (400 MHz, CDCl3) δ 8.21 (d, J= 5.6 Hz, IH), 7.54 (s, IH), 7.51 (d, J= 5.2 Hz, IH), 7.34-7.21 (m, 4H), 6.89-6.86 (m, IH), 6.56-6.55 (m, IH), 6.49 (s, IH), 6.33 (s, IH), 4.62 (d, J = 6.0 Hz, 2H), 3.84 (s, 3H), 2.26 (s, 3H); TLC i?/(CH2Cl2:Me0H 10:1) = 0.31.
Figure imgf000377_0003
4-(2-((5-(2-Hydroxyphenyl)-lH-pyrazol-3-yl)methylamino)pyridin-4-yl)-3- methylbenzonitrile (566)
1H NMR (400 MHz, CD3OD) δ 8.06 (d, J= 5.2 Hz, IH), 7.62 (s, IH), 7.58-7.55 (m, 2H), 7.33 (d, J= 8.0 Hz, IH), 7.15-7.10 (m, 2H), 6.88-6.66 (m, 2H), 6.66 (s, IH), 6.50-6.54 (m, IH), 6.50 (s, IH), 4.61 (s, 2H), 2.50 (s, 3H); TLC ^(CH2Cl2 :MeOH 20:1) = 0.92.
Figure imgf000378_0001
4-(2-((5-(3-Hydroxyphenl)-lH-pyrazol-3-yl)methylamino)pyridin-4-yl)-3- methylbenzonitrile (567)
1H NMR (400 MHz, CDCl3) δ 8.15 (d, J= 5.6 Hz, IH), 7.49 (s, IH), 7.47 (s, IH), 7.31-7.20 (m, 2H), 7.17 (d, J = 9.6 Hz, IH), 7.12 (d, J= 7.6 Hz, IH), 6.90-6.88 (m, IH), 6.56 (d, J = 5.2 Hz, IH), 6.42 (s, IH), 6.31 (s, IH), 4.58 (d, J= 5.6 Hz, IH), 2.15 (s, 3H); TLC Rf (CH2Cl2:Me0H 20:1) = 0.46.
Figure imgf000378_0002
4-(2-((5-(6-Butyl-5-chloropyridin-2-yl)-lJΪ-pyrazol-3-yI)methyIamino)pyridin-4-yl)-3- methylbenzonitrile (568)
1H NMR (400 MHz, CDCl3) δ 8.18 (d, J= 5.2 Hz, IH), 7.64 (d, J= 8.4 Hz, IH), 7.51 (s, IH), 7.49 (d, J= 8.0 Hz, IH), 7.40 (d, J= 8.4 Hz, IH), 7.25-7.23 (m, IH), 6.67 (s, IH), 6.52-6.50 (m, IH), 6.33 (s, IH), 4.60 (d, J= 5.6 Hz, 2H), 2.94-2.91 (m, 2H), 2.24 (s, 3H), 1.70-1.71 (m, 2H), 1.46-1.37 (m, 2H), 0.95-0.82 (m, 3H); TLC i?/(CH2Cl2:Me0H 20:1) = 0.13.
Figure imgf000378_0003
3-Methyl-4-(2-((7-nitro-lΛT-benzo[(/]imidazol-2-yl)methylamino)pyridin-4- yl)benzonitrile (569)
1H NMR (400 MHz, CDCl3) δ 8.38 (d, J= 5.2 Hz, IH), 8.13 (d, J= 8.0 Hz, IH), 8.03 (d, J= 8.0 Hz, IH), 7.54 (s, IH), 7.52 (d, J= 8.0 Hz, IH), 7.35-7.27 (m, IH), 7.24 (s, IH), 6.66 (d, J = 5.2 Hz, IH), 6.44 (s, IH), 4.90 (d, J= 5.6 Hz, 2H), 2.04 (s, 3H); TLC i?/(«-Hexanes:EtOAc 1 :1) = 0.38.
Figure imgf000379_0001
4-(2-((5-(5-Chloropyridin-2-yl)-lH-pyrazol-3-yl)methylamino)pyridin-4-yl)-3- methylbenzonitrile (570)
1H NMR (400 MHz, CDCl3) δ 8.49 (t, J= 1.6 Hz, IH), 8.17 (d, J= 5.2 Hz, IH), 7.65 (s, IH), 7.49-7.46 (m, IH), 7.22-7.16 (m, IH), 6.68 (s, IH), 6.51 (d, J= 5.2 Hz, IH), 6.30 (s, IH), 4.58 (d, J= 5.6 Hz, 2H), 2.25 (s, 3H); TLC ^/(CH2Cl2: MeOH 20:1) = 0.68.
Figure imgf000379_0002
4-(2-((7-Amino-lH-benzo[rf]imidazol-2-yl)methylamino)pyridin-4-yl)-3- methylbenzonitrile (571)
1H NMR (400 MHz, CD3OD) δ 8.08 (d, J= 4.8 Hz, IH), 7.65 (s, IH), 7.59 (d, J= 8.0 Hz, IH), 7.33 (d, J= 8.0 Hz, IH), 7.12-7.03 (m, 2H), 6.90 (s, IH), 6.59-6.57 (m, IH), 6.53 (s, IH), 4.58 (s, 2H), 2.27 (s, 3H); LRMS (electrospray) m/z calculated for C2jH18N6 (M+H)+ 354.41, found 354.40.
Figure imgf000379_0003
4-(3-((5-(4-Fluorophenyl)-lJE-r-pyrazol-3-yl)methylamino)-l,2,4-triazin-5-yl)-3- methylbenzonitrile (572)
1H NMR (400 MHz, CDCl3) δ 8.73 (s, IH), 7.65-7.53 (m, 5H), 7.22-7.16 (m, IH), 7.05 (t, J= 8.8 Hz, 2H), 6.48 (s, IH), 4.81 (s 2H), 2.46 (s, 3H).
Figure imgf000379_0004
4-(2-((5-(5-Fluoropyridin-2-yl)-lH-pyrazol-3-yl)methylamino)pyridin-4-yl)-3- methylbenzonitrile (573)
1HNMR (400 MHz, CD3OD) δ 8.06 (d, J= 5.2 Hz, IH), 7.96-7.90 (m, IH), 7.73 (s, IH), 7.64 (s, IH), 7.60-7.58 (m, IH), 7.35 (d, J= 8.0 Hz, IH), 6.96-6.93 (m, IH), 6.82 (s, IH), 6.58- 6.53 (m, IH), 6.51 (s, IH), 4.60 (s 2H), 2.27(s, 3H); TLC i?/(CH2Cl2:Me0H 20:1) = 0.43.
Figure imgf000380_0001
4-(2-((3H-Imidazo[4,5-6]pyridin-2-yl)methylamino)pyridin-4-yl)-3-methylbenzoiiitrile
(574)
1U NMR (400 MHz, CD3OD) δ 8.31 (d, J= 3.6 Hz, IH), 8.06 (d, J= 5.2 Hz, IH), 7.93 (d, J= 8.0 Hz, IH), 7.65 (s, IH), 7.60 (d, J= 8.8 Hz, IH), 7.35 (d, J= 8.0 Hz, IH), 7.28-7.25 (m, IH), 6.60-6.58 (m, IH), 4.59 (s, 2H), 2.15 (s, 3H)
Figure imgf000380_0002
4-(2-((5-(2-Chloro-4-fluorophenyl)-ljHr-pyrazol-3-yl)methylamino)pyridin-4-yI)-3- methylbenzonitrile (575)
1H NMR (400 MHz, CDCl3) δ 8.22 (d, J= 5.2 Hz, IH), 7.69-7.66 (m, IH), 7.54 (s, IH), 7.52 (d, J= 7.6 Hz, IH), 7.25-7.19 (m, 2H), 7.06-7.01 (m, IH), 6.61 (s, IH), 6.58-6.56 (m, IH), 6.35 (s, IH), 4.63 (d, J= 5.6 Hz, 2H), 2.32 (s, 3H); TLC i?/(CH2Cl2:Me0H 20:1) = 0.10.
Figure imgf000380_0003
4-(2-((5-(4-Methoxypyridin-2-yl)-lH-pyrazol-3-yl)methylamino)pyridin-4-yl)-3- methylbenzonitrile (576)
1H NMR (400 MHz, CDCl3) δ 8.42 (d, J= 5.2 Hz, IH), 8.20 (d, J= 4.8 Hz, IH), 7.53 (s, IH), 7.51 (d, J= 8.0 Hz, IH), 7.31-7.22 (m, 2H), 6.77-6.75 (m, IH), 6.72 (s, IH), 6.53 (d, J= 5.2 Hz, IH), 6.37 (s, IH), 4.63 (d, J= 4.4 Hz, 2H), 3.94 (s, 3H), 2.25 (s, 3H); TLC Rf (CH2Cl2:Me0H 20:1) = 0.46.
Figure imgf000381_0001
3-Methyl-4-(2-((5-nitro-l/-r-indazol-3-yl)methylamino)pyridiiι-4-yl)benzonitrile (577)
1H NMR (400 MHz, DMSO-J6) δ 8.94 (d, J= 2.0 Hz, IH), 8.15-8.12 (m, IH), 8.07 (d, J= 5.2 Hz, IH), 7.78 (s, IH), 7.70 (d, J= 8.0 Hz, IH), 7.64 (d, J= 9.2 Hz, IH), 7.40-7.32 (m, IH), 6.50-6.48 (m, IH), 4.88 (d, J= 6.4 Hz, 2H), 2.23 (s, 3H); TLC i?/(«-Hexanes:EtOAc 1:1) = 0.10.
Figure imgf000381_0002
4-(2-((5-Amino-lJΪ-indazol-3-yl)methyIamino)pyridin-4-yl)-3-methylbenzonitrile (578)
1H NMR (400 MHz, CDCl3) δ 8.19 (d, J= 5.2 Hz, IH), 7.53 (s, IH), 7.51 (d, J= 8.0 Hz, IH), 7.27-7.25 (m, 2H), 6.99 (t, J= 2.2 Hz, IH), 6.66-6.86 (m, IH), 6.52-6.51 (m, IH), 6.41 (s, IH), 4.84 (d, J= 5.2 Hz, 2H), 2.25 (s, 3H); TLC i?/(CH2Cl2:Me0H 15:1) = 0.39.
Figure imgf000381_0003
4-(3-((l/ir-pyrazolo [3,4-ϋ>] py ridin-3-yl)methylamino)-l ,2,4-triazin-5-yl)-3- chlorobenzonitrile (579)
1H NMR (400 MHz, CD3OD) δ 8.91 (s, IH), 8.46 (d, J= 4.8 Hz, IH), 8.29 (bs, IH), 7.98 (s, IH), 7.79 (m, 2H), 7.12 (q, J= 4.4 Hz, IH), 5.03 (s, 2H); TLC ^/(CH2Cl2 :MeOH 20:1) = 0.16.
Figure imgf000381_0004
3-Chloro-4-(3-((6-fluoro-lH-pyrazolo[3,4-6]pyridin-3-yl)methylamino)-l,2,4-triazin[-5- yl)benzonitrile (580)
1H NMR (400 MHz, CD3OD) δ 8.91 (s, IH), 8.35 (bs, IH), 7.99 (s, IH), 7.77 (m, 2H), 6.78 (d, J= 8.8 Hz, IH), 5.00 (s, 2H); TLC Λ/(CH2Cl2:Me0H 20:1) = 0.24; LRMS (electrospray) m/z calculated for Ci7HnClFN8(M+H)+ 381.08, found 381.13.
Figure imgf000382_0001
5-(3-((4-(4-Cyano-2-methylphenyl)pyridin-2-yIamino)methyl)-lJEr-pyrazol-5-yl)-iV- methylfuran-2-carboxamide (581)
1H NMR (400 MHz, CD3OD) δ 8.07 (t, J= 5.4 Hz, IH), 7.66 (s, IH), 7.60 (d, J= 8.0 Hz, IH), 7.35 (d, J= 7.6 Hz, IH), 7.12 (d, J= 3.6 Hz, IH), 6.78 (d, J= 3.6 Hz, IH), 6.65 (s, IH), 6.58 (t, J= 6.4 Hz, IH), 6.51 (d, J= 6.8 Hz, IH), 4.62 (s, 2H), 2.91 (s, 3H), 2.28 (s, 3H); TLC ^7(CH2Cl2IMeOH 20:1) = 0.19; LRMS (electrospray) m/z calculated for C23H2 iN6O2(M+H)+ 413.17, found 413.38.
Figure imgf000382_0002
3-Chloro-4-(3-((5-(pyridin-2-yl)-lH-pyrazol-3-yl)methylamino)-l,2,4-triazin-5- yl)benzonitrile (582)
1H NMR (400 MHz, CD3OD) δ 8.97 (s, IH), 8.59 (d, J= 5.6 Hz, IH), 8.17 (d, J= 8.4 Hz, IH), 8.09 (d, J= 8.0 Hz, IH), 8.02 (s, IH), 7.84 (s, 2H), 7.57 (t, J= 6.4 Hz, IH), 6.96 (s, IH), 4.80 (s, 2H); TLC i?/(CH2Cl2:Me0H 20:1) = 0.25; LRMS (electrospray) m/z calculated for C19Hi4ClN8(M+H)+ 389.10, found 389.36.
Figure imgf000382_0003
3,5-DimethyI-4-(2-((5-(pyridin-2-yl)-lJΪ-pyrazoI-3-yl)methylamino)pyridin-4- yl)benzonitrile (583) 1H NMR (400 MHz, CD3OD) δ 8.51 (d, J= 4.8 Hz, IH), 8.08 (d, J- 5.2 Hz, IH), 7.82 (d, J= 5.6 Hz, 2H), 7.43 (s, 2H), 7.29 (q, J= 3.6 Hz, IH), 6.79 (s, IH), 6.36 (dd, J= 5.2, 1.2 Hz, IH), 6.33 (s, IH); TLC i?/(CH2Cl2:Me0H 20:1) = 0.13; LRMS (electrospray) m/z calculated for C23H21N6(M+H)+ 381.18, found 381.41.
Figure imgf000383_0001
3-Methyl-4-(2-(((l-phenyl-lH-l,2,3-triazoI-4-yl)methyl)amino)pyrimidin-4- yl)benzonitrile (584)
1K NMR (400 MHz, CD3OD) δ 8.41 (d, J= 4.8 Hz, IH), 8.38 (s, IH), 7.80 (d, J= 8.0 Hz, 2H), 7.66 (s, IH), 7.63 (d, J= 8.0 Hz, IH), 7.57 (t, J= 7.0 Hz, 3H), 7.48 (t, J= 7.2 Hz, IH), 6.79 (d, J= 5.2 Hz, IH), 4.78 (s, 2H), 2.38 (s, 3H); TLC i?/(«-Hexanes:EtOAc 1 :1) = 0.42; LRMS (electrospray) m/z calculated for C21Hj8N7(M+H)+ 368.16, found 368.35.
Figure imgf000383_0002
3-Methyl-4-(2-((l-(pyridin-3-yl)-lJϊ-l,2,3-triazol-4-yl)methylamino)pyrimidiii-4- yl)benzonitrile (585)
1H NMR (400 MHz, CD3OD) δ 9.08 (d, J= 2.4 Hz, IH), 8.67 (d, J= 4.8 Hz, IH), 8.53 (s, IH), 8.43 (d, J= 5.2 Hz, IH), 8.31 (d, J= 8.8 Hz, IH), 7.65 (m, 3H), 7.57 (d, J= 8.0 Hz, IH), 6.81 (d, J= 5.2 Hz, IH), 4.80 (s, 2H), 2.39 (s, 3H); TLC JJy(CH2Cl2=MeOH 20:1) = 0.23; LRMS (electrospray) m/z calculated for C20H17N8(M+H)+ 369.16, found 369.37.
Figure imgf000383_0003
4-(2-((l-(4-Methoxyphenyl)-lJHr-l,2,3-triazol-4-yl)methylamino)pyrimidin-4-yl)-3- methylbenzonitrile (586)
1H NMR (400 MHz, CD3OD) δ 8.39 (d, J= 5.2 Hz, IH), 8.24 (s, IH), 7.65 (m, 3H), 7.61 (d, J = 8.0 Hz, IH), 7.53 (d, J= 8.0 Hz, IH), 7.06 (d, J= 9.2 Hz, 2H), 6.77 (d, J= 5.2 Hz, IH), 4.55 (s, 2H), 3.84 (s, 3H), 2.35 (s, 3H); TLC i?/(«-Hexanes:EtOAc 2:3) = 0.49; LRMS (electrospray) m/z calculated for C22H20N7O(M+H)+ 398.17, found 398.41.
Figure imgf000384_0001
3-Methyl-4-(2-((l-(2-nitrophenyl)-lH-l,2,3-triazol-4-yl)methylamino)pyrimidin-4- yl)benzonitrile (587)
1H NMR (400 MHz, CD3OD) δ 8.39 (d, J= 5.2 Hz, IH), 8.21 (s, IH), 8.11 (dd, J= 8.2, 1.4 Hz, IH), 7.86 (td, J= 7.8, 1.2 Hz, IH), 7.77 (td, J= 8.0, 1.6 Hz, IH), 7.68 (d, J= 7.6 Hz, IH), 7.64 (s, IH), 7.61 (d, J= 9.2 Hz, IH), 7.54 (d, J= 8.0 Hz, IH), 6.78 (d, J= 4.8 Hz, IH), 4.72 (s, 2H), 2.39 (s, 3H); TLC i?/(«-Hexanes:EtOAc 1:1) = 0.13; LRMS (electrospray) m/z calculated for C21H17N8O2(M+H)+ 413.15, found 413.38.
Figure imgf000384_0002
4-(2-((l-(2-Aminophenyl)-l/r-l,2,3-triazol-4-yl)methylamino)pyrimidin-4-yl)-3- methylbenzonitrile (588)
1U NMR (400 MHz, CD3OD) δ 8.34 (d, J= 4.8 Hz, IH), 8.07 (s, IH), 7.58 (m, 3H), 7.49 (d, J = 8.0 Hz, IH), 7.18 (s, IH), 7.14 (dd, J= 8.6, 2.2 Hz, IH), 6.85 (d, J= 8.8 Hz, IH), 6.73 (d, J = 4.8 Hz, IH), 4.50 (s, 2H), 2.33 (s, 3H); TLC i?/(CH2Cl2:Me0H 20:1) = 0.32; LRMS (electrospray) m/z calculated for C2iH19N8(M+H)+ 383.17, found 383.38.
Figure imgf000384_0003
3-Methyl-4-(2-((l-(3-nitrophenyl)-lJΪ-l,2,3-triazol-4-yl)methylamino)pyrimidin-4- yl)benzonitrile (589)
1U NMR (400 MHz, CD3OD) δ 8.70 (s, IH), 8.57 (s, IH), 8.44 (bs, IH), 8.31 (d, J= 8.4 Hz, IH), 8.25 (d, J= 7.2 Hz, IH), 7.81 (t, J= 8.2 Hz, IH), 7.62 (t, J= 7.8 Hz, 2H), 7.54 (d, J= 8.0 Hz, IH), 6.79 (d, J= 4.0 Hz, IH), 4.77 (s, 2H), 2.40 (s, 3H); TLC Λ/fø-HexanesiEtOAc 2:3) = 0.40; LRMS (electrospray) m/z calculated for C21H17N8O2(M+H)+ 413.15, found 413.38.
Figure imgf000385_0001
4-(2-((l-(3-Aminophenyl)-lJHr-l,2,3-triazoI-4-yl)methylamino)pyrimidin-4-yl)-3- methylbenzonitrile (590)
1H NMR (400 MHz, CD3OD) δ 8.34 (d, J- 4.8 Hz, IH), 8.17 (s, IH), 7.59 (s, IH), 7.56 (d, J = 8.0 Hz, IH), 7.48 (d, J= 7.6 Hz, IH), 7.15 (t, J= 8.0 Hz, IH), 7.02 (s, IH), 6.90 (d, J= 7.6 Hz, IH), 6.72 (d, J= 5.2 Hz, IH), 6.68 (m, IH), 4.50 (s, 2H), 2.30 (s, 3H); TLC Rf (CH2Cl2:Me0H 20:1) = 0.30; LRMS (electrospray) m/z calculated for C21H19N8(M+H)+ 383.17, found 383.38.
Figure imgf000385_0002
3-Methyl-4-(2-((l-(4-nitrophenyl)-lH-l,2,3-triazol-4-yI)methylamino)pyrimidin-4- yl)benzonitrile (591)
1H NMR (400 MHz, CD3OD) δ 8.55 (s, IH), 8.42 (d, J= 9.2 Hz, 2H), 8.33 (bs, IH), 8.11 (d, J= 9.2 Hz, 2H), 7.62 (t, J= 7.0 Hz, 2H), 7.53 (d, J= 7.6 Hz, IH), 6.78 (d, J= 4.8 Hz, IH), 4.68 (s, 2H), 2.35 (s, 3H); TLC i?/(n-Hexanes:EtOAc 2:3) = 0.42; LRMS (electrospray) m/z calculated for C21H17N8O2(M+H)+ 413.15, found 413.38.
Figure imgf000385_0003
4-(2-((l-(4-Aminophenyl)-ljHr-l,2,3-triazoI-4-yl)methyIamino)pyrimidin-4-yl)-3- methylbenzonitrile (592)
1H NMR (400 MHz, CD3OD) δ 8.33 (d, J= 5.2 Hz, IH), 8.08 (s, IH), 7.59 (s, IH), 7.56 (d, J = 8.0 Hz, IH), 7.48 (d, J= 7.6 Hz, IH), 7.36 (d, J= 8.8 Hz, 2H), 6.72 (m, 3H), 4.50 (s, 2H), 2.30 (s, 3H); TLC i?/(CH2Cl2:Me0H 10:1) = 0.35; LRMS (electrospray) m/z calculated for C21H19N8(M+H)+ 383.17, found 383.38.
Figure imgf000386_0001
3-Methyl-4-(2-((5-(4-nitrophenyl)-lH-pyrazol-3-yl)methylamino)pyridin-4- yl)benzonitrile (593)
1H NMR (400 MHz, CD3OD) δ 8.25 (d, J= 8.4 Hz, 2H), 8.06 (d, J= 5.6 Hz, IH), 7.95 (m, 2H), 7.63 (s, IH), 7.58 (d, J= 8.0 Hz, IH), 7.33 (d, J= 7.6 Hz, IH), 6.75 (s, IH), 6.55 (d, J= 4.4 Hz, IH), 6.50 (s, IH), 4.61 (s, 2H), 2.26 (s, 3H); TLC i?/(CH2Cl2:Me0H 20:1) = 0.24; LRMS (electrospray) m/z calculated for C23H19N6O2(M+H)+ 411.16, found 411.47.
Figure imgf000386_0002
4-(2-((5-(4-Aminophenyl)-liϊ-pyrazol-3-yI)methylamino)pyridin-4-yl)-3- methylbenzonitrile (594)
1H NMR (400 MHz, CD3OD) δ 8.05 (d, J= 5.6 Hz, IH), 7.64 (s, IH), 7.59 (dd, J= 7.6, 1.2 Hz, IH), 7.41 (d, J= 8.4 Hz, 2H), 7.34 (d, J= 7.6 Hz, IH), 6.73 (d, J= 8.8 Hz, 2H), 6.55 (dd, J= 5.4, 1.4 Hz, IH), 6.51 (s, IH), 6.41 (s, IH), 4.53 (s, 2H), 2.26 (s, 3H); TLC Rf (CH2Cl2:Me0H 10:1) = 0.35; LRMS (electrospray) m/z calculated for C23H21N6(MH-H)+ 381.18, found 381.41.
Figure imgf000386_0003
Methyl 5-(3-((5-(4-cyano-2-methylphenyl)-l,2,4-triazin-3-ylamino)methyl)-ljHr-pyrazol- 5-yl)furan-2-carboxylate (595)
1H NMR (400 MHz, CD3OD) δ 8.78 (s, IH), 7.70 (s, IH), 7.67 (s, 2H), 7.27 (d, J= 3.6 Hz, IH), 6.80 (d, J= 3.6 Hz, IH), 6.64 (s, IH), 4.73 (s, 2H), 3.86 (s, 3H), 2.41 (s, 3H); TLC Rf (CH2Cl2:Me0H 20:1) = 0.13; LRMS (electrospray) m/z calculated for C21H18N7O3(M+H)+ 416.15, found 416.37.
Figure imgf000387_0001
5-(3-((5-(4-Cyano-2-methylphenyl)-l,2,4-triazin-3-ylamino)methyl)-lH-pyrazol-5- yl)furan-2-carboxylic acid (596)
1H NMR (400 MHz, CD3OD) δ 9.72 (s, IH), 8.66 (s, IH), 8.62 (d, J= 9.2 Hz, IH), 8.52 (d, J = 8.0 Hz, IH), 8.06 (d, J= 3.6 Hz5 IH), 7.64 (d, J= 3.6 Hz, IH), 7.34 (s, IH), 4.78 (s, 2H), 3.31 (s, 3H).
Figure imgf000387_0002
5-(3-((5-(4-Cyano-2-methyIphenyl)-l,2,4-triazin-3-ylamino)methyl)-lH-pyrazol-5-yl)-iV- methylfuran-2-carboxamide (597)
1H NMR (400 MHz, CD3OD) δ 8.81 (s, IH), 7.72 (s, IH), 7.69 (s, 2H), 7.12 (d, J= 4.0 Hz, IH), 6.78 (d, J= 3.6 Hz, IH), 6.67 (s, IH), 4.76 (s, 2H), 3.25 (s, 3H), 2.43 (s, 3H); TLC R1 (CH2Cl2:Me0H 20:1) = 0.09; LRMS (electrospray) m/z calculated for C21H19N8O2(M+H)+ 415.16, found 415.42.
Figure imgf000387_0003
5-(3-((5-(4-Cyano-2-methyIphenyl)-l,2,4-triazin-3-ylamino)methyl)-ljyr-pyrazol-5-yl)- 7V,iV-dimethylfuran-2-carboxamide (598)
1H NMR (400 MHz, CD3OD) δ 8.80 (s, IH), 7.72 (s, IH), 7.68 (s, 2H), 7.11 (d, J= 4.0 Hz, IH), 6.81 (d, J= 3.6 Hz, IH), 6.64 (s, IH), 4.74 (s, 2H), 3.26 (s, 3H), 3.20 (s, 3H), 2.43 (s, 3H); TLC 22/(CH2Cl2=MeOH 20:1) = 0.12; LRMS (electrospray) m/z calculated for C22H21N8O2(M+H)+ 429.18, found 429.43.
Figure imgf000388_0001
4-(3-((4-(4-Cyano-2-methylphenyl)pyridin-2-ylamino)methyl)-li?-pyrazol-5-yl)-iV,iV- dimethylbenzenesulfonamide (599)
1H NMR (400 MHz, CDCl3) δ 11.32 (bs, IH), 8.24 (d, J= 5.2 Hz, IH), 7.91 (d, J= 8.4 Hz, 2H), 7.78 (d, J= 8.8 Hz, 2H), 7.52 (m, 2H), 7.23 (s, IH), 6.59 (dd, J= 5.4, 1.4 Hz, IH), 6.54 (s, IH), 6.33 (s, IH), 4.98 (m, IH), 4.63 (d, J= 6.0 Hz, 2H), 2.71 (s, 6H), 2.26 (s, 3H); TLC Rf (CH2Cl2:Me0H 20:1) = 0.23; LRMS (electrospray) m/z calculated for C25H25N6O2S(M+H)+ 473.18, found 473.50.
Figure imgf000388_0002
3-Methyl-4-(3-((5-(4-nitrophenyI)-lJHr-pyrazol-3-yl)methylamino)-l,2,4-triazin-5- yl)benzonitrile (600)
1H NMR (400 MHz, CD3OD) δ 8.68 (s, IH), 8.13 (d, J= 8.8 Hz, 2H), 7.84 (d, J= 8.0 Hz, 2H), 7.79 (s, IH), 7.58 (s, IH), 7.55 (s, IH), 6.66 (s, IH), 4.60 (s, 2H), 2.30 (s, 3H); TLC R1 (CH2Cl2:Me0H 20:1) = 0.34; LRMS (electrospray) m/z calculated for C21H17N8O2(M+H)+ 413.15, found 413.38.
Figure imgf000388_0003
4-(3-((5-(4-Aminophenyl)-lH-pyrazol-3-yl)methylamino)-l,2,4-triaziii-5-yl)-3- methylbenzonitrile (601)
1H NMR (400 MHz, CD3OD) δ 8.77 (s, IH), 7.71 (s, IH), 7.68 (s, 2H), 7.40 (d, J= 8.0 Hz, 2H), 6.72 (d, J= 8.4 Hz, 2H), 6.42 (s, IH), 4.69 (s, 2H), 2.44 (s, 3H); TLC i?/(CH2Cl2:Me0H 20:1) = 0.20; LRMS (electrospray) m/z calculated for C21Hi9N8(M+H)+ 383.17, found 383.38.
Figure imgf000389_0001
3-MethyI-4-(2-((5-(4-nitrophenyI)-ljBr-pyrazol-3-yl)methylamino)pyrimidin-4- yl)benzonitrile (602)
1U NMR (400 MHz, CD3OD) δ 8.42 (d, J= 5.2 Hz, IH), 8.27 (d, J= 8.8 Hz, 2H), 7.96 (d, J- 6.4 Hz, 2H), 7.64 (m, 2H), 7.55 (d, J= 8.0 Hz, IH), 6.80 (d, J= 5.2 Hz, IH), 6.74 (s, IH), 4.70 (s, 2H), 2.36 (s, 3H); TLC ^-(CH2Cl2: MeOH 20:1) = 0.12; LRMS (electrospray) m/z calculated for C22H18N7O2(M+H)+ 412.15, found 412.36.
Figure imgf000389_0002
4-(2-((5-(2-Chlorophenyl)-lJfiT-pyrazol-3-yl)methylamino)pyridm-4-yl)-3- methylbenzonitrile (603)
1B. NMR (400 MHz, CD3OD) δ 8.06 (d, J= 4.8 Hz, IH), 7.65 (s, IH), 7.59 (d, J= 8.0 Hz, 2H), 7.47 (bs, IH), 7.34 (m, 3H)5 6.63 (s, IH), 6.56 (d, J= 4.8 Hz, IH), 6.52 (s, IH), 4.60 (s, 2H), 2.27 (s, 3H); TLC i?/(n-Hexanes:EtOAc 1 :2) = 0.56; LRMS (electrospray) m/z calculated for C23H19C1N5(M+H)+ 400.13, found 400.38.
Figure imgf000389_0003
4-(2-((5-(3-Chlorophenyl)-l/7-pyrazol-3-yl)methylamino)pyridin-4-yl)-3- methylbenzonitrile (604)
1H NMR (400 MHz, CD3OD) δ 8.07 (d, J= 5.2 Hz, IH), 7.75 (s, IH), 7.65 (s, 2H), 7.60 (d, J = 8.0 Hz, IH), 7.37 (m, 2H), 7.32 (m, IH), 6.63 (s, IH), 6.57 (d, J= 5.6 Hz, IH), 6.52 (s, IH), 4.60 (s, 2H), 2.32 (s, 3H); TLC i?/(rc-Hexanes:EtOAc 1 :2) = 0.64; LRMS (electrospray) m/z calculated for C23H19C1N5(M+H)+ 400.13, found 400.38.
Figure imgf000390_0001
4-(2-((5-(4-Chlorophenyl)-l/f-pyrazol-3-yl)methyIamino)pyridin-4-yl)-3- methylbenzonitrile (605)
1H NMR (400 MHz, CD3OD) δ 8.06 (d, J= 5.2 Hz, IH), 7.72 (bs, 2H), 7.69 (s, IH), 7.59 (d, J= 8.0 Hz, IH), 7.39 (d, J= 7.2 Hz, 2H), 7.35 (d, J= 8.0 Hz, IH), 6.60 (s, IH), 6.56 (d, J = 4.4 Hz, IH), 6.51 (s, IH), 4.59 (s, 2H), 2.27 (s, 3H); TLC i?/(«-Hexanes:EtOAc 1:1) = 0.23; LRMS (electrospray) m/z calculated for C23H19C1N5(M+H)+ 400.13, found 400.38.
Figure imgf000390_0002
4-(2-((5-(4-ChIoropyridin-2-yl)-lH-pyrazol-3-yl)methylamino)pyridiii-4-yI)-3- methylbenzonitrile (606)
1H NMR (400 MHz, CD3OD) δ 8.47 (s, IH), 8.07 (d, J= 5.2 Hz, IH), 7.94 (bs, IH), 7.65 (s, IH), 7.59 (dd, J= 8.0, 1.2 Hz, IH), 7.34 (m, 2H), 6.85 (s, IH), 6.57 (m, IH), 6.52 (s, IH), 4.62 (s, 2H), 2.27 (s, 3H); TLC i?/(CH2Cl2:Me0H 20:1) = 0.19; LRMS (electrospray) m/z calculated for C22H18C1N6(M+H)+ 401.13, found 401.47.
Figure imgf000390_0003
4-(2-((5-(6-Chloropyridin-2-yl)-lH-pyrazol-3-yl)methylamino)pyridin-4-yl)-3- methylbenzonitrile (607)
1H NMR (400 MHz, CD3OD) δ 8.03 (d, J= 4.8 Hz, IH), 7.79 (m, 2H), 7.62 (d, J= 6.0 Hz, IH), 7.56 (d, J= 8.0 Hz, IH), 7.29 (m, 2H), 6.81 (s, IH), 6.52 (m, IH), 6.48 (s, IH), 4.57 (s, 2H), 2.24 (s, 3H); TLC i?/(CH2Cl2:Me0H 20:1) = 0.19; LRMS (electrospray) m/z calculated for C22H18C1N6(M+H)+ 401.13, found 401.34.
Figure imgf000391_0001
4-(3-((5-(3-Fluorophenyl)-lfiT-pyrazol-3-yl)methylamino)-l,2,4-triaziii-5-yl)-3- methylbenzonitrile (608)
1H NMR (400 MHz, CD3OD) δ 8.80 (s, IH), 7.72 (s, IH), 7.69 (s, 2H), 7.52 (bs, IH), 7.44 (m, 2H), 7.04 (bs, IH), 6.65 (s, IH), 4.76 (s, 2H), 2.44 (s, 3H); TLC i?/(CH2Cl2:Me0H 20:1) = 0.25; LRMS (electrospray) m/z calculated for C21H17FN7(M+H)+ 386.15, found 386.37.
Figure imgf000391_0002
4-(3-((5-(2-Fluorophenyl)-li7-pyrazol-3-yl)methylamino)-l,2,4-triazin-5-yl)-3- methylbenzonitrile (609)
1H NMR (400 MHz, CD3OD) δ 8.77 (s, IH), 7.80 (bs, IH), 7.70 (s, IH), 7.67 (s, 2H), 7.32 (bs, IH), 7.20 (m, 2H), 6.64 (s, IH), 4.73 (s, 2H), 2.42 (s, 3H); TLC tf/(CH2Cl2:Me0H 20:1) = 0.12.
Figure imgf000391_0003
4-(2-((5-(4-(Difluoromethoxy)phenyI)-l£T-pyrazol-3-yl)methylamiiio)pyridiii-4-yl)-3- methylbenzonitrile (610)
1H NMR (400 MHz, CD3OD) δ 8.06 (d, J= 5.6 Hz, IH), 7.73 (m, 2H), 7.65 (s, IH), 7.59 (d, J = 9.2 Hz, IH), 7.35 (d, J= 7.6 Hz, IH), 7.17 (d, J= 8.0 Hz, 2H), 6.84 (t, J= 74.2 Hz, IH), 6.58 (s, IH), 6.56 (d, J= 5.6 Hz, IH), 6.51 (s, IH), 4.58 (s, 2H), 2.27 (s, 3H); TLC Rf (CH2Cl2:Me0H 20:1) = 0.19; LRMS (electrospray) m/z calculated for C24H20F2N5O(M+H)+ 432.16, found 432.42.
Figure imgf000392_0001
4-(2-((5-(2,5-Dichlorophenyl)-lH-pyrazol-3-yl)methylamino)pyridin-4-yl)-3- methylbenzonitrile (611)
1H NMR (400 MHz, CD3OD) δ 8.08 (d, J= 5.6 Hz, IH), 7.70 (m, IH), 7.67 (s, IH), 7.61 (d, J = 8.0 Hz, IH), 7.47 (m, IH), 7.35 (m, 2H), 6.72 (s, IH), 6.58 (d, J= 5.2 Hz, IH), 6.53 (s, IH), 4.64 (s, 2H), 2.29 (s, 3H); TLC i?/(CH2Cl2:Me0H 20:1) = 0.30; LRMS (electrospray) m/z calculated for C23H18C12N5(M+H)+ 434.09, found 434.33.
Figure imgf000392_0002
4-(2-((5-(5-Methoxypyridin-2-yl)-lH-pyrazol-3-yl)methyIammo)pyridin-4-yl)-3- methylbenzonitrile (612)
1U NMR (400 MHz, CD3OD) δ 8.21 (bs, IH), 8.04 (d, J= 5.2 Hz, IH), 7.80 (bs, IH), 7.63 (s, IH), 7.58 (d, J- 7.6 Hz, IH), 7.41 (dd, J= 8.8, 2.8 Hz, IH), 7.33 (d, J= 8.0 Hz, IH), 6.70 (s, IH), 6.54 (d, J= 5.2 Hz, IH), 6.50 (s, IH), 4.57 (s, 2H), 3.88 (s, 3H), 2.25 (s, 3H); TLC Rf (CH2Cl2:Me0H 20:1) = 0.11; LRMS (electrospray) m/z calculated for C23H2 !N60(M+H)+ 397.18, found 397.46.
Figure imgf000392_0003
4-(2-((5-(5-Hydroxypyridin-2-yl)-lH-pyrazol-3-yl)methylamino)pyridm-4-yl)-3- methylbenzonitrile (613)
1H NMR (400 MHz, CD3OD) δ 8.10 (s, IH), 8.06 (d, J= 5.2 Hz, IH), 7.70 (bs, IH), 7.65 (s, IH), 7.60 (d, J= 7.6 Hz, IH), 7.35 (d, J= 7.6 Hz, IH), 7.24 (dd, J= 8.8, 2.8 Hz, IH), 6.68 (s, IH), 6.55 (d, J= 5.2 Hz, IH), 6.51 (s, IH), 4.58 (s, 2H), 2.27 (s, 3H); TLC i?/(CH2Cl2:Me0H 10:1) = 0.23.
Figure imgf000393_0001
4-(2-((5-(4-Chloro-3-nitrophenyl)-liϊ-pyrazol-3-yl)methylamino)pyridin-4-yI)-3- methylbenzonitrile (614)
1H NMR (400 MHz, CD3OD) δ 8.28 (s, IH), 8.07 (t, J= 5.4 Hz, IH), 7.98 (d, J= 8.4 Hz, IH), 7.67 (d, J= 8.8 Hz, 2H), 7.60 (d, J= 9.2 Hz5 IH), 7.35 (d, J= 8.0 Hz, IH), 6.73 (s, IH), 6.57 (d, J= 5.6 Hz, IH), 6.51 (s, IH), 4.62 (s, 2H), 2.28 (s, 3H); TLC ^(CH2Cl2MeOH 20:1) = 0.35.
Figure imgf000393_0002
Methyl 5-(3-((4-(4-cyano-2-methylphenyl)pyridin-2-ylamino)methyl)-l//-pyrazol-5- yl)furan-2-carboxy!ate (615)
1H NMR (400 MHz, CD3OD) δ 8.04 (d, J= 5.6 Hz, IH), 7.62 (s, IH), 7.56 (d, J= 8.4 Hz, 1H),7.32 (d, J= 8.0 Hz, IH), 7.25 (d, J= 3.6 Hz, IH), 6.79 (d, J= 3.2 Hz, IH), 6.60 (s, IH), 6.53 (d, J= 4.8 Hz, IH), 6.48 (s, 1H),4.58 (s, 2H), 3.84 (s, 3H), 2.25 (s, 3H); LRMS (electrospray) m/z calculated for C23H20N5O3(M+H)+ 414.44, found 414.26.
Figure imgf000393_0003
5-(3-((4-(4-Cyano-2-methylphenyl)pyridin-2-yIamino)methyI)-l/T-pyrazoI-5-yl)furan-2- carboxylic acid (616)
1H NMR (400 MHz, CD3OD) δ 7.94 (d, J= 6.8 Hz, IH), 7.71 (s, IH), 7.66 (d, J= 8.0 Hz, IH), 7.43 (d, J= 8.0 Hz, IH), 7.25 (d, J= 3.2 Hz, IH), 7.05 (s, IH), 6.94 (dd, J= 6.8, 1.6 Hz, IH), 6.84 (d, J= 3.6 Hz, IH), 6.74 (s, IH), 4.68 (s, 2H), 3.84 (s, 3H), 2.30 (s, 3H); LRMS (electrospray) m/z calculated for C23H18N5O3 (M+H)+ 400.41, found 400.32.
Figure imgf000394_0001
Isopropyl 5-(3-((4-(4-cyano-2-methylphenyI)pyridin-2-ylamino)methyl)-lH-pyrazol-5- yl)furan-2-carboxylate (617)
1H NMR (400 MHz, CD3OD) δ 8.02 (bs, IH), 7.61 (s, IH), 7.55 (d, J= 9.2 Hz, IH), 7.31 (d, J= 7.6 Hz, IH), 7.21 (bs, IH), 6.77 (bs, IH), 6.59 (s, IH), 6.54-6.53 (m, IH), 6.46 (s, IH), 5.15 (t, J= 7.6 Hz, IH), 4.57 (s, 2H), 2.23 (s, 3H), 1.35-1.30 (m, 6H).
Figure imgf000394_0002
Benzyl 5-(3-((4-(4-cyano-2-methylphenyI)pyridin-2-yIamino)methyl)-lJΪ-pyrazol-5- yl)furan-2-carboxylate (618)
1H NMR (400 MHz, CD3OD) δ 8.03 (d, J= 5.2 Hz, IH), 7.61 (s, IH), 7.56 (d, J= 9.2 Hz, IH), 7.42-7.40 (m, 2H), 7.36-7.28 (m, 7H), 6.79 (d, J= 3.2 Hz, IH), 6.60 (s, IH), 6.53 (d, J= 4.4 Hz, IH), 6.47 (s, IH), 5.31 (s, 2H), 4.58 (s, 2H), 2.24 (s, 3H); TLC £/(«-Hexanes:EtOAc 1 :2) = 0.58; LRMS (electrospray) m/z calculated for C29H24N5O3(MH-H)+ 490.19, found 490.37
Figure imgf000394_0003
619
Ethyl 5-(3-((4-(4-cy ano-2-methylphenyl)pyridin-2-ylamino)methyl)-liϊ-pyrazol-5- yl)furan-2-carboxylate (619)
1U NMR (400 MHz, CD3OD) δ 8.03 (d, J= 5.6 Hz, IH), 7.61 (s, IH), 7.56 (d, J= 8.0 Hz, IH), 7.32 (d, J= 7.6 Hz, IH), 7.24 (d, J= 3.6 Hz, IH), 6.78 (d, J= 3.2 Hz, IH), 6.60 (s, IH), 6.53 (d, J= 4.8 Hz, IH), 6.49 (s, IH), 4.58 (s, 2H), 4.34-4.28 (m, 2H), 2.24 (s, 3H), 1.33 (t, J = 7.2 Hz, 3H); TLC i?/(«-Hexanes:EtOAc 1 :2) = 0.43; LRMS (electrospray) m/z calculated for C24H22N5O3 (M+H)+ 428.17, found 428.34
Figure imgf000395_0001
N-benzyl-5-(3-((4-(4-cyano-2-methylphenyl)pyridin-2-ylamino)methyl)-lH-pyrazol-5- yl)furan-2-carboxamide (620)
1H NMR (400 MHz, CD3OD) δ 8.03 (d, J= 5.2 Hz, IH), 7.61 (s, IH), 7.56 (d, J= 6.8 Hz, IH), 7.36-7.13 (m, 7H), 6.76-6.75 (m, IH), 6.62 (s, IH), 6.53 (d, J= 5.2 Hz, IH), 6.46 (s, IH), 4.57 (s, 2H), 4.52 (s, 2H), 2.24 (s, 3H); TLC tf/(«-Hexanes:EtOAc 1:2) = 0.42; LRMS (electrospray) m/z calculated for C29H25N6O2(M+H)+ 489.20, found 489.42.
Figure imgf000395_0002
5-(3-((4-(4-Cyano-2-methylphenyl)pyridin-2-ylamino)methyl)-lH-pyrazol-5-yl)-7V,iV- diethylfuran-2-carboxamide (621)
1H NMR (400 MHz, CD3OD) δ 8.04 (d, J= 5.6 Hz, IH), 7.62 (s, IH), 7.56 (d, J= 8.0 Hz, IH), 7.32 (d, J= 8.0 Hz, IH), 7.07 (d, J= 3.6 Hz, IH), 6.77 (d, J= 3.2 Hz, IH), 6.55-6.53 (m, 2H), 6.48 (s, IH), 4.58 (s, 2H), 4.52 (s, 2H), 3.80-3.40 (m, 4H), 2.24 (s, 3H), 1.25-1.13 (m, 6H); TLC #/(ra-Hexanes:EtOAc 1:2) = 0.23; LRMS (electrospray) m/z calculated for C26H27N6O2 (M+H)+ 455.52, found 455.41.
Figure imgf000395_0003
5-(3-((4-(4-Cyano-2-methylphenyl)pyridin-2-ylamino)methyl)-lH-pyrazol-5-yl)-7V,iV- dimethylfuran-2-carboxamide (622)
1R NMR (400 MHz, CD3OD) δ 8.02 (bs, IH), 7.61 (s, IH), 7.55 (d, J= 8.0 Hz, IH), 7.31 (d, J= 8.0 Hz, IH), 7.07 (d, J= 3.6 Hz, IH), 6.77 (bs, IH), 6.58 (s, IH), 6.53 (m, IH), 6.47 (s, IH), 4.57 (s, 2H), 3.09 (s, 6H), 2.24 (s, 3H); TLC i?/(EtOAc only) = 0.30; LRMS (electrospray) m/z calculated for for C24H23N6O2 (M+H)+ 427.19, found 427.39.
Figure imgf000396_0001
3-Methyl-4-(2-((5-(5-(morpholine-4-carbonyl)furan-2-yl)-lf/-pyrazol-3- yl)methyIamino)pyridin-4-yl)benzonitrile (623)
1H NMR (400 MHz, CD3OD) δ 8.04 (d, J= 5.6 Hz, IH)5 7.62 (s, IH), 7.56 (d, J= 7.6 Hz, IH), 7.32 (d, J= 8.0 Hz, IH), 7.08 (d, J= 3.6 Hz, IH), 6.77 (d, J= 3.6 Hz, IH), 6.57 (s, IH), 6.53 (d, J= 5.2 Hz, IH), 6.47 (d, J= 5.2 Hz, IH), 4.58 (s, 2H), 3.81-3.69 (m, 4H), 3.59-3.55 (m, 4H), 2.24 (s, 3H); TLC i?/(CH2Cl2:Me0H 10:1) = 0.31; LRMS (electrospray) m/z calculated for C26H25N6O3 (M+H)+ 469.20, found 469.42
Figure imgf000396_0002
4-(3-((5-(5-Bromofuran-2-yl)-lH-pyrazol-3-yl)methylamino)-l,2,4-triazin-5-yl)-3- methylbenzonitrile (624)
1H NMR (400 MHz, CDCl3) δ 8.66 (s, IH), 7.52-7.46 (m, 3H), 6.52 (d, J= 3.2 Hz, IH), 6.38 (s, IH), 6.27 (d, J= 3.2 Hz, IH), 4.73 (bs, 2H), 2.38 (s, 3H); TLC i?/(«-Hexanes:EtOAc 1 :2) = 0.40; LRMS (electrospray) m/z calculated for C19H15BrN7O(M+H)+ 436.05, found 438.20
Figure imgf000396_0003
5-(3-((5-(4-Cyano-2-methylphenyl)-l,2,4-triazin-3-ylamino)methyl)-lJfiT-pyrazoI-5- yI)furan-2-carbonitrile (625)
1H NMR (400 MHz, CD3OD) δ 8.77 (s, IH), 7.68 (s, IH), 7.65-7.64 (m, 2H), 7.33 (d, J= 3.2 Hz, IH), 6.81 (d, J= 3.6 Hz, IH), 6.62 (s, IH), 4.68 (bs, 2H), 2.39 (s, 3H); TLC Rf(n- Hexanes:EtOAc 1 :2) = 0.37; LRMS (electrospray) m/z calculated for C20H15N8O(M+H)+ 383.14, found 383.24.
Figure imgf000397_0001
3-Methyl-4-(2-((5-(2-nitrophenyl)-lH-pyrazol-3-yl)methylamino)pyridin-4- yl)benzonitrile (626)
1K NMR (400 MHz, CDCl3) δ 8.21 (d, J= 4.8 Hz, IH), 7.71-7.66 (m, 2H), 7.58-7.50 (m, 3H), 7.44 (d, J= 8.4 Hz, IH), 7.23-7.19 (m, IH), 6.57 (d, J= 4.8 Hz, IH), 6.32 (bs, 2H), 5.00 (bs, IH), 4.59 (d, J= 5.6 Hz, 2H), 2.26 (s, 3H); TLC i?/(rc-Hexanes:EtOAc 1:2) = 0.60; LRMS (electrospray) m/z calculated for C23H19N6O2(M+H)+ 411.16, found 411.40.
Figure imgf000397_0002
4-(2-((5-(2-Aminophenyl)-ljHr-pyrazol-3-yl)methylamino)pyridin-4-yl)-3- methylbenzonitrile (627)
1H NMR (400 MHz, CDCl3) δ 8.22 (bs, IH), 7.53-7.43 (m, 3H), 7.08 (t, J= 7.6 Hz, IH), 6.73-6.72 (m, 2H), 6.57-6.56 (m, IH), 6.48 (s, IH), 6.31 (s, IH), 5.00 (bs, IH), 4.63 (d, J = 8.0 Hz, 2H), 2.26 (s, 3H); TLC i?/(«-Hexanes:EtOAc 1:2) = 0.57; LRMS (electrospray) m/z calculated for C23H21N6(M+H)+ 381.18, found 381.41.
Figure imgf000397_0003
3-Methyl-4-(2-((5-(3-nitrophenyl)-lH-pyrazol-3-yl)methylamino)pyridin-4- yl)benzonitrile (628)
1H NMR (400 MHz, CDCl3) δ 8.56 (d, J= 2.0 Hz, IH), 8.21 (d, J= 5.6 Hz, IH), 8.12-8.08 (m, 2H), 7.54-7.48 (m, 3H), 7.24-7.21 (m, IH), 6.57-6.55 (m, 2H), 6.33 (s, IH), 4.62 (d, J= 6.0 Hz, 2H), 2.24 (s, 3H); TLC ^(w-Hexanes: EtOAc 1:2) = 0.56; LRMS (electrospray) m/z calculated for C23Hi9N6O2(M+H)+ 411.16, found 411.40.
Figure imgf000398_0001
4-(2-((5-(3-Aininophenyl)-lH-pyrazoI-3-yl)methylamino)pyridin-4-yl)-3- methylbenzonitrile (629)
1H NMR (400 MHz, CDCl3) δ 8.20 (d, J= 5.2 Hz, IH), 7.52-7.49 (m, 2H), 7.17 (t, J= 7.2 Hz, IH), 7.04-7.01 (m, 3H), 6.64 (d, J= 8.4 Hz, IH), 6.54 (d, J= 4.8 Hz, IH), 6.44 (s, IH), 6.32 (s, IH), 5.00 (bs, IH), 4.59 (d, J= 5.2 Hz, 2H), 2.25 (s, 3H); TLC .fy(n-Hexanes:EtOAc 1:2) - 0.39 ; LRMS (electrospray) m/z calculated for C23H21N6(M+H)+ 381.18, found 381.41.
Figure imgf000398_0002
4-(2-(Benzo[rf]thiazoI-2-ylmethylamino)pyridin-4-yl)-3-methylbenzonitrile (630)
1H NMR (400 MHz, CDCl3) 5 8.18 (d, J= 4.8 Hz, IH), 7.96 (d, J= 8.0 Hz, IH), 7.82 (d, J= 8.1 Hz, 1H),7.51-7.44 (m, 3H), 7.35 (t, J= 7.4 Hz, IH), 7.23-7.22 (m, IH), 6.56 (d, J= 4.8 Hz, IH), 6.39 (s, IH), 5.53 (bs, IH), 5.00 (d, J= 6.0 Hz, 2H), 2.21 (s, 3H); TLC Rf(n- Hexanes:EtOAc 2:1) = 0.20.
Figure imgf000398_0003
4-(2-(Benzo [d\ oxazol-2-y lmethylamino)pyridin-4-yl)-3-methylbenzonitrile (631)
1H NMR (400 MHz, CDCl3) δ 8.15 (d, J= 5.2 Hz, IH), 7.68-7.65 (m, IH), 7.52-7.48 (m, 3H), 7.33-7.28 (m, 2H), 7.25-7.23 (m, IH), 6.54 (dd, J= 5.0, 1.4 Hz, IH), 6.45 (s, IH), 5.37 (t, J= 5.4 Hz, IH), 4.89 (d, J= 5.6 Hz, 2H), 2.24 (s, 3H); TLC i?/(rc-Hexanes:EtOAc 2:1) = 0.30; LRMS (electrospray) m/z calculated for C2iH17N4O (M+H)+ 341.14, found 341.34.
Figure imgf000398_0004
3-Methyl-4-(2-((4-nitrobenzo [d\ oxazol-2-yl)methylamino)pyridin-4-yl)benzonitrile (632)
1H NMR (400 MHz, CDCl3) δ 8.58 (d, J= 5.2 Hz, IH), 7.87 (d, J= 8.4 Hz, IH), 7.56-7.52 (m, 2H), 7.30 (d, J= 7.6 Hz, IH), 7.22 (d, J= 8.0 Hz, IH), 7.13 (s, IH), 7.01-6.93 (m, 2H), 4.79 (s, 2H), 2.30 (s, 3H); TLC i?/(«-Hexanes:EtOAc 2:1) = 0.43; LRMS (electrospray) m/z calculated for C21H16N5O3(M+H)+ 386.13, found 386.37.
Figure imgf000399_0001
4-(2-((5-(2-Fluorophenyl)-lJfir-pyrazol-3-yl)methylamino)pyridin-4-yl)-3- methylbenzonitrile (633)
1H NMR (400 MHz, CD3OD) δ 8.04 (d, J= 5.2 Hz, IH), 7.75 (bs, IH), 7.62 (s, IH), 7.57 (d, J= 8.8 Hz, IH), 7.33 (d, J= 8.0 Hz, 2H), 7.21-7.13 (m, 2H), 6.62 (d, J= 3.2 Hz, IH), 6.53 (d, J= 5.2 Hz, IH), 6.50 (s, IH), 4.56 (bs, 2H), 2.24 (s, 3H); TLC i?/(«-Hexanes:EtOAc 1:2) = 0.62; LRMS (electrospray) m/z calculated for C23Hi9N5(M+H)+ 384.16, found 384.40.
Figure imgf000399_0002
4-(2-(((5-(3-Fluorophenyl)-lH-pyrazol-3-yl)methyl)amino)pyridin-4-yl)-3- methylbenzonitrile (634)
1H NMR (400 MHz, CD3OD) δ 8.02 (d, J= 5.2 Hz, IH), 7.60 (s, IH), 7.54 (d, J= 8.0 Hz, IH), 7.50-7.38 (m, 3H), 7.30 (d, J- 7.6 Hz, IH), 6.99-6.98 (m, IH), 6.58 (s, IH), 6.51 (d, J= 4.0 Hz, IH), 6.46 (s, IH), 4.55 (bs, 2H), 2.22 (s, 3H); TLC i?/(«-Hexanes:EtOAc 1:2) = 0.66; LRMS (electrospray) m/z calculated for C23H19N5(M+H)+ 384.16, found 384.47.
Figure imgf000399_0003
635
4-(2-((4-Bromo-5-(5-bromothiophen-2-yl)-ljHr-pyrazol-3-yl)methylamino)pyridin-4-yl)-3- methylbenzonitrile (635) 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J= 5.2 Hz, IH), 7.49-7.45 (m, 2H), 7.36 (d, J= 4.0 Hz, IH), 7.17 (d, J= 8.0 Hz, IH), 6.98 (d, J= 4.0 Hz, IH), 6.51 (d, J= 5.2 Hz, IH), 6.33 (s, IH), 5.59 (bs, IH), 4.53 (d, J= 4.4 Hz, 2H), 2.22 (s, 3H); TLC i?/(«-Hexanes: EtOAc 2:1) = 0.21.
Figure imgf000400_0001
636
4-(2-((4-Bromo-5-(thiophen-2-yI)-lH-pyrazol-3-yl)methylamino)pyridin-4-yl)-3- methylbenzonitrile (636)
1H NMR (400 MHz, CD3OD) δ 7.99 (d, J= 5.2 Hz, IH), 7.56-7.54 (m, 2H), 7.51 (dd, J= 7.8, 1.4 Hz, IH), 7.38-7.37 (m, IH), 7.26 (d, J= 8.0 Hz, IH), 7.05-7.03 (m, IH), 6.48 (dd, J- 5.4, 1.4 Hz, IH), 6.44 (s, IH), 4.50 (s, 2H), 2.19 (s, 3H); TLC i?/(«-Hexanes:EtOAc 1 :2) = 0.26.
Figure imgf000400_0002
3-Methyl-4-(2-(oxazolo[4,5-6]pyridin-2-ylmethylamino)pyridin-4-yl)benzonitrile (637)
1H NMR (400 MHz, CD3OD) δ 8.40 (d, J= 4.8 Hz, IH), 7.99 (d, J= 8.0 Hz, IH), 7.95 (d, J= 5.6 Hz, IH), 7.61 (s, IH), 7.56 (d, J= 8.4 Hz, IH), 7.36-7.31 (m, 2H), 6.58 (s, IH), 6.52 (d, J - 5.2 Hz, IH), 4.84 (s, 2H), 2.25 (s, 3H); LRMS (electrospray) m/z calculated for C20H16N5O(M+H)+ 342.14, found 342.43.
Figure imgf000400_0003
638
4-(2-((5-(2,4-DichlorophenyI)-lHr-pyrazol-3-yl)methylamino)pyridiii-4-yl)-3- methylbenzonitrile (638)
1H NMR (400 MHz, CDCl3) δ 8.14 (d, J= 5.2 Hz, IH), 7.59 (d, J= 8.4 Hz, IH), 7.48-7.46 (m, 2H), 7.41 (d, J= 2.0 Hz, IH), 7.22-7.18 (m, 2H), 6.62 (s, IH), 6.51 (dd, J= 3.2, 2.0 Hz, IH), 6.31 (s, IH), 5.42 (bs, IH), 4.58 (d, J= 5.6 Hz, 2H), 2.21 (s, 3H); TLC i?/(«-Hexanes:EtOAc 2:1) = 0.61; LRMS (electrospray) m/z calculated for C23Hi8Cl2N5O(M+H)+ 434.09, found 434.46.
Figure imgf000401_0001
639
4-(2-((5-(2-Chloro-4-methoxyphenyl)-lH-pyrazol-3-yl)methylamino)pyridin-4-yl)-3- methylbenzonitrile (639)
1H NMR (400 MHz, CDCl3) δ 8.18 (d, J= 5.6 Hz, IH), 7.55-7.49 (m, 3H), 7.25-7.24 (m, IH), 6.97 (d, J= 2.4 Hz, IH), 6.85 (dd, J= 8.8, 2.4 Hz, IH), 6.55-6.52 (m, 2H), 6.33 (s, IH), 5.16 (bs, IH), 4.60 (d, J= 5.6 Hz, 2H), 3.81 (s, 3H), 2.25 (s, 3H); TLC i?/(«-Hexanes: EtOAc 1:2) = 0.33; LRMS (electrospray) m/z calculated for C24H2 ,C1N5O(M+H)+ 430.14, found 430.45.
Figure imgf000401_0002
4-(2-((5-(2-Chloro-4-hydroxyphenyl)-liϊ-pyrazol-3-yl)methyIamino)pyridin-4-yl)-3- methylbenzonitrile (640)
1H NMR (400 MHz, CD3OD) δ 7.99 (d, J= 5.6 Hz, IH), 7.57 (s, IH), 7.52 (dd, J= 8.0, 1.2 Hz, IH), 7.32-7.26 (m, 2H), 6.83 (d, J= 2.4 Hz, IH), 6.70 (dd, J= 8.4, 2.4 Hz, IH), 6.48 (dd, J= 5.4, 1.4 Hz, IH), 6.45 (d, J= 1.2 Hz, 2H), 4.50 (s, 2H), 2.19 (s, 3H); TLC Rf(n- Hexanes:EtOAc 1 :2) = 0.31; LRMS (electrospray) m/z calculated for C23H19C1N5O(M+H)+ 416.13, found 416.44.
Figure imgf000401_0003
4-(2-((5-(2-Fluoro-4-methoxyphenyl)-l/T-pyrazol-3-yl)methylamino)pyridiii-4-yl)-3- methylbenzonitrile (641)
1K NMR (400 MHz, CDCl3) δ 8.17 (d, J= 4.8 Hz, IH), 7.63 (t, J= 9.0 Hz, IH), 7.51-7.47 (m, 2H), 7.24-7.22 (m, IH), 6.72 (dd, J= 8.6, 2.6 Hz, IH), 6.66 (dd, J= 13.0, 2.6 Hz, IH), 6.51- 6.50 (m, 2H), 6.33 (s, IH), 4.57 (d, J= 5.6 Hz, 2H), 3.80 (s, 3H), 2.23 (s, 3H); TLC Rf(n- Hexanes:EtOAc 1:2) = 0.35; LRMS (electrospray) m/z calculated for C24H21FN5O(M+H)+ 414.17, found 414.53.
Figure imgf000402_0001
642
4-(2-((5-(2-Fluoro-4-hydroxyphenyl)-l£r-pyrazol-3-yl)methylamino)pyridin-4-yl)-3- methylbenzonitrile (642)
1H NMR (400 MHz, CD3OD) δ 8.16 (t, J= 2.8 Hz, IH), 7.62 (t, J= 8.8 Hz, IH), 7.53-7.47 (m, 2H), 7.24 (t, J= 8.0 Hz, IH), 6.74-6.65 (m, 2H), 6.55-6.50 (m, 2H), 6.33 (s, IH), 4.607 (d, J- 8.0 Hz, 2H), 2.23 (s, 3H); TLC i?/(«-Hexanes: EtOAc 1 :2) - 0.30; LRMS (electrospray) m/z calculated for C23Hi9FN5O (M+H)+ 400.16, found 400.38.
Figure imgf000402_0002
643
4-(2-((5-(3-Chloro-4-fluorophenyI)-ljfir-pyrazol-3-yl)methylamino)pyridin-4-yl)-3- methylbenzonitrile (643)
1H NMR (400 MHz, CDCl3) δ 8.22 (d, J= 5.2 Hz, IH), 7.78 (dd, J= 7.0, 2.2 Hz, IH), 7.62- 7.58 (m, IH), 7.53-7.50 (m, 2H), 7.24-7.22 (m, IH), 7.14 (t, J= 8.8 Hz, IH), 6.57 (dd, J= 5.2, 1.2 Hz, IH), 6.42 (s, IH), 6.32 (s, IH), 5.03 (bs, IH), 4.60 (d, J= 5.6 Hz, 2H), 2.25 (s, 3H); TLC i?/(«-Hexanes:EtOAc 1:2) = 0.45; LRMS (electrospray) m/z calculated for C23H18C1FN5(M+H)+ 418.12, found 418.41.
Figure imgf000402_0003
644
4-(2-((5-(4-Fluoro-3-methoxyphenyl)-lH-pyrazoI-3-yl)methylamino)pyridin-4-yl)-3- methylbenzonitrile (644)
1H NMR (400 MHz, CD3OD) δ 7.98 (d, J= 5.2 Hz, IH), 7.56 (s, IH), 7.51 (d, J= 7.2 Hz, IH), 7.37-7.35 (m, IH), 7.26 (d, J= 7.6 Hz, IH), 7.18-7.12 (m, IH), 7.04-6.99 (m, IH), 6.50 (s, !H), 6.47 (d, J= 4.8 Hz, IH), 6.43 (s, IH), 4.50 (s, 2H), 3.83 (s, 3H), 2.18 (s, 3H); TLC Rf (rc-Hexanes:EtOAc 1 :2) = 0.33; LRMS (electrospray) m/z calculated for C24H21FN5O(MH-H)+ 414.17, found 414.53.
Figure imgf000403_0001
645
4-(2-((5-(6-Methoxypyridin-2-yl)-lJHr-pyrazol-3-yI)methylamino)pyridin-4-yl)-3- methylbenzonitrile (645)
1U NMR (400 MHz, CDCl3) δ 8.17 (d, J= 5.2 Hz, IH), 7.59 (t, J= 7.0 Hz, IH), 7.51-7.48 (m, 2H), 7.25-7.20 (m, 2H), 6.67 (d, J= 4.4 Hz, 2H), 6.51 (d, J= 5.2 Hz, IH), 6.34 (s, IH), 5.28 (bs, IH), 4.60 (d, J= 5.2 Hz, 2H), 3.97 (s, 3H), 2.24 (s, 3H); TLC i?/(n-Hexanes: EtOAc 1:2) = 0.44; LRMS (electrospray) m/z calculated for C23H2 ΪN60(M+H)+ 397.18, found 397.46.
Figure imgf000403_0002
646
4-(2-((5-(2-Bromo-4-fluorophenyl)-lH-pyrazol-3-yl)methyIamino)pyridin-4-yl)-3- methylbenzonitrile (646)
1H NMR (400 MHz, CDCl3) δ 8.14 (d, J= 5.2 Hz, IH), 7.55-7.47 (m, 3H), 7.35 (dd, J= 8.2, 2.6 Hz, IH), 7.23 (t, J= 7.9 Hz, IH), 7.04-6.99 (m, IH), 6.56 (s, IH), 6.52 (dd, J= 5.2, 1.2 Hz, IH), 6.33 (s, IH), 5.49 (bs, IH), 4.59 (bs, 2H), 2.23 (s, 3H); TLC i?/(«-Hexanes:EtOAc 1 :2) = 0.53.
Figure imgf000403_0003
4-(2-((5-(4-FIuoro-3-hydroxyphenyI)-lJE-r-pyrazol-3-yl)methylamino)pyridin-4-yl)-3- methylbenzonitrile (647)
1H NMR (400 MHz, CDCl3) δ 8.01 (bs, IH), 7.44-7.39 (m, 2H), 7.25-7.24 (m, IH), 7.08-7.02 (m, IH), 6.95-6.93 (m, IH), 6.82-6.79 (m, IH), 6.43 (bs, IH), 6.21 (s, IH), 6.08-6.04 (m, IH), 5.55 (bs, IH), 4.47 (bs, 2H), 2.10 (s, 3H); TLC £/ (CH2Cl2 :MeOH 10:1) = 0.22; LRMS (electrospray) m/z calculated for C23H18FN5O(M+H)+ 400.16, found 400.38.
Figure imgf000404_0001
4-(2-((5-(5-Fluoropyridin-2-yl)-lH-pyrazol-3-yl)methylamino)pyridin-4-yl)-3- methylbenzonitrile (648)
1H NMR (400 MHz, CDCl3) δ 8.41 (bs, IH), 8.16 (d, J= 5.6 Hz, IH), 7.72-7.70 (m, IH), 7.49-7.39 (m, 3H), 7.21 (d, J= 7.6 Hz, IH), 6.67 (s, IH), 6.49 (d, J= 5.2 Hz, IH), 6.34 (s, IH), 5.57 (bs, IH), 4.59 (bs, 2H), 2.21 (s, 3H); LRMS (electrospray) m/z calculated for C22HlgFN6(M+H)+ 385.16, found 385.35.
Figure imgf000404_0002
4-(2-((6-Methoxy-l//-pyrazolo[3,4-£]pyridin-3-yl)methylamino)pyridin-4-yl)-3- methylbenzonitrile (649)
1H NMR (400 MHz, CD3OD) δ 8.05 (d, J= 5.2 Hz, IH), 8.01 (d, J- 8.4 Hz, IH), 7.62 (s, IH), 7.58-7.56 (m, IH), 7.31 (d, J= 7.6 Hz, IH), 6.55-6.51 (m, 3H), 4.78 (s, 2H), 3.94 (s, 3H), 2.21 (s, 3H); TLC i?/(«-Hexanes:EtOAc 1:1) = 0.53.
Figure imgf000404_0003
3-Methyl-4-(2-((6-oxo-6,7-dihydro-l//-pyrazolo[3,4-6]pyridin-3- yl)methylamino)pyridin-4-yl)benzonitrile (650)
1H NMR (400 MHz, CD3OD) δ 8.08 (d, J= 5.6 Hz, IH), 7.90 (d, J= 9.2 Hz, IH), 7.65 (s, IH), 7.59 (t, J= 4.0 Hz, IH), 7.34 (d, J= 8.0 Hz, IH), 6.58-6.56 (m, IH), 6.49 (s, IH), 6.19 (d, J= 9.2 Hz, IH), 4.72 (s, 2H), 2.25 (s, 3H); TLC i?/(CH2Cl2:Me0H 10:1) = 0.48. References
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12. Tatematsu, H., Kilkuskie, R.E., Corrigan, A. J., Bodner, A.J. and Lee, K-H. 1991. Anti- Aids Agents, 3. Inhibitory effects of colchicine derivatives on HIV replication in H9 lymphocyte cells. J. Nat. Prod. 54:632-637.
13. Gao, W-Y., Johns, D. G., Tanaka, M. and Mitsuya, H. 1999. Suppression of replication of multidrug-resistant HIV type 1 variants by combinations of thymidylate synthase inhibitors with zidovudine or stavudine. MoI. Pharmacol. 55:535-540. Table 1 :
Compound EC 50 Compound EC 50
Figure imgf000406_0001
Activity ranqe: +++ indicates < 1 uM, ++ indicates between 1-5 uM, + indicates > 5 uM Compound EC 50 Compound EC 50
Figure imgf000407_0001
Activity range: +++ indicates < 1 uM, ++ indicates between 1 -5 uM, + indicates > 5 uM Compound EC, 50 Compound EC 50
Figure imgf000408_0001
Activity range: +++ indicates < 1 uM, ++ indicates between 1-5 uM, + indicates > 5 uM Compound EC 50 Compound EC 50
Figure imgf000409_0001
Activity range: +++ indicates < 1 uM, ++ indicates between 1-5 uM, + indicates > 5 uM Compound EC50 Compound EC 50
Figure imgf000410_0001
Activity range: +++ indicates < 1 uM, ++ indicates between 1-5 uM, + indicates > 5 uM Compound EC.50 Compound EC 50
Figure imgf000411_0001
Activity range: +++ indicates < 1 uM, ++ indicates between 1-5 uM, + indicates > 5 uM Compound EC 50 Compound EC 50
Figure imgf000412_0001
Activity range: +++ indicates ≤ 1 uM, ++ indicates between 1-5 uM, + indicates > 5 uM Compound EC 50 Compound EC 50
Figure imgf000413_0001
Activity range: +++ indicates < 1 uM, ++ indicates between 1-5 uM, + indicates > 5 uM Compound EC 5Q Compound EC 50
Figure imgf000414_0001
Activity range: +++ indicates < 1 uM, ++ indicates between 1-5 uM, + indicates > 5 uM Compound EC 50 Compound EC 50
Figure imgf000415_0001
Activity range: +++ indicates < 1 uM, ++ indicates between 1-5 uM, + indicates > 5 uM Compound EC 50 Compound EC 50
Figure imgf000416_0001
Activity range: +++ indicates < 1 uM, ++ indicates between 1-5 uM, + indicates > 5 uM Compound EQ 50 Compound EC 50
Figure imgf000417_0001
Activity range: +++ indicates ≤ 1 uM, ++ indicates between 1-5 uM, + indicates > 5 uM Compound EC •50 Compound EC ■50
Figure imgf000418_0001
Activity range: +++ indicates ≤ 1 uM, ++ indicates between 1-5 uM, + indicates > 5 uM Compound EC ■50 Compound EC 50
Activity range: +++ indicates ≤ 1 uM, ++ indicates between 1-5 uM, + indicates > 5 uM Compound EC 50 Compound EC 50
Figure imgf000420_0001
Figure imgf000420_0002
Activity range: +++ indicates < 1 uM, ++ indicates between 1-5 uM, + indicates > 5 uM Compound EC 50 Compound EC 50
Figure imgf000421_0001
Activity range: +++ indicates ≤ 1 uM, ++ indicates between 1-5 uM, + indicates > 5 uM Compound EC50 Compound EC50
Figure imgf000422_0001
Activity range: +++ indicates < 1 uM, ++ indicates between 1-5 uM, + indicates > 5 uM Compound EC50 Compound EC50
Figure imgf000423_0001
Activity range: +++ indicates < 1 uM, ++ indicates between 1-5 uM, + indicates > 5 uM Compound EC50 Compound EC50
Figure imgf000424_0001
Activity range: +++ indicates ≤ 1 uM, ++ indicates between 1-5 uM, + indicates > 5 uM Compound EC 50 Compound EC50
Figure imgf000425_0001
Activity range: +++ indicates ≤ 1 uNI, ++ indicates between 1-5 uM, + indicates > 5 uM Compound EC 50 Compound EC 50
Figure imgf000426_0001
Activity range: +++ indicates ≤ 1 uM, ++ indicates between 1-5 uM, + indicates > 5 uM Compound EC 50 Compound EC 50
Figure imgf000427_0001
Activity range: +++ indicates ≤ 1 uNl, ++ indicates between 1-5 uNI, + indicates > 5 uM Compound EC 50 Compound EC 50
Figure imgf000428_0001
Activity range: +++ indicates ≤ 1 uM, ++ indicates between 1 -5 uM, + indicates > 5 uM Compound EC 50 Compound EC 50
Figure imgf000429_0001
Activity range: +++ indicates ≤ 1 uM, ++ indicates between 1-5 uM, + indicates > 5 uM Compound EC 50 Compound EC 50
Figure imgf000430_0001
Activity range: +++ indicates ≤ 1 uM, ++ indicates between 1-5 uM, + indicates > 5 uM Compound EC 50 Compound EC 50
Figure imgf000431_0001
Activity range: +++ indicates ≤ 1 uM, ++ indicates between 1-5 uM, + indicates > 5 uM Compound EC 50 Compound EC 50
Figure imgf000432_0001
Activity range: +++ indicates < 1 uM, ++ indicates between 1-5 uM, + indicates > 5 uM Compound EC 50 Compound EC 50
Figure imgf000433_0001
Activity range: +++ indicates ≤ 1 uM, ++ indicates between 1-5 uM, + indicates > 5 uM Compound EC50 Compound EC 5Q
Figure imgf000434_0001
Activity range: +++ indicates ≤ 1 uWI, ++ indicates between 1-5 uM, + indicates > 5 uM Compound EC 50 Compound EC50
Figure imgf000435_0001
Activity range: +++ indicates < 1 uM, ++ indicates between 1-5 uM, + indicates > 5 uM Compound EC 50 Compound EC 50
Figure imgf000436_0001
Activity range: +++ indicates < 1 uM, ++ indicates between 1-5 uM, + indicates > 5 uM Compound EC.50 Compound EC 50
Figure imgf000437_0001
Activity range: +++ indicates < 1 uM, ++ indicates between 1-5 uM, + indicates > 5 uWI Compound EC 5Q Compound EC 50
Figure imgf000438_0001
Activity range: +++ indicates < 1 uM, ++ indicates between 1-5 uM, + indicates > 5 uM Compound EC 50 Compound EC 5, 0
Figure imgf000439_0001
Activity range: +++ indicates ≤ 1 uWI, ++ indicates between 1-5 uM, + indicates > 5 uM

Claims

Claims
1. A compound of the formula II:
Figure imgf000440_0001
II
wherein, m is 1, 2, 3, or 4; n is 1, 2, or 3; o is 1, 2, or 3;
A is C5-C12 aryl or C5-Ci2 heteroaryl;
B, C, D and E are each independently selected from the group consisting of C(R2), C(O), C(S),
N, or N oxide; each R1 is independently selected from the group consisting of hydrogen, halogen, -CN, C1-C5 alkyl, C1-C3 haloalkyl, , C2-C5 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, hydroxyl, C1-C8 alkoxy, -C(O)OR3, -C(O)N(R3)2, aryl, oxo, -OH, -OR3, -OCH2R3, -R4CN, -NO2, -
N(R3)C(O)R3, -N(R3)2, aryl, benzyl, or heteroaryl; each R2 is independently selected from the group consisting of hydrogen, halogen, C1-C5 alkyl,
Ci-C3 haloalkyl, C3-C7 cycloalkyl, -OH, -OR3, -CN, -NO2, -N(R3)2, aryl, benzyl, or heteroaryl; each R3 is independently selected from the group consisting of hydrogen, C1-C8 alkyl, C1-C3 haloalkyl, C3-C7 cycloalkyl, C1-C3 alkylaryl, aryl, benzyl, or; heteroaryl; each R4 is independently selected from the group consisting of Ci-C6 alkyl, C1-C8 alkylene,
C1-C8 alkenylene, C1-C8 alkynylene, each optionally substituted with at least one hydroxyl or hydrogen;
X and Y are each independently selected from the group consisting of -C(R5R6)-, -N(R5)-, -
0-, -S-, -S(O)2-, or -C(O)-;
R5 and R6 are each independently selected from the group consisting of hydrogen, halogen,
Ci-C8 alkyl, aryl, or C(O)R1;
Z is selected from the group consisting of:
Figure imgf000441_0001
Figure imgf000442_0001
Aryl is C4-C12 aryl and is optionally substituted;
HetA and heteroaryl are C3-C10 heteroaryl and are optionally substituted,
R7, R8, R9 and R10 are each independently selected from the group consisting of hydrogen, halogen, C1-Ci0 alkyl, C1-C3 haloalkyl, C3-C7 cycloalkyl, hydroxyl, oxo, -OR11, -C(O)OR11, -
C(O)R11, -C(O)N(R1 %, -CN, -NO2, -NH2, -N(R1 *)2, -OR4HetA, -OR4N(R1 ^2, -
C(O)N(Rn)HetA, -C(O)HetA, -C(O)N(R1 ^R4S(O)2R11; -S(O)2N(R11^, -S(O)2R11, -
N(R1 ^C(O)R4SR11, -N(R1 ^R4S(O)2R11, or -N(R1 ^S(O)2R11, aryl, benzyl, or heterocyclyl; R11 is each independently selected from the group consisting of hydrogen, C1-C8 alkyl optionally substituted with at least one hydroxyl or halogen; C3-C7 cycloalkyl, aryl; benzyl, or heterocyclyl.
2. The compound according to claim 1, which is one of the formulas 324-650 as shown in Table 1 as well as shown in Example 3 including
Figure imgf000443_0001
Figure imgf000444_0001
Figure imgf000445_0001
Figure imgf000446_0001
Figure imgf000447_0001
Figure imgf000448_0001
Figure imgf000449_0001
Figure imgf000450_0001
Figure imgf000451_0001
450
Figure imgf000452_0001
Figure imgf000453_0001
3. A compound having the general formula I:
Figure imgf000453_0002
wherein
A is selected from the group consisting of;
Figure imgf000454_0001
m is 1, 2, 3 or 4; n is 1, 2, or 3;
X is selected from the group consisting of NR4, O, or S;
Y and Z are independently selected from the group consisting of NR4, C, O, or S;
R1 is selected from the group consisting of hydrogen, halogen, C1-C10 alkyl, C3-C1O cycloalkyl,
C2-C10 alkenyl, C3-C10 cycloalkenyl, C2-Ci0 alkynyl, C1-C10 haloalkyl, -OH, -OR5, C1-C10 alkoxy, C3-C10 cycloalkoxy, C3-C15 cycloalkylalkoxy, C3-C15 cycloalkylalkyl, -CN, -NO2, -
NH2, -N(R5)2, -C(O)R5, -C(O)OR5, -C(O)N(R5)2, -SR5, -S(O)R5, -S(O)2R5, -S(O)2N(R5),, aryl, benzyl, heteroaryl, or heterocyclyl;
R2 is each independently selected from the group consisting of hydrogen, halogen, C1-C10 alkyl, C3-C10 cycloalkyl, hydroxyl, -OR5, -CN, -NO2, -NH2, -N(R5)C(O)R5, -C(O)R5, -
C(O)OR5, -C(O)N(R5)2; -S(O)R5, -S(O)2R5, -S(O)2N(R5)2, aryl, benzyl, heteroaryl, heterocyclyl or two groups of R are connected each other to make five or six membered cyclic and heterocyclic rings; each R3 is independently selected from the group consisting of hydrogen, halogen, C1-C10 alkyl, C3-C10 cycloalkyl, hydroxyl, -OR5, -CN, -NO2, -NH2, -N(R5)C(O)R5, -C(O)R5, -
C(O)OR5, -C(O)N(R5X S(O)R5, -S(O)2R5, -S(O)2N(R5)2, aryl, benzyl, heteroaryl, heterocyclyl, or two groups of R3 are connected each other to make five or six membered cyclic and heterocyclic rings;
R4 is independently selected from the group consisting from hydrogen, C1-C10 alkyl, C3-C10 cycloalkyl, C2-C10 alkenyl, C3-C10 cycloalkenyl, C2-Ci0 alkynyl, C1-C10 haloalkyl, -C(O)R5, -
C(O)OR5, -C(O)N(R5)2, -S(O)R5, -S(O)2R5, -S(O)2N(R5)2, aryl, benzyl, heteroaryl, or heterocyclyl;
R5 is independently selected from the group consisting from hydrogen, Ci-Ci0 alkyl, C3-Ci0 cycloalkyl, C2-Ci0 alkenyl, C3-C10 cycloalkenyl, C2-C10 alkynyl, C1-Ci0 haloalkyl, aryl, benzyl, heteroaryl, or heterocyclyl.
4. The compound according to claim 3 having one of the formulas 1-323 as shown in Table 1 as well as shown in Example 3 including
Figure imgf000455_0001
Figure imgf000456_0001
Figure imgf000457_0001
Figure imgf000458_0001
Figure imgf000459_0001
Figure imgf000460_0001
Figure imgf000461_0001
Figure imgf000462_0001
Figure imgf000463_0001
Figure imgf000464_0001
Figure imgf000465_0001
5. A use of a compound according to any of claims 1-4 for manufacturing a pharmaceutical composition for treatment of a viral infection.
6. The use according to claim 5, in which the viral infection is human immunodeficiency virus (HIV) infection.
7. A pharmaceutical composition comprising a compound according to any of claims 1-4 and a pharmaceutically acceptable carrier.
8. A method of treatment of a viral infection, comprising administering an effective amount of a compound according to any of claims 1-4 to a subject in need thereof.
9. The method according to claim 8, wherein the viral infection is human immunodeficiency virus (HIV) infection.
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