MXPA06005033A - Macrocyclic kinase inhibitors - Google Patents
Macrocyclic kinase inhibitorsInfo
- Publication number
- MXPA06005033A MXPA06005033A MXPA/A/2006/005033A MXPA06005033A MXPA06005033A MX PA06005033 A MXPA06005033 A MX PA06005033A MX PA06005033 A MXPA06005033 A MX PA06005033A MX PA06005033 A MXPA06005033 A MX PA06005033A
- Authority
- MX
- Mexico
- Prior art keywords
- group
- hydrogen
- oxo
- alkyl
- epiazeno
- Prior art date
Links
- 239000003757 phosphotransferase inhibitor Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 258
- 102000001253 Protein Kinases Human genes 0.000 claims abstract description 10
- 108060006633 Protein Kinases Proteins 0.000 claims abstract description 4
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 3
- 239000000203 mixture Substances 0.000 claims abstract description 3
- 239000001257 hydrogen Substances 0.000 claims description 848
- 229910052739 hydrogen Inorganic materials 0.000 claims description 848
- 125000000217 alkyl group Chemical group 0.000 claims description 550
- 125000003545 alkoxy group Chemical group 0.000 claims description 527
- 125000003118 aryl group Chemical group 0.000 claims description 501
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 405
- 150000002431 hydrogen Chemical group 0.000 claims description 382
- 229910052736 halogen Inorganic materials 0.000 claims description 292
- 150000002367 halogens Chemical class 0.000 claims description 291
- -1 alkoxyalkoxyalkoxy Chemical group 0.000 claims description 270
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 243
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 240
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 239
- 125000005083 alkoxyalkoxy group Chemical group 0.000 claims description 237
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 236
- 125000005113 hydroxyalkoxy group Chemical group 0.000 claims description 235
- 125000003342 alkenyl group Chemical group 0.000 claims description 233
- 125000005280 halo alkyl sulfonyloxy group Chemical group 0.000 claims description 231
- 125000001424 substituent group Chemical group 0.000 claims description 230
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 226
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 175
- 125000005016 hydroxyalkynyl group Chemical group 0.000 claims description 141
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 129
- 125000004441 haloalkylsulfonyl group Chemical group 0.000 claims description 127
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 123
- 125000004692 haloalkylcarbonyl group Chemical group 0.000 claims description 122
- 229910052701 rubidium Inorganic materials 0.000 claims description 120
- 125000000623 heterocyclic group Chemical group 0.000 claims description 116
- 125000001072 heteroaryl group Chemical group 0.000 claims description 66
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 49
- 125000001188 haloalkyl group Chemical group 0.000 claims description 48
- 125000005114 heteroarylalkoxy group Chemical group 0.000 claims description 43
- 125000005143 heteroarylsulfonyl group Chemical group 0.000 claims description 37
- 125000005223 heteroarylcarbonyl group Chemical group 0.000 claims description 36
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 31
- 125000000304 alkynyl group Chemical group 0.000 claims description 27
- 125000005326 heteroaryloxy alkyl group Chemical group 0.000 claims description 18
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 11
- 125000004429 atoms Chemical group 0.000 claims description 6
- 150000002118 epoxides Chemical class 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 239000011780 sodium chloride Substances 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 125000002947 alkylene group Chemical group 0.000 claims description 3
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 3
- 201000011510 cancer Diseases 0.000 claims description 3
- 125000005020 hydroxyalkenyl group Chemical group 0.000 claims description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims 5
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 claims 4
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims 4
- QLNJFJADRCOGBJ-UHFFFAOYSA-N Propanamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 claims 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 3
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims 2
- ROPZSSDOSDTJPL-UHFFFAOYSA-N 1-fluoroethanesulfonamide Chemical compound CC(F)S(N)(=O)=O ROPZSSDOSDTJPL-UHFFFAOYSA-N 0.000 claims 1
- 125000001137 3-hydroxypropoxy group Chemical group [H]OC([H])([H])C([H])([H])C([H])([H])O* 0.000 claims 1
- VFQXVTODMYMSMJ-UHFFFAOYSA-N Isonicotinamide Chemical compound NC(=O)C1=CC=NC=C1 VFQXVTODMYMSMJ-UHFFFAOYSA-N 0.000 claims 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims 1
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims 1
- 125000000477 aza group Chemical group 0.000 claims 1
- 125000002648 azanetriyl group Chemical group *N(*)* 0.000 claims 1
- 125000005243 carbonyl alkyl group Chemical group 0.000 claims 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims 1
- 125000005102 carbonylalkoxy group Chemical group 0.000 claims 1
- 125000004181 carboxyalkyl group Chemical group 0.000 claims 1
- 239000000969 carrier Substances 0.000 claims 1
- 239000003610 charcoal Substances 0.000 claims 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims 1
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 claims 1
- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 claims 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 1
- DFPAKSUCGFBDDF-UHFFFAOYSA-N nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims 1
- 235000005152 nicotinamide Nutrition 0.000 claims 1
- 239000011570 nicotinamide Substances 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- IBBMAWULFFBRKK-UHFFFAOYSA-N picolinamide Chemical compound NC(=O)C1=CC=CC=N1 IBBMAWULFFBRKK-UHFFFAOYSA-N 0.000 claims 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 257
- 125000004076 pyridyl group Chemical group 0.000 description 96
- 125000004438 haloalkoxy group Chemical group 0.000 description 46
- 125000002757 morpholinyl group Chemical group 0.000 description 46
- 125000003386 piperidinyl group Chemical group 0.000 description 45
- 125000002883 imidazolyl group Chemical group 0.000 description 24
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 24
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 18
- 239000000758 substrate Substances 0.000 description 11
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Chemical group [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 8
- 108091000081 Phosphotransferases Proteins 0.000 description 6
- 210000004027 cells Anatomy 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 229910052759 nickel Inorganic materials 0.000 description 4
- 125000005819 alkenylalkoxy group Chemical group 0.000 description 3
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 3
- 125000005093 alkyl carbonyl alkyl group Chemical group 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 125000005191 hydroxyalkylamino group Chemical group 0.000 description 2
- 230000003463 hyperproliferative Effects 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- 108060006672 BUB1 Proteins 0.000 description 1
- 101700051654 CDK1 Proteins 0.000 description 1
- 101700048555 CDK2 Proteins 0.000 description 1
- 101710015564 CHEK1 Proteins 0.000 description 1
- 108060006647 CHEK2 Proteins 0.000 description 1
- 108010025464 Cyclin-Dependent Kinase 4 Proteins 0.000 description 1
- 102000013701 Cyclin-Dependent Kinase 4 Human genes 0.000 description 1
- 230000033616 DNA repair Effects 0.000 description 1
- 101700025368 ERBB2 Proteins 0.000 description 1
- 102100016662 ERBB2 Human genes 0.000 description 1
- 108091008101 FGF receptors Proteins 0.000 description 1
- 102100013180 KDR Human genes 0.000 description 1
- 108060005170 MYT1 Proteins 0.000 description 1
- 102100004939 PDGFRB Human genes 0.000 description 1
- 101710018346 PDGFRB Proteins 0.000 description 1
- 101700011770 PDK1 Proteins 0.000 description 1
- 101710012541 SPEAR1 Proteins 0.000 description 1
- 101710009384 SRC Proteins 0.000 description 1
- 102000001332 SRC Human genes 0.000 description 1
- 241000282890 Sus Species 0.000 description 1
- 102100016327 TEK Human genes 0.000 description 1
- 101710037124 TEK Proteins 0.000 description 1
- 101710012548 TIE1 Proteins 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 108091007928 VEGF receptors Proteins 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 125000004450 alkenylene group Chemical group 0.000 description 1
- 125000004948 alkyl aryl alkyl group Chemical group 0.000 description 1
- 125000005418 aryl aryl group Chemical group 0.000 description 1
- 125000005325 aryloxy aryl group Chemical group 0.000 description 1
- 235000013877 carbamide Nutrition 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000003831 deregulation Effects 0.000 description 1
- 102000017256 epidermal growth factor-activated receptor activity proteins Human genes 0.000 description 1
- 108040009258 epidermal growth factor-activated receptor activity proteins Proteins 0.000 description 1
- 102000017175 fibroblast growth factor-activated receptor activity proteins Human genes 0.000 description 1
- 125000005027 hydroxyaryl group Chemical group 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000000394 mitotic Effects 0.000 description 1
- 230000000051 modifying Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000002989 phenols Chemical group 0.000 description 1
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 230000022983 regulation of cell cycle Effects 0.000 description 1
- 230000001105 regulatory Effects 0.000 description 1
- 230000028617 response to DNA damage stimulus Effects 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
Abstract
Compounds having the formula (I) are useful for inhibiting protein kinases. Also disclosed are methods of making the compounds, compositions containing the compounds, and methods of treatment using the compounds
Description
INHIBITORS OF MACROCICLICOS KINASE
This application claims priority of the Provisional Patent Application of E.U.A. No. 60 / 517,627, filed November 5, 2003, incorporated herein by reference.
Technical Field The present invention relates to substituted ureas, which are useful for inhibiting protein kinases, methods for making the compounds, compositions containing the compounds, and methods of treatment using the compounds.
BACKGROUND OF THE INVENTION Protein kinases have clearly been shown to be important in the establishment progress of many diseases that are induced by inadequate cell proliferation. These kinases have often been found to be over-regulated in many hyperproliferative states such as cancer. These kinases may be important in cell signaling, where their inappropriate activation induces cells to proliferate (eg, EGFR, ERBB2, VEGFR, FGFR, PDGFR, c-Met, IGF-1R, RET,
TIE2). Alternatively, these are involved in signal translation within the cell (e.g., c-Src, PKC, Akt, PKA, c-Abl,
PDK-1). Often these signal transduction genes are recognized as proto-oncogenes. Many of these kinases
control the progress of the cell cycle near the transition of G1-S (for example, Cdk2, Cdk4), and the G2-M transition (for example, Weel, Myt1, Chk1, Cdc2) or at the control point of the mitotic spindle (P1k, Auroral or 2, Bub1 or 3). Furthermore, the kinases are intimately bound to the DNA damage response (eg, ATM, ATR, Chk2). The deregulation of these cellular functions: cell signaling, signal transduction, cell cycle control, and DNA repair are all hallmarks of hyperproliferative diseases, particularly cancer. Therefore it is likely that the pharmacological modulation of one or more of the kinases could be useful to slow or stop the progress of the disease in these diseases.
COMPENDIUM OF THE INVENTION
In this initial embodiment the present invention provides a compound of the formula (!)
or a therapeutically acceptable salt thereof, wherein
it is an individual or double link; A is selected from the group consisting of aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted with one, two, or three substituents independently selected from the group consisting of alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, cyano, halogen, haloalkylsulfonyloxy haloalkoxy, heteroarylalkoxy, heterocycle, heterocyclealkoxy, heterocyclealkoxy, heterocycleoxyalkyl, heterocyclealkylamino, heteroarylcarbonylalkoxy, haloalkyl, hydroxyalkenyl, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, hydroxy, nitro, NRaRb, (NRaRb) alkoxy, (NRaRb) alkyl, and (NRaRb) alkynyl; R1 is selected from the group consisting of hydrogen, alkoxycarbonyl, alkyl, carboxy, cyano, halogen, and nitro; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylsulfonyl, arylsulfonyl, halogen, hydroxy, and NRaRb; or R2 and R3, together with the atoms to which they are attached, form an epoxide; X1 and X2 are independently selected from the group consisting of CH and N; Y and Z are independently selected from the group consisting of CH2, O, and NRZ, wherein Rz is selected from the group consisting of hydrogen and alkyl; L1 and L2 are independently selected from the group consisting of a bond and alkylene;
Ra and R are independently selected from the group consisting of hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkyl, arylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, heteroaryl, heteroarylalkyl, heteroarylcarbonium, heteroarylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (1) wherein L1 is CH2; L2 is a link; and A, X1, X2, Y, Z, R1, R2, R3, and are as defined in the Formula
(I) - In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH2; L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro,
NRaR, and (NRaR) alkoxy; it is an individual link; Ra and R ° are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting
of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH2; L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, (NRaRb) alkoxy, and heterocycloalkoxy, wherein the heterocycle portion of the heterocycloalkoxy is selected from the group consisting of morpholinyl, piperidinyl, and pyrrolidinyl; it is an individual link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH2; L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl,
alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaR, (NRaRb) alkoxy, heteroarylalkoxy, and heteroarylcarbonylalkoxy, wherein the heteroaryl portion of the heteroarylalkoxy and the heteroarylcarbonylalkoxy is selected from the group consisting of imidazolyl and pyridinyl; it is an individual link; Ra and R are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH2; L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, NRaRb, (NRaRb) alkoxy, (NRaRb) alkynyl, heterocyclooxyalkoxy, heterocyclooxyalkyl, and heterocyclooxyalkynyl, wherein the heterocycle portion of the heterocyclooxyalkoxy, heterocycleoxyalkyl, and heterocycleoxyalkynyl is tetrahydropyranyl; it is an individual link; Ra and Rb are selected
independently of the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Ra are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH2; L2 is a link; X1 is N; X2 is N; Cast; Z is O; R is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it is an individual link; and Ra and
Rb both are hydrogen. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH2; L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl,
hydroxyalkynyl, nitro, and NRaRb; it is an individual link; Ra is hydrogen; and Rb is heteroarylalkyl wherein the heteroaryl portion of the heteroarylalkyl is pyridinyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH2; L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaR; it is an individual link; Ra is hydrogen, and Rb is heteroarylcarbonyl wherein the heteroaryl portion of the heteroarylcarbonyl is pyridinyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH2; L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaR; it is an individual link; Ra is
hydrogen; and Rb is arylsulfonyl wherein the aryl portion of the aryl sulfonyl is phenyl optionally substituted with a substituent selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, and hydroxy. In another embodiment, the present invention provides a compound of the formula (1) wherein L1 is CH2; L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it is an individual link; Ra is hydrogen; and Rb is heteroarylsulfonyl wherein the heteroaryl portion of the heteroarylsulfonyl is pyridinyl optionally substituted with a substituent selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, hydroxy, and heterocycle, wherein the heterocycle is morpholinyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH2; L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or
two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, (NRaR) alkoxy, and heterocycle, wherein the heterocycle is piperidinyl; it is an individual link; Ra and R ° are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH2; L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3, together with the atoms to which they are attached, form an epoxide; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, and (NRaRb) alkoxy; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, (NRcRd) alkylcarbonyl, and heteroarylalkyl, wherein the heteroaryl portion of the heteroarylalkyl is pyridinyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl.
In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH2; L2 is a link; X1 is N; X2 is N; Cast; Z is O; R is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaR, and (NRaRb) alkoxy; it's a double link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH2; L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaR, (NRaRb) alkoxy, and heterocycloalkoxy, wherein the heterocycle portion of the heterocycloalkoxy is selected from the group consisting of morpholinyl, piperidinyl, and pyrrolidinyl; It is a link
double; Ra and R are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH2; L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaR, (NRaR) alkoxy, heteroarylalkoxy, and heteroarylcarbonylalkoxy, wherein the heteroaryl portion of the heteroarylalkoxy and the heteroarylcarbonylalkoxy is selected from the group consisting of imidazolyl and pyridinyl; it's a double link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and R are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH2; L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group that
it consists of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, NRaR °, (NRaR alkoxy, (NRaR °) alkynyl, heterocyclooxyalkoxy, heterocyclooxyalkyl, and heterocyclooxyalkynyl, wherein the heterocycle portion of the heterocyclooxyalkoxy, heterocycleoxyalkyl, and heterocycleoxyalkynyl is tetrahydropyranyl; it's a double link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and R c and R 1 are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH2; L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it's a double link; and Ra and R ° both are hydrogen.
In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH2; L2 is a link; X1 is N; X2 is N; Cast; Z is O; "R1 is selected from the group consisting of hydrogen and cyano, R2 and R3 are both hydrogen, A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy , alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaR, is a double bond, Ra is hydrogen, and Rb is heteroarylalkyl wherein the heteroaryl portion of the heteroarylalkyl is pyridinyl. invention provides a compound of formula (I) wherein L1 is CH2, L2 is a bond, X1 is N, X2 is N, Y is O, Z is O, R1 is selected from the group consisting of hydrogen and cyano; and R3 both are hydrogen, A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, roxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it's a double link; Ra is-hydrogen; and Ra is heteroarylcarbonyl wherein the heteroaryl portion of the heteroarylcarbonyl is pyridinyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH2; L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group that
it consists of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it's a double link; Ra is hydrogen; and Rb is arylsulfonyl wherein the aryl portion of the arylsulfonyl is phenyl optionally substituted with a substituent selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, and hydroxy. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH2; L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxycoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NR to Rb.; it's a double link; Ra is hydrogen; and R is heteroarylsulfonyl wherein the heteroaryl portion of the heteroarylsulfonyl is pyridinyl optionally substituted with a substituent selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, hydroxy, and heterocycle, wherein the heterocycle is morpholinyl. In another embodiment, the present invention provides a
compound of the formula (I) wherein L1 is CH2; L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, (NRaRb) alkoxy, and heterocycle, wherein the heterocycle is piperidyl; it's a double link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and R ° and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH2; L2 is CH2; and A, X1,
X2, Y, Z, R1, R2, R3, and are as defined in Formula (I). In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH2; L2 is CH2; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen,
haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro,
NRaR, and (NRaRb) alkoxy; it is an individual link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH2; L2 is CH2; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, (NRaR °) alkoxy , and heterocycloalkoxy, wherein the heterocycle portion of the heterocycloalkoxy is selected from the group consisting of morpholinyl, piperidinyl, and pyrrolidinyl; it is an individual link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and R c and R 1 are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a
compound of the formula (I) wherein L1 is CH2; L2 is CH2; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, (NRaR) alkoxy, heteroarylalkoxy, and heteroarylcarbonylalcoxy, wherein the heteroaryl portion of the heteroarylalkoxy and the heteroarylcarbonylalkoxy is selected from the group consisting of imidazolyl and pyridinyl; it is an individual link; Ra and R are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH2; L2 is CH2; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen,
haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, NRaRb, (NRaR) alkoxy, (NRaR) alkynyl, heterocyclooxyalkoxy, heterocyclooxyalkyl, and heterocyclooxyalkynyl, wherein the heterocycle portion of the heterocyclooxyalkoxy, heterocycleoxyalkyl, and heterocycleoxyalkynyl is tetrahydropyranyl; it is an individual link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and R1 and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH2; L2 is CH2; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaR; it is an individual link; and Ra and Rb are both hydrogen. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH2; L2 is CH2; X1 is N '; X2 is N; Cast; Z is O; R1 is selected from the group consisting of
hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaR; it is an individual link; Ra is hydrogen; and Rb is heteroarylalkyl wherein the heteroaryl portion of the heteroarylalkyl is pyridinyl. In another embodiment, the present invention provides a compound of the formula (1) wherein L is CH 2; L2 is CH2; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it is an individual link; Ra is hydrogen; and R is heteroarylcarbonyl wherein the heteroaryl portion of the heteroarylcarbonyl is pyridinyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH2; L2 is CH2; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected
from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it is an individual link; Ra is hydrogen; and Rb is arylsulfonyl wherein the aryl portion of the arylsulfonyl is phenyl optionally substituted with a substituent selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, and hydroxy. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH2; L2 is CH2; X1 is N; X: is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it is an individual link; Ra is hydrogen; and R is heteroarylsulfonyl wherein the heteroaryl portion of the heteroarylsulfonyl is pyridinyl optionally substituted with a substituent selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, hydroxy, and heterocycle, wherein the heterocyclic is morpholinyl.
In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH2; L2 is CH2; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaR, (NRaRb) akoxy, and heterocycle, wherein the heterocycle is piperidinyl; it is an individual link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH2; L2 is CH2; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaR °, and (NR aanRbD ) ialcoxy; it's a double link; Ra and Rb are
independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH2; L2 is CH2; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R: and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaR, (NRaRb) alkoxy, and heterocycloalkoxy, wherein the heterocycle portion of the heterocycloalkoxy is selected from the group consisting of morpholinyl, piperidinyl, and pyrrolidinyl; it's a double link; Ra and R are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH2; L2 is CH2; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aril where
the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, (NRaRb) alkoxy, heteroarylalkoxy, and heteroarylcarbonylalkoxy , wherein the heteroaryl portion of the heteroarylalkoxy and the heteroarylcarbonylalkoxy is selected from the group consisting of imidazolyl and pyridinyl; it's a double link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH2; L2 is CH2; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, NRaRb, (NRaR) alkoxy, (NRaRb) alkynyl, heterocyclooxyalkoxy, heterocyclooxyalkyl, and heterocyclooxyalkynyl, wherein the heterocycle portion of the heterocyclooxyalkoxy, heterocycleoxyalkyl, and heterocycleoxyalkynyl is tetrahydropyranyl;
it's a double link; Re R [are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRa) alkylcarbonyl; and Rc and R ° are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH2; L2 is CH2; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaR; it's a double link; and Ra and Rb are both hydrogen. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH2; L2 is CH2; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaR; it's a double link; Ra is
hydrogen; and Rb is heteroarylalkyl wherein the heteroaryl portion of the heteroarylalkyl is pyridinyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH2; L2 is CH2; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaR; it's a double link; Ra is hydrogen; and Rb is heteroarylcarbonyl wherein the heteroaryl portion of the heteroarylcarbonyl is pyridinyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH2; L2 is CH2; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkylene, nitro, and NRaRb; it's a double link; Ra is hydrogen; and Rb is aryl-isonyl wherein the aryl portion of the arylsulfonyl is phenyl optionally substituted with a substituent selected from the group consisting of alkoxy, alkyl, haloalkoxy,
haloalkyl, halogen, and hydroxy. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH2; L2 is CH2; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it's a double link; Ra is hydrogen; and R is heteroarylsulfonyl wherein the heteroaryl portion of the heteroarylsulfonyl is pyridinyl optionally substituted with a substituent selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, hydroxy, and heterocycle, wherein the heterocycle is morpholinyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH2; L2 is CH2; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaR, (NRaRb) alkoxy, and heterocycle, wherein the heterocyclic is piperidinyl; it's a double link; Ra and Rb are selected
independently of the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and R ° and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH (CH3) CH2; L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRD, and (NR aaR __jbD ) Nalcoxi is an individual link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, halogen alkylcarbonyl, haloalkylsulfonyl, and (NR ° Rd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH (CH3) CH2; L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and
hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, (NRaR) alkoxy , and heterocycloalkoxy, wherein the heterocycle portion of the heterocycloalkoxy is selected from the group consisting of morpholinyl, piperidinyl, and pyrrolidinyl; it is an individual link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and R c and R 1 are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (!) Wherein L1 is CH (CH3) CH2; L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, (NRaRb) alkoxy, heteroarylalkoxy, and heteroarylcarbonylalkoxy, wherein the heteroaryl portion of the heteroarylalkoxy and the heteroarylcarbonylalkoxy is selected from the group consisting of imidazolyl and pyridinyl; it is an individual link; Ra and Rb are
independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and R ° and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH (CH3) CH2; L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, NRaR, (NRaR) alkoxy, (NRaRb) alkynyl, heterocyclooxyalkoxy, heterocyclooxyalkyl, and heterocyclooxyalkynyl, wherein the heterocycle portion of the heterocyclooxyalkoxy, heterocycleoxyalkyl, and heterocycleoxyalkynyl is tetrahydropyranyl; it is an individual link; Ra and R are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a
compound of the formula (I) wherein L1 is CH (CH3) CH2; L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it is an individual link; and Ra and Rb are both hydrogen. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH (CH3) CH2; L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it is an individual link; Ra is hydrogen; and Rb is heteroarylalkyl wherein the heteroaryl portion of the heteroarylalkyl is pyridinyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH (CH3) CH2; L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group
which consists of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it is an individual link; Ra is hydrogen; and Rb is heteroarylcarbonyl wherein the heteroaryl portion of the heteroarylcarbonyl is pyridinyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L is CH (CH 3) CH 2; L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it is an individual link; Ra is hydrogen; and Rb is arylsulfonyl wherein the aryl portion of the arylsulfonyl is phenyl optionally substituted with a substituent selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, and hydroxy. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH (CH3) CH2; L2 is a
link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaR; it is an individual link; Ra is hydrogen; and R is heteroarylsulfonyl wherein the heteroaryl portion of the heteroarylsulfonyl is pyridinyl optionally substituted with a substituent selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, hydroxy, and heterocycle, wherein the heterocycle is morpholinyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH (CH3) CH2; L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, (NRaRb) alkoxy, and heterocycle, wherein the heterocycle is piperidinyl; it is an individual link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl,
alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH (CH3) CH2; L2 is a link; X1 is N; X2 is N; Cast; Z is O; R is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro,
ÑRaR, and (NRaRb) alkoxy; it's a double link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, • alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH (CH3) CH2; L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, • alkoxyalkoxyalkoxy, alkyl, halogen,
haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaR, (NRaRb) alkoxy, and heterocyclylkoxy, wherein the heterocycle portion of the heterocycle or alkoxy is selected from the group consisting of morpholinyl, piperidinyl, and pyrrolidinyl; it's a double link; Ra and R are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and R ° and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH (CH3) CH2; L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; Rz and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or more substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl or, nitro, NRaRb, (NRaRb) alkoxy, heteroarylalkyl, and heteroarylcarbonylalkoxy, wherein the poorrcciioonn h heetteerrooaarriilloo d deell h heetteerrooaarriillaallccooxxii e heteroarylcarbonylalkoxy is selected from the group consisting of imidazolyl and pyridinyl; it's a double link; Ra and Rb are independently selected d i < the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting
of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH (CH3) CH2; L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyan; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, NRaR, (NRaRb) alkoxy, (NRaR) alkynyl, heterocyclooxyalkoxy, heterocyclooxyalkyl, and heterocycloxyalkynyl, wherein the heterocycle portion of the heterocyclooxyalkoxy, heterocycleoxyalkyl, and heterocycleoxyaquinoline is tetrahydropyranyl; it's a double link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonium, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and R ° and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (1) wherein L 1 is CH (CH 3) CH 2; L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl,
alkoxy, alkoxyalkoxy, alkoxyalkoxylalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it's a double link; and Ra and Rb are both hydrogen. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH (CH3) CH2; L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it's a double link; Ra is hydrogen; and Rb is heteroarylalkyl wherein the heteroaryl portion of the heteroarylalkyl is pyridinyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH (CH3) CH2; L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it's a double link; Ra is hydrogen; and R is heteroarylcarbonyl wherein the portion
heteroaryl of the heteroarylcarbonyl is pyridinyl. In another embodiment, the present invention provides a compound of the formula (1) wherein L1 is CH (CH3) CH2; L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it's a double link; Ra is hydrogen; and Rb is arylsulfonyl wherein the aryl portion of arylsuiphenyl is phenyl optionally substituted with a substituent selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, and hydroxy. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH (CH3) CH2; L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it's a double link; Ra is hydrogen; and Rb is heteroarylsulfonyl wherein the heteroaryl portion of the heteroarylsulfonyl is pyridinyl optionally substituted with a
substituent selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, hydroxy, and heterocycle, wherein the heterocycle is morphoiinyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH (CH3) CH2; L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, (NRaRb) alkoxy, and heterocycle, wherein the heterocycle is piperidinyl; it's a double link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L 1 is CH 2 CH (OH); L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl,
alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro,
NRaRD, and (NR aanRbDi) alkoxy; it is an individual link; Ra and R are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L 1 is CH 2 CH (OH); L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, (NRaR) alkoxy, and heterocycloalkoxy, wherein the heterocycle portion of the heterocycloalkoxy is selected from the group consisting of morpholinyl, piperidinyl, and pyrrolidinyl; it is an individual link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl.
In another embodiment, the present invention provides a compound of the formula (I) wherein L 1 is CH 2 CH (OH); L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, (NRaRb) alkoxy, heteroarylalkoxy, and heteroarylcarbonylalkoxy, wherein the heteroaryl portion of the heteroarylalkoxy and the heteroarylcarbonylalkoxy is selected from the group consisting of imidazolyl and pyridinyl; it is an individual link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L 1 is CH 2 CH (OH); L2 is a link; X1 is N; X2 is N; Cast; Z is O; R is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl,
alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, NRaR, (NRaRb) alkoxy, (NRaRb) alkynyl, heterocyclooxyalkoxy, heterocyclooxyalkyl, and heterocyclooxyalkynyl, wherein the heterocycle portion of the heterocyclooxyalkoxy, heterocycleoxyalkyl , and heterocyclooxyalkynyl is tetrahydropyranyl; it is an individual link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and R c and R 1 are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L 1 is CH 2 CH (OH); L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it is an individual link; and Ra and
Rb both are hydrogen. In another embodiment, the present invention provides a compound of the formula (I) wherein L 1 is CH 2 CH (OH); L2 is a
link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it is an individual link; Ra is hydrogen; and Rb is heteroarylalkyl wherein the heteroaryl portion of the heteroarylalkyl is pyridinyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L 1 is CH 2 CH (OH); L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it is an individual link; Ra is hydrogen; and R is heteroarylcarbonyl wherein the heteroaryl portion of the heteroarylcarbonyl is pyridinyl. In another embodiment, the present invention provides a compound of the formula (1) wherein L 1 is CH 2 CH (OH); L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group
which consists of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxyl, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaR; it is an individual link; Ra is hydrogen; and R is arylsulfonyl wherein the aryl portion of the arylsulfonyl is phenyl optionally substituted with a substituent selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, and hydroxy. In another embodiment, the present invention provides a compound of the formula (I) wherein L 1 is CH 2 CH (OH); L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyl, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaR; it is an individual link; Ra is hydrogen; and Rb is heteroarylsulfonyl wherein the heteroaryl portion of the heteroarylsulfonyl is pyridinyl optionally substituted with a substituent selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, hydroxy, and heterocycle, wherein the
heterocycle is morpholinyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L is CH 2 CH (OH); L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, (NRaRb) alkoxy, and heterocycle, where the heterocycle is piperidinyl; it is an individual link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (1) wherein L 1 is CH 2 CH (OH); L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro,
NRaRb, and (NRaRb) alkoxy; it's a double link; Ra and R are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L 1 is CH 2 CH (OH); L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaR, (NRaRb) alkoxy, and heterocycloalkoxy, wherein the heterocycle portion of the heterocycloalkoxy is selected from the group consisting of morpholinyl, piperidinyl, and pyrrolidinyl; it's a double link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L 1 is CH 2 CH (OH); L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group
which consists of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, (NRaRb) alkoxy , heteroarylalkoxy, and heteroarylcarbonylalcoxy, wherein the heteroaryl portion of the heteroarylalkoxy and the heteroarylcarbonylalkoxy is selected from the group consisting of imidazolyl and pyridinyl; it's a double link; Ra and R are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L 1 is CH 2 CH (OH); L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, NRaRb, (NRaR) alkoxy, (NRaRb) alkynyl, heterocyclooxyalkoxy, heterocyclooxyalkyl, and heterocyclooxyalkynyl, wherein the heterocyclic portion of the heterocyclooxyalkoxy,
heterocyclooxyalkyl, and heterocyclooxyalkynyl is tetrahydropyranyl; it's a double link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L 1 is CH 2 CH (OH); L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaR; it's a double link; and Ra and Rb are both hydrogen. In another embodiment, the present invention provides a compound of the formula (I) wherein L is CH 2 CH (OH); L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl,
hydroxyalkynyl, nitro, and NR i a p R b.; _____; it's a double link; Ra is hydrogen; and Rb is heteroarylalkyl wherein the heteroaryl portion of the heteroarylalkyl is pyridinyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L 1 is CH 2 CH (OH); L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of 'alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it's a double link; Ra is hydrogen; and Rb is heteroarylcarbonyl wherein the heteroaryl portion of the heteroarylcarbonyl is pyridinyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L 1 is CH 2 CH (OH); L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R: and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it's a double link; Ra is hydrogen; and Rb is arylsulfonyl wherein the aryl portion of the arylsulfonyl is phenyl optionally substituted with a substituent
selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, and hydroxy. In another embodiment, the present invention provides a compound of the formula (I) wherein L 1 is CH 2 CH (OH); L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R1 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halo, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyquinyl, hydroxyalkynyl, nitro, and NRaRb; it's a double link; Ra is hydrogen; and R is heteroarylsulfonyl wherein the heteroaryl portion of the heteroarylsulfonyl is pyridinyl optionally substituted with a substituent selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, hydroxy, and heterocycle, wherein the heterocycle is morpholinyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L 1 is CH 2 CH (OH); L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, (NRaRb) alkoxy , and heterocycle, where the heterocycle is
piperidinyl; it's a double link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and R c and R 1 are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro,
NRaRD, and (NR aaR__jbD) alkoxy; it is an individual link; Ra and R are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; X1
is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, (NRaR) alkoxy , and heterocycloalkoxy, wherein the heterocycle portion of the heterocycloalkoxy is selected from the group consisting of morpholinyl, piperidinyl, and pyrrolidinyl; it is an individual link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro,
NRaRb, (NRaRb) alkoxy, heteroarylalkoxy, and heteroarylcarbonylalkoxy, wherein the heteroaryl portion of the heteroarylalkoxy and the heteroarylcarbonylalkoxy is selected from the group consisting of imidazolyl and pyridinyl; it is an individual link; Ra and R are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and R ° and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, NRaRb, (NRaRb) alkoxy, (NRaR) alkynyl, heterocyclooxyalkoxy, heterocyclooxyalkyl, and heterocyclooxyalkynyl, wherein the heterocycle portion of the heterocyclooxyalkoxy, heterocycleoxyalkyl, and heterocycleoxyalkynyl is tetrahydropyranyl; it is an individual link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl,
alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; X1 is N; X1 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R- and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl unsubstituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, niir, and NRaR; it is an individual link; and Ra and
Rb both are hydrogen. In another embodiment, the invention provides a compound of formula (I) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; X1 is N; X2 is N; Cast; Z is O; R is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is substituted phenyl with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen,
haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, niir, and NRaRb; it is an individual link; Ra is hydrogen; and Rb is heeroarylalkyl wherein the heeroaryl portion of the heyarylalkyl is pyridinyl. In another embodiment, the invention provides a compound of formula (I) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl unsubstituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, niir, and NRaRb; it is an individual link; Ra is hydrogen; and Rb is heeroarylcarbonyl wherein the heeroaryl portion of the ironarylcarbonyl is pyridinyl. In another embodiment, the invention provides a compound of formula (I) wherein L is selected from the group consisting of CH2CH (OCH3) and CH2CH (OCH2CH3); L2 is a link; X1 is N; X2 is N; Cast; Z is O; R is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl unsubstituted with one or two substituents selected from the group consisting of alkenyl,
alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, niir, and NRaR; it is an individual link; Ra is hydrogen; and Rb is arylsulfonyl wherein the aryl portion of the arylsulfonyl is phenyl optionally susiiuuid with a susíiyenyen selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, and hydroxy. In another embodiment, the invention provides a compound of formula (I) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl unsubstituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, niir, and NRaR; it is an individual link; Ra is hydrogen; and Rb is heeroarylsulfonyl wherein the heeroaryl portion of the hephenoarylsulfonyl is pyridinyl optionally susiiuuid with a substituent selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, hydroxy, and heterocycle, wherein the heterocycle is morpholinyl. In another embodiment, the invention provides a compound of formula (I) wherein L1 is selected from the group
consisted of CH2CH (OCH3) and CH2CH (OCH2CH3); L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl unsubstituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, niira, NRaRb, (NRaR) alkoxy, and heerocycle, where the heerocycle is piperidinyl; it is an individual link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkycarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the invention provides a compound of formula (I) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl unsubstituted with one or two subsitutes selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkylamino, NRaRb, and (NRaRb) alkoxy; it's a double link; Ra and Rb are
independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of formula (I) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl unsubstituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, (NRaRb) alkoxy , and heterocycloalkoxy, wherein the heyerocycle portion of the heterocycloalkoxy is selected from the group consisting of morpholinyl, piperidinyl, and pyrrolidinyl; it's a double link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and R1 are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the invention provides a compound of formula (1) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; X1
is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl unsubstituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyaryl, nickel, NRaRb, (NRaRb) alkoxy, heeroarylalkoxy, and hephenoarylcarbonylalkoxy, wherein the heeroaryl portion of the heteroarylalkoxy and the heteroarylcarbonylalkoxy is selected from the group consisting of imidazolyl and pyridinyl; it's a double link; Ra and Rb are selected independently from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the invention provides a compound of formula (I) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; X1 is N; X2 is N; Cast; Z is O; R is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl unsubstituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halo, haloalkylsulfonyloxy, hydroxy, hydroxy alkoxy, hydroxyalkyl, hydroxyalkynyl, niR, NRaRb, (NRaRb) alkoxy, (NRaRb) alkynyl,
Hetero-cyclooxyalkoxy, heteroaryloxyalkyl, and heteroaryloxyalkynyl, wherein the heyerocycle portion of the heterocyclocycloalkyloxy, heteroaryloxyalkyl, and heteroaryloxyalkynyl is tetrahydropyranyl; it's a double link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and R1 are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the invention provides a compound of formula (I) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl unsubstituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, niir, and NRaRb; it's a double link; and Ra and Rb are both hydrogen. In another embodiment, the invention provides a compound of formula (I) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is
aryl wherein the aryl is phenyl unsubstituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaR; it's a double link; Ra is hydrogen; and Rb is heeroarylalkyl wherein the heeroaryl portion of the heyarylalkyl is pyridinyl. In another embodiment, the invention provides a compound of formula (I) wherein L is selected from the group consisting of CH2CH (OCH3) and CH2CH (OCH2CH3); L2 is a link; X1 is N; X2 is N; Cast; Z is O; R is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl unsubstituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, niir, and NRaR; it's a double link; R3 is hydrogen; and Rb is heeroarylcarbonyl wherein the heeroaryl portion of the ironarylcarbonyl is pyridinyl. In another embodiment, the invention provides a compound of formula (I) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two
selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, niir, and NRaRb; it's a double link; Ra is hydrogen; and Rb is arylsulfonyl wherein the aryl portion of the arylsulfonyl is optionally substituted phenyl with a substituent selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, and hydroxy. In another embodiment, the invention provides a compound of formula (I) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; X1 is N; X2 is N; Cast; Z is O; R is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl unsubstituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it's a double link; Ra is hydrogen; and Rb is heteroarylsulfonyl wherein the heeroaryl portion of the ironaryl sulfonyl is optionally substituted pyridinyl with a substituent selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, hydroxy, and heterocycle, wherein the heterocycle is morpholinyl. In another embodiment, the invention provides a compound of the formula (I) wherein L 1 is selected from the group
consisted of CH2CH (OCH3) and CH2CH (OCH2CH3); L2 is a link; X1 is N; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl unsubstituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaR, (NRaRb) alkoxy, and heterocyclic, wherein the heterocycle is piperidinyl; it's a double link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and R c and R d are selected independently from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the invention provides a compound of the formula (I) wherein L1 is CH2; L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl unsubstituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, niira, NRaRb, and (NRaRb) alkoxy; it is an individual link; Ra and R are independently selected from the group consisting of
hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcR) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the invention provides a compound of formula (I) wherein L 1 is CH 2; L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl unsubstituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkylamino, NRaRb, (NRaRb) alkoxy, and heyerocycloalkoxy, wherein the hemerocycle portion of the heterocycloalkoxy is selected from the group consisting of morpholinyl, piperidinyl, and pyrrolidinyl; it is an individual link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkycarbonyl; and R1 and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkio. In another embodiment, the present invention provides a compound of formula (I) wherein L1 is CH2; L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are selected
independently of the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxylalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, niR, NRaRb, (NRaRb) alkoxy , heeroarylalkoxy, and heeroarylcarbonylalcoxy, wherein the heeroaryl portion of the aryloxyaryl and the heteroarylcarbonylalkoxy is selected from the group consisting of imidazolyl and pyridinyl; it is an individual link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the invention provides a compound of formula (I) wherein L 1 is CH 2; L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl unsubstituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, niR, NRaRb, (NRaRb) alkoxy, (NRaR) alkynyl, heteroaryloxy alkoxy, heteroaryloxyalkyl, and heterocyclooxyalkynyl,
wherein the heyerocycle portion of the heterocyclocycloalkoxy, heteroaryloxyalkyl, and heteroaryloxyalkylanyl is hydrohydranyranyl; it is an individual link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of formula (I) wherein L1 is CH2; L: it's a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl unsubstituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, niir, and NRaR; it is an individual link; and Ra and
Rb both are hydrogen. In another embodiment, the invention provides a compound of formula (I) wherein L 1 is CH 2; L-is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is seed from the group consisting of hydrogen and cyano; R2 and R3 are independently seed from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or
two subsystems seed from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxylalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, niir, and NRaR; it is an individual link; Ra is hydrogen; and Rb is heeroarylalkyl wherein the heeroaryl portion of the heyarylalkyl is pyridinyl. In another embodiment, the invention provides a compound of formula (I) wherein L 1 is CH 2; L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is seed from the group consisting of hydrogen and cyano; R2 and R3 are independently seed from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl unsubstituted with one or two substituents seed from the group consisting of alkenyl, alkoxy, akoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloacylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it is an individual link; Ra is hydrogen; and Rb is heeroarylcarbonyl wherein the heeroaryl portion of the ironarylcarbonyl is pyridinyl. In another embodiment, the invention provides a compound of formula (I) wherein L 1 is CH 2; L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is seed from the group consisting of hydrogen and cyano; R2 and R3 are independently seed from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl unsubstituted with one or two substituents seed from the group consisting of alkenyl,
alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, niir, and NRaRb; it is an individual link; Ra is hydrogen; and Rb is arylsulfonyl wherein the aryl portion of the arylsulfonyl is optionally phenylene subsumed with a substituent seed from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, and hydroxy. In another embodiment, the invention provides a compound of formula (I) wherein L 1 is CH 2; L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is seed from the group consisting of hydrogen and cyano; R2 and R3 are independently seed from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl unsubstituted with one or two substituents seed from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, and NRaRb; it is an individual link; Ra is hydrogen; and Rb is heteroarylsulfonyl wherein the heeroaryl portion of the heteroaryl is pyridinyl optionally susíifuido with a susíiyenyen seed from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, hydroxy, and heterocycle, wherein the heterocycle is morpholinyl. In another embodiment, the invention provides a compound of formula (I) wherein L 1 is CH 2; L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is seed from the group that
Consist of hydrogen and cyano; R2 and R3 are independently seed from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents seed from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nickel, NRaR, (NRaRb) alkoxy, and heyerocycle, wherein the heterocycle is piperidinyl; it is an individual link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L 1 is CH 2; L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3, June with the atoms to which they are united, form an epoxide; A is aryl wherein the aryl is phenyl unsubstituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, niR, NRaRb, and (NRaRb) alkoxy; Ra and R are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, (NRcRd) alkylcarbonyl, and
heeroarylalkyl, wherein the heeroaryl portion of the heeroarylalkyl is pyridinyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the invention provides a compound of formula (I) wherein L 1 is CH 2; L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl unsubstituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, ni,
NRaR, and (NRaR) aIcoxi; it's a double link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NR ° Rd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of formula (I) wherein L 1 is CH 2", L 2 is a bond, X 1 is N, X 2 is CH, Y is O, Z is O, R 1 is selected from the group consisting of of hydrogen and cyano, R2 and R3 are both hydrogen, A is aryl wherein the aryl is phenyl which is suspended with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy , hydroxyalky, ni,
NRaRb, (NRaRb) alkoxy, and heioerocycloalkoxy, wherein the heyerocycle portion of the heterocyclecycloalkoxy is selected from the group consisting of morpholinyl, piperidinyl, and pyrrolidinyl; it's a double link; Ra and R are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the invention provides a compound of formula (I) wherein L 1 is CH 2; L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyan; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl unsubstituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, niira, NRaRb, (NRaRb) alkoxy, heeroarylalkoxy, and heteroarylcarbonylalkoxy, wherein the heeroaryl portion of the heteroarylalkoxy and the heteroarylcarbonylalkoxy is selected from the group consisting of imidazolyl and pyridinyl; it's a double link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and R1 are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl.
In another embodiment, the invention provides a compound of formula (I) wherein L 1 is CH 2; L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is substituted phenyl with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, niir, NRaRb, (NRaRb) alkoxy, (NRaRb) alkynyl, heteroaryloxyalkoxy, heteroaryloxyalkyl, and heteroaryloxyalkynyl, wherein the heyerocycle portion of the cyclooxyalkoxy, heterocyclooxyalkyl, and heterocyclooxyalkynyl is tetrahydropyranyl; it's a double link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and R1 are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the invention provides a compound of formula (I) wherein L 1 is CH 2; L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is an aryl wherein the aryl is substituted phenyl with one or two substrates selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen,
haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it's a double link; and Ra and R both are hydrogen. In another embodiment, the present invention provides a compound of formula (I) wherein L1 is CH2; L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl suspended with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, niir, and NRaRb; it's a double link; Ra is hydrogen; and Rb is heeroarylalkyl wherein the heeroaryl portion of the heyarylalkyl is pyridinyl. In another embodiment, the invention provides a compound of formula (I) wherein L 1 is CH 2; L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl unsubstituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, niir, and NRaRb; it's a double link; Ra is hydrogen; and Rb is heeroarylcarbonyl wherein the heeroaryl portion of the ironarylcarbonyl is pyridinyl.
In another embodiment, the invention provides a compound of formula (I) wherein L 1 is CH 2; L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl unsubstituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nyl, and NRaRb; it's a double link; Ra is hydrogen; and Rb is arylsulfonyl wherein the aryl portion of the arylsulfonyl is phenyl optionally susiuuid with a susiiuyenyen selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, and hydroxy. In another embodiment, the invention provides a compound of formula (I) wherein L 1 is CH 2; L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl unsubstituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, niir, and NRaR; it's a double link; Ra is hydrogen; and Rb is heteroarylsulfonyl wherein the heeroaryl portion of the aryl sulphonyl is pyridinyl optionally susiiuid with a substituent selected from the group consisting of alkoxy, alkyl,
haloalkoxy, haloalkyl, halogen, hydroxy, and heterocycle, wherein the heterocycle is morpholinyl. In another embodiment, the invention provides a compound of the formula (I) wherein L1 is CH2; L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl suspended with one or two substrates selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxylalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, (NRaR) alkoxy , and heerocycle, wherein the heiierocycle is piperidinyl; it's a double link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the invention provides a compound of formula (I) wherein L1 is CH2; L2 is CH2; and A, X1, X2, Y, Z, R1, R2, R3, and are as defined in Formula (I). In another embodiment, the invention provides a compound of formula (I) wherein L 1 is CH 2; L2 is CH2; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl in
wherein the aryl is phenyl unsubstituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nickel, NRaRD, and
it is an individual link; Ra and R are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd,) alkylcarbonyl; and Rc and Rd are selected independently from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the invention provides a compound of formula (I) wherein L 1 is CH 2; L2 is CH2; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl unsubstituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, niira, NRaRb, (NRaRb) alkoxy, and heyerocycloalkoxy, wherein the heterocycle portion of the heterocycloalkoxy is selected from the group consisting of morpholinyl, piperidinyl, and pyrrolidinyl; it is an individual link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc
and R1 are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the invention provides a compound of formula (I) wherein L 1 is CH 2; L2 is CH2; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyan; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, (NRaR) alkoxy, heteroarylalkoxy, and heteroarylcarbonylalkoxy, wherein the heteroaryl portion of the heteroarylalkoxy and the heteroarylcarbonylalkoxy is selected from the group consisting of imidazolyl and pyridinyl; it is an individual link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the invention provides a compound of formula (I) wherein L is CH2; L2 is CH2; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are selected independently from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl in
wherein the aryl is phenyl unsubstituted with one or two subsitutes selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, niir, NRaR, (NRaR) alkoxy, (NRaRb alkynyl, heteroaryloxy alkoxy, heteroaryloxyalkylamino, and heteroaryloxyalkynyl, wherein the heyerocyclic portion of the heterocyclocycloalkoxy, heteroaryloxyalkyl, and heteroaryloxyalkylanyl is tetrahydropyranyl; it is an individual link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In present form, the invention provides a compound of the formula (I) wherein L1 is CH2; L2 is CH2; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl suspended with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, niir, and NRaRb; it is an individual link; and Ra and Rb are both hydrogen.
In another embodiment, the invention provides a compound of formula (I) wherein L 1 is CH 2; L2 is CH2; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl-susiiuid with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, niir, and NRaR; it is an individual link; Ra is hydrogen; and Rb is heeroarylalkyl wherein the heteroaryl portion of the heteroarylalkyl is pyridinyl. In another embodiment, the present invention provides a compound of formula (I) wherein L1 is CH2; L2 is CH2; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl suspended with one or two subsitutes selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaR; it is an individual link; Ra is hydrogen; and Rb is heteroarylcarbonyl wherein the heteroaryl portion of the heteroarylcarbonyl is pyridinyl. In another embodiment, the present invention provides a
compound of formula (I) wherein L1 is CH2; L2 is CH2; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, niir, and NRaRb; it is an individual link; Ra is hydrogen; and Rb is arylsulfonyl wherein the aryl portion of the arylsulfonyl is phenyl optionally susiiuuid with a susíiyenyen selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, and hydroxy. In another embodiment, the invention provides a compound of the formula (I) wherein L 1 is CH 2; L2 is CH2; X1 is N; X1 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are selected independently from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, niir, and NRaRb; it is an individual link; Ra is hydrogen; and Rb is heeroarylsulfonyl wherein the hephenoaryl portion of the arylarylsulfonyl is pyridinyl optionally susfused with a
is selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, hydroxy, and heterocycle, wherein the heterocycle is morpholinyl. In another embodiment, the invention provides a compound of formula (I) wherein L 1 is CH 2; L2 is CH2; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaR, (NRaRb) alkoxy, and heterocycle, wherein the heterocycle is piperidinyl; it is an individual link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and R1 are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH2; L2 is CH; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is substituted phenyl with one or two alkyls selected from the group consisting of alkenyl, alkoxy,
alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro,
NRaRb, and (NRaRb) alkoxy; it's a double link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Ra are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of formula (I) wherein L1 is CH2; L2 is CH2; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, niira, NRaRb, (NRaRb) alkoxy, and heterocycloalkoxy, wherein the heyerocycle portion of the heterocycloalkoxy is selected from the group consisting of morpholinyl, piperidinyl, and pyrrolidinyl; it's a double link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are selected independently from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a
compound of the formula (I) wherein L is CH2; L2 is CH2; X1 is N; X2 is CH, Y is O; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, (NRaRb) alkoxy, heteroarylalkoxy, and heteroarylcarbonylalkoxy, wherein the heteroaryl portion of the heteroarylalkoxy and the heteroarylcarbonylalkoxy is selected from the group consisting of imidazolyl and pyridinyl; it's a double link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcR) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH2; L2 is CH2; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substrates selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxylalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, NRaRb, (NRaRb) alkoxy, (NRaRb) alkynyl,
heteroaryloxy alkoxy, heterocyclooxyalkyl, and heterocycloxyalkynyl, wherein the heterocycle portion of the heterocyclooxyalkoxy, heterocyclooxyalkyl, and heteroaryloxyalkynyl is tetrahydropyranyl; it's a double link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of formula (I) wherein L1 is CH2; L2 is CH2; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two susíifuyeníes selected from the group consisting of alkenyl alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulphonyloxy, hydroxyl, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, niir, and NRaRb; it's a double link; and Ra and Rb are both hydrogen. In another embodiment, the invention provides a compound of formula (I) wherein L 1 is CH 2; L2 is CH2; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl alkoxy,
alkoxyalkoxy, alkoxyalkoxylalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaR; it's a double link; Ra is hydrogen; and Rb is heteroarylalkyl wherein the heeroaryl portion of the arylaryl alkyl is pyridinyl. In another embodiment, the invention provides a compound of formula (I) wherein L 1 is CH 2; L2 is CH2; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl unsubstituted with one or two subsitutes selected from the group consisting of alkenyl alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it's a double link; Ra is hydrogen; and Rb is heteroarylcarbonyl wherein the heeroaryl portion of the heteroarylcarbonyl is pyridinyl. In another embodiment, the present invention provides a compound of formula (I) wherein L1 is CH2; L2 is CH2; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is substituted phenyl with one or two substrates selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaR; it's a double link; Ra is
hydrogen; and Rb is arylsulfonyl wherein the aryl portion of the arylsulfonyl is optionally phenyl substi tuted with a substituent selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, and hydroxy. In another embodiment, the invention provides a compound of formula (I) wherein L1 is CH2; L2 is CH2; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaR; it's a double link; Ra is hydrogen; and R is heteroarylsulfonyl wherein the heteroaryl portion of the heteroarylsulfonyl is optionally substituted pyridinyl with a substituent selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, hydroxy, and heterocycle, wherein the heterocycle is morpholinyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH2; L2 is CH2; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyan; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substrates selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen,
haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, (NRaR) alkoxy, and heterocycle, wherein the heterocyclic is piperidinyl; it's a double link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkyloxycarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of formula (I) wherein L 1 is CH (CH 3) CH 2; L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R1 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro,
NRaRb, and (NRaRb) alkoxy; it is an individual link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and R c and R 1 are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of formula (I) wherein L 1 is CH (CH 3) CH 2; L2 is a
link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, (NRaRb) alkoxy, and heterocycloalkoxy, wherein the heyerocycle portion of the heterocycloalkoxy is selected from the group consisting of morpholinyl, piperidinyl, and pyrrolidinyl; it is an individual link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NR ° Rd) alkylcarbonyl; and R c and R 1 are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the invention provides a compound of the formula (I) wherein L 1 is CH (CH 3) CH 2; L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, (NRaRb) alkoxy, heteroarylalkoxy, and heteroarylcarbonylalkoxy, in
wherein the heeroaryl portion of the heteroarylalkoxy and the heteroarylcarbonylalkoxy is selected from the group consisting of imidazolyl and pyridinyl; it is an individual link; Ra and R are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the invention provides a compound of formula (I) wherein L 1 is CH (CH 3) CH 2; L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl unsubstituted with one or two subsitutes selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, niR, NRaRb, (NRaRb) alkoxy, (NRaR) alkynyl, heyerocyclooxyalkoxy, heteroaryloxyalkyl, and heteroaryloxyalkynyl, wherein the heterocycle portion of the heterocyclooxyalkoxy, heterocyclooxyalkyl, and heteroaryloxyalkylanyl is hydrohydranyranyl; it is an individual link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are
independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of formula (I) wherein L 1 is CH (CH 3) CH 2; L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is substituted phenyl with one or two substrates selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it is an individual link; and Ra and
Rb both are hydrogen. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH (CH3) CH2; L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl unsubstituted with one or two subsitutes selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaR; it is an individual link; Ra is hydrogen; and Rb is heteroarylalkyl wherein the heeroaryl portion of the heyarylalkyl is pyridinyl.
In another embodiment, the present invention provides a compound of the formula (1) wherein L is CH (CH 3) CH 2; L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is substituted phenyl with one or two substrates selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyquinyl, hydroxyalkynyl, niir, and NRaRb; it is an individual link; Ra is hydrogen; and Rb is heeroarylcarbonyl wherein the heeroaryl portion of the heteroarylcarbonyl is pyridinyl. In another embodiment, the present invention provides a compound of formula (I) wherein L 1 is CH (CH 3) CH 2; L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are selected independently from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl which is suspended with one or two subsitutes selected from the group consisting of alkenylene, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyl, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it is an individual link; Ra is hydrogen; and Rb is arylsulfonyl wherein the aryl portion of the arylsulifonyl is optionally phenyl substi tuted with a sus siid selected from the group consisting of alkoxy, alkyl, halogen
alkoxy, haloalkyl, halogen, and hydroxy. In another embodiment, the invention provides a compound of the formula (I) wherein L 1 is CH (CH 3) CH 2; L2 is a link; X1 is N, X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two susfifuyeníes selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it is an individual link; Ra is hydrogen; and Rb is heteroarylsulfonyl wherein the heteroaryl portion of the heteroarylsulfonyl is pyridinyl optionally substituted with a susifuyenie selected from the group consisting of alkoxy, alkyl, haloalkoxy, halogen alkyl, halogen, hydroxy, and heterocycle, wherein the heterocycle is morpholinyl. In another embodiment, the invention provides a compound of the formula (I) wherein L 1 is CH (CH 3) CH 2; L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro,
NRaRb, (NRaRb) alkoxy, and heterocycle, where the heiierocycle is piperidini lo; it is an individual link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of formula (I) wherein L 1 is CH (CH 3) CH 2; L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substrates selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro,
NRaRb, and (NRaRb) alkoxy; it's a double link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and R1 are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of formula (I) wherein L 1 is CH (CH 3) CH 2; L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are
hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, (NRaRb) alkoxy , and heterocycloalkoxy, wherein the heyerocycle portion of the heterocycloalkoxy is selected from the group consisting of morpholinyl, piperidinyl, and pyrrolidinyl; it's a double link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the invention provides a compound of formula (I) wherein L 1 is CH (CH 3) CH 2; L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, niira, NRaRb, (NRaRb) alkoxy, heeroarylalkoxy, and heteroarylcarbonylalkoxy, wherein the heteroaryl portion of the heteroarylalkoxy and the heteroarylcarbonylalkoxy is selected from the group consisting of imidazolyl and pyridinyl; it's a double link; Ra and Rb are independently selected from the group consisting of
hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and R ° and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH (CH3) CH2; L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, NRaRb, (NRaRb) alkoxy, (NRaRb) alkynyl, heteroaryloxyalkoxy, heteroaryloxyalkyl, and heteroaryloxyalkynyl, wherein the heyerocycle portion of the heterocyclocycloalkoxy, heterocyclooxyalkyl, and heterocyclooxyalkynyl is hydrohydranyranyl; it's a double link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of formula (i) wherein L1 is CH (CH3) CH2; L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from
group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is substituted phenyl with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nifro, and NRaRb; it's a double link; and Ra and R both are hydrogen. In another embodiment, the present invention provides a compound of the formula (I) wherein L 1 is CH (CH 3) CH 2; L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyl, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, niir, and NRaRb; it's a double link; Ra is hydrogen; and R b is heteroarylalkyl wherein the hephenoaryl portion of the phenyl arylalkyl is pyridinyl. In another embodiment, the invention provides a compound of formula (I) wherein L 1 is CH (CH 3) CH 2; L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl which is suspended with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen,
haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it's a double link; Ra is hydrogen; and Rb is heteroarylcarbonyl wherein the heteroaryl portion of the heteroarylcarbonyl is pyridinyl. In another embodiment, the invention provides a compound of formula (1) wherein L 1 is CH (CH 3) CH 2; L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it's a double link; Ra is hydrogen; and Rb is arylsulfonyl wherein the aryl portion of the arylsulfonyl is phenyl optionally susiiuuid with a susiiuyenyen selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, and hydroxy. In another embodiment, the invention provides a compound of formula (I) wherein L 1 is CH (CH 3) CH 2; L: it's a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substrates selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyl, hydroxy, hydroxyalkoxy, hydroxyalkyl,
hydroxyalkynyl, ni, and NRaRb; it's a double link; Ra is hydrogen; and Rb is heeroarylsulfonyl wherein the heteroaryl portion of the ironaryl sulfonyl is pyridinyl optionally substituted with a substituent selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, hydroxy, and heterocycle, wherein the heterocyclic is morpholinyl. In another embodiment, the present invention provides a compound of formula (I) wherein L 1 is CH (CH 3) CH 2; L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substitutes selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, (NRaR) alkoxy, and heterocycle, wherein the heterocycle is piperidinyl; it's a double link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and R1 and R are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the invention provides a compound of formula (I) wherein L 1 is CH 2 CH (OH); L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are selected
independently of the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl unsubstituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro,
NRaRD, and (NR aa or R b ° i) alkoxy is an individual bond; Ra and R are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L 1 is CH 2 CH (OH); L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is substituted phenyl with one or two subsitutes selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, (NRaRb) alkoxy, and heterocycloalkoxy, wherein the heterocycle portion of the heterocycloalkoxy is selected from the group consisting of morpholinyl, piperidinyl, and pyrrolidinyl; it is an individual link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl,
haloalkylcarbonyl, haloalkylsulfonyl, and (NRCR) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L is CH 2 CH (OH); L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, (NRaRb) alkoxy, heteroarylalkoxy, and heteroarylcarbonylalkoxy, wherein the heeroaryl portion of the heteroarylalkoxy and the heteroarylcarbonylalkoxy is selected from the group consisting of imidazolyl and pyridinyl; it is an individual link; Ra and R are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L 1 is CH 2 CH (OH); L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are selected
independently of the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl unsubstituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxy alkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, NRaRb, ( NRaR) alkoxy, (NRaR) alkynyl, heterocyclooxyalkoxy, heteroaryloxyalkyl, and heterocycloxyalkynyl, wherein the heyerocycle portion of the heterocyclocycloalkoxy, heteroaryloxyalkyl, and heterocyclooxyalkynyl is tetrahydropyranyl; it is an individual link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and R1 are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of formula (I) wherein L 1 is CH 2 CH (OH); L1 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaR; it is an individual link; and Ra and
Rb both are hydrogen. In another embodiment, the present invention provides a compound of formula (I) wherein L 1 is CH 2 CH (OH); L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it is an individual link; Ra is hydrogen; and Rb is heeroarylalkyl wherein the heeroaryl portion of the heyarylalkyl is pyridinyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L is CH 2 CH (OH); L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it is an individual link; Ra is hydrogen; and Rb is heteroarylcarbonyl wherein the heteroaryl portion of the heteroarylcarbonyl is pyridinyl.
In another embodiment, the present invention provides a compound of the formula (I) wherein L 1 is CH 2 CH (OH); L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, akoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nyl, and NRaRb; it is an individual link; Ra is hydrogen; and R is arylsulfonyl wherein the aryl portion of the arylsulfonyl is optionally phenyl substi tuted with a susiiuyenyen selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, and hydroxy. In another embodiment, the invention provides a compound of formula (I) wherein L 1 is CH 2 CH (OH); L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are selected independently from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, niir, and NRaR; it is an individual link; Ra is hydrogen; and R is heeroarylsulfonyl wherein the heteroaryl portion
of the ironaryl sulfonyl is optionally substituted pyridinyl with a substitute selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, hydroxy, and heterocycium, wherein the heterocycle is morpholinyl. In another embodiment, the invention provides a compound of formula (I) wherein L 1 is CH 2 CH (OH); L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaR, (NRaR) alkoxy, and heterocycle, wherein the heterocycle is piperidinyl; it is an individual link; Ra and R are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of formula (I) wherein L 1 is CH 2 CH (OH); L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or
two subsitutes selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro,
NRaRb, and (NRaRb) alkoxy; it's a double link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and R c and R 1 are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L 1 is CH 2 CH (OH); L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaR, (NRaRb) alkoxy, and heterocycloalkoxy, wherein the heterocycle portion of the heterocycloalkoxy is selected from the group consisting of morpholinyl, piperidinyl, and pyrrolidinyl.; it's a double link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NR ° Rd) alkylcarbonyl; and R ° and R1 are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl.
In another embodiment, the present invention provides a compound of formula (I) wherein L 1 is CH 2 CH (OH); L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenol substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, (NRaRb) alkoxy, heteroarylalkoxy, and heteroarylcarbonylalkoxy, wherein the heeroaryl portion of the heteroarylalkoxy and the heteroarylcarbonylalkoxy is selected from the group consisting of imidazolyl and pyridinyl; it's a double link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of formula (I) wherein L 1 is CH 2 CH (OH); L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl,
hydroxyalkynyl, nitro, NRaRb, (NRaR) akoxy, (NRaR) alkynyl, heyerocyclooxyalkoxy, heteroaryloxycycloalkyl, and heteroaryloxyalkynyl, wherein the heterocycle portion of the heterocyclooxyalkoxy, heterocyclooxyalkyl, and heteroaryloxyalkynyl is tetrahydropyranyl; it's a double link; Ra and Rb are selected
Depending on the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of formula (I) wherein L is CH 2 CH (OH); L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is substituted phenyl with one or two subsitutes selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it's a double link; and Ra and Rb are both hydrogen. In another embodiment, the present invention provides a compound of formula (I) wherein L 1 is CH 2 CH (OH); L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or
two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxy alkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it's a double link; Ra is hydrogen; and Rb is heteroarylalkyl wherein the heteroaryl portion of the heeroarylalkyl is pyridinyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L 1 is CH 2 CH (OH); L-is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R1 both are hydrogen; A is aryl, wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, niir, and NRaRb; it's a double link; Ra is hydrogen; and R is heeroarylcarbonyl wherein the heteroaryl portion of the heteroarylcarbonyl is pyridinyl. In another embodiment, the invention provides a compound of formula (I) wherein L 1 is CH 2 CH (OH); L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl,
hydroxyalkynyl, nitro, and NR > to R _- > b.; ______ is a double link; Ra is hydrogen; and Rb is arylsulfonyl wherein the aryl portion of the arylsulfonyl is optionally substituted phenyl with a substitute selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, and hydroxy. In another embodiment, the invention provides a compound of formula (I) wherein L 1 is CH 2 CH (OH); L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl unsubstituted with one or two subsitutes selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it's a double link; Ra is hydrogen; and Rb is heteroarylsulfonyl wherein the heteroaryl portion of the heteroarylsulfonyl is pyridinyl optionally substituted with a substituent selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, hydroxy, and heterocycle, wherein the heterocycle is morpholinyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L 1 is CH 2 CH (OH); L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl unsubstituted with one or two subsitutes selected from the group consisting of alkenyl,
alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, (NRaRb) alkoxy, and heterocycle, wherein the heterocycle is piperidinyl; it's a double link; Ra and Rb are selected
Independently of the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment the present invention provides a compound of formula (1) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substrates selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRD, and (NRaRb) alkoxy; it is an individual link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl.
In another embodiment, the invention provides a compound of the formula (I) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxylalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, (NRaRb) akoxy, and heterocycloalkoxy, wherein the heyerocycle portion of the heterocycloalkoxy is selected from the group consisting of morpholinyl, piperidinyl, and pyrrolidinyl; it is an individual link; Ra and R are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NR ° Rd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the invention provides a compound of the formula (I) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or
two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxylalkoxy, hydroxyalkyl, nitro, NRaRb, (NRaRb) alkoxy, heteroarylalkoxy, and heteroarylcarbonylalkoxy, wherein the heeroaryl portion of the heteroarylalkoxy and the heeroarylcarbonylalkoxy is selected from the group consisting of imidazolyl and pyridinyl; it is an individual link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the invention provides a compound of formula (I) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are selected independently from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is substituted phenyl with one or two subsitutes selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, niR, NRaRb, (NRaR) alkoxy, (NRaRb) alkynyl, heyerocyclohexyalkoxy, heteroaryloxyalkyl, and heterocyclooxyalkynyl, wherein the heyerocycle portion of the heterocyclooxyalkoxy,
Hetero-cyclooxyalkyl, and heyerocyclohexyalkynyl is tetrahydropyranyl; it is an individual link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and R1 and R1 are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is substituted phenyl with one or two subsitutes selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nipro, and NRaRb; it is an individual link; and Ra and
Rb both are hydrogen. In another embodiment, the invention provides a compound of formula (I) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and
hydroxy; A is aryl wherein the aryl is substituted phenyl with one or two subsitutes selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, niir, and NRaR; it is an individual link; Ra is hydrogen; and Rb is heeroarylalkyl wherein the heeroaryl portion of the heyarylalkyl is pyridinyl. In another embodiment, the invention provides a compound of formula (I) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, niir, and NRaRb; it is an individual link; Ra is hydrogen; and Rb is heteroarylcarbonyl wherein the heteroaryl portion of the heteroarylcarbonyl is pyridinyl. In another embodiment, the invention provides a compound of the formula (I) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are selected
independently of the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two susfifuyeníes selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it is an individual link; Ra is hydrogen; and R is arylsulfonyl wherein the aryl portion of the arylsulfonyl is phenyl optionally substituted with a substituent selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, and hydroxy. In another embodiment, the present invention provides a compound of the formula (1) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is substituted phenyl with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaR; it is an individual link; Ra is hydrogen; and Rb is heteroarylsulfonyl wherein the heteroaryl portion of the heteroarylsulfonyl is pyridinyl optionally substituted with a substituent selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, hydroxy, and heterocycle, wherein the
heerocycle is morpholinyl. In another embodiment, the invention provides a compound of formula (I) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is substituted phenyl with one or two subsitutes selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, niira, NRaRb, (NRaRb) alkoxy, and heyerocycle, wherein the heterocycle is piperidinyl; it is an individual link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of formula (I) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is substituted phenyl with one or two substituents selected from the group consisting of alkenyl, alkoxy,
alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro,
NRaRb, and (NRaR) alkoxy; it's a double link; Ra and R are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and R ° and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment the present invention provides a compound of formula (i) wherein L1 is selected from the group consisting of CH2CM (OCH3) and CH2CH (OCH2CH3); L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R1 both are hydrogen; A is aryl wherein the aryl is substituted phenyl with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, (NRaRb) alkoxy, and heterocycloalkoxy, wherein the heterocycle portion of the heterocycloalkoxy is selected from the group consisting of morpholinyl, piperidinyl, and pyrrolidinyl.; it's a double link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haioalkylsulfonyl, and (NRcR) alkylcarbonyl; and R ° and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl.
In another embodiment, the present invention provides a compound of the formula (I) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, (NRaRb) alkoxy, heteroarylalkoxy, and heteroarylcarbonylalkoxy, wherein the heeroaryl portion of the heteroarylalkoxy and the heteroarylcarbonylalkoxy is selected from the group consisting of imidazolyl and pyridinyl; it's a double link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of formula (I) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R1 and R1 both are hydrogen; A is aryl wherein the aryl is phenyl suspended with one or two substrates selected from the group consisting of alkenyl,
alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, NRaRb, (NRaRb) alkoxy, (NRaRb) alkynyl, heterocyclooxyalkoxy, heteroaryloxyalkyl, and heterocyclooxyalkynyl, wherein the heyerocyclic portion of the heterocycloxyalkoxy, heteroaryloxyalkyl and heyerocyclohexyalkynyl is iorahydropyranyl; it's a double link; and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of formula (1) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaR; it's a double link; and Ra and Rb are both hydrogen. In another embodiment, the present invention provides a compound of formula (I) wherein L1 is selected from the group
consisted of CH2CH (OCH3) and CH2CH (OCH2CH3); L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R1 and R3 both are hydrogen; A is aryl wherein the aryl is substituted phenyl with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nickel, and NRaRb; it's a double link; Ra is hydrogen; and R is heeroarylalkyl wherein the heeroaryl portion of the heyarylaryl alkyl is pyridinyl. In another embodiment, the present invention provides a compound of formula (I) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl unsubstituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it's a double link; Ra is hydrogen; and R is heteroarylcarbonyl wherein the heteroaryl portion of the heteroarylcarbonyl is pyridinyl. In another embodiment the present invention provides a compound of formula (I) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; X1
is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is substituted phenyl with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, niir, and NRaRb; it's a double link; Ra is hydrogen; and R is arylsulfonyl wherein the aryl portion of the arylsulfonyl is optionally substituted phenyl with a substituent selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, and hydroxy. In another embodiment, the invention provides a compound of formula (1) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is substituted phenyl with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it's a double link; Ra is hydrogen; and R is heteroarylsulfonyl wherein the heteroaryl portion of the heteroarylsulfonyl is pyridinyl optionally substituted with a susity selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, hydroxy, and heterocycle, wherein the
heerocycle is morpholinyl. In another embodiment, the present invention provides a compound of formula (I) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; X1 is N; X2 is CH; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is substituted phenyl with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxylalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, (NRaR) alkoxy, and heterocycle, wherein the heterocycle is piperidinyl; it's a double link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and R1 are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the invention provides a compound of formula (I) wherein L 1 is CH 2; L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen,
haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, ni,
NRaRb, and (NRaRb) alkoxy; it is an individual link; Ra and Rb are selected independently from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH2; L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl suspended with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, (NRaRb) alkoxy, and heterocycloalkoxy, wherein the heterocyclic portion of the heterocycloalkoxy is selected from the group consisting of morpholinyl, piperidinyl, and pyrrolidinyl.; it is an individual link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another form, the present invention provides a
compound of the formula (I) wherein L is CH2; L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, (NRaR) alkoxy, heteroarylalkoxy, and heteroarylcarbonylalkoxy, wherein the heteroaryl portion of the heteroarylalkoxy and the heteroarylcarbonylalkoxy is selected from the group consisting of imidazolyl and pyridinyl; it is an individual link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and R1 and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of formula (I) wherein L1 is CH2; L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R1 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen,
haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, NRaRb, (NRaR) alkoxy, (NRaRb) alkynyl, heteroaryloxyalkoxy, heteroaryloxyalkylamino, and heterocyclooxyalkynyl, wherein the heterocycle moiety of the heterocyclooxyalkoxy, heterocycleoxyalkyl, and heteroaryloxyalkynyl is the hydrohydranyranyl; it is an individual link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and R1 are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L 1 is CH 2; L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is substituted phenyl with one or two subsitutes selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaR; it is an individual link; and Ra and
Rb both are hydrogen. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH2; L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R is selected from the group that
Consist of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, niir, and NRaR; it is an individual link; Ra is hydrogen; and R b is heeroarylalkyl wherein the heeroaryl portion of the alkyl aryl alkyl is pyridinyl. In another embodiment, the invention provides a compound of the formula (I) wherein L1 is CH2; L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are selected independently from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted by one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaR; it is an individual link; Ra is hydrogen; and Rb is heteroarylcarbonyl wherein the heteroaryl portion of the heteroarylcarbonyl is pyridinyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH2; L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are selected
independently of the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl in which the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it is an individual link; Ra is hydrogen; and Rb is arylsulfonyl wherein the aryl portion of the arylsulfonyl is phenyl optionally substituted with a susiigene selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, and hydroxy. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH2; L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are selected independently from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it is an individual link; Ra is hydrogen; and Rb is heteroarylsulfonyl wherein the heteroaryl portion of the heteroarylsulfonyl is pyridinyl optionally substituted with a substituent selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, hydroxy, and heterocycle, wherein the heterocycle is morpholinyl.
In another embodiment, the invention provides a compound of the formula (I) wherein L1 is CH2; L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxylalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, (NRaR) alkoxy, and heterocycle, wherein the heterocyclic is piperidinyl; it is an individual link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the invention provides a compound of formula (I) wherein L 1 is CH 2; L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3, together with the atoms to which they are bound, form an epoxide; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, and (NRaRb) alkoxy; Ra and Rb
are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, (NRcRd) alkylcarbonyl, and heteroarylalkyl, wherein the heteroaryl portion of the heteroarylalkyl is pyridinyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH2; L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, niR, NRaR, and (NRaRb) alkoxy; it's a double link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and R1 are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of formula (i) wherein L1 is CH2; L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl where the aryl is substituted phenyl with one or two
sustiíuyeníes selected from the group consisíe alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, Niiro, NRaRb, (NRaRb) alkoxy, and heíerocicloalcoxi, where the heterocycle of heterocycloalkoxy portion is selected from the group which consists of morpholinyl, piperidinyl, and pyrrolidinyl; it's a double link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH2; L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, (NRaRb) alkoxy, heteroarylalkoxy, and heteroarylcarbonylalkoxy, wherein the heteroaryl portion of the heteroarylalkoxy and the heteroarylcarbonylalkoxy is selected from the group consisting of imidazolyl and pyridinyl; it's a double link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl,
haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and R ° and R1 are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH2; L2 is a link; X1 is CH, X1 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of a-anhenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, NRaRb, (NRaRb) alkoxy, (NRaRb) alkynyl, heterocyclooxyalkoxy, heterocyclooxyalkyl, and heterocyclooxyalkynyl, wherein the heterocycle portion of the heterocyclooxyalkoxy, heterocycleoxyalkyl, and heterocycleoxyalkynyl is tetrahydropyranyl; it's a double link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Ra are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH2; L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is
aryl wherein the aryl is substituted phenyl with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaR; it's a double link; and Ra and Rb are both hydrogen. In another embodiment, the present invention provides a compound of formula (I) wherein L1 is CH2; L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl unsubstituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it's a double link; Ra is hydrogen; and Rb is heteroarylalkyl wherein the heeroaryl portion of the heyarylalkyl is pyridinyl. In another embodiment, the invention provides a compound of formula (I) wherein L1 is CH2; L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is substituted phenyl with one or two subsitutes selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl,
hydroxyalkynyl, ni, and NRaRb; it's a double link; Ra is hydrogen; and Rb is hephenoarylcarbonyl wherein the heeroaryl portion of the heteroarylcarbonyl is pyridinyl. In another embodiment, the present invention provides a compound of formula (I) wherein L1 is CH2; L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is substituted phenyl with one or two sushiluyenyes selected from the group consisting of alkenyl, akoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, niir, and NRaRb; it's a double link; Ra is hydrogen; and Rb is arylsulfonyl wherein the aryl portion of the arylsulfonyl is phenyl optionally susíifuido with a susíituyeníe selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, and hydroxy. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH2; L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is substituted phenyl with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaR; it's a double link; Ra is
hydrogen; and Rb is heteroarylsulfonyl wherein the heteroaryl portion of the heteroarylsulfony is pyridinyl optionally substituted with a substituent selected from the group consisting of alkoxy, alkyl, halogen alkoxy, haloalkyl, halogen, hydroxy, and heterocycle, wherein the heterocycle is morpholinyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L is CH2; L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyan; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, (NRaRb) alkoxy, and heterocycle, wherein the heterocycle is piperidinyl; it's a double link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and R are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of formula (I) wherein L1 is CH2; L2 is CH2; and A, X1,
X2, Y, Z, R1, R2, R3, and are as defined in Formula (I). In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH2; L2 is CH2; X1 is
CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, ni,
NRaRb, and (NRaRb) alkoxy; it is an individual link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of formula (I) wherein L1 is CH2; L2 is CH2; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, (NRaRb) alkoxy, and heterocycloalkoxy, wherein the heterocycle portion of the heterocycloalkoxy is selected from the group consisting of morpholinyl, piperidinyl, and pyrrolidinyl; It is a link
individual; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of formula (I) wherein L1 is CH2; L2 is CH2; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are selected independently from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, (NRaRb) alkoxy, heteroarylalkoxy, and heteroarylcarbonylalkoxy, wherein the heteroaryl portion of the heteroarylalkoxy and the heteroarylcarbonylalkoxy is selected from the group consisting of imidazolyl and pyridinyl; it is an individual link; Ra and Rb are selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are selected independently from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (1) wherein L 1 is CH 2; L2 is CH2; X1 is
CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl unsubstituted with one or two subsitutes selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, niR, NRaRb, (NRaRb) alkoxy, (NRaR) alkynyl, heteroaryloxyalkoxy, heteroaryloxyalkyl, and heteroaryloxyalkynyl, wherein the heyerocycle portion of the cyclooxyalkoxy, heteroaryloxyalkyl, and helerocyclohexyalkynyl is hydrohydranyranyl; it is an individual link; Ra and Rb are selected
Depending on the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Ra are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the invention provides a compound of formula (I) wherein L 1 is CH 2; L2 is CH2; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen,
haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it is an individual link; and Ra and
Rb both are hydrogen. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH2; L: is CH2; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is substituted phenyl with one or two subsitutes selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it is an individual link; Ra is hydrogen; and Rb is heteroarylalkyl wherein the heeroaryl portion of the heyarylaryl alkyl is pyridinyl. In another embodiment, the invention provides a compound of formula (I) wherein L1 is CH2; L2 is CH2; X1 is CH; X2 is N; Cast; Z is O; R is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it is an individual link; Ra is
hydrogen; and R is heeroarylcarbonyl wherein the heeroaryl portion of the heteroarylcarbonyl is pyridinyl. In another embodiment, the present invention provides a compound of formula (I) wherein L1 is CH2; L2 is CH2; X1 is CH; X2 is N; Cast; Z is O; R is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it is an individual link; Ra is hydrogen; and Rb is arylsulfonyl wherein the aryl portion of the arylsulfonyl is phenyl optionally substituted with a substituent selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, and hydroxy. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH2; L2 is CH2; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is substituted phenyl with one or two subsitutes selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkyl sulphonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl,
hydroxyalkynyl, nitro, and NRaRb; it is an individual link; Ra is hydrogen; and Rb is heteroarylsulfonyl wherein the heteroaryl portion of the heteroarylsulfonyl is pyridinyl optionally substituted with a substituent selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, hydroxy, and heterocycle, wherein the heterocycle is morpholinyl. In another embodiment, the present invention provides a compound of the formula (I) i wherein L1 is CH2; L2 is CH2; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl unsubstituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, niira, NRaRb, (NRaRb) alkoxy, and heterocycle, wherein the heterocycle is piperidinyl; it is an individual link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH2; L2 is CH2; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of
of hydrogen and cyano; R2 and R3 both are hydrogen; A is where the aryl is phenyl which is suspended with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxyl, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, ni,
NRaR, and (NRaRb) alkoxy; it's a double link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH2; L2 is CH2; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R- and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, (NRaR) alkoxy, and heterocycloalkoxy, wherein the heterocyclecycloalkoxy heterocycle portion is selected from the group consisting of morpholinyl, piperidinyl, and pyrrolidinyl; it's a double link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc
and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the invention provides a compound of formula (I) wherein L 1 is CH 2; L2 is CH2; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, (NRaRb) alkoxy, heteroarylalkoxy, and heteroarylcarbonylalkoxy, wherein the heeroaryl portion of the heteroarylalkoxy and the heteroarylcarbonylalkoxy is selected from the group consisting of imidazolyl and pyridinyl; it's a double link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and R1 are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the invention provides a compound of formula (I) wherein L 1 is CH 2; L2 is CH2; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is substituted phenyl with one or two substituents selected from the group consisting of alkenyl, alkoxy,
alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nilro, NRaRb, (NRaRb) alkoxy, (NRaR) alkynyl, heterocyclohexyalkoxy, heyerocyclohexyalkyl, and heterocyclooxyalkynyl, wherein the heyerocyclic portion of the heterocyclocycloalkoxy, heteroaryloxyalkyl, and Hetero-cyclooxyalkynyl is tetrahydropyranyl; it's a double link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NR ° Rd) alkylcarbonyl; and Rc and R1 are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the invention provides a compound of formula (I) wherein L 1 is CH 2; L2 is CH2; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R1 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl unsubstituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalicylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, niir, and NRaRb; it's a double link; and Ra and R both are hydrogen. In another embodiment, the present invention provides a compound of the formula (I) wherein L 1 is CH 2; L2 is CH2; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of
of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is substituted phenyl with one or two subsitutes selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it's a double link; Ra is hydrogen; and R is heteroarylalkyl wherein the heteroaryl portion of the heteroarylalkyl is pyridinyl. In another embodiment, the present invention provides a compound of formula (I) wherein L1 is CH2; L2 is CH2; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, niir, and NRaRb; - .- is a double link; Ra is hydrogen; and Rb is heteroarylcarbonyl wherein the heteroaryl portion of the heteroarylcarbonyl is pyridinyl. In another embodiment, the present invention provides a compound of formula (I) wherein L1 is CH2; L2 is CH2; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is substituted phenyl with one or two substrates selected from the group consisting of alkenyl, alkoxy,
alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, niir, and NRaRb; it's a double link; Ra is hydrogen; and R is arylsulfonyl wherein the aryl portion of the arylsulfonyl is phenyl optionally susiiuuid with a susiiuyenyen selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, and hydroxy. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH2; L2 is CH2; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkisulphonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it's a double link; Ra is hydrogen; and Rb is heteroarylsulfonyl wherein the heteroaryl portion of the heteroarylsulfonyl is pyridinyl optionally substituted with a susifuyenie selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, hydroxy, and heterocycle, wherein the heterocycle is morpholinyl. In another embodiment, the present invention provides a compound of formula (I) wherein L1 is CH2; L2 is CH2; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl in
wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxy alkoxy, hydroxyalkyl, nitro, NRaRb, (NRaRb) alkoxy, and heterocycle, in where the heiierocycle is piperidinyl; it's a double link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of formula (I) wherein L 1 is CH (CH 3) CH 2; L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R: and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl unsubstituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro,
NRaRb, and (NRaRb) alkoxy; it is an individual link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NR1R1) alkylcarbonyl; and Rc and Rd are selected independently from the group that
consists of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of formula (I) wherein L 1 is CH (CH 3) CH 2; L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is substituted phenyl with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, (NRaRb) alkoxy, and heterocycloalkoxy, wherein the heterocycle portion of the heterocycloalkoxy is selected from the group consisting of morpholinyl, piperidinyl, and pyrrolidinyl; it is an individual link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and R ° and R1 are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the invention provides a compound of formula (I) wherein L1 is CH (CH3) CH2", L2 is a bond, X1 is CH, X2 is N, Y is O, Z is O, R1 is selected of the group consisting of hydrogen and cyano R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl,
alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyaryloxy, hydroxyalkyl, nitro, NRaR, (NRaR) alkoxy, heteroarylalkoxy, and heteroarylcarbonylalkoxy, wherein the heeroaryl moiety of the aryloxy alkoxy and the heteroarylcarbonylalkoxy is selected from the group consisting of imidazolyl and pyridinyl; it is an individual link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and R1 are selected independently from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of formula (I) wherein L 1 is CH (CH 3) CH 2; L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein aryl is phenyl sustiíuido with one or two susíiíuyeníes selected from the group consisíe alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, NRaRb, (NRaRb) alkoxy, (NRaRb) alkynyl, heterociclooxialcoxi, heterocycleoxyalkyl, and heíerociclooxialquinilo, wherein the portion of helerociclooxialcoxi heferociclo, heíerociclooxialquilo and heíerociclooxialquinilo is íeírahidropíranilo; it is an individual link; Ra and Rb are selected
independently of the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH (CH3) CH2; L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two sustiíuyentes selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, Niiro, and NRaRb; it is an individual link; and Ra and
R both are hydrogen. In another embodiment, the invention provides a compound of formula (I) wherein L 1 is CH (CH 3) CH 2; L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two selected from the group sustiíuyeníes consisíe alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl,
hydroxyalkynyl, ni, and NRaR; it is an individual link; Ra is hydrogen; and Rb is heteroarylalkyl wherein the heteroaryl portion of the heteroarylalkyl is pyridinyl. In another embodiment, the present invention provides a compound of formula (I) wherein L 1 is CH (CH 3) CH 2; L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein aryl is phenyl sustiíuido with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it is an individual link; Ra is hydrogen; and R is heteroarylcarbonyl wherein the heeroaryl portion of the heteroarylcarbonyl is pyridinyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L 1 is CH (CH 3) CH 2; L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl unsubstituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it is an individual link; Ra is
hydrogen; and R is arylsulfonyl wherein the aryl portion of the arylsulfonyl is optionally substituted phenyl with a substituent selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, and hydroxy. In another embodiment, the invention provides a compound of the formula (I) wherein L 1 is CH (CH 3) CH 2; L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it is an individual link; Ra is hydrogen; and Rb is heteroarylsulfonyl wherein the heeroaryl portion of the ironaryl sulfonyl is optionally substituted pyridinyl with a substituent selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, hydroxy, and heterocycle, wherein the heterocycle is morpholinyl. In another embodiment, the invention provides a compound of formula (I) wherein L 1 is CH (CH 3) CH 2; L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or
two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, niira, NRaR, (NRaRb) alkoxy, and heterocycle, wherein the heterocycle is piperidinyl; it is an individual link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of formula (I) wherein L 1 is CH (CH 3) CH 2; L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, and (NRaRb) alkoxy; it's a double link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a
compound of the formula (I) wherein L1 is CH (CH3) CH2; L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is substituted phenyl with one or two subsitutes selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, (NRaRb) alkoxy, and heterocycloalkoxy, wherein the heterocycle portion of the heterocycloalkoxy is selected from the group consisting of morpholinyl, piperidinyl, and pyrrolidinyl; it's a double link; Ra and R are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NR ° Rd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L is CH (CH 3) CH 2; L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, niR, NRaRb, (NRaRb) alkoxy, heeroarylalkoxy, and heteroarylcarbonylalkoxy, wherein the heteroaryl portion of the heleroarylalkoxy and the
The heteroarylcarbonylalkoxy is selected from the group consisting of imidazolyl and pyridinyl; it's a double link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the invention provides a compound of formula (1) wherein L 1 is CH (CH 3) CH 2; L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, NRaRb, (NRaR) alkoxy, (NRaRb) alkynyl, heterocyclooxyalkoxy, heterocyclooxyalkyl, and heterocyclooxyalkynyl, wherein the heterocycle portion of the heterocyclooxyalkoxy, heteroaryloxyalkyl, and heteroaryloxyalkynyl is tetrahydropyranyl; it's a double link; Re R1 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and R c and R 1 are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl.
In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH (CH,) CH2; L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it's a double link; and Ra and R both are hydrogen. In another embodiment, the present invention provides a compound of the formula (I) wherein L, is CH (CH 3) CH 2; L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl unsubstituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaR; it's a double link; Ra is hydrogen; and R is heteroarylalkyl wherein the heteroaryl portion of the heteroarylalkyl is pyridinyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH (CH3) CH2; L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are
hydrogen; A is aryl wherein the aryl is substituted phenyl with one or two susyls selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it's a double link; Ra is hydrogen; and R is heteroarylcarbonyl wherein the heteroaryl portion of the heteroarylcarbonyl is pyridinyl. In another embodiment, the present invention provides a compound of formula (I) wherein L 1 is CH (CH 3) CH 2; L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; It's a double link; Ra is hydrogen; and R is arylsulfonyl wherein the aryl portion of the arylsulfonyl is phenyl optionally susi fi ed with a susiiuyenyen selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, and hydroxy. In another embodiment, the invention provides a compound of formula (I) wherein L 1 is CH (CH 3) CH 2; L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or
two susíifuyentes selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulphonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nifro, and NR aa DR b is a double bond; Ra is hydrogen; and R is heteroarylsulfonyl wherein the heeroaryl portion of the heteroarylsulfonyl is pyridinyl optionally substituted with a substitute selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, hydroxy, and heterocyclic, wherein the heterocycle is morpholinyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L1 is CH (CH3) CH2; L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, akoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, (NRaR) alkoxy, and heterocycle, wherein the heterocycle is piperidinyl; it's a double link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a
compound of the formula (!) wherein L1 is CH2CH (OH); L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxylalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, and (NRaR) alkoxy; it is an individual link; Ra and R are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L 1 is CH 2 CH (OH); L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; Rz and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, (NRaRb) alkoxy, and heterocycloalkoxy, wherein the heterocyclecycloalkoxy heterocycle portion is selected from the group
consists of morpholinyl, piperidinyl, and pyrrolidinyl; it is an individual link; Ra and R are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of formula (I) wherein L 1 is CH 2 CH (OH); L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, (NRaRb) alkoxy, heteroarylalkoxy, and heteroarylcarbonylalkoxy, wherein the heeroaryl portion of the heteroarylalkoxy and the heteroarylcarbonylalkoxy is selected from the group consisting of imidazolyl and pyridinyl; it is an individual link; Ra and R are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and R1 are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another form, the present invention provides a
compound of the formula (I) wherein L is CH 2 CH (OH); L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from! group consisting of hydrogen and cyano; R2 and R3 are selected independently from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, NRaRb, (NRaRb) alkoxy, (NRaRb) alkynyl, heterocyclooxyalkoxy, heteroaryloxyalkyl, and heterocyclooxyalkynyl, wherein the heterocycle portion of the heterocyclooxyalkoxy, heterocycleoxyalkyl, and heterocycleoxyalkynyl is terahydropyranyl; - it is an individual link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and R1 are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the invention provides a compound of formula (I) wherein L is CH2CH (OH); L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl,
alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it is an individual link; and Ra and
R both are hydrogen. In another embodiment, the present invention provides a compound of formula (I) wherein L 1 is CH 2 CH (OH); L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it is an individual link; Ra is hydrogen; and R is heeroarylalkyl wherein the hephenoaryl portion of the hephenoarylalkyl is pyridinyl. In another embodiment, the invention provides a compound of formula (I) wherein L 1 is CH 2 CH (OH); L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl unsubstituted with one or two subsitutes selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl,
hydroxyalkynyl, nitro, and NRaRb; it is an individual link; Ra is hydrogen; and Rb is heteroarylcarbonyl wherein the heteroaryl portion of the heteroarylcarbonyl is pyridinyl. In another embodiment, the invention provides a compound of the formula (I) wherein L 1 is CH 2 CH (OH); L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, niir, and NRaR; it is an individual link; Ra is hydrogen; and R is arylsulfonyl wherein the aryl portion of the arylsulfonyl is phenyl optionally substituted with a substitute selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, and hydroxy. In another embodiment, the invention provides a compound of formula (I) wherein L 1 is CH 2 CH (OH); L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen,
haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaR; it is an individual link; Ra is hydrogen; and Rb is heteroarylsulfonyl wherein the heeroaryl portion of the heteroarylsulfonyl is pyridinyl optionally substituted with a susity selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, hydroxy, and heterocycle, wherein the heterocycle is morpholinyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L 1 is CH 2 CH (OH); L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, (NRaR) alkoxy, and heterocycle, wherein the heterocycle is piperidinyl; it is an individual link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L 1 is CH 2 CH (OH); L2 is a
link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted by one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro,
NRaRb, and (NRaRb) alkoxy; it's a double link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L 1 is CH 2 CH (OH); L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl,
'alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, (NRaRb) alkoxy, and heterocycloalkoxy, wherein the heterocycle portion of the heterocycloalkoxy is selected from the group consisting of morpholinyl, piperidinyl, and pyrrolidinyl; it's a double link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl,
haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the invention provides a compound of formula (1) wherein L 1 is CH 2 CH (OH); L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, (NRaR) alkoxy, heteroarylalkoxy, and heteroarylcarbonylalkoxy, wherein the heteroaryl portion of the heteroarylalkoxy and the heteroarylcarbonylalkoxy is selected from the group consisting of imidazolyl and pyridinyl; it's a double link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L 1 is CH 2 CH (OH); L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or
two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, NRaRb, (NRaR) alkoxy, (NRaR) alkynyl, heterocycleoxyalkoxy, heterocycleoxyalkyl, and heterocycleoxyalkynyl , wherein the heterocycle portion of the heterocyclooxyalkoxy, heterocycleoxyalkyl, and heterocycleoxyalkynyl is tetrahydropyranyl; it's a double link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and R ° and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L 1 is CH 2 CH (OH); L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it's a double link; and Ra and Rb are both hydrogen. In another embodiment, the present invention provides a compound of the formula (I) wherein L 1 is CH 2 CH (OH); L2 is a
link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl suspended with one or two substrates selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it's a double link; Ra is hydrogen; and Rb is heteroarylalkyl wherein the heteroaryl portion of the heteroarylalkyl is pyridinyl. In another embodiment, the present invention provides a compound of formula (I) wherein L is CH 2 CH (OH); L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, niir, and NRaRb; it's a double link; Ra is hydrogen; and Rb is heteroarylcarbonyl wherein the heteroaryl portion of the heteroarylcarbonyl is pyridinyl. In another embodiment, the present invention provides a compound of formula (I) wherein L 1 is CH 2 CH (OH); L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl where the aryl is phenyl substituted with one or
two substitutes selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxylalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it's a double link; Ra is hydrogen; and Rb is arylsulfonyl wherein the aryl portion of the arylsulfonyl is phenyl optionally susiiuuid with a sushtyuyeniye selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, and hydroxy. In another embodiment, the present invention provides a compound of the formula (I) wherein L is CH 2 CH (OH); L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is substituted phenyl with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it's a double link; Ra is hydrogen; and Rb is heteroarylsulfonyl wherein the heteroaryl portion of the heteroarylsulfonyl is pyridinyl optionally substituted with a substituent selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, hydroxy, and heterocycle, wherein the heterocycle is morpholinyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L 1 is CH 2 CH (OH); L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from
group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, (NRaRb) alkoxy, and heterocycle, wherein the heterocyclic is piperidinyl; it's a double link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and R1 and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of formula (1) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl unsubstituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro,
NRaR, and (NRaR) alkoxy; it is an individual link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl,
haloalkylcarbonyl, haloalicylsulfonyl, and (NRCR) aikylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the invention provides a compound of the formula (I) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is substituted phenyl with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, (NRaRb) alkoxy, and heterocycloalkoxy, wherein the heyerocycle portion of the heterocycloalkoxy is selected from the group consisting of morpholinyl, piperidinyl, and pyrrolidinyl; it is an individual link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group that
it consists of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, (NRaRb) alkoxy, heteroarylalkoxy, and heteroarylcarbonylalkoxy, wherein the heteroaryl portion of the heteroarylalkoxy and the heteroarylcarbonylalkoxy is selected from the group consisting of imidazolyl and pyridinyl; it is an individual link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the invention provides a compound of formula (I) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L: it's a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl,
hydroxyalkynyl, nitro, NRaRb, (NRaR °) alkoxy, (NRaRb) alkynyl, heterocyclooxyalkoxy, heterocyclooxyalkyl, and heterocyclooxyalkynyl, wherein the heterocycle portion of helerocyclooxy alkoxy, heteroaryloxyalkyl, and heteroaryloxyalkynyl is hydroxyaryl; it is an individual link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the invention provides a compound of formula (I) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl unsubstituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, niir, and NRaRb; it is an individual link; and Ra and
Rb both are hydrogen. In another embodiment, the present invention provides a compound of the formula (I) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; X1
it's CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it is an individual link; Ra is hydrogen; and R is heteroarylalkyl wherein the heeroaryl portion of the arylaryl alkyl is pyridinyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, niir, and NRaRb; it is an individual link; Ra is hydrogen; and Rb is heeroarylcarbonyl wherein the heeroaryl portion of the ironarylcarbonyl is pyridinyl. In another embodiment, the invention provides a compound of formula (I) wherein L1 is selected from the group
consists of CH2CH (OCH3) and CH2CH (OCH2CH3); L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl unsubstituted with one or two subsitutes selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, niir, and NRaR; it is an individual link; Ra is hydrogen; and Rb is arylsulfonyl wherein the aryl portion of the arylsulfonyl is phenyl optionally substituted with a substituent selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, and hydroxy. In another embodiment, the present invention provides a compound of the formula (I) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it is an individual link; Ra is hydrogen; and Rb is heteroarylsulfonyl wherein the heteroaryl portion
of the heteroarylsulfonyl is pyridinyl optionally substituted with a substituent selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, hydroxy, and heterocycle, wherein the heterocycle is morpholinyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, (NRaR) alkoxy, and heterocycle, wherein the heterocycle is piperidinyl; it is an individual link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and R are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group that
Consists of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is substituted phenyl with one or two substrates selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro,
NRaRb, and (NRaRb) alkoxy; it's a double link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Ra are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the invention provides a compound of formula (I) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, (NRaRb) alkoxy, and heterocycloalkoxy, wherein the heterocycle portion of the heterocycloalkoxy is selected from the group consisting of morpholinyl, piperidinyl, and pyrrolidinyl; it's a double link; Ra and Rb are selected independently from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl,
haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRa) alkylcarbonyl; and R and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment the present invention provides a compound of formula (I) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R1 and R3 both are hydrogen; A is aryl wherein the aryl is substituted phenyl with one or two subsitutes selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, (NRaR) akoxy, heteroarylalkoxy, and heteroarylcarbonylalkoxy, wherein the heteroaryl portion of the heteroarylalkoxy and the heteroarylcarbonylalkoxy is selected from the group consisting of imidazolyl and pyridinyl; it's a double link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the invention provides a compound of formula (I) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group that
it consists of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl unsubstituted with one or two subsitutes selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, NRaRb, (NRaRb) alkoxy, (NRaRb) alkynyl, heterocyclooxalkoxy, heterocyclooxyalkyl, and heterocyclooxyalkynyl, wherein the heyerocycle portion of the heterocyclocycloalkoxy, heteroaryloxyalkyl, and heterocyclooxyalkynyl is tetrahydropyranyl; it's a double link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and R ° and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaR; it's a double link; and Ra and R
both are hydrogen. In another embodiment, the present invention provides a compound of formula (I) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is substituted phenyl with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, niir, and NRaRb; it's a double link; Ra is hydrogen; and Rb is heeroarylalkyl wherein the heeroaryl portion of the heyarylalkyl is pyridinyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, niir, and NRaRb; it's a double link; Ra is hydrogen; and R is heeroarylcarbonyl wherein the heeroaryl portion of the ironarylcarbonyl is pyridinyl.
In another embodiment, the present invention provides a compound of the formula (I) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it's a double link; Ra is hydrogen; and Rb is arylsulfonyl wherein the aryl portion of the arylsulfonyl is optionally phenyl substi tuted with a substituent selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, and hydroxy. In another embodiment, the present invention provides a compound of formula (I) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, nitro, and NRaRb; it's a double link; Ra is hydrogen; and Rb is heteroarylsulfonyl wherein the heteroaryl portion
of the heteroarylsulfonyl is pyridinyl optionally substituted with a substituent selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, hydroxy, and heterocycle, wherein the heterocycle is morpholinyl. In another embodiment, the present invention provides a compound of the formula (I) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; X1 is CH; X2 is N; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 both are hydrogen; A is aryl wherein the aryl is phenyl substituted with one or two substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, (NRaR) alkoxy, and heterocycle, wherein the heterocycle is piperidinyl; it's a double link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (II)
or an ipaeuíicamente acceptable salt of the same, where it is an individual or double bond; R1 is selected from the group consisting of hydrogen, alkoxycarbonyl, alkyl, carboxy, cyano, halogen, and nitro; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylsulfonyl, arylsulfonyl, halogen, hydroxy, and NRaR; or R2 and R3, June with the atoms to which they are united, form an epoxide; R4 is selected from the group consisting of alkoxy, alkyl, cyano, halogen, heterocyclooxyalkoxy, heterocyclooxyalkyl, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, and (NRaR) alkoxy; R5 is selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonyl, alkyl, alkylsulfonyl, arylsulfonyl, alkylsulfonyl, arylsulfonyl, carboxy, carboxyalkyl, haloalkylsulfonyloxy, heteroarylalkoxy, heteroarylcarbonylalkoxy,
Heterocyclic, heyerocycloalkoxy, heteroaryloxyalkyl, heteroaryloxyalkynyl, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, NRaRc (NRaRD) alkoxy, (NR> aaoR b °) alkyl,
(NRaR) alkynyl, (NRaRD) carbonyl, (NRaRD) carbonylalkoxy, and (NRaRb) carbonylalkyl; Y and Z are independently selected from the group consisting of CH2, O, and NRZ, wherein Rz is selected from the group consisting of hydrogen and alkyl; L1 and L2 are independently selected from the group consisting of a bond and alkylene; Ra and Rb are independently selected from the group consisting of hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkyl, arylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heteroarylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another form, the present invention provides a compound of formula (II) wherein R 1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is hydrogen; Cast; Z is O; L1 is CH2; and L2 and are as defined in Formula (II). In another embodiment, the present invention provides a compound of the formula (II) wherein L1 is CH2; L2 is a link; Y
that; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro,
NRaRD, and (NRaRD) alkoxy; it is an individual link; Ra and R ° are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and R c and R 1 are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of formula (11) wherein L 1 is CH 2; L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R1 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R 4 is selected from the group consisting of alkoxy, alkyl, heterocyclooxyalkoxy, heterocycleoxyalkyl, hydroxy, hydroxyalkyl, nitro, and (NRaRb) alkoxy, wherein the heterocycle portion of the cyclooxyalkoxy and heteroaryloxyalkyl is heteroarylhydropyranyl; R5 is hydrogen; it is an individual link; and Ra and Rb are independently selected from the group consisting of hydrogen and alkyl. In another embodiment, the present invention provides a compound of formula (II) wherein L1 is CH '; L2 is a link; Y
that; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is heterocycloalkoxy, wherein the heterocyclecycloalkoxy heterocycle moiety is selected from the group consisting of morpholinyl, piperidinyl, and pyrrolidinyl; and it is an individual link. In another embodiment, the present invention provides a compound of the formula (II) wherein L1 is CH2; L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R 5 is selected from the group consisting of heteroarylalkoxy, and heteroarylcarbonylalkoxy, wherein the heeroaryl portion of the aryloxyaryloxy and the heteroarylcarbonylalkoxy is selected from the group consisting of imidazolyl and pyridinyl; and it is an individual link. In another embodiment, the invention provides a compound of formula (II) wherein L1 is CH2; L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is selected from the group consisting of (NRaRb) alkynyl, heterocyclooxyalkoxy, heterocyclooxyalkyl, and heterocyclooxyalkynyl, wherein the heterocyclic portion of heterocyclooxyalkoxy, heteroaryloxyalkyl, and heterocycloxyalicynil is tetrahydropyranyl;
is an individual link In another embodiment, the invention provides a compound of formula (II) wherein L1 is CH2; L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are selected independently from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is
NRaRb; it is an individual link; and Ra and Rb are selected from the group consisting of hydrogen and alkyl. In another embodiment, the present invention provides a compound of formula (II) wherein L1 is CH2; L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is NRaRb; it is an individual link; Ra is hydrogen; and Rb is heteroarylalkyl wherein the heteroaryl portion of the heteroarylalkyl is pyridinyl. In another embodiment, the invention provides a compound of formula (II) wherein L1 is CH2; L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R1 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is
NRaRb; it is an individual link; Ra is hydrogen; and Rb is heteroarylcarbonyl wherein the heteroaryl portion of the heteroarylcarbonyl is pyridinyl. In another embodiment, the present invention provides a
composed of the formula (II) wherein L1 is CH2; L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is NRaRb; it is an individual link; Ra is hydrogen; and R is arylsulfonyl wherein the aryl portion of the arylsulfonyl is phenyl optionally substituted with a substituent selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, and hydroxy. In another embodiment, the present invention provides a compound of the formula (II) wherein L1 is CH2; L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is NRaRb; it is an individual link; Ra is hydrogen; and R is heteroarylsulfonyl wherein the heteroaryl portion of the heteroarylsulfonyl is pyridinyl optionally substituted with a substituent selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, hydroxy, and heterocycle, wherein the heterocycle is morpholinyl. In another embodiment, the present invention provides a compound of the formula (II) wherein L1 is CH2; L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is
heerocycle, where the heerocycle is piperidinyl; It is an individual link. In another embodiment, the invention provides a compound of formula (II) wherein L1 is CH2; L2 is a link; Cast; Z is O; R is selected from the group consisting of hydrogen and cyano; R2 and R3, together with the atoms to which they are attached, form an epoxide; R4 is halogen; R5 is selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyl, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, and (NRaRb) alkoxy; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, (NRcRd) alkylcarbonyl, and heteroarylalkyl, wherein the heteroaryl portion of the heteroarylalkylary is pyridinyl; and R c and R 1 are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of formula (II) wherein L1 is CH2; L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, niir, NRaRb, and (NRaRb) alkoxy; it's a double link; Ra and Rb are
independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (II) wherein L1 is CH2; L2 is a link; Cast; Z is O; R is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R 4 is selected from the group consisting of alkoxy, alkyl, heterocyclooxyalkoxy, heterocyclooxyalkyl, hydroxy, hydroxyalkyl, nitro, and (NRaRb) alkoxy, wherein the heterocyclic portion of the heterocyclocycloalkoxy and heteroaryloxyalkyl is hydrohydranyranyl; R5 is hydrogen; it's a double link; and Ra and R1 are independently selected from the group consisting of hydrogen and alkyl. In another embodiment, the present invention provides a compound of the formula (II) wherein L1 is CH2; L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are selected independently from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R 5 is heyerocycloalkoxy, wherein the heyerocycle portion of the heterocycloalkoxy is selected from the group consisting of morpholinyl, piperidinyl, and pyrrolidinyl; and it's a double link. In another embodiment, the present invention provides a
compound of formula (II) wherein L1 is CH2; L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is selected from the group consisting of heeroarylalkoxy; and heeroarylcarbonylalcoxy, wherein the heeroaryl portion of the heteroarylalkoxy and the heteroarylcarbonylalkoxy is selected from the group consisting of imidazolyl and pyridinyl; and it's a double link. In another embodiment, the present invention provides a compound of formula (II) wherein L1 is CH2; L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is selected from the group consisting of (NRaRb) alkynyl, heyerocyclooxyalkoxy, heteroaryloxy-oxalkyl, and heterocyclooxyalkynyl, wherein the heyerocycle portion of the cyclooxyalkoxy, heteroaryloxyalkyl, and heteroaryloxyalkynyl is tetrahydropyranyl; and it's a double link. In another embodiment, the present invention provides a compound of formula (11) wherein L 1 is CH 2; L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R1 is halogen; R5 is NRaR; it's a double link; and Ra and Rb are selected from the group consisting of hydrogen and alkyl.
In another embodiment, the invention provides a compound of formula (II) wherein L1 is CH2; L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4is halogen; R5is NRaR; it's a double link; Ra is hydrogen; and R is heeroarylalkyl wherein the heeroaryl portion of the heyarylaryl alkyl is pyridinyl. In another embodiment, the invention provides a compound of formula (II) wherein L1 is CH:; L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy,. and hydroxy; R4 is halogen; R5 is
NRaRE is a double link; Ra is hydrogen; and Rb is heteroarylcarbonyl wherein the heteroaryl portion of the heteroarylcarbonyl is pyridinyl. In another embodiment, the invention provides a compound of formula (II) wherein L1 is CH2; L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4is halogen; R5is NRaRb; it's a double link; Ra is hydrogen; and R is arylsulfonyl wherein the aryl portion of the arylsulfonyl is phenyl optionally substituted with a substituent selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, and hydroxy. In another embodiment, the present invention provides a
compound of formula (II) wherein L1 is CH2; L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is NRaR; it's a double link; Ra is hydrogen; and Rb is heteroarylsulfonyl wherein the heteroaryl portion of the heteroarylsulfonyl is optionally substituted pyridinyl with a substituent selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, hydroxy, and heterocycle, wherein the heterocycle is morpholinyl. In another embodiment, the present invention provides a compound of the formula (II) wherein L1 is CH2; L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; -R4 is halogen; R5 is heterocyclic, wherein the heterocycle is piperidinyl; It is a double link. In another embodiment, the invention provides a compound of formula (II) wherein L1 is CH2; L2 is CH2; and A, X, Y, Z, R1, R2 and R3 are as defined in Formula (I). In another embodiment, the present invention provides a compound of the formula (II) wherein L1 is CH2; L2 is CH2; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is
selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro,
NRaRb, and (NRaRb) alkoxy; it is an individual link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the invention provides a compound of formula (II) wherein L1 is CH2; L2 is CH2; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R 4 is selected from the group consisting of alkoxy, alkyl, heterocyclooxyalkoxy, heterocyclooxyalkyl, hydroxy, hydroxyalkyl, nii, and (NRaRb) alkoxy, wherein the heterocycle portion of the heterocyclooxyalkoxy and heteroaryloxyalkyl is hydrohydranyranyl; R5 is hydrogen; it is an individual link; and Ra and Rb are independently selected from the group consisting of hydrogen and alkyl. In another embodiment, the present invention provides a compound of the formula (II) wherein L1 is CH2; L2 is CH2; Cast;
Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is
Heterocycloalkoxy, wherein the heyerocyclic portion of the heterocycloalkoxy is selected from the group consisting of morpholinyl, piperidinyl, and pyrrolidinyl; and it is an individual link. In another embodiment, the present invention provides a compound of the formula (II) wherein L1 is CH2; L2 is CH2; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is selected from the group consisting of heeroarylalkoxy, and heleroarylcarbonylalkoxy, wherein the heteroaryl portion of the heteroarylalkoxy and the heteroarylcarbonylalkoxy is selected from the group consisting of imidazolyl and pyridinyl; and it is an individual link. In another embodiment, the present invention provides a compound of the formula (II) wherein L1 is CH2; L2 is CH2; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is selected from the group consisting of (NRaR) alkynyl, heyerocyclooxyalkoxy, heteroaryloxyalkyl, and heteroaryloxyalkynyl, wherein the heyerocycle portion of the cyclooxyalkoxy, heterocyclooxyalkyl, and heterocyclooxyalkylene is tetrahydropyranyl; and it is an individual link. In another embodiment, the present invention provides a compound of the formula (II) wherein L1 is CH2; L2 is CH2; Cast;
Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is
NRaR; it is an individual link; and Ra and Rb are selected from the group consisting of hydrogen and alkyl. In another embodiment, the invention provides a compound of formula (II) wherein L1 is CH2; L2 is CH2; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is
NRaRb; it is an individual link; Ra is hydrogen; and Rb is heeroarylalkyl wherein the heteroaryl portion of the heteroarylalkyl is pyridinyl. In another embodiment, the invention provides a compound of formula (II) wherein L1 is CH2; L2 is CH2; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is
NRaaRr_.b. it is an individual link; Ra is hydrogen; and R is heteroarycarbonyl wherein the heteroaryl portion of the heteroarylcarbonyl is pyridinyl. In another embodiment, the present invention provides a compound of formula (II) wherein L1 is CH2; L2 is CH2; Cast;
Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group that
consists of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is
NRaRb; it is an individual link; Ra is hydrogen; and R is arylsulfonyl wherein the aryl portion of the arylsulfonyl is phenyl optionally substituted with a substitute selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, and hydroxy. In another embodiment, the present invention provides a compound of formula (II) wherein L1 is CH2; L2 is CH2; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is
NRaRb; it is an individual link; Ra is hydrogen; and Rb is heteroarylsulfonyl wherein the heteroaryl portion of the heteroarylsulfonyl is pyridinyl optionally substituted with a substitute selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, hydroxy, and heterocycle, wherein the heterocycle is morpholinyl. In another embodiment, the present invention provides a compound of the formula (II) wherein L1 is CH2; L2 is CH2; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is heterocycle, wherein the heterocycle is piperidinyl; It is an individual link. In another embodiment, the present invention provides a
composed of the formula (II) wherein L1 is CH2; L2 is CH2; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3, together with the atoms to which they are attached, form an epoxide; R4 is halogen; R5 is selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaR, and (NRaR) alkoxy; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, (NRcRd) alkylcarbonyl, and heteroarylalkyl, wherein the heteroaryl portion of the heteroarylalkyl is pyridinyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (II) wherein L1 is CH2; L2 is CH2; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nyl,
NRaRb, and (NRaRb) alkoxy; it's a double link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc
and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the invention provides a compound of formula (II) wherein L1 is CH2; L2 is CH2; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is selected from the group consisting of alkoxy, alkyl, heterocyclooxyalkoxy, heterocyclooxyalkyl, hydroxy, hydroxyalkyl, nitro, and (NRaRb) alkoxy, wherein the heterocycle portion of the heterocycleoxyalkoxy and heterocycleoxyalkyl is tefrahydropyranyl; R5 is hydrogen; it's a double link; and Ra and Rb are independently selected from the group consisting of hydrogen and alkyl. In another embodiment, the invention provides a compound of formula (II) wherein L1 is CH2; L2 is CH2; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is heterocycloalkoxy, wherein the helerocycle portion of the helerocycloalkoxy is selected from the group consisting of morpholinyl, piperidinyl, and pyrrolidinyl; and it's a double link. In another embodiment, the present invention provides a compound of the formula (II) wherein L1 is CH2; L2 is CH2; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group that
consists of hydrogen, alkoxy, and hydroxy; R4 is halogen; Rs is selected from the group consisting of heteroarylalkoxy, and heteroarylcarbonylalkoxy, wherein the heteroaryl portion of the heteroarylalkoxy and the heteroarylcarbonylalkoxy is selected from the group consisting of midazolyl and pyridinyl; and it's a double link. In another embodiment, the present invention provides a compound of the formula (II) wherein L1 is CH2; L2 is CH2; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is selected from the group consisting of (NRaRb) alkynyl, heterocyclooxyalkoxy, heterocyclooxyalkyl, and heterocyclooxyalkynyl, wherein the heterocycle portion of the heterocyclooxyalkoxy, heterocycleoxyalkyl, and heterocycleoxyalkynyl is tetrahydropyranyl; and it's a double link. In another embodiment, the present invention provides a compound of the formula (II) wherein L1 is CH2; L2 is CH2; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are selected independently from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is
NRaRb; it's a double link; and Ra and Rb are selected from the group consisting of hydrogen and alkyl. In another embodiment, the present invention provides a compound of formula (II) wherein L1 is CH2; L2 is CH2; Cast; Z is O; R1 is selected from the group consisting of hydrogen and
cyanus; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is
NRaRb; it's a double link; Ra is hydrogen; and Rb is heeroarylalkyl wherein the heeroaryl portion of the heteroarylalkyl is pyridinyl. In another embodiment, the present invention provides a compound of formula (II) wherein L1 is CH2; L2 is CH2; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is
NRaRb; it's a double link; Ra is hydrogen; and Rb is heeroarylcarbonyl wherein the heeroaryl portion of the heteroarylcarbonyl is pyridinyl. In another embodiment, the present invention provides a compound of the formula (II) wherein L1 is CH2; L2 is CH2; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is NRaRb; it's a double link; Ra is hydrogen; and Rb is arylsulfonyl wherein the aryl portion of the arylsulfonyl is phenyl optionally susiiuuid with a susiiuyenyen selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, and hydroxy. In another embodiment, the present invention provides a compound of the formula (II) wherein L1 is CH2; L2 is CH2; Cast; Z is O; R1 is selected from the group consisting of hydrogen and
cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is
NRaR; it's a double link; Ra is hydrogen; and Rb is heteroarylsulfonyl wherein the heteroaryl portion of the heteroarylsulfony is pyridinyl optionally susiiuuid with a substituent selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, hydroxy, and heterocycle, wherein the heterocycle is morpholinyl. In another embodiment, the present invention provides a compound of the formula (II) wherein L1 is CH2; L2 is CH2; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is heterocycle, wherein the heterocycle is piperidinyl; It is a double link. In another embodiment, the invention provides a compound of formula (II) wherein L1 is CH (CH3) CH2; L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, and (NRaRb) alkoxy; it is an individual link; Ra and Rb are independently selected from the group consisting of
hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the invention provides a compound of formula (II) wherein L 1 is CH (CH 3) CH:; L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R 4 is selected from the group consisting of -alkoxy, alkyl, heterocyclooxyalkoxy, heterocyclooxyalkyl, hydroxy, hydroxyalkyl, nii, and (NRaR) alkoxy, wherein the heterocycle portion of the heterocyclooxyalkoxy and heterocycleoxyalkyl is terahydropyranyl; R5 is hydrogen; it is an individual link; and Ra and Rb are independently selected from the group consisting of hydrogen and alkyl. In another embodiment, the invention provides a compound of formula (II) wherein L 1 is CH (CH 3) CH 2; L2 is a link; Cast; Z is O; R is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is heterocycloalkoxy, wherein the heterocycle portion of the heterocycloalkoxy is selected from the group consisting of morpholyl, piperidinyl, and pyrrolidinyl; and it is an individual link.
In another embodiment, the present invention provides a
compound of the formula (II) wherein L1 is CH (CH3) CH2; L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; Rz and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is selected from the group consisting of heteroarylalkoxy, and heteroarylcarbonylalkoxy, wherein the heeroaryl portion of the arylalkoxy and the arylarylcarbonylalkoxy is selected from the group consisting of imidazolyl and pyridinyl; and it is an individual link. In another embodiment, the invention provides a compound of formula (II) wherein L 1 is CH (CH 3) CH 2; L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is selected from the group consisting of (NRaRb) alkynyl, heterocyclooxyalkoxy, heterocyclooxyalkyl, and heterocyclooxyalkynyl, wherein the heterocycle portion of the heterocyclooxyalkoxy, heterocycleoxyalkyl, and heterocycleoxyalkynyl is tetrahydropyranyl; and it is an individual link. In another embodiment, the present invention provides a compound of the formula (II) wherein L 1 is CH (CH 3) CH 2; L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R is NRaR; it is an individual link; and Ra and R are
selected from the group consisting of hydrogen and alkyl. In another embodiment, the present invention provides a compound of the formula (II) wherein L 1 is CH (CH 3) CH 2; L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is NRaRb; it is an individual link; Ra is hydrogen; and Rb is heteroarylalkyl wherein the heteroaryl portion of the heeroarylalkyl is pyridinyl. In another embodiment, the invention provides a compound of formula (II) wherein L 1 is CH (CH 3) CH 2; L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is NRaRb; it is an individual link; Ra is hydrogen; and Rb is heteroarylcarbonyl wherein the heteroaryl portion of the heteroarylcarbonyl is pyridinyl. In another embodiment, the invention provides a compound of formula (II) wherein L1 is CH (CH3) CH2; L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is NRaRb; it is an individual link; Ra is hydrogen; and Rb is arylsulfonyl wherein the aryl portion of the arylsulfonyl is phenyl optionally substituted with a substituent
selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, and hydroxy. In another embodiment, the present invention provides a compound of formula (II) wherein L1 is CH (CH3) CH2; L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are selected independently from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is NRaRb; it is an individual link; Ra is hydrogen; and Rb is heteroarylsulfonyl wherein the heeroaryl portion of the heteroarylsulfonyl is pyridinyl optionally substituted with a susíituyenfe selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, hydroxy, and heterocycle, wherein the heterocycle is morpholinyl. In another embodiment, the present invention provides a compound of formula (II) wherein L1 is CH (CH3) CH2; L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen 'alkoxy, and hydroxy; R4 is halogen; R5 is a heterocycle, wherein the heterocycle is piperidinyl; It is an individual link. In another embodiment, the present invention provides a compound of formula (II) wherein L1 is CH (CH3) CH2; L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3, together with the atoms to which they are attached, form an epoxide; R4 is halogen; R5 is selected from
a group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaR, and (NRaRb) alkoxy; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, (NRcR) alkylcarbonyl, and heteroarylalkyl, wherein the heteroaryl portion of the arylaryl alkyl is pyridinyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of formula (II) wherein L1 is CH (CH3) CH2; L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are selected independently from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro,
NRaR, and (NRaRb) alkoxy; it's a double link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and R1 are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the invention provides a compound of formula (II) wherein L 1 is CH (CH 3) CH 2; L2 is a
link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R 4 is selected from the group consisting of alkoxy, alkyl, heterocycloxyalkoxy, heteroaryloxyalkyl, hydroxy, hydroxyalkyl, nickel, and (NRaRb) alkoxy, wherein the heyerocycle portion of the heterocyclocycloalkoxy and heteroaryloxyalkyl is tetrahydropyranyl; R5 is hydrogen; it's a double link; and Ra and Rb are independently selected from the group consisting of hydrogen and alkyl. In another embodiment, the present invention provides a compound of the formula (II) wherein L 1 is CH (CH 3) CH 2; L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R 5 is heyerocycloalkoxy, wherein the heyerocycle portion of the heterocycloalkoxy is selected from the group consisting of morpholinyl, piperidinyl, and pyrrolidinyl.; and it's a double link. In another embodiment, the present invention provides a compound of formula (II) wherein L 1 is CH (CH 3) CH 2; L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is selected from the group consisting of heeroarylalkoxy, and heteroarylcarbonylalkoxy, wherein the heeroaryl portion of the heteroarylalkoxy and the heteroarylcarbonylalkoxy are
selects from the group consisting of imidazolyl and pyridinyl; and it's a double link. In another embodiment, the present invention provides a compound of the formula (II) wherein L 1 is CH (CH 3) CH 2; L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are selected independently from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is selected from the group consisting of (NRaR) alkynyl, heyerocyclooxyalkoxy, heteroaryloxyalkyl, and heterocyclooxyalkynyl, wherein the heterocycle portion of the heterocyclocycloalkoxy, heteroaryloxyalkyl, and heteroaryloxyalkylanyl is tetrahydropyranyl; and it's a double link. In another embodiment, the invention provides a compound of formula (ll) wherein L 1 is CH (CH 3) CH 2; L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R ° is NR aanRb. it's a double link; and Ra and R are selected from the group consisting of hydrogen and alkyl. In another embodiment, the present invention provides a compound of formula (II) wherein L1 is CH (CH3) CH2; L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is NRaR; it's a double link; Ra is hydrogen; Y
Rb is heeroarylalkyl wherein the heeroaryl portion of the heteroarylalkyl is pyridinyl. In another embodiment, the present invention provides a compound of the formula (II) wherein L 1 is CH (CH 3) CH 2; L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is NRaRb; it's a double link; Ra is hydrogen; Y
R b is heeroarylcarbonyl wherein the heeroaryl portion of the ironarylcarbonyl is pyridinyl. In another embodiment, the present invention provides a compound of the formula (II) wherein L is CH (CH 3) CH 2; L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is NRaRb; it's a double link; Ra is hydrogen; Y
Rb is arylsulfonyl wherein the aryl portion of the arylsulfonyl is phenyl optionally substituted with a susíiyenyen selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, and hydroxy. In another embodiment, the invention provides a compound of the formula (II) wherein L 1 is CH (CH 3) CH 2; L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is
halogen; R5 is NRaR; __. it's a double link; Ra is hydrogen; and Rb is heteroarylsulfonyl wherein the heteroaryl portion of the heteroarylsulfonyl is pyridinyl optionally substituted with a substituent selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, hydroxy, and heterocycle, wherein the heterocycle is morpholinyl. In another embodiment, the present invention provides a compound of formula (II) wherein L1 is CH (CH3) CH2; L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is heterocycle, wherein the heterocycle is piperidinyl; It is a double link. In another embodiment, the present invention provides a compound of formula (II) wherein L 1 is CH 2 CH (OH); L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are selected independently from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro,
NRaRb, and (NRaRb) alkoxy; it is an individual link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc
and R1 are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (II) wherein L 1 is CH 2 CH (OH); L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R 4 is selected from the group consisting of alkoxy, alkyl, heterocyclooxyalkoxy, heterocyclooxyalkyl, hydroxyl, hydroxyalkyl, nickel, and (NRaRb) alkoxy, wherein the heterocyclic portion of the heterocyclooxyalkoxy and heterocyclooxyalkyl is tetrahydropyranyl; R5 is hydrogen; it is an individual link; and Ra and Rb are independently selected from the group consisting of hydrogen and alkyl. In another embodiment, the present invention provides a compound of the formula (II) wherein L 1 is CH 2 CH (OH); L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is heterocycloalkoxy, wherein the heterocycle portion of the heterocycloalkoxy is selected from the group consisting of morpholinyl, piperidinyl, and pyrrolidinyl; and it is an individual link.
In another embodiment, the present invention provides a compound of formula (ll) wherein L 1 is CH 2 CH (OH); L2 is a link; Cast; Z is O; R1 is selected from the group consisting of
hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is selected from the group consisting of heteroarylalkoxy, and heteroarylcarbonylalkoxy, wherein the heeroaryl portion of the aryloxycarboxyloxy and the heteroarylcarbonylalkoxy is selected from the group consisting of midazolyl and pyridinyl; and it is an individual link. In another embodiment, the invention provides a compound of the formula (II) wherein L 1 is CH 2 CH (OH); L2 is a link; Cast; Z is O; R is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is selected from the group consisting of (NRaRb) alkynyl, heteroaryloxyalkoxy, heteroaryloxyalkyl, and heterocyclooxyalkynyl, wherein the heterocycle portion of heterocyclooxyalkoxy, heteroaryloxyalkyl, and heteroaryloxyalkynyl is feyrahydropyranyl; and it is an individual link. In another embodiment, the present invention provides a compound of the formula (II) wherein L 1 is CH 2 CH (OH); L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is NRaRb; it is an individual link; and Ra and R are selected from the group consisting of hydrogen and alkyl. In another form, the present invention provides a
compound of formula (II) wherein L1 is CH2CH (OH); L2 is a link; Cast; Z is O; R is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is NRaRb; it is an individual link; Ra is hydrogen; and Rb is heteroarylalkyl wherein the heteroaryl portion of the heteroarylalkyl is pyridinyl. In another embodiment, the present invention provides a compound of the formula (II) wherein L 1 is CH 2 CH (OH); L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is NRaRb; it is an individual link; Ra is hydrogen; and R is heeroarylcarbonyl wherein the heeroaryl portion of the heteroarylcarbonyl is pyridinyl. In another embodiment, the present invention provides a compound of the formula (II) wherein L 1 is CH 2 CH (OH); L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is NRaRb; it is an individual link; Ra is hydrogen; and R is arylsulfonyl wherein the aryl portion of the arylsulfonyl is phenyl optionally susiiluted with a susity selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, and hydroxy.
In another embodiment, the present invention provides a compound of the formula (II) wherein L 1 is CH 2 CH (OH); L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is NRaRb; it is an individual link; RD is hydrogen; and R is heteroarylsulfonyl wherein the heteroaryl portion of the heteroarylsulfonyl is pyridinyl optionally substituted with a susity selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, hydroxy, and heterocycle, wherein the heterocycle is morpholinyl. In another embodiment, the present invention provides a compound of formula (II) wherein L is CH 2 CH (OH); L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is a heterocycle, wherein the heterocycle is piperidinyl; It is an individual link. In another embodiment, the present invention provides a compound of formula (II) wherein L 1 is CH 2 CH (OH); L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3, together with the atoms to which they are attached, form an epoxide; R4 is halogen; R5 is selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy,
hydroxyalkoxy, hydroxyalkyl, nitro, NRaR, and (NRaRb) alkoxy; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, (NRcRd) alkylcarbonyl, and heteroarylalkyl, wherein the heteroaryl portion of the heteroarylalkyl is pyridinyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the invention provides a compound of formula (II) wherein L 1 is CH 2 CH (OH); L2 is a link; Cast; Z is O; R is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, ni,
NRaRb, and (NRaR) alkoxy; it's a double link; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (II) wherein L 1 is CH 2 CH (OH); L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected
of the group consisting of hydrogen, alkoxy, and hydroxy; R 4 is selected from the group consisting of alkoxy, alkyl, heteroaryloxy alkoxy, heterocycloxyalkyl, hydroxy, hydroxyalkyl, nickel, and (NRaRb) alkoxy, wherein the heyerocycle portion of the heterocyclocycloalkoxy and heteroaryloxyalkyl is tetrahydropyranyl; R5 is hydrogen; it's a double link; and Ra and Rb are independently selected from the group consisting of hydrogen and alkyl. In another embodiment, the present invention provides a compound of formula (ll) wherein L is CH 2 CH (OH); L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is heterocycloalkoxy, wherein the heterocyclecycloalkoxy heterocycle portion is selected from the group consisting of morpholinyl, piperidinyl, and pyrrolidinyl; and it's a double link. In another embodiment, the present invention provides a compound of the formula (II) wherein L1 is CH2CH (OH); L2 is a link; Cast; Z is O; R is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is selected from the group consisting of heteroarylalkoxy, and heteroarylcarbonylalkoxy, wherein the heteroaryl portion of the heteroarylalkoxy and the heteroarylcarbonylalkoxy is selected from the group consisting of imidazolyl and pyridinyl; and it's a double link.
In another embodiment, the invention provides a compound of the formula (II) wherein L 1 is CH 2 CH (OH); L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is selected from the group consisting of (NRaRb) alkynyl, heterocyclooxyalkoxy, heterocyclooxyalkyl, and heterocyclooxyalkynyl, wherein the heterocycle portion of the heterocyclocycloalkoxy, heterocycleoxyalkyl, and heterocycleoxyalkynyl is terahydropyranyl; and it's a double link. In another embodiment, the present invention provides a compound of formula (II) wherein L 1 is CH 2 CH (OH); L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is NRaR; it's a double link; and Ra and Rb are selected from the group consisting of hydrogen and alkyl. In another embodiment, the present invention provides a compound of formula (II) wherein L 1 is CH 2 CH (OH); L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is NRaR; it's a double link; Ra is hydrogen; Y
R is heeroarylalkyl wherein the heeroaryl portion of the heleroarylalkyl is pyridinyl.
In another embodiment, the present invention provides a compound of formula (II) wherein L 1 is CH 2 CH (OH); L2 is a link; Cast; Z is O; R is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is NRaR; it's a double link; Ra is hydrogen; Y
R is heteroarylcarbonyl wherein the heteroaryl portion of the heteroarylcarbonyl is pyridinyl. In another embodiment, the present invention provides a compound of formula (II) wherein L 1 is CH 2 CH (OH); L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is NRaRb; it's a double link; Ra is hydrogen; and Rb is arylsulfonyl wherein the aryl portion of the arylsulfonyl is phenyl optionally substituted with a sustiluyenie selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, and hydroxy. In another embodiment, the present invention provides a compound of formula (ll) wherein L 1 is CH 2 CH (OH); L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is NRaR; it's a double link; Ra is hydrogen; and Rb is heteroarylsulfonyl wherein the heteroaryl portion of the
The amino acid is optionally substituted pyridinyl with a substituent selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, hydroxy, and heterocycle, wherein the heterocycle is morpholinyl. In another embodiment, the invention provides a compound of formula (II) wherein L 1 is CH 2 CH (OH); L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R 5 is a heterocycle, wherein the heterocycle is piperidinyl; It is a double link. In another embodiment, the invention provides a compound of formula (II) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, ni,
NRaRD, and (NR aanRbDi) alkoxy is an individual bond; Ra and R are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, halogen alkylcarbonyl, halogen alkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are selected independently of the group that
consists of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of formula (11) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R 4 is selected from the group consisting of alkoxy, alkyl, heterocyclooxyalkoxy, heterocyclooxyalkyl, hydroxy, hydroxyalkyl, nitro, and (NRaRb) alkoxy, wherein the heterocycle portion of the heterocyclooxyalkoxy and heterocycleoxyalkyl is tetrahydropyranyl; R5 is hydrogen; it is an individual link; and Ra and R are independently selected from the group consisting of hydrogen and alkyl. In another embodiment, the present invention provides a compound of the formula (11) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is heterocycloalkoxy, wherein the heterocycle portion of the heterocycloalkoxy is selected from the group consisting of morpholinyl, piperidinyl, and pyrrolidinyl; and it is an individual link. In another embodiment, the present invention provides a compound of the formula (II) wherein L is selected from the group consisting of CH2CH (OCH3) and CH2CH (OCH2CH3); L2 is a link; And it is
OR; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is selected from the group consisting of heteroarylalkoxy, and heteroarylcarbonylalkoxy, wherein the heeroaryl portion of the heteroarylalkoxy and the heteroarylcarbonylalkoxy is selected from the group consisting of imidazolyl and pyridinyl; and it is an individual link. In another embodiment, the present invention provides a compound of formula (II) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is selected from the group consisting of (NRaRb) alkynyl, heterocyclooxyalkoxy, heterocyclooxyalkyl, and heterocyclooxyalkynyl, wherein the heyerocycle portion of the heterocycloxyalkoxy, heteroaryloxyalkyl, and heteroaryloxyalkylanyl is tetrahydropyranyl; and it is an individual link. In another embodiment, the present invention provides a compound of the formula (II) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is
NRaRb; it is an individual link; and Ra and Rb are selected from the group consisting of hydrogen and alkyl. In another embodiment, the present invention provides a compound of formula (II) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is NRaRb; it is an individual link; Ra is hydrogen; and Rb is heeroarylalkyl wherein the heeroaryl portion of the heyarylalkyl is pyridinyl. In another embodiment, the invention provides a compound of formula (II) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is
NRaRb; it is an individual link; Ra is hydrogen; and R is heteroarylcarbonyl wherein the heteroaryl portion of the heteroarylcarbonyl is pyridinyl. In another embodiment, the present invention provides a compound of the formula (II) wherein L is selected from the group consisting of CH2CH (OCH3) and CH2CH (OCH2CH3); L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group that
Consists of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is
NRaRb; it is an individual link; Ra is hydrogen; and Rb is arylsulfonyl wherein the aryl portion of the arylsulfonyl is phenyl optionally substituted with a substituent selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, and hydroxy. In another embodiment, the invention provides a compound of formula (II) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is
NRaR; it is an individual link; Ra is hydrogen; and R is heteroarylsulfonyl wherein the heeroaryl portion of the heteroarylsulfonyl is pyridinyl optionally substituted with a substitute selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, hydroxy, and heterocycle, wherein the heterocycle is morpholinyl. In another embodiment, the present invention provides a compound of formula (II) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is a heterocycle, wherein the heterocycle is piperidinyl; It is a link
individual. In another embodiment, the invention provides a compound of formula (II) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3, together with the atoms to which they are attached, form an epoxide; R4 is halogen; R5 is selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NRaRb, and (NRaR) alkoxy; Ra and R are selected independently from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, (NRcRd) alkylcarbonyl, and heteroarylalkyl, wherein the heteroaryl portion of the heteroarylalkyl is pyridinyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment, the present invention provides a compound of the formula (II) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, halogen, haloalkylsulfonyloxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, ni,
NRaRD, and
it's a double link; Ra and R are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In another embodiment the present invention provides a compound of formula (II) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R: and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R 4 is selected from the group consisting of alkoxy, alkyl, heterocyclooxyalkoxy, heterocyclooxyalkyl, hydroxy, hydroxyalkyl, nitro, and (NRaR) alkoxy, wherein the heterocycle portion of the heterocycleoxyalkoxy and heterocycleoxyalkyl is terahydropyranyl; R5 is hydrogen; it's a double link; and Ra and R are independently selected from the group consisting of hydrogen and alkyl. In another embodiment, the invention provides a compound of formula (11) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is heyerocycloalkoxy, wherein the heterocycle portion of the
Hetero-cycloalkoxy is selected from the group consisting of morpholinyl, piperidinyl, and pyrrolidinyl; and it's a double link. In another embodiment, the present invention provides a compound of the formula (II) wherein L1 is selected from the group consisting of CH2CH (OCH3) and CH2CH (OCH2CH3); L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is selected from the group consisting of heeroarylalkoxy, and heleroarylcarbonylalkoxy, wherein the heeroaryl portion of the heteroarylalkoxy and the heteroarylcarbonylalkoxy is selected from the group consisting of imidazolyl and pyrldinyl; and it's a double link. In another embodiment, the invention provides a compound of the formula (II) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is selected from the group consisting of (NRaRb) alkynyl, heterocyclooxyalkoxy, heterocyclochloryalkyl, and heterocyclooxyalkynyl, wherein the heterocycle portion of the heterocyclocycloalkoxy, heterocycleoxyalkyl, and heterocycleoxyalkynyl is tetrahydropyranyl; and it's a double link. In another embodiment the present invention provides a compound of the formula (II) wherein L1 is selected from the group
consisted of CH2CH (OCH3) and CH2CH (OCH2CH3); L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R1 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is NRaRb; it's a double link; and Ra and Rb are selected from the group consisting of hydrogen and alkyl. In another embodiment, the present invention provides a compound of the formula (II) wherein L1 is selected from the group consisting of CH2CH (OCH3) and CH2CH (OCH2CH3); L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is
NRaR; it's a double link; Ra is hydrogen; and Rb is heeroarylalkyl wherein the heleroaryl portion of the phenyl arylalkyl is pyridinyl. In another embodiment, the invention provides a compound of formula (II) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are selected independently from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is
NRaRb; it's a double link; Ra is hydrogen; and Rb is heteroarylcarbonyl wherein the heteroaryl portion of the heteroarylcarbonyl is pyridinyl. In another form, the present invention provides a
compound of the formula (II) wherein L1 is selected from the group consisting of CH2CH (OCH3) and CH2CH (OCH2CH3); L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is
NRaR; it's a double link; Ra is hydrogen; and Rb is aryl sulphonyl wherein the aryl portion of the arylsulfonyl is phenyl optionally substituted with a susity selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, and hydroxy. In another embodiment, the present invention provides a compound of formula (II) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R5 is
NRaRb; it's a double link; Ra is hydrogen; and Rb is heteroarylsulfonyl wherein the heteroaryl portion of the heteroarylsulfonyl is pyridinyl optionally substituted with a susity selected from the group consisting of alkoxy, alkyl, haloalkoxy, haloalkyl, halogen, hydroxy, and heterocycle, wherein the heterocycle is morpholinyl. In another embodiment, the present invention provides a compound of the formula (II) wherein L 1 is selected from the group consisting of CH 2 CH (OCH 3) and CH 2 CH (OCH 2 CH 3); L2 is a link; Cast; Z is O; R1 is selected from the group consisting of hydrogen and
cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy; R4 is halogen; R 5 is a heterocycle, wherein the heterocycle is piperidinyl; It is a double link. In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, in combination with a therapeutically acceptable carrier. In another embodiment, the invention provides a method for inhibiting protein kinases in a patient with a recognized need for irradiation comprising administering to the patient a therapeutically acceptable amount of a compound of claim 1, or a therapeutically acceptable salt thereof. In another embodiment, the invention provides a method for bringing cancer in a patient with the recognized need for such treatment comprising administering to the patient a pharmaceutically acceptable amount of a compound of claim 1, or an acceptable therapeutic salt thereof.
DETAILED DESCRIPTION OF THE INVENTION All publications, published countries, and country requests cited in the present are incorporated by means of this reference. As used in the present specification, the following terms have the indicated meanings:
As used in the present, the singular forms "a," "one," and "the" include plural reference unless the context clearly dictated otherwise. The term "alkoxy," as used herein, refers to an alkyl group attached to the parent molecular moiety through an oxygen atom. The term "alkoxyalkoxy", as used herein, refers to an alkoxy group substituted with an alkoxy group. The term "alkoxyalkoxyalkoxy", as used herein, refers to an alkoxyalkoxy group substituted with an alkoxy group. The term "alkoxyalkyl", as used herein, refers to a substituted alkyl group with at least one alkoxy group. The term "alkoxycarbonyl," as used herein, refers to an alkoxy group attached to the parent molecular moiety through a carbonyl group. The term "alkoxycarbonylalkyl", as used herein, refers to an alkyl group substituted with at least one alkoxycarbonyl group. The term "alkyl", as used herein, refers to a group derived from a straight or branched saturated hydrocarbon chain, which confers from one to ten carbon atoms. Preferably, alkyl groups containing one to four carbon atoms. The term "alkylcarbonyl," as used herein, refers to an alkyl group attached to the progenitor molecular moiety at
You come from a carbonyl group. The term "alkylene" means a bivalenic group derived from a straight or branched hydrocarbon chain of 1 to 6 carbon atoms. The alkylene is optionally substituted with 1 or 2 susyituyenyes selected from the group consisting of alkoxy and hydroxy. Representative examples of alkylene include, but were not limited to, -CH2-, -CH (CH3) -, -C (CH3) 2-, -CH2CH2-, -CH2CH (CH3) -, -CH2CH (OH) -, - CH2CH (OCH3) -, -CH2CH (OCH2CH3) -, -CH2CH2CH2-, -CH2C H2C H2CH2-, and - CH CH (CH3) CH2-. The term "alkylsulfanyl", as used in the present, refers to an alkyl group attached to the parent molecular person through a sulfur atom. The term "alkylsulfinyl", as used herein, refers to an alkyl group attached to the parent molecular moiety through a sulfonyl group. The term "aryl", as used herein, refers to a phenyl group, or a system of fused bicyclic or tricyclic rings wherein one or more of the fused rings is a phenyl group. The bicyclic fused ring systems are exemplified by a phenyl group fused to a monocyclic cycloalkenyl group, as defined herein, a monocyclic cycloalkyl group, as defined herein, or another phenyl group. The fused tricyclic ring systems are exemplified by a system of bicyclic rings fused to a monocyclic cycloalkenyl group, as defined herein, a
monocyclic cycloalkyl group, as defined herein, or other phenyl group. Representative examples of aryl groups include, but were not limited to, ampracenyl, azulenyl, fluorenyl, indanyl, naphthyl, phenyl, and tetrahydronaphthyl. Aryl groups of the present invention can be optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, cyano, halogen, haloalkylsulfonyloxy, haloalkoxy, heteroarylalkoxy, heterocycle, heterocycloalkoxy, heterociclooxialcoxi, heterocycleoxyalkyl, heterociclooxialquinilo, heteroarilcarbonilalcoxi, haloalkyl, hydroxyalkenyl, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, hydroxy, nitro, NRaRb, (NRaRb) alkoxy, (NRaRb) alkyl, and (NRaRb) alkynyl. The term "arylalkyl", as used herein, refers to an alkyl substituted with at least one aryl group. The term "arylsulfanyl," as used in the present, refers to an aryl group attached to the parent molecular moiety through a sulfur atom. The term "arylsulfonyl", as used herein, refers to an aryl group attached to the parent molecular moiety through a sulfonyl group. The term "carbonyl", as used herein, refers to -C (O) -. The term "carboxy", as used herein, refers to -CO2H.
The term "carboxyalkyl", as used herein, refers to an alkyl group substituted with at least one carboxy group. The term "cyano", as used herein, refers to -CN. The "cicioalquilo" íérmino, as uíiliza in preseníe, refers to a saturated cyclic hydrocarbon group containing from 3 to 8 carbons, examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, ciciohexilo, ciclohepíilo and cicloocíilo. The cycloalkyl group of the present invention can be optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of alkoxy, alkoxyalkoxy, alkyl, cyano, halogen, haloalquilsufoniloxi, haloalkoxy, haloalkyl, hydroxyalkenyl, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl , hydroxy, NRaR, (NRaRb) alkoxy, (NRaRb) alkyl, and (NRaRb) alkynyl. The term "epoxide", as used in the present, refers to
Or a group / \. The terms "halo" and "halogen", as used herein, refer to F, Cl, Br, or I. The term "haloalkoxy", as used herein, refers to a haloalkyl group attached to the molecular progenitor portion through an oxygen atom. The term "haloalkyl", as used in the present, refers to an alkyl group substituted by one, two, three or four halogen atoms. The term "haloalkylcarbonyl", as used in the present,
refers to a haloalkyl group attached to the parent molecular moiety through a carbonyl group. The term "haloalkylsulfonyl", as used herein, refers to a haloalkyl group attached to the parent molecular moiety through a sulfonyl group. The term "haloalkylsulfonyloxy", as used herein, refers to a haloalkylsulfonyl group attached to the parent molecular moiety through an oxygen atom. The term "heteroaryl", as used herein, refers to a five or six member aromatic ring wherein at least one atom is selected from the group consisting of N, O, and S, and the remaining atoms are carbon . The five-member ring has two double bonds, and the six-member ring has three double bonds. The heteroaryl groups are connected to the parent molecular moiety through a suitable carbon or nitrogen atom in the ring. The term "heteroaryl" also includes bicyclic systems wherein the heteroaryl ring is fused to a phenyl group, a monocyclic cycloalkenyl group, as defined herein, a monocyclic cycloalkyl group, as defined herein, a monocyclic heterocycle group , as defined herein, or an additional monocyclic heteroaryl group; and tricyclic systems where a bicyclic sisíema is fused to a phenyl group, a monocyclic cycloalkenyl group, as defined herein, a monocyclic cycloalkyl group, as defined herein, one heíerociclilo group, as defined in preseníe or a
additional monocyclic heteroaryl group. Representative examples of heteroaryl groups include, but are not limited to benzoxadiazolyl, benzoxazolyl, benzofuranyl, benzothienyl, cinolinyl, dibenzofuranyl, furanyl, imidazolyl, indazolyl, indolyl, isoxazolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, quinolinyl, thiazolyl, thienopyridinyl, thienyl, triazolyl, thiadiazolyl, triazinyl, and the like. The heteroaryl groups of the present invention may be substituted with one, two, four, or five substituents independently selected from the group consisting of alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, cyano, halogen, haloalkylsulfonyloxy, haloalkoxy, haloalkyl, heteroarylalkoxy, heterocycle. Hetero-cycloalkoxy, heteroaryloxyalkoxy, heterocyclooxyalkyl, heterocyclooxyalkynyl, heteroarylcarbonylalkoxy, haloalkyl, hydroxyalkenyl, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, hydroxy, ni, NRaRb, (NRaRb) alkoxy, (NRaRb) alkyl, and (NRaRb) alkynyl, wherein the heeroaryl portion of the alkyl arylalkoxy and the heteroarylcarbonylalkoxy may optionally be unsubstituted with one, two, four, or five independently selected from the group consisting of alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, cyano, halogen, haloalkylsulfonyloxy, haloalkoxy, haloaquinyl, haloalkyl, hydroxyalkylene, Hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, hydroxy, niir, NRaRb, (NRaR) alkoxy, (NRaRb) alkyl, and (NRaRb) alkynyl.
The term "heteroarylalkoxy", as used in the present, refers to a substituted alkoxy group with at least one heleroaryl group. The term "heteroarylalkyl", as used in the present, refers to a substituted alkyl group with at least one heteroaryl group. The term "heteroarylcarbonyl", as used herein, refers to a heteroaryl group attached to the parent molecular moiety through a carbonyl group. The term "heeroarylcarbonylalkoxy," as used herein, refers to an alkoxy group substituted with heteroarylcarbonyl group. The term "heteroarylsulfonyl", as used herein, refers to a heteroaryl group attached to the parent molecular moiety through a sulfonyl group. The term "heterocycle" or "heterocyclic", as used herein, refers to a heterocyclic monocyclic ring or a heterocyclic bicyclic ring. The monocyclic heterocyclic ring consists of a 3, 4, 5, 6 or 7 member ring containing at least one heterogeneous atom independently selected from the group consisting of O; N; and S. The 3- or 4-membered ring contains a heterogeneous atom selected from the group consisting of O, N. and S. The 5-membered ring contains zero or one double bond and one, two or three heterogeneous atoms selected from the group consisting of consists of O, N and S. The 6 or 7 member ring coniiene
zero, one or two double bonds and one, two or three heterogeneous atoms selected from the group consisting of O, N. and S. Representative examples of heterocyclic monocyclic ring include, but were not limited to, azeidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxylamino, 1,3-dithiolanyl, 1,3-di-annyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isoiazolidinyl, isoxazolinyl, isoxazolidinyl, morphylinnyl, oxadeiazonyl, oxadiazolidinyl, oxazolinyl, oxazolidinium piperazinyl, piperidinyl, pyranyl, pyrazolyl, pyrazolidyl, pyrrolinyl, pyrrolidinyl, teofhydrofuranyl, hydroalienyl, diazodiazolinyl, thiadiazolidinyl, iazolinyl, iazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl (thiomorpholin sulfone), thiopyranyl, and lithium. The bicyclic heterocyclic ring consists of the monocyclic heterocyclic ring fused to a phenyl group or the monocyclic heterocyclic ring fused to a cycloalkyl group or the monocyclic heterocyclic ring fused to a cycloalkenyl group or the monocyclic heterocyclic ring fused to another monocyclic heterocyclic ring. Representative examples of bicyclic heterocyclic rings include, but are not limited to, 1,3-benzodioxolyl, 1,3-benzoditiolyl, 2,3-dihydro-1,4-benzodioxinyl, 2,3-dihydro-1-benzofuranyl, 2,3-dihydro-1-benzothienyl , 2,3-dihydro-1 H-indolyl, and 1, 2,3,4-tetahydroquinolinyl. The heterocycles of this invention may be optionally substituted with one, two, or three substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl,
alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkylthioalkyl, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, NRaRb and (NRaRb) carbonyl. The term "heterocycloalkoxy" as used herein, refers to the heterocycle group, as defined herein, attached to the parent molecular moiety through an alkoxy group, as defined herein. The term "heyerocyclohexy" as used in the present, refers to a heterocycle group, as defined herein, attached to the parent molecular moiety through an oxygen atom.
The term "heterocyclooxyalkoxy" as used herein, refers to an alkoxy group, as defined herein, substituted with a heterocyclooxy group, as defined herein. The term "heteroaryloxyalkyl" as used herein, refers to an alkyl group, as defined herein, substituted with a heteroaryloxy group, as defined herein. The term "heyerocyclohexyalkynyl" as used in the present patent, refers to an alkynyl group, as defined herein, subsituted with a heterocyclooxy group, as defined herein. The term "hydroxy," as used herein, refers to -OH.
The term "hydroxyalkenyl", as used in the present, refers to a substituted alkenyl group with at least one hydroxy group. The term "hydroxyalkoxy", as used herein, refers to a substituted alkoxy group with at least one hydroxy group. The term "hydroxyalkyl," as used herein, refers to an alkyl group, susi fi ed with at least one hydroxy group. The term "hydroxyalkynyl", as used herein, refers to an alkynyl group substituted with at least one hydroxy group.
The term "nitro", as used herein, refers to -NO2. The term "NRaRb", as used in the present, refers to two groups, Ra and Rb, which are attached to the parent molecular moiety through a hydrogen atom. Ra and Rb are independently selected from the group consisting of hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkyl, arylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heteroarylsulfonyl, and (NRcRd) alkylcarbonyl. The term (NRaRb) alkoxy, as used in the present, refers to an NRaR group attached to the progenitor portion through an alkoxy group. The term "(NRaRb) alkyl", as used in the present, refers to a substituted alkyl group with at least one NRaRb group. The term "(NRaRb) alkynyl", as used herein,
refers to an alkynyl group substituted with at least one group
NRaRb. The term "(NRaRb) carbonyl", as used herein, refers to a NRaRb group attached to the parent molecular moiety through a carbonyl group. The term "(NRaRb) carbonylalkoxy", as used in the present, refers to a group (NRaR) carbonyl bonded to the parent molecular moiety through an alkoxy group. The term "(NRaRb) carbonylalkyl", as used herein, refers to an alkyl group substituted with at least one NRaRb group. The term "NRcRd", as used herein, refers to two groups, Rc and Rd, which are attached to the molecular parent portion through a nitrogen atom. Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. The term "(NRcRd) alkyl," as used herein, refers to an alkyl group substituted with at least one NRcRd group. The term "(NRcRd) alkylcarbonyl," as used herein, refers to a group (NRcRd) alkyl attached to the progenitor molecular moiety through a carbonyl group. The term "oxo", as used in the present, refers to = O. The term "sulfonyl", as used herein, refers to -SO2-.
The compounds of the present invention can exist as pharmaceutically acceptable salts. The term "therapeutically acceptable salt", as used in the present, represented salts or zwitterionic forms of the compounds of the present invention which are soluble or dispersible in water or oil, which are suitable for the irradiation of diseases without undue toxicity. , irriation, and allergic response; which are in accordance with a reasonable proportion of benefit / risk, and which are effective for the intended use. The salts can be prepared during the final isolation and purification of the compounds or separately by reacting an amino group with a suitable acid. Representative salts as acid addition include acetamide, adipation, alginate, citraio, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphor sulphonate, glycolophosphate, hemisulfate, heptanoate, hexanoate, formate, fumarate, hydrochloride, hydrobromide, iodohydrate, 2-hydroxyethanesulfonate, lactate, maleate, mesitylenesulfonate, methanesulfonate, naphthylene sulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinic acid, iron, ichloroacetic acid, fluoride, phosphate, glutamate, bicarbonate, para-toluenesulfonate, and undecanoate. Also, the amino groups in the compounds of the present invention can be quaternized with methyl, ethyl, propyl and buylyl chlorides, bromides, and iodides; sulphates of dimethy, diethyl, dibutyl, and diamyl; chlorides, bromides and
decyl, lauryl, myrisyl and estenium iodides; and benzyl bromides, and phenethyl. Examples of acids that can be used to form acid-additive addition salts include organic acids such as hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric. The present compounds can also exist as therapeutically acceptable prodrugs. The term "therapeutically acceptable prodrug" refers to those prodrugs or zwitterions which are suitable for use in contact with the tissues of patients without undue toxicity, irritation, and allergic response, are corresponding with a reasonable benefit / risk ratio, and they are effective for the intended use. The term "prodrug" refers to compounds that are rapidly transformed in vivo into parent compounds of the formula (I), for example, by hydrolysis in the blood. There are asymmetric centers in the compounds of the present invention. These kernels are designated by the "R" or "S" symbols, depending on the configuration of substitutes around the chiral carbon atom. It should be understood that the invention encompasses all isomeric stereochemical forms, or mixtures thereof, which possess the ability to inhibit protein kinases. Individual stereoisomers of the compounds can be prepared synthetically from commercially available starting materials, which contain either the quintal centers or by preparation of mixtures of enantiomeric products followed by separation as
conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, or direct separation of enantiomers in chiral chromatographic columns. The starting compounds of particular stereochemistry may be either commercially available or may be made and resolved by techniques known in the art. Because the carbon-carbon double bonds exist in the present compounds, the invention contemplates various geometric isomers and mixtures thereof resulting from the arrangement of the substituyeníes around these carbon-carbon double bonds. It should be understood that the invention encompasses both isomeric forms (trans or cis), or mixtures thereof, which possess the ability to inhibit protein kinases. These substituents are indicated as belonging to the E (rans) or Z (cis) configuration where the term "E" represented high-order subsitutes on opposite sides of the carbon-carbon double bond and the term "Z" represented suffixes of order. elevated on the same side of the carbon-carbon double bond. When it is possible that, for use in therapy, therapeutically effective amounts of a compound of the formula (I), as well as the therapeutically acceptable salts thereof, can be administered as the unpurified chemical, it is possible to present the active ingredient as a pharmaceutical composition. Accordingly, the invention further provides pharmaceutical compositions, which include epinephrineically
effective of the compounds of the formula (I) or acceptable therapeutically acceptable salts thereof and one or more pharmaceutically acceptable additives, diluents or excipients. The compounds of formula (I) and therapeutically acceptable salts thereof are as previously described. The supplier (s), diluyeníes or excipieníes must be acceptable in the sense that they are comparable with the other ingredients of the formulation and not harmful for the recepíor of the same. In accordance with another aspect of the invention, there is also provided a process for the preparation of a pharmaceutical formulation which includes the mixture of a compound of the formula (I) or a therapeutically acceptable salt thereof, with one or more diluent or pharmaceutically acceptable excipients. acceptable ,. The pharmaceutical formulations may be presented in dosage unit forms that contain a predetermined amount of an active ingredient per unit dose. Such a unit can contain, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, more preferably 5 mg to 100 mg of a compound of the formula (I), depending on the condition to be irradiated, the severity of the condition, the time of administration, the administration time, the rate of excretion of the compound used, the duration of the treatment, and the age, sex, weight and condition of the patient, or the pharmaceutical formulations can be presented in unit dose forms containing a predetermined amount of an active ingredient per dose. Preferred dose formulations
Uniíaria are those that contain a daily dose or sub-dose, as mentioned previously in the presence, or an appropriate fraction thereof, of an active ingredient. In addition, such pharmaceutical formulations can be prepared by any of the methods well known in the pharmaceutical art. The pharmaceutical formulations can be adapted for administration by an appropriate route, for example by oral (including buccal or sublingual), recial, nasal, topical (including buccal, sublingual, or transdermal), vaginal or parenteral routes (including subcutaneous, inhramuscular, intravenous, or intradermal). Such formulations can be prepared by any known method in the pharmaceutical art, for example by combining the active ingredient with the carrier (s) or excipients. Pharmaceutical formulations adapted for oral administration can be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; Complimentary or mixed foams; or liquid emulsions of oil in water or emulsions of water in oil. For example, for oral administration in the form of a tablet or capsule, the active drug component can be combined with a pharmaceutically acceptable non-toxic inert oral portion such as ethanol, glycerol, water, and the like. The powders are prepared by grinding the compound to a suitable size and mixing with a similarly ground pharmaceutical carrier like a carbohydrate.
comestible, such as, for example, starch or mannitol. A flavoring, conservative, dispersing agency, and the color may also be present. The capsules are made by preparing a powder mixture, as previously described, and filling the formed gelatin covers. Slippers and lubricants such as colloidal silica, falco, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture prior to the filling operation. A disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate may also be added to improve the availability of the medicament when the capsule is ingested. In addition, when desired or necessary, adhesives, lubricants, disintegrating agents, and suitable coloring agents can be incorporated into the mixture. Suitable adhesives include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, naíural gums and synalic gums such as acacia, adraganie or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in those dosage forms include sodium oleate, sodium chloride, and the like. The disinfection agents include, without limitation, starch, cellulose, agar, benignium, xanían gum, and the like. Tablets are formulated, for example, by preparing a powder mix, granulating or milling, adding a lubricant and disintegrator, and pressing into tablets. A mixture of dust prepare by mixing the compound, properly ground, with a diluent or base as previously described, and optionally, with an adhesion agent such as carboxymethylcellulose, an alginate, gelaine or polyvinylpyrrolidone, a retardant solution as paraffin, a resorption accelerator such as a quaternary salt and / or an absorption agent such as bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by moistening with a sticking agent such as syrup, starch paste, acacia mucilage, or solutions of cellulose or polymeric materials and forcing through a sieve. As an additive to the granulate, the powder mixture can be passed through an ice machine and the result is imperfectly formed particles fractioned into granules. The granules can be lubricated to prevent the tablet from sticking to the forming dies by the addition of stearic acid, a stearic salt, falco or mineral oil. The lubricated mixture is then compressed into competitors. The compounds of the present invention can also be combined with an inert free-flowing portion and compressed into tablets without passing through the granulation or grinding steps. A transparent or opaque projection cover consisting of a sealed sheath of shellac, a sugar cube or polymeric material, and a polishing wax coating may be provided. Dyes can be added to these covers to distinguish different dosage units. Oral fluids such as solution, syrups and elixirs and
Elixirs can be prepared in unit dosage forms so that a given amount contains a predetermined amount of the compound. The syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while the elixirs are prepared through the use of a non-toxic vehicle. Stabilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavoring such as peppermint oil or natural sweeteners, or saccharin or other arificial sweeteners, and the like may also be added. Where appropriate, the unit dose formulations for oral administration can be microencapsulated. The formulation can also be prepared for prolonged or sustained release such as by coating or incorporating particulate material into polymers, waxes or the like. The compounds of the formula (I), and therapeutically acceptable salts thereof, may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and mellilamillary vesicles. Liposomes can be formed from a variety of fofolipids, such as cholesterol, sterilamine, or phosphaidylcholines. The compounds of formula (I) and therapeutically acceptable salts thereof can also be administered by the use of monoclonal antibodies as individual promoters to the
which are the molecules of the compound. The compounds can also be coupled with soluble polymers as recognizable carriers of the drug. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspamidemidephenol, or polyallyneoxidepolylysin subsituted with palitoyl residues. In addition, the compounds can be coupled to a class of biodegradable, biodegradable polymers to achieve conjoined release of the drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxybuiric acid, polyiodides, polyacetals, polyhydropyrans, polycyanoacrylates, and crosslinked or unfriendly hydrogel copolymer blocks. . Pharmaceutical formulations adapted for transdermal administration may be presented as discrete patches which are intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. For example, the active ingredient can be administered from the patch by iontophoresis as generally described in Pharmaceufical Research, 3 (6), 318 (1986). Pharmaceutical formulations adapted for lopic administration can be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, or oils. For eye treatments or other external tissues, for example mouth and skin, the formulations are preferably applied as
ointments or topical creams. When formulated in an ointment, the acive ingredient can be used with an ointment base either paraffinic or water miscible. Alternately, the active ingredient can be formulated in a cream with an oil-in-water cream base or a water-in-oil base. Pharmaceutical formulations adapted for optic administration in the eye include optic gofas wherein the active ingredient is dissolved or suspended in a suitable carrier, especially in aqueous solvents. Pharmaceutical formulations adapted for lipid administration in the mouth include dragees, lozenges, and mouth rinses. Pharmaceutical formulations adapted for serial administration may be presented as suppositories or as enemas. Pharmaceutical formulations adapted for nasal administration wherein the carrier is a solid include a flow of powder having a particle size for example in the range of 20 to 500 microns which is administered in the manner in which inhalation is induced. , that is, by rapid inhalation through the nasal passage of a powder container that is maintained in straight contact with the nose. Suitable formulations in which the carrier is a liquid, to be administered as a nasal aomizer or nasal gofas, include aqueous or oily solutions enyre the active ingredient. Pharmaceutical formulations adapted for administration by inhalation include fine particles of powder or
fog, which can be generated by means of various types of time-controlled compressed dosing aerosols, nebulizers, or insufflators. Pharmaceutical formulations adapted for vaginal administration may be presented as formulations of invarious disposition, buffers, creams, gels, pastries, foams, or sprays. Pharmaceutical formulations adapted for parenteral administration include sterile aqueous and non-aqueous injection solutions which may contain antioxidants, buffers, bacilli, and soutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be present in single-dose or multi-dose containers, for example sealed vials and flasks, and may be stored in an ice-dried (lyophilized) condition that requires only the addition of the sterile liquid carrier, eg water for injections, Immediately before use. The solutions of extemporaneous injections and suspensions can be prepared from sterile powders, granules, and tablets. It may be suggested that in addition to the ingredients mentioned above, the formulations may include other agents conventional in the art with respect to the type of formulation in question, for example those suitable
for oral administration they may include flavoring agents. An eerapeuically effective amount of a compound of the present invention will depend on the number of factors including, for example, the age and weight of the animal, the precise condition requiring treatment, and its severity, the nature of the formulation, and the administration, and ulimately will be at the discretion of the attending physician or veterinarian. However, an effective amount of a compound of formula (I) for the treatment of a neoplastic growth, for example colon or breast carcinoma, will generally be in the range of 0.1 to 100 mg / kg of body weight of the recipient (mammalian). ) per day and more usually in the range of 1 to 10 mg / kg of body weight per day.
Determination of Biological Activity The Chk1 enzyme assay was carried out by monitoring the recombinant kinase domain of the Chk1 proiein that covers the amino acid residues from 1 hash 289 and a polyhisidin tag in the C-terminal exíremo. The human peptide subset cdc25c containing a sequence of the amino acid residues from 104 to 225. The reaction mixture contains 25 mM HEPES at pH 7.4, 10 mM MgCl2, 0.08 mM Trikon X-100, 0.5 mM DTT, 5 μM of ATP, 4 nM 33P ATP, 5 μM of peptide substrate cdc25c, and 6.3 nM of the recommended protein Chk1. The DMSO vehicle of the compound was maintained at 2% in the final reaction. After 30 minutes at room temperature, the reaction was stopped by adding
an equal amount of NaCl 4M and EDTA 0.1M, pH 8. An aliquot of 40 μL of the reaction was added to a well in a Flash Píate (NEN Life Science Products, Boston, MA) containing 160 μL of saline regulated in its pH with phosphate (PBS) without calcium chloride or magnesium chloride and incubating for 10 minutes at room temperature. The plate was then washed 3 times in PBS with 0.05% Tween-20 and counted in a Packard TopCouni conifer (Packard BioScience Company, Meriden, CT). The compounds of the present invention inhibited Chk1 at 1C50 values between about 1 nM and about 5 μM. Preferred compounds inhibited Chk1 at IC50 values ranging from approximately 1 nM to approximately 25 nM. Therefore, the compounds of the invention are useful for irradiating disorders that are caused or recorded by an increase in proinin kinase levels.
The compounds of the invention, which include but are not limited to those specified in the examples, possess the ability to inhibit proinins kinases. As protein kinase inhibitors, compounds are useful in the treatment of both primary and metastatic solid tumors, including carcinomas of the breast, colon, rectum, lung, oropharynx, hypopharynx, esophagus, stomach, pancreas, liver, gall bladder, and bile ducts. Intestine thin, urinary tract (including kidneys, bladder
and urothelium), female genital tract (including cervix, uterus, and ovaries as well as choriocarcinoma and trophoblastic gestational disease), male genital tract (including prostate, seminal vesicle, testes, and germ cell tumors), endocrine glands (including the thyroid, glands adrenals, and skin), and skin, as well as hemangiomas, melanomas, sarcomas (including those that originate from bone and soft tissues as well as Kaposi's sarcoma) and brain tumors, nerves, eyes, and meninges (including asyrocytomas, gliomas , glycobasins, renoonoblastomas, neuromas, neuroblastomas, Schwannomas, and meningiomas). Such compounds may also be useful in the treatment of solid tumors originating from hemapropoelemal malignancies such as leukemias (ie, chloromas, plasmacyigns, and fungal plaques and fungal tumors of mycosis and lymphoma / cutaneous T-cell leukemia) as well as in the treatment of lymphomas (Hodgkin's and non-Hodgkin's lymphomas). Additionally, these components may be useful in the prevention of meiasis of the tumors previously described either when used alone or in combination with radio-therapy and / or other chemo-therapeutic agents.
Synthetic Methods The abbreviations that have been used in the description of the scheme and the examples that follow are: EtOAc for ethyl acetate; DMF for N, N-dimethylylformamide; dppf for 1,1'-bis (diphenylphosphino) ferrocene; dba for dibenzylideneacetone; THF for
Ietahydrofuran; PPh3 for triphenylphosphine; and DMSO for dimethyl superoxide. The compounds and processes of the present invention will be better understood in connection with the following syn- thetic schemes that illustrate the methods by which the compounds of the invention can be prepared. The starting materials can be obtained from commercial sources or prepared by methods well known in the literature known to those with ordinary experience in the art. Groups A, R1, R2, R3, X, Y, Z, m, and n are as previously defined unless otherwise noted below. This invention is intended to encompass the compounds that come with formula (I) when they are prepared by means of synnemic processes or by means of meiabolic processes. The preparation of the compounds of the invention by metabolic processes includes those that occur in the body of a human or an animal (in vivo) or processes that occur in vitro.
Scheme 1
Scheme 1 shows the synthesis of the compounds of the formula (la), (Ib), and (le). The compounds of the formula (3), which can be prepared by method numbers by those with ordinary experience in the art, can be converted to compounds of the formula (a) by the catalyst trait.
Grubbus (first or second generation). Solvents which are typically used in this reaction include dichloromean, chloroform, and methyl-ery-builyl ether. The typical reaction is carried out at a temperature of about 50 ° C to about 70 ° C for about 12 to about 24 hours. The compounds of the formula (la) can be converted to
compounds of formula (Ib) by treatment by an oxidizing agent such as OsO 4, KMnO 4, H 2 O 2, N-methylmorpholin-N oxide, and mixtures thereof. Examples of solvents used in this reaction include THF, water, 2-methyl-2-propanol, meilyylbuterol, and mixtures thereof. The typical reaction is conducted at about 0 ° C to about 30 ° C for about 12 to about 24 hours. The hydroxyl groups in the compounds of the formula (Ib) can be converted to several other functional groups using methods known to those of ordinary skill in the art.
Scheme 2
As shown in Scheme 2, the compounds of the formula (la) can be converted to compounds of the formula (Id) wherein R2 and R3 are hydrogen by means of hydrogenation using a metal catalyst in the presence of hydrogen. Representative palladium cayalizers include Pd / C, RhCl (PPh3) 3, and P02. Examples of solvents used in the reaction include meinol, THF, ethanol, methyl tert-butyl ether, and mixtures thereof. The
Typically, the reaction is conducted at about 20 ° C to about 40 ° C for about 5 min to about 2 hours. The compounds of formula (la) can be converted to compounds of formula (Id) wherein R2 and R3 are selected from a group consisting of hydroxy and NRaRb by methods known to those of ordinary skill in the art. The compounds of the formula (Id) wherein at least one of R2 and R3 either hydroxy or NRaRb can be further functionalized using methods known to those of ordinary skill in the art. The present invention will now be described in connection with certain preferred embodiments which do not intend to limit its scope. On the contrary, the present invention covers all alimentaries, modifications, and equivalents that may be included within the scope of the claims. Thus, the following examples, which include preferred embodiments, will illustrate the preferred practice of the present invention, it being understood that the examples are for purposes of illuminating certain preferred embodiments and are presented to provide what is believed to be the most useful description. and easy to understand their procedures and conceptual aspects. The compounds of the invention were named by ACD / ChemSketch version 5.03 (developed by Advanced Chemisíry Developmení, Inc., Toronío, ON, Canada) or consisieron names were given with the ACD nomenclature.
EXAMPLE 1 18-Chloro-11,14-dihydro-1 H.10H-8.4-epiazeno-9.15,1,3,6-benzodioxatriazacycloheptadecin-2-one
EXAMPLE 1A 2- (Allyloxy) -5-chloroaniline A mixture of 2-amino-4-chlorophenol (10 g, 69.65 mmol) and K2CO3 (14.53 g, 105 mmol) in acetone (160 mL) was treated with allyl bromide ( 9.03 mL, 104 mmol), stirred at ambient temperature overnight, and filtered. The filtrate was washed with oil and the combined filtrates were concentrated. The residue was purified by chromatography on an insanitary vaporization column eluting with hexanes / acetyl ether (10: 1) to give 8.31 g (65%) of the desired product. MS (DCI / NH3) m / z 184.02 (M + H) +; 1 H NMR (500 MHz, DMSO-de) d 4.51 (m, 2H), 5.02 (s, 2H), 5.24 (dd, J = 10.53, 1.68 Hz, 1H), 5.42 (m, 1H), 6.04 (m, 1H), 6.47 (dd, J = 8.54, 2.44 Hz, 1H), 6.66 (d, J = 2.75 Hz, 1H), 6.75 (d, J = 8.54 Hz, 1H).
EXAMPLE 1B 1- (Allyloxy) -4-chloro-2-isocyanatobenzene A solution of 20% phosgene (5 mL, 47.3 mmol) in uence (6 mL) at reflux was slowly evaporated with a solution of
Example IA (1g, 5.44 mmoles) in toluene (10 mL). The mixture was refluxed at 110 ° C for 20 hours, cooled to ambient temperature, and concentrated to give the desired product. 1H NMR (500
MHz, CD2CI2) d 4.62 (d, J = 5.30 Hz, 2H), 5.33 (dd, J = 10.76, 1.40 Hz, 1H), 5.46 (dd, J = 17.31, 1.40 Hz, 1H), 6.07 (m, 1H ), 6.84 (d, J = 8.73 Hz, 1H), 6.99 (d, J = 2.50 Hz, 1H), 7.10 (dd, J = 8.74, 2.50 Hz, 1H).
EXAMPLE 1C 6- (3-Butenyloxy) -2-pyrazinamine A suspension of NaH (60%, 618 mg, 15.45 mmol) in dioxane (30 mL) was treated at 0 ° C with 3-buten-1-ol (1.33 mL). , 15.45 mmol), stirred for 2 hours, was irritated with 2-amino-6-chloropyrazine (1 g, 7.72 mmol), stirred at 100 ° C for 2.5 days, cooled to ambient temperature, and diluted with acetyl. of eyelus. The mixture was washed with water, dried (MgSO), filtered, and concentrated. The concentrate was purified by chromazography in an instantaneous vaporization column eluting with hexanes / ethyl ace (2: 1) to give the desired product (390 mg, 31%). MS (DCI / NH3) m / z 166.12 (M + H) +; 1H NMR (500 MHz, benzene-d6) d 2.66 (m, 2H), 4.42 (t, J = 6.87 Hz, 2H), 5.24 (dd, J = 10.22, 1.98 Hz, 1H), 5.30 (m, 1H) , 6.04 (m, 1H), 7.64 (s, 1H), 7.65 (s, 1H).
EXAMPLE 1D N-f2- (allyloxy) -5-chlorophenin-N, -f6- (3-butenyloxy) -2-pyrazinolurea A mixture of Example 1B (201 mg, 0.96 mmol) was stirred and the
Example 1C (158 mg, 0.96 mmol) in ileol (15 mL) at 110 ° C lasted 15 hours and was concentrated. The concentrate was purified by chromazography in an insannant vaporization column eluting with
hexanes / ethyl ether (1: 1) to give the desired yield (185 mg, 52%). MS (DCI / NH3) m / z 375.12 (M + H) +; 1 H NMR (500 MHz, DMSO-de) d 2.52 (m, 2 H), 4.33 (i, J = 6.55 Hz, 2 H), 4.70 (d, J = 5.30 Hz, 2 H), 5.09 (dd, J = 10.29, 1.25 Hz, 1H), 5.16 (dd, J = 17.31, 1.40 Hz, 1H), 5.31 (d, J = 10.61 Hz, 1H), 5.43 (dd, J = 17.16, 1.25 Hz, 1H), 5.88 (m, 1H), 6.08 (m, 1H), 7.02 (d, J = 8.75 Hz, 1H), 7.06 (dd, J = 8.75 Hz, 2.5 Hz, 1H), 7.89 (s, 1H), 8.22 (d, J = 2.50 Hz, 1H), 8.69 (s, 1H), 9.07 (s, 1H), 10.08 (s, 1H).
EXAMPLE 1E 18-Chloro-11,14-dihydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecin-2-one A mixture of Example 1D (60 mg, 0.16 mmol) was alloyed CH2CI2 (66 mL) with the second generation Grubbs cayalizer (20 mg, 0.024 mmol), was stirred at 50 ° C overnight, and concentrated. The residue was purified by flash column chromatography eluting with hexanes / ethyl ether (1: 1) to give the desired yield (22 mg, 40%). MS (DC1 / NH3) m / z 347.11 (M + H) +; 1 H NMR (500 MHz, CD 2 Cl 2) d 2.70 (d, J = 7.25 Hz, 2 H), 4.63 (m, 4 H), 6.05 (m, 2 H), 6.90 (d, J = 8.73 Hz, 1 H), 7.02 (dd) , J = 8.73, 2.57 Hz, 1H), 7.15 (s, 1H), 7.72 (s, 1H), 7.84 (s, 1H), 8.25 (d, J = 2.57 Hz, 1H), 10.55 (s, 1H) .
EXAMPLE 2 18-Chloro-11,12,13,14-tetrahydro-1 H, 10 H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecin-2-one A suspension of Pl / C %, 2mg) in 3: 1 mefanol / THF (3 mL) was treated with Example 1E (17 mg, 0.049 mmol). The reaction mixture was bubbled with hydrogen for 10 minutes and filtered through diatomaceous earth (Celite®). The filtrate was concentrated and the residue was purified by crystallization from ethyl acetate to give the desired product (13.7 mg, 80%). MS (DCI / NH3) m / z 349.11 (M + H) +; 1 H NMR (500 MHz, DMSO-de) d 1.64 (m, 2 H), 1.84 (m, 2 H), 1.89 (m, 2 H), 4.14 (,, J = 5.16 Hz, 2 H), 4.48 (,, J = 7.80 Hz, 2H), 7.08 (d, J = 2.50 Hz, 1H), 7.09 (s, 1H), 7.89 (s, 1H), 7.95 (s, 1H), 8.23 (d, J = 2.50 Hz, 1H) , 10.26 (s, 1H), 10.32 (s, 1H).
EXAMPLE 3 18-Chloro-12,13-dihydroxy-11,12,13,14-tetrahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecin-2-one A solution of Example 1E (20 mg, 0.081 mmol) and N-methylmorpholine-N-oxide (14 mg, 0.12 mmol) in THF (1.6 mL) and H2O (0.2 mL) at 0 ° C were irradiated with 2.5% by weight of OsO4 in 2- methyl-2-propanol (0.065 mL), was stirred overnight at room temperature, and filtered. The filter cake was washed with water and dried to give the desired product (22 mg, 73%). MS (DCI / NH3) m / z 381.1 (M + H) +; 1 H NMR (500 MHz, DMSO-d 6) d 1.84 (m, 1 H), 2.29 (m, 1 H), 3.82 (m, 2 H), 4.12 (m, 2 H), 4.46 (m, 2 H), 4.57 (m, 2H), 7.11 (dd,
J = 8.73 Hz, 2.50 Hz, 1H), 7.15 (d, J = 9.05 Hz, 1H), 7.85 (s, 1H), 7.93 (s, 1H), 8.17 (d, J = 2.81 Hz, 1H), 10.03 (s, 1H), 10.25 (s, 1H).
EXAMPLE 4 17-Chloro-10,13-dihydro-1 H -8,4-epiazeno-9,14,1,3,6-benzodioxatriazacyclohexadecin-2-one
EXAMPLE 4A 6- (Allyloxy) -2-pyrazinamine A mixture of allylic alcohol (0.21 mL, 3.08 mmol) in dioxane (4 mL) was brought in with NaH (60%, 3.08 mmol), stirred for 30 min. brought with 2-amino-6-chloropyrazine (200 mg, 1.54 mmol), was heated at 140 ° C in a Smith Sinitizer for 2200 seconds, and filtered. The filtrate was concentrated and purified by flash column chromatography eluting with hexanes / ethyl acetate (2: 1) to give the desired product (133 mg, 57%). MS (DCI / NH3) m / z 152.0 (M + H) +; 1 H NMR (500 MHz, CD 2 Cl 2) d 4.75 (m, 2 H), 5.24 (m, 1 H), 5.37 (m, 1 H), 6.05 (m, 1 H), 7.50 (s, 1 H), 7.53 (s, 1 H) .
EXAMPLE 4B N-r2- (allyloxy) -5-chlorophenin-N'-r6- (allyloxy) -2-pyrazinylurea The desired production was prepared (650 mg, 66% yield) by suspending Example 4A by Example 1C in the Example ID. MS (DCI / NH3) m / z 361.1 (M + H) +; 1 H NMR (400 MHz, DMSO-d 6) d 4.69
(d, J = 5.52 Hz, 2H), 4.82 (d, J = 5.52 Hz, 2H), 5.28 (m, 2H), 5.38 (dd, J = 8 29, 1.53 Hz, 1H), 5.43 (dd, J = 8.r3, 1.69 Hz, 1H), 6.07 (m, 2H), 7.01 (m, 1H), 7.05 (m, 1H), 7.93 (s, 1H), 8.21 (d, J = 2.45 Hz, 1H) , 8.69 (s, 1H), 9.07 (s, 1H), 10.08 (s, 1H).
EXAMPLE 4C 17-Chloro-10,13-dihydro-1H-8.4-epiazeno-9,14,1,3,6-benzodioxatriazacyclohexadecin-2-one The desired product (144 mg, 56% yield) was prepared by substituting Example 4B for Example 1D in Example 1E. MS (DCI / NH3) m / z 333.0 (M + H) +; 1 H NMR (500 MHz, DMSO-d 6) d 4.70 (d, J = 3.12 Hz, 2 H), 5.44 (d, J = 4.68 Hz, 2 H), 5.82 (m, 2 H), 7.08 (dd, J-8.73, 2.81 Hz, 1H), 7.17 (d, J = 8.73 Hz, 1H), 7.85 (s, 1H), 7.91 (s, 1H), 8.33 (d, J = 2.50Hz, 1H), 10.31 (s, 1H) , 11.04 (s, 1H).
EXAMPLE 5 17-Chloro-10,11,12,13-tetrahydro-1H-8.4-epiazeno-9,14,1,3,6-benzodioxatriazacyclohexadecin-2-one The desired production was prepared (10 mg, 50% yield) susliuuyendo Example 4C for Example 1E in Example 2. MS (DCI / NH3) m / z 335.0 (M + H) +; 1 H NMR (500 MHz, DMSO-d 6) d 1.85 (m, 2 H), 2.01 (m, 2 H), 4.16 (t, J = 7.2 Hz, 2 H), 4.64 (t, J = 5.6 Hz, 2 H), 7.04 (dd, J = 8.58, 2.65 Hz, 1H), 7.14 (d, J = 8.73 Hz, 1H), 7.84 (s, 1H), 7.92 (s, 1H), 8.34 (d, J = 2.50 Hz, 1H) , 10.28 (s, 1H), 10.99 (s, 1H).
EXAMPLE 6 17-Chloro-11.12-Didrohydroxy-10,11,12,13-tetrahydro-1H-8,4-epiazeno-9,14,1,3,6-benzodioxatriazacyclohexadecin-2-one The desired product was prepared (21.7 mg, 70% yield) suspending Example 4C by Example 1E in Example 3. MS (DCI / NH3) m / z 367.0 (M + H) +; 1 H NMR (400 MHz, DMSO-d 6) d 4.06 (m, 3 H), 4.18 (m, 2 H), 5.14 (d, J = 25.8 Hz, 1 H), 5.19 (1, J = 6.5 Hz, 1 H), 5.28 (d, J = 6.5 Hz, 1H), 7.06 (dd, J = 8.75, 2.61 Hz, 1H), 7.20 (d, J = 8.90 Hz, 1H), 7.87 (s, 1H), 7.92 (s, 1H) , 8.36 (d, J = 2.76 Hz, 1H), 10.28 (s, 1H), 10.88 (s, 1H).
EXAMPLE 7 18-Chloro-2-oxo-2,3,11,14-tetrahirdro-1H, 10H-8,4-epiazeno-9,15,1, 3,6-benzodioxatriazacycloheptadecin-7-carbonitrile
EXAMPLE 7A 2-Chloro-3- (dichloromethyl) pyrazine A mixture of 2-chloro-3-methypypyrazine (10 g, 77.8 mmol), acetic acid (90 mL), and chlorine (23.6 g) was combined and heated to 100 g. ° C lasted 3 hours, and concentrated. The residue was suspended in dichloromethane, washed with water and 5% NaHCO3, dried (MgSO4), filtered, and concentrated. The crude product was purified by flash column chromatography eluting with hexanes / ethyl efflux (3: 1) to give the desired product (3.8 g, 25%). MS (DCI / NH3) m / z 197.0 (M + H) +; 1H NMR (400 MHz, benzene-
d6) d 7.70 (s, 1H), 8.67 (d, J = 2.15 Hz, 1H), 8.83 (d, J = 2.45 Hz, 1H).
EXAMPLE 7B 5-Amino-3-chloro-2-pyrazinecarbaldehyde oxime A solution of NH2OH-HCl (7.04 g, 101.3 mmol) in H2O (20 mL) and ethanol (20 mL) was regulated in its pH to pH 7.5 with 10M. NaOH was brought with Example 7A (2 g, 10.13 mmol), heated at reflux at 95 ° C for 6 hours, partially concentrated, and cooled to 0 ° C overnight. The precipitate was collected by filtration and dried to give the desired product (500 mg, 29%). MS (DC1 / NH3) m / z 173.0 (M + H) +; 1 H NMR (500 MHz, acetone-d 6) d 7.26 (s, 2 H), 7.88 (s, 1 H), 8.15 (s, 1 H), 11.40 (s, 1 H).
EXAMPLE 7C 5-Amino-3-chloro-2-pyrazinecarbaldehyde-O-acetyloxime A solution of Example 7B (450 mg, 2.60 mmol) in 1N NaOH (10 mL) was brought dropwise with acetic anhydride (1 mL) while maintaining the temperature of the reaction mixture at 20 ° C. The reaction mixture was stirred for 10 minutes and the precipitate was collected by filtration, washed with water, and dried to give the desired product (460 mg, 82%). MS (DC1 / NH3) m / z 215.12.0 (M + H) +; 1 H NMR (400 MHz, DMSO-d 6) d 2.19 (s, 3 H), 7.69 (s, 2 H), 7.96 (s, 1 H), 8.57 (s, 1 H).
EXAMPLE 7D 5-Amino-3-chloro-2-pyrazinecarbonitrile A suspension of Example 7C (460 mg, 2.14 mmol) in o-xylene (22 mL) was stirred at 160 ° C for 20 hours, fermented with charcoal (10 ml). mg), and filtered. The filtrate was cooled to ambient temperature and the resulting precipitate was collected by filtration to give the desired yield (250 mg, 75%). MS (ESI) m / z 152.93 (M-H) "; 1 H NMR (500 MHz, DMSO-d 6) d 7.88 (s, 1H), 8.09 (s, 2H).
EXAMPLE 7E 5-Amino-3- (3-butenyloxy) -2-pyrazinecarbonitrile A suspension of NaH (60%, 52 mg, 1.3 mmol) in dioxane (3 mL) in a microwave flask was boiled with 3-buyen-1. -ol (0.112 mL, 1.3 mmol), was stirred at ambient temperature for 30 min., and was fused with Example 7D (100 mg, 0.65 mmol). The resulting mixture was heated at 100 ° C for 3000 seconds in a Smihy Synthesizer, cooled, and concentrated. The residue was purified by flash column chromatography eluting with hexanes / ethyl acetate (1: 1) to give the desired yield (74 mg, 60%). MS (DCI / NH3) m / z 208.12 (M + NH4) +; 1 H NMR (500 MHz, acetone-d 6) d 2.49 (m, 2 H), 4.35 (f, J = 6.71 Hz, 2 H), 5.09 (dd, J = 10.22, 1.98 Hz, 1 H), 5.15 (dd, J = 17.09, 1.83 Hz, 1H), 5.85 (m, 1H), 7.51 (s, 1H), 7.66 (s, 2H).
EXAMPLE 7F 6- (3-Butenyloxy) -5-cyano-2-pyrrazinylcarbamate phenyl A suspension of Example 7E (200 mg, 1.05 mmol) in pyridine (0.17 mL, 2.1 mmol) and CH 2 Cl 2 (10 mL) at 0 ° C. It was irradiated with chloroformiade phenyl (0.145 mL, 2.1 mmol), was stirred at ambient temperature for 3 hours, and was applied directly in a column of insanitary vaporization. The column was eluted with dichloromethane to give the desired product (130 mg, 40%). MS (DCI / NHs) m / z 328.13 (M + NH 4) +; 1 H NMR (500 MHz, DMSO-d 6) d 2.56 (q, J = 6.71 Hz, 2 H), 4.49 (t, J = 6.71 Hz, 2 H), 5.11 (dd, J = 10.22, 1.68 Hz, 1 H), 5.19 (dd, J = 17.24, 1.68 Hz, 1H), 5.88 (m, 1H), 7.27 (d, J = 7.63 Hz, 2H), 7.31 (i, .J = 7.32 Hz, 1H), 7.47 (i, J) = 7.93 Hz, 2H), 8.73 (s, 1H), 11.62 (s, 1H).
EXAMPLE 7G N-r2- (allyloxy) -5-chlorophenyl-N'-f6- (3-butenyloxy) -5-cyano-2-pyrazinylurea A mixture of Example 1A (108.8 mg, 0.59 mmol) and Example 7F was heated. (116 mg, 0.37 mmol) in toluene (10 mL) at 90 ° C for 24 hours and concentrated. The residue was purified by flash column chromatography eluting with hexanes / ethyl acetate (3: 1) to give the desired product (86 mg, 58%). MS (DCI / NH3) m / z 400.09 (M + H) +; 1 H NMR (400 MHz, DMSO-de) d 2.53 (q, J-6.65 Hz, 2 H), 4.45 (t, J = 6.60 Hz, 2 H), 4.70 (m, 2 H), 5.10 (dd, J = 10.28, 1.99 Hz, 1H), 5.17 (m, 1H), 5.30 (m, 1H), 5.42 (m,
1H), 5.85 (m, 1H), 6.07 (m, 1H), 7.06 (d, J = 2.15 Hz, 1H), 7.06 (s, 1H), 8.19 (d, J = 2.15 Hz, 1H), 8.86 ( s, 1H), 9.05 (s, 1H), 10.69 (s, 1H).
EXAMPLE 7H 18-Chloro-2-oxo-2,3,11,14-tetrahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacyclohe tadecin-7-carbonitrile The product was prepared desired (40 mg, 66% yield) substituting Example 7G for Example 1D in Example 1E. MS (DCVNH3) m / z 389.09 (M + NH4) +; 1 H NMR (500 MHz, DMSO-d 6) d 2.71 (q, J = 7.49 Hz, 2 H), 4.68 (,, J = 7.05 Hz, 2 H), 4.70 (d, J = 6.86 Hz, 2 H), 6.02 (m , 1H), 6.09 (m, 1H), 7.12 (dd, J = 8.89, 2.65 Hz, 1H), 7.22 (d, J = 9.04 Hz, 1H), 7.98 (s, 1H), 8.12 (d, J = 2.49 Hz, 1H), 10.35 (s, 1H), 10.97 (s, 1H). EXAMPLE 8 18-C lor o-2-oxo-2.3.11,12, 13,14-hexah id ro-1H, 10 H-8,4-ep iazeno- 9,15,1,3,6-benzodioxatriazacicloheptadecin- 7-carbonitrile The desired yield was prepared (7 mg, 70% yield) suspending Example 7H by Example 1E in Example 2. MS (DCI / 1MH3) m / z 391.3 (M + NH4) +; 1 H NMR (500 MHz, DMSO-d 6) d 1.61 (dd, J = 12.16, 6.24 Hz, 2H), 1.82 (m, 2H), 1.95 (m, 2H), 4.19 (i, J = 5.15 Hz, 2H) , 4.62 (t, J = 8.45 Hz, 2H), 7.13 (m, 2H), 7.99 (s, 1H), 8.20 (d, J = 2.18 Hz, 1H), 9.95 (s, 1 H), 10.94 (s) , 1 HOUR).
EXAMPLE 9 18-Chloro-12,13-dihydroxy-2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecin- 7- carbonitrile The desired production (8.5 mg, 88% yield) was prepared by substituting Example 7H for Example 1E in Example 3. MS (ESI) m / z 404.01 (MH) '; 1 H NMR (500 MHz, DMSO-d 6) d 1.93 (m, 1 H), 2.33 (m, 1 H), 3.82 (m, 2 H), 4.12 (m, 2 H), 4.61 (m, 1 H), 4.69 (m, 1H), 4.90 (d, J = 4.99 Hz, 1H), 5.08 (d, J = 4.99 Hz, 1H), 7.14 (dd, J = 8.89, 2.34 Hz, 1H), 7.18 (d, J = 9.05 Hz, 1H), 8.00 (s, 1H), 8.16 (d, J = 2.49 Hz, 1H), 9.79 (s, 1H), 10.93 (s, 1H).
EXAMPLE 10 18-Chloro-17-hydroxy-2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecin- 7- carbonitrile
EXAMPLE 10A 2,5-Dichloro-4-nitrophenol A solution of 2,5-dichlorophenol (10 g.
61. 3 mmol) in CCI4 (400 mL) at 0 ° C 4.7 mL (73.6 mmol) of 70% HNO3 in 30 mL of CCI4 for 30 min. The reaction mixture was heated slowly to ambient temperature and stirred for 1 hour. The yellow precipitate was collected by filtration and dried to give the desired product (8.4 g) at 62% yield. MS (DCI / NH3)
m / z 224.91 (M + NH 4) +; 1 H NMR (500 MHz, DMSO-D 6) d ppm 7.17 (s, 1 H) 8.25 (s, 1 H) 12.12 (s, 1 H).
EXAMPLE 10B. { 2-f (2,5-Dichloro-4-nitrophenoxy) methoxyethyl) (trimethyl) silane To a solution of Example 10A (2 g, 9.62 mmol) in CH2Cl2 (50 mL) SEMCl (2.04 mL, 11.54 mmol) was added. and DIEA (diisopropylamine) (2.01 mL, 20.96 mmol). The reaction was stirred at ambient temperature for 1 hour and concentrated. The residue was suspended in oil effile and washed with water. The organic layer was dried over MgSO 4 and evaporated to give the desired yield. MS (DCI / NH3) m / z 355.06 (M + NH4) +; 1 H NMR (500 MHz, DMSO-D 6) d ppm 0.00 (s, 6 H) 0.04 (s, 3 H) 0.92-0.96 (m, 2 H) 3.78-3.83 (m, 2 H) 5.56 (s, 2 H 7.61 (s, 1 H) 8.36 (s, 1 H).
EXAMPLE 10C (2-5- (Allyloxy) -2-chloro-4-nitrophenoxymethoxy) ethyltrimethyl) silane was added to a suspension of NaH (95%, 717 mg, 28.38 mmol) in THF (40 mL) alcohol allyl (1.93 mL, 28.38 mmol). The mixture was stirred at room temperature for 1 hour and then added to gofas to a solution of Example 10B (8 g, 23.65 mmol) in THF (60 mL). The reaction was stirred for 2 hours and concentrated. The residue was purified by flash chromatography eluting with 9% ethyl acetate in hexane. The desired product (4.7 g) was obtained at 55% of
performance. MS (DCI / NH3) m / z 377.11 (M + NH4) +; 1H NMR (500 MHz, DMSO-D6) d ppm 0.00 (s, 9 H) 0.92-0.95 (m, 2 H) 3.77-3.83 (m, 2 H) 4.79 (d, J = 5.30 Hz, 2H) 5.34 ( m, 1 H) 5.49 (m, 1 H) 5.52 (s, 2 H) 6.07 (m, 1 H) 7.13 (s, 1 H) 8.13 (s, 1 H).
EXAMPLE 10D 2- (Allyloxy) -5-chloro-4-. { r2- (trimethylsilyl) ethoxy-1-methoxy} Aniline To a solution of Example 10C (1.33 g, 3.69 mole) and SnCl2 (4.16 g, 18.47 mmol) in ethanol (120 mL), pepethylamine (10 mL, 110.7 mmol) was added. Broad canifices of yellow precipitates formed. The suspension was heated to 70 ° C for 3 hours, cooled and filtered. The precipitates were washed with CH2Cl2, and the combined filtrate was concentrated. The residue was purified by flash chromatography eluting with 9% ethanoyl acetate in hexane. The desired production (0.5 g) was obtained in 47% yield. MS (DCI / NH3) m / z 330.07 (M + H) +; 1 H NMR (500 MHz, DMSO-D 6) d ppm 0.00 (s, 9 H) 0.88-0.92 (m, 2 H) 3.74-3.77 (m, 2 H) 4.53 (s, 1 H) 4.54 (s, 1 H ) 4.64 (s, 2 H) 5.12 (s, 2 H) 5.26 (d, J = 0.61 Hz, 1 H) 5.43 (dd, J = 17.16, 1.25 Hz, 1 H) 6.05 (m, 1 H) 6.68 ( s, 1 H) 6.77 (s, 1 H).
EXAMPLE 10E N- (2- (allyloxy) -5-chloro-4- { R2- (trimethylsilylethoxy-1-methoxy phenyl) -N'-r6- (but-3-enyloxy) -5-cyanopyrazin-2-illurea One was stirred mixture of Example 7F (1925 g, 6.21 mmol) and the
Example 10D (2.049 g, 6.21 mmol) in DMF (25 ml) at 70 ° C lasted 6 hours. DMF was removed by evaporation, and the residue was suspended in a mixture of hexane and ethyl ether. The precipitates were collected by filtration and dried in a vacuum pump. The desired product (3 g, 88%) was obtained as a white solid. MS (DCI / I4H3) m / z 546.18 (M + H) +; 1H NMR (500 MHz, DMSO-D6) d ppm 0.00 (s, 9H) 0.90-0.93 (m, 2H) 2.56 (q, J = 6.76Hz, 2H) 3.75-3.79 (m, 2H) 4.47 (t, J = 6.55 Hz, 2H) 4.71 (d, J = 5.30Hz, 2H) 5.13 (d, J = 10.29Hz, 1 H) 5.19 (dd, J = 17.31, 1.72 Hz, 1 H) 5.31 (s, 2 H) 5.33 (dd, J = 10.45, 1.40 Hz, 1 H) 5.46 (dd, J = 17.31, 1.40 Hz, 1 H) 5.89 (m, 1 H) 6.09 (m, 1 H) 7.02 (s, 1 H) 8.13 (s, 1 H) 8.85 (s, 1 H) 8.94 (s, 1 H) 10.59 (s, 1 H).
EXAMPLE 10F 18-Chloro-2-oxo-17- (r 2 - (trimethylsilyne-p-methoxy-2,3,11,14-tetrahydro-1H, 10H-8,4-epiazeno-9, 15, 1,3,6-benzodioxatriazacycloheptadecin- 7-carbonitrile A mixture of Example 10E (2.87 g, 5.26 mmol) and the Grubbs Catalyst (2nd generation, 439 mg, 0.526 mmol) in CH2Cl2 (3.5 L) was stirred at room temperature overnight, and then DMSO ( 7.46 mL, 105 mmol) The reaction mixture was further stirred for 24 hours and concentrated.The residue was purified by flash chromatography eluting with 9% acetyl ether in dichloromethane to give the desired yield (2.5 g. 92%) .MS (DCI / NH3) m / z 535.14 (M + NH4) +; H NMR (400 MHz,
DMSO-De) d ppm 0.00 (s, 9 H) 0.90-0.94 (m, 2 H) 2.73 (q, J = 7.36Hz, 2H) 3.76-3.80 (m, 2H) 4.66-4.73 (m, 4H) 5.36 (s, 2H) 5.99-6.14 (m, 2 H) 7.13 (s, 1 H) 7.99 (s, 1 H) 8.07 (s, 1 H) 10.24 (s, 1 H) 10.93 (s, 1 H).
EXAMPLE 10G 18-Chloro-2-oxo-17- (r 2 - (trimethylsilyl) ethoxy) methoxy-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1 , 3,6-benzadioxatriazacycloheptadecin-7-carbonitrile A mixture of Example 10F (2 g, 3.86 mmol) and 10% Pd / C (160 mg, 0.151 mmol) in THF under a hydrogen atmosphere was stirred for 3 hours, and the Insoluble maferial was leaked. The filtrate was concentrated, and the residue was purified by flash evaporation chromatography eluting with 9% ethyl acetate in dichloromethane. The desired product (1.83 g, 91%) was obtained as a white solid. MS (DCI / NH3) m / z 537.20 (M + NH4) +; 1H NMR (500 MHz, DMSO-D6) d ppm 0.00 (s, 9H) 0.90-0.94 (m, 2H) 1.59-1.65 (m, 2H) 1.83-1.87 (m, 2H) 1.94-2.01 (m, 2H) 3.77-3.80 (, 2H) 4.19-4.21 (m, 2H) 4.60-4.63 (m, 2H) 5.35 (s, 2H) 7.05 (s, 1 H) 8.00 (s, 1 H) 8.17 (s, 1 H) 9.84 (s, 1 H) 10.90 (s, 1 H).
EXAMPLE 10H 18-Chloro-17-hydroxy-2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacicloheptadecin-7 carbonitrile
To a solution of Example 10G (1.8 g, 3.46 mmol) in a mixture of dichloromean (100 mL) and ethylene (300 mL) was added dropwise, 9 mL of 4 N HCl in 1,4-dioxane. The reaction mixture was stirred overnight, and the white precipitate was collected by filtration and dried. The desired product (1.3 g, 96%) was obtained as a white solid. MS (DCI / NH3) m / z 407.08 (M + NH4) +; 1 H NMR (500 MHz, DMSO-D 6) d ppm 1.60-1.65 (m, 2 H) 1.81-1.85 (m, 2 H) 1.94-2.00 (m, 2 H) 4.11 (,, J = 5.15 Hz, 2 H ) 4.59 (í, J = 8.11 Hz, 2 H) 6.72 (s, 1 H) 7.99 (s, 1 H) 8.06 (s, 1 H) 9.75 (s, 1 H) 10.78 (s, 1 H). EXAMPLE 11 18-Chloro-17- (3-hydroxy-propoxy) -2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H -8,4 -epiazene-9, 15 1, 3,6-benzodioxatriazacycloheptadecin-7-carbonitrile It was heated to a mixture of Example 10H (20 mg, 0.051 mmol),
3-bromopropanol (11 mg, 0.077 mmol) and Cs2CO3 (33.4 mg, 0.102 mmol) in DMF (2 mL) were heated at 40 ° C overnight. The inorganic salts were filtered, and the filtrate was concentrated. The residue was purified by HPLC eluting with a gradient of 0% -70% acetyloiryl in 0.1% TFA aqueous solution. The desired production (8.2 mg, 36%) was made. MS (ESI) m / z 445.98 (M-H) '; 1 H NMR (500 MHz, DMSO-D 6) d ppm 1.57-1.62 (m, 2 H) 1.80-1.84 (m, 2 H) 1.85-1.90 (m, 2 H) 1.93-1.99 (m, 2 H) 3.58 ( q, J = 5.90 Hz, 2 H) 4.15 (,, J = 6.26 Hz, 2 H) 4.24 (,, J = 5.03 Hz, 2 H) 4.56-4.61 (m, 3 H) 6.92 (s, 1 H) 7.99 (s, 1 H) 8.11 (s, 1 H) 9.79 (s, 1 H) 10.88 (s, 1 H).
EXAMPLE 12 18-Chloro-17- (2,3-dihydroxypropoxy) -2-oxo-2,3, 11,12,13, 4- hexahydro-1H, 10H-8,4-epiazeno-9,15,1 , 3,6-benzodioxatriazacycloheptadecin-7-carbonitrile A mixture of Example 10H (52 mg, 0.13 mmol), allyl bromide (0.0138 mL, 0.16 mmol) and K2CO3 (36.8 mg, 0.267 mmol) in DMF (5 mL) was stirred. At night ambienle duraníe night. The inorganic salts were filtered, and the filtrate was concentrated. The residue was dissolved in a mixture of THF (20 mL) and water (2 mL), and the solution was evaporated with N-methyl-morpholin-N-oxide (36 mg, 0.31 mmol), followed by the addition of 2.5% (% in weight) of OsO4 in 2-meityl-2-propanol (0.19 mL) at 0 ° C. The reaction mixture was stirred overnight and concentrated. The residue was purified by HPLC eluting with the gradient from 0% -70% acetonitrile in 0.1% TFA aqueous solution. The desired product (22 mg, 36%) was obtained as a white solid. MS (ESI) m / z 462.20 (M-H); 1H NMR (500 MHz, DMSO-D6) d ppm 1.57-1.62 (m, 2H) 1.80-1.85 (m, 2H) 1.92-1.99 (m, 2H) 3.44-3.52 (m, 2H) 3.82 (m, 1 H ) 4.00 (m, 1 H) 4.08 (m, 1 H) 4.23 (t, J = 5.19 Hz, 2 H) 4.58 (í, J = 8.24 Hz, 2 H) 4.69 (t, J = 5.65 Hz, 1 H 4.98 (d, J = 4.88 Hz, 1 H) 6.93 (s, 1 H) 7.98 (s, 1 H) 8.12 (s, 1 H) 9.79 (s, 1 H) 10.87 (s, 1 H).
EXAMPLE 13 18-Chloro-17- (2-hydroxyethoxy) -2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1,3, 6-Benzodioxatriazacycloheptadecin-7-carbonitrile A mixture of Example 10H (30 mg, 0.077 mmol) was heated.
2- (2-bromoehyoxy) tetrahydropyran (32 mg, 0.154 mmol) and Cs2CO3 (33.4 mg, 0.102 mmol) in DMF (2 mL) at 40 ° C during the night. The inorganic salts were filtered, and the filtrate was concentrated. The residue was brought with HOAc / THF / H 2 O (4: 2: 1, 8 mL) at 45 ° C overnight. The solvent was removed, and the residue was purified by HPLC eluting with a gradient of 0% -70% acetylonil in 0.1% TFA aqueous solution. The desired yield was obtained (25 mg, 76%). MS (ESI) m / z 432.04 (MH) "; 1 H NMR (400 MHz, DMSO-D6) d ppm 1.57-1.63 (m, 2 H) 1.80-1.85 (m, 2 H) 1.92-2.00 (m, 2 H) 3.74 (q, J = 5.22 Hz, 2 H) 4.11 (,, J = 5.06 Hz, 2 H) 4.23 (,, J = 5.06 Hz, 2 H) 4.59 (,, J = 8.29 Hz, 2 H) 4.88 (t, J = 5.37 Hz, 1 H) 6.94 (s, 1 H) 7.99 (s, 1 H) 8.12 (s, 1 H) 9.80 (s, 1 H) 10.86 (s, 1 H) The Examples 14-26, shown in Table 1, were prepared using a similar procedure as described in Example 11 substituting 3-bromopropanol with the appropriate organic chloride or bromide.
Table 1
EXAMPLE 27 17-Amino-18-chloro-2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxatuazacycloheptadecin- 7- carbonitrile
EXAMPLE 27A 2- (Allyloxy) -5-chloro-4-nitroaniline It was added to a mixture of 2-amino-4-chloro-5-nitrophenol (10 g,
0. 053 moles) and allyl bromide (5.05 mL, 0.058 moles) in DMF (100 mL)
K2CO3. The reaction mixture was stirred at room temperature for 3 hours, and then the inorganic salts were filtered. Filtering
it was concentrated, and the residue was dissolved in ethyl acetate and washed with aqueous NH 4 Cl. The organic layer was dried over MgSO4 and concentrated to give the desired product (10.9 g, 90%) as a yellow solid. MS (DCI / NH3) m / z 246.04 (M + NH4) +; 1 H NMR (500 MHz, DMSO-D 6) d ppm 4.68 (d, J = 4.99 Hz, 2 H) 5.29 (dd, J = 10.60, 1.56 Hz, 1 H) 5.48 (dd, J = 17.47, 1.56 Hz, 1 H) 6.05 (m, 1 H) 6.48 (s, 2 H) 6.76 (s, 1 H) 7.59 (s, 1 H).
EXAMPLE 27B N-r2- (allyloxy) -5-chloro-4-nitrophenin-N'-r6- (but-3-enyloxy) -5-cyanopyrazin-2-yl > urea A mixture of Example 27A (10.62 g, 46.45 mmol) and Example 7F (12 g, 38.71 mmol) in DMF (150 mL) was heated at 80 ° C for 40 hours. The solvent was removed, and the residue was triturated with ethyl acetate to give the desired product (16 g, 93%). MS (DCI / NH3) m / z 462.1 (M + NH4) +; 1H NMR (500 MHz, DMSO-D6) d ppm 2.31 (q, J = 6.76 Hz, 2 H) 4.22 (t, J = 6.71 Hz, 2 H) 4.61 (d, J = 5.30 Hz, 2 H) 4.88 ( d, J = 10.29 Hz, 1 H) 4.94 (dd, J = 17.31, 1.72 Hz, 1 H) 5.13 (dd, J = 10.45, 1.40 Hz, 1 H) 5.24 (dd, J = 17.47, 1.56 Hz, 1 H) 5.64 (m, 1 H) 5.85 (m, 1 H) 7.56 (s, 1 H) 8.25 (s, 1 H) 8.66 (s, 1 H) 9.11 (d, J = 1.56 Hz, 1 H) 10.58 (s, 1 H).
EXAMPLE 27C N-r2- (allyloxy) -4-amino-5-chlorophenyl-N'-f6- (but-3-enyloxy) -5-cyanopyrazin-2-inurea A mixture of Example 27B was heated (3.5 g, 7.86 g. mmoles), iron powder (4.4 g, 78.65 mmol) and NH4CI (210 mg, 3.93 mmol) in ethanol (80 mL) and water (20 mL) was heated at 80 ° C for 8 hours. The insoluble material was filtered, and the filtrate was concentrated. The residue was purified by insanphoracization chromatography eluting with 6% ethyl acetate in dichloromethane. The desired production (2.3 g, 70.6%) was obtained as a yellow solid. MS (DCI / NH3) m / z 415.08 (M + H) +; H NMR (500 MHz, DMSO-D6) d ppm 2.51-2.57 (m, 5 H) 4.45 (t, J = 6.56 Hz, 2 H) 4.57 (d, J = 5.19Hz, 2H) 5.11 (dd, J = 10.37, 1.83 Hz, 1 H) 5.15-5.19 (m, 3H) 5.30 (dd, J = 10.68, 1.53 Hz, 1 H) 5.43 (dd, J = 17.39, 1.53 Hz, 1 H) 5.87 (m, 1 H ) 6.07 (m, 1 H) 6.53 (s, 1 H) 7.82 (s, 1 H) 8.74 (s, 1 H) 8.80 (s, 1 H) 10.48 (s, 1 H).
EXAMPLE 27D 17-Amino-18-chloro-2-oxo-2,3,11,14-tetrahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecin-7-carbonitrile An agitated mixture of Example 27 ° C (2.93 g, 7.06 mmol) and
Grubbs catalyst (2nd generation) (0.6 g, 0.71 mmol) in dichloromethane (3.6 L) at ambient temperature during the night, and then DMSO (10 mL, 141 mmol) was added. The mixture was stirred for a further 24 hours and concentrated. The residue was purified by
flash chromatography eluting with 9% ethyl acetate in dichloromethane to give the desired yield (2.1 g, 77%) as a yellow solid. MS (DCIINH3) m / z 404.08 (M + NH4) +; 1 H NMR (500 MHz, DMSO-D 6) d ppm 2.71 (g, J = 7.70 Hz, 2 H) 4.58 (d, J = 6.86 Hz, 2 H) 4.65 (,, J = 7.64 Hz, 2 H) 5.17 (s) , 2H) 5.95-6.07 (m, 2H) 6.64 (s, 1 H) 7.81 (s, 1 H) 7.96 (s, 1 H) 10.10 (s, 1 H) 10.79 (s, 1 H).
EXAMPLE 27E 17-Amino-18-chloro-2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacicloheptadecin-7 carbonitrile A mixture of Example 27D (1 g, 2.58 mmole) and 10% Pd / C (50 mg, 0.047 mmole) in THF (250 ml) was stirred under a hydrogen atmosphere at room temperature overnight. The insoluble material was filtered, and the filtrate was concentrated. The residue was purified by flash chromatography eluting with 16% ethyl acetate in dichloromethane to give the desired yield (0.8 g, 80%) as an orange solid. MS (DCI / NH3) m / z 406.11 (M + NH4) +; 1 H NMR (500 MHz, DMSO-D 6) d ppm 1.54-1.59 (m, 2 H) 1.76-1.81 (m, 2 H) 1.90-1.96 (m, 2 H) 4.05 (d, J = 5.49 Hz, 2 H ) 4.55 (l, J = 8.24 Hz, 2 H) 5.19 (s, 2 H) 6.56 (s, 1 H) 7.87 (s, 1 H) 7.95 (s, 1 H) 9.64 (s, 1 H) 10.76 (s) s, 1 H).
EXAMPLE 28 18-Chloro-2-oxo-17-r (pyridin-3-ylmethyl) amino1-2,3,11, 2,13,14-hexahydro-1H.10H-8,4-epiazeno-9,15, 1,3,6-benzodloxatriazacycloheptadecin-7-carbonitrile To a solution of Example 27E (20 mg, 0.0514 mmol) in THF (3 mL) at 0 ° C was added a reaction mixture (Mixture A) of carboxylaldehyde 3. -pyridine (0.022 mL), 3 M H2SO4 (0.203 mL) and meianol (1 mL), followed by the addition of NaBH (4 mg, 0.11 mmol). The reaction mixture was stirred at 0 ° C for 30 minutes and monitored by LC-MS. The addition of Mixture A and NaBH 4 was repeated until the reaction was completed. Saturated NaHCO3 was added to adjust the pH > 7. The precipitates were collected, carefully washed with water, and purified by reverse phase HPLC eluting with the gradient of 0% -70% acetylonitrile in 0.1% TFA aqueous solution. The desired product was produced in 90% yield. MS (DCI / NH3) m / z 480.11 (M + H) +; H NMR (500 MHz, DMSO-De) d ppm 1.45-1.50 (m, 2 H) 1.64-1.69 (m, 2 H) 1.86-1.92 (m, 2 H) 4.01 (i, J = 5.30 Hz, 2 H ) 4.47 (d, J = 6.24 Hz, 2 H) 4.50 (t, J = 8.11 Hz, 2 H) 6.01 (t, J = 6.40 Hz, 1 H) 6.33 (s, 1 H) 7.33 (dd, J = 7.49, 4.37 Hz, 1 H) 7.75-7.77 (m, 1 H) 7.84 (s, 1 H) 7.97 (s, 1 H) 8.43 (dd, J = 4.68, 1.S6 Hz, 1 H) 8.61 (d) , J = 1.87 Hz, 1 H) 9.60 (s, 1 H) 10.75 (s, 1 H).
EXAMPLE 29 18-Chloro-2-oxo-17-r (pyridin-4-yl-methyl) amino1-2.3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1,3, 6- benzodioxatriazacycloheptadecin-7-carbonitrile The desired product was prepared using a similar procedure described in Example 28 by suspending the 3-pyridine carboxylaldehyde with 4-pyridine carboxylaldehyde. MS (ESI) m / z 480.12 (M + H) +, 478.15 (MH) "; 1 H NMR (300 MHz, DMSO-D6) d ppm 1.42-1.53 (m, 2 H) 1.58-1.70 (m, 2 H ) 1.84-1.95 (m, 2 H) 3.96 (í, J = 4.75 Hz, 2 H) 4.53 (í, J = 8.81 Hz, 2 H) 4.60 (d, J = 4.07 Hz, 2 H) 6.23 (s, 1 H) 6.28 (s, br, 1 H) 7.60 (s, 1 H) 7.61 (s, 1 H) 7.96 (s, 2 H) 8.62 (s, 1 H) 8.64 (s, 1 H) 9.63 (s) , 1 H) 10.79 (s, 1 H).
EXAMPLE 30 N- (18-chloro-7-cyano-2-oxo-2,3.11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecin -17-pyridine-2-carboxamide To a solution of Example 27E (10 mg, 0.026 mmol) and pyridine (1 mL) in dichloromethane (5 mL) was added hydrochloric pyridine-2-carbonyl chloride salt (20.7 g). mg, 0.12 mmol) The reaction mixture was stirred at ambient temperature for 2 days The precipitates were collected by filtration and washed with methanol to give the desired product (9.7 mg, 76%) MS (DCI / NH3) m / z 494.15 (M + H) +; 1 H NMR (400 MHz, DMSO-D6) d ppm 1.61-1.70 (m, 2 H) 1.84-1.91 (m, 2 H) 1.94-2.01 (m, 2 H) 4.20 -4.26 (m, 2 H) 4.63 (t,
J = 8.29 Hz, 2 H) 7.73 (m, 1 H) 8.01 (s, 1 H) 8.12 (m, 1 H) 8.20 (m, 1 H) 8.26 (s, 1 H) 8.33 (s, 1 H) 8.77 (d, J = 4.30 Hz, 1 H) 9.96 (s, 1 H) 10.56 (s, 1 H) 10.96 (s, 1 H).
EXAMPLE 31 N- (18-chloro-7-cyano-2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6 -benzodioxatriazac¡cloheptadec¡n-17-il.piridin-4-carboxamide The desired product was prepared (10 mg, 78%) using a similar procedure described in Example 30. MS (ESI) m / z 494.11 (MH) + , 492.12 (MH) -; 1 H NMR (400 MHz, DMSO-D6) 7 ppm 1.58-1.67 (m, 2H) 1.80-1.87 (m, 2H) 1.93-2.01 (m, 2H) 4.19 (dd, J- 5.68, 4.76 Hz, 2H) 4.63 (t, J = 8.29 Hz, 2H) 7.37 (s, 1 H) 7.89 (d, J = 5.52Hz, 2H) 8.01 (s, 1 H) 8.32 (s, 1 H) 8.79-8.81 (m, 2 H) 9.98 (s, 1 H) 10.34 (s, 1 H) 10.97 (s, 1 H).
EXAMPLE 32 2-CI gold-N- (18-cl gold-7-cyan or -2 -oxo -2, 3, 11, 12, 13,14-hexahydro-1 H, 10H-8,4-epiazeno-9 , 15,1,3,6-benzodioxatriazacycloheptadecin-17-yl) isonicotinamide was added to a suspension of Example 27E (34.5 mg,
0. 089 mmol) in dichloromethane (4 mL) under N2 was added anhydrous pyridine (1 mL), followed by the addition of 2-chloro-isonicoyinyl chloride (31.2 mg, 0.18 mmol) in dichloromethane (1 mL). The reaction mixture was stirred at ambient temperature during the
night, and solvenie and pyridine were removed using a vacuum pump. Then the saturated NaHCO3 solution (3 mL) was added. The precipitate was subjected to ionisation, filtered, washed with meianol (2 mLx3), and dried to give the compound of the extract (13.9 mg, 30%). MS (ESI) m / z 526.00 (M-H) '; H NMR (500 MHz, DMSO-D6) d ppm 1.58-1.68 (m, 2H) 1.80-1.87 (m, 2H) 1.93-2.02 (m, 2H) 4.16-4.21 (m, 2H) 4.60-4.66 (m, 2 H) 7.37 (s, 1 H) 7.89 (d, J = 5.30 Hz, 1 H) 7.99 (s, 1 H) 8.02 (s, 1 H) 8.32 (s, 1 H) 8.64 (d, J = 4.99 Hz, 1 H) 9.99 (s, 1 H) 10.45 (s, 1 H) 10.97 (s, 1 H).
EXAMPLE 33 N- (18-chloro-7-cyano-2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecin -17-pyridine-3-carboxamide The compound of the invention (13 mg, 51%) was described, and a similar procedure was used in Example 32 by replacing the 2-chloro-isonicholine chloride with nicoininoyl chloride. ) m / z 491.98 (MH) "; 1 H NMR (300 MHz, DMSO-D6) d ppm 1.57-1.69 (m, 2 H) 1.77-1.89 (m, 2H) 1.91-2.03 (m, 2H) 4.15-4.23 (m, 2H) 4.59-4.69 (m, 2H) 7.39 (s, 1 H) 7.59 (dd, J = 8.14, 5.09 Hz, 1 H) 8.02 (s, 1 H) 8.29-8.36 (m, 2 H) 8.78 (dd, J = 4.92, 1.86 Hz, 1 H) 9.14 (d, J = 1.36 Hz, 1 H) 9.98 (s, 1 H) 10.29 (s, 1 H) 10.99 (s, 1 H).
EXAMPLE 34 - (18-chloro-7-cyanoan-2-oxo-2,3,11,12,13,14-exahydro-1H, 10H-8, 4-epiazeno-9,15,1,3, 6-benzodioxatriazacycloheptadecin-17-Dacetamide A mixture of Example 27E (10 mg, 0.026 mmol) and pyridine (1 mL) in dichloromean (10 mL), acetyl chloride (0.011 mL, 0.154 mmol) was added per trophy. The reaction was allowed to agitate for 3 hours, and meianol (1 mL) was added to quench the reaction.The resulting mixture was concentrated, and the residue was rinsed with a mixture of dichloromethane and methanol to give the desired product (9.8 mg, 89%). solid white cream MS (DCI / NH3) m / z 430.96 (M + H) +, 429.01 (MH) '; 1H NMR (400 MHz, DMSO-D6) d ppm 1.58-1.64 (m, 2 H) 1.78- 1.84 (m, 2 H) 1.90-1.99 (m, 2 H) 2.08 (s, 3 H) 4.11-4.14 (m, 2 H) 4.60 (t, J = 8.29 Hz, 2 H) 7.50 (s, 1 H) ) 7.99 (s, 1 H) 8.22 (s, 1 H) 9.45 (s, 1 H) 9.91 (s, 1 H) 10.91 (s, 1 H).
EXAMPLE 35 N- (18-chloro-7-cyan or-2-oxo-2,3,11,12,13,14-hexahydro-1 H, 10H-8, 4-epiazeno-9,15,1 , 3,6-benzodioxatriazacycloheptadecin-17-yl) -2- (di methylamino) to cet amide The desired yield was prepared by using a similar procedure described in Example 34 substituting acetyl chloride with 2-dimethylacetyl chloride. MS (ESI) m / z 474.10 (M + H) +, 472.02
(M-H) -; 1H NMR (400 MHz, DMSO-D6) d ppm 1.60-1.66 (m, 2 H) 1.80-1.87 (m, 2 H) 1.93-2.00 (m, 2H) 2.87 (s, 6 H) 4.15-4.17 (m , 4H) 4.62
(í, J = 7.98 Hz, 2 H) 7.47 (s, 1 H) 8.01 (s, 1 H) 8.29 (s, 1 H) 9.81 (s, 1 H) 9.96 (s, 1 H) 10.24 (s, 1 H) 10.97 (s, 1 H).
EXAMPLE 36 N- (18-chloro-7-cyano-2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8.4- epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecin -17-yl) -3- (cyclopentylamino) propanamide
EXAMPLE 36A 3-Chloro-N- (18-chloro-7-cyano-2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1 , 3,6-benzodioxatriazacycloheptadecin-17-ippropanamide To a mixture of Example 27E (50 mg, 0.13 mmol) and pyridine (5 mL) in dichloromethane (25 mL) was added 3-chloropropionyl chloride (0.037 mL, 0.39 mmol) ) at 0 ° C. The reaction mixture was stirred at 0 ° C. until Example 27 was completely consumed, the solvent was carefully removed at low temperature (<10 ° C) to provide the unpurified product, which was used directly for the next stage.
EXAMPLE 36B N-M8-chloro-7-cyano-2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6- benzodioxatriazacycloheptadecin-17-yl) -3- (cyclopentylamino) propanamide A mixture of Example 36A (0.13 mmol) was heated and
Cyclopentylamine (3 mL) at 80 ° C lasted 1 hour and concentrated. The residue was purified by reverse phase HPLC eluting with the gradient from 0% -70% acetonitrile in 0.1% TFA aqueous solution to give the desired product (TFA salt, 66.8 mg, 80% during two steps). MS (ESI) m / z 528.07 (M + H) +, 526.16 (MH) "; 1 H NMR (400 MHz, DMSO-De) d ppm 1.50-1.66 (m, 8 H) 1.66-1.74 (m, 2 H ) 1.79-1.87 (m, 2 H) 1.92-2.03 (m, 4 H) 2.82-2.85 (m, 2 H) 3.21 (m, 1 H) 3.52 (m, 1 H) 4.13 (í, J = 4.30 Hz , 2 H) 4.61 (í, J = 7.98 Hz, 2 H) 7.53 (s, 1 H) 8.01 (s, 1 H) 8.26 (s, 1 H) 8.40 (s, br, 1 H) 9.76 (s, 1 H) 9.93 (s, 1 H) 10.94 (s, 1 H).
EXAMPLE 37 N- (18-chloro-7-cyan 0-2-0X0-2.3, 11, 12, 13,14-hexah id ro-1H, 10 H-8, 4- epiazeno-9,15,1 , 3,6-benzodioxatriazacycloheptadecin-17-yl) -3-rcyclohexyl (methyl) aminolpropanamide The desired product was prepared (66.2 mg, 76% over two steps) using a similar procedure described in Example 36 replacing cyclopenylamine with N-methyleneamino-hexane. . MS (ESI) m / z 556.14 (M + H) +, 554.16 (MH) "; 1 H NMR (400 MHz, DMSO-D6) d ppm 1.14 (m, 1 H) 1.22-1.35 (m, 2 H) 1.38 -1.51 (m, 2 H) 1.57-1.66 (m, 3 H) 1.78-1.88 (m, 4 H) 1.92-2.01 (m, 4H) 2.74 (d, J = 4.91 Hz, 3H) 2.92 (t, J = 6.44 Hz, 2 H) 3.19-3.32 (m, 2H) 3.50 (m, 1 H) 4.09-4.16 (m, 2H) 4.58-4.65 (m, 2H) 7.51 (s, 1 H) 8.01 (s, 1 H) 8.26 (s, 1 H) 9.12 (s, 1 H) 9.76 (s, 1 H) 9.93 (s, 1 H) 10.94 (s, 1 H).
EXAMPLE 38 N- (18-chloro-7-cyano-2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6 -benzodioxatriazacycloheptadecin-17-D methanesulfonamide To a solution of Example 27E (20 mg, 0.051 mmol) and pyridine (3 mL) in dichloromethane (10 mL) methanesulfonyl chloride (0.016 mL, 0.24 mmol) at 0 ° C was added. The reaction mixture was stirred 6 hours, and saturated NaHCO3 was added to adjust the pH value to 9. The precipitate was collected by filtration and washed with water completely, purified by reverse phase HPLC to give the desired product (20.2 mg, 85 mg). %) MS (DCI / NH3) m / z 484.06 (M + H) +; 1 H NMR (400 MHz, DMSO-D6) d ppm 1.66-1.73 (m, 2 H) 1.87-1.93 (m, 2 H) 1.98-2.06 (m, 2H) 3.10 (s, 3H) 4.24 (t, J = 5.22 Hz, 2 H) 4.68 (í, J = 7.98 Hz, 2 H) 7.19 (s, 1H) 8.07 (s, 1 H) ) 8.35 (s, 1 H) 9.48 (s, 1 H) 10.01 (s, 1 H) 11.02 (s, 1 H).
EXAMPLE 39 N- (18-chloro-7-cyano-2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecin -17-yl) -6- morpholin-4-yl iridin-3-sulfonamide The desired product (23.7 mg, 75%) was prepared using a similar procedure described in Example 38 substituting methanesulfonyl chloride with 6-morpholine chloride. -4-yl-pyridin-3-sulfonyl. MS (ESI) m / z 615.03 (M + H) +, 613.06 (MH) "; 1 H NMR (500 MHz, DMSO-De) d ppm 1.60-1.65 (m, 2 H) 1.77-1.83 (m, 2 H ) 1.91-
1. 98 (m, 2 H) 3.59 (i, J = 5.30 Hz, 4 H) 3.67 (t, J = 5.30 Hz, 4 H) 4.07 (i, J = 4.99 Hz, 2 H) 4.60 (t, J = 8.11 Hz, 2H) 6.90 (d, J = 9.05 Hz, 1 H) 6.97 (s, 1 H) 7.71 (dd, J = 9.05, 2.50 Hz, 1 H) 7.99 (s, 1 H) 8.17 (s, 1 H 8.29 (d, J = 2.50 Hz, 1 H) 9.73 (s, 1 H) 9.90 (s, 1 H) 10.93 (s, 1 H).
EXAMPLE 40 N- (18-chloro-7-cyano-2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6 -benzodioxatriazacycloheptadecin-17-yl, -2,2,2-trifluoroethanesulphonamide The desired yield (22 mg, 80%) was prepared by using a similar procedure described in Example 38 with the addition of measulfonyl chloride with 2,2,2-dihydrochloride. urea (ESI) m / z 532.99 (MH) "; 1 H NMR (500 MHz, DMSO-D6) d ppm 1.61-1.67 (m, 2H) 1.81-1.86 (m, 2H) 1.93-1.99 (m, 2H ) 4.20 (í, J = 4.99 Hz, 2H) 4.53 (q, J = 9.67 Hz, 2 H) 4.62 (f, J = 8.11 Hz, 2 H) 7.14 (s, 1 H) 8.01 (s, 1 H) 8.31 (s, 1 H) 9.97 (s, 1 H) 10.14 (s, 1 H) 10.97 (s, 1 H).
EXAMPLE 41 N- (18-chloro-7-cyan or-2-oxo-2,3,11.12, 13, 4-hexah-dro-1 H.10H-8, 4- epiazeno-9,15,1,3 , 6-benzodioxatriazacicheheptadecin-17-yl) -4-fluorobenzenesulfonamide The desired yield was prepared (18.3 mg, 65%) using a similar procedure described in Example 38 suspending the measulfonyl chloride with 4-fluorobenzenesulfonyl chloride. MS
(ESI) m / z 545.00 (M-H) '; 1H NMR (500 MHz, DMSO-D6) d ppm 1.59-1.65 (m, 2 H) 1.77-1.82 (m, 2H) 1.91-1.97 (m, 2H) 4.06 (I, J = 4.99 Hz, 2 H) 4.60 (,, J = 7.80 Hz, 2H) 6.94 (s, 1 H) 7.39-7.43 (m, 2 H) 7.74-7.78 (m, 2 H) 7.99 (s, 1 H) 8.17 (s, 1 H) 9.91 (s, 1 H) 10.00 (s, 1 H) 10.94 (s, 1 H).
EXAMPLE 42 N- (18-chloro-7-cyano-2-oxo-2,3, 11, 12, 13,14-hexah id ro-1H, 10 H-8, 4- epiazeno-9,15,1 , 3,6-benzodioxatriazacycloheptadecin-17-yl) -4- (trifluoromethoxy) benzenesulfonamide The desired yield was prepared (17.6 mg, 56%) using a similar procedure described in Example 38 by suspending methylene sulfonyl chloride with 4-trifluoromethioxybenzenesulfonyl chloride. . MS (ESI) m / z 610.98 (MH) "; 1 H NMR (500 MHz, DMSO-De) d ppm 1.59-1.64 (m, 2 H) 1.75-1.80 (m, 2 H) 1.91-1.97 (m, 2 H) 4.02 (,, J = 4.99 Hz, 2 H) 4.60 (,, J = 8.11 Hz, 2 H) 6.87 (s, 1 H) 7.57 (d, J = 8.73 Hz, 2 H) 7.83 (d, J = 8.73 Hz, 2 H) 7.99 (s, 1 H) 8.18 (s, 1 H) 9.91 (s, 1 H) 10.11 (s, 1 H) 10.94 (s, 1 H).
EXAMPLE 43 18-Chloro-17- (3-hydroxyprop-1-ynyl) -2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15, 1,3,6-benzodioxatriazacicloheptadecin-7-carbonitrilo
EXAMPLE 43A
Trifluoromethanesulfonate of 18-chloro-7-cyano-2-oxo-2,3,11,12,13,14-hexa idro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacicloheptadecin-17 -yl To a mixture of Example 10H (100 mg, 0.26 mmole) and triethylamine (0.039 mL, 0.28 mmole) in DMF (5 mL) was added at 0 ° C frifluoromeansulfonyl chloride (0.03 mL, 0.28 mmole). The reaction mixture was stirred at 0 ° C for 30 minutes, and water with ice was added to expel the reaction. The resulting mixture was concentrated, and the residue was purified by insanitary vapor chromatography eluting with 9% ethyl acetate in dichloromethane. The desired product (110 mg, 82%) was obtained as a white solid. MS (ESI)
520. 58 (M-H) -; 1 H NMR (400 MHz, DMSO-D6) d ppm 1.61-1.67 (m.2H)
1. 81-1.87 (m.2H) 1.92-1.99 (m, 2H) 4.24 (í, J = 5.22 Hz, 2 H) 4.61 (t,
J = 7.98 Hz, 2 H) 7.38 (s, 1 H) 8.01 (s, 1 H) 8.46 (s, 1 H) 10.03 (s, 1 H) 11.06 (s, 1 H).
EXAMPLE 43B 18-Chloro-2-oxo-17-r3- (tetrahydro-2H-pyran-2-yloxy) prop-1-inip-2,3,11,12,13,14-hexahydro-1H, 10H-8 , 4-epiazene-9,15,1,3,6-benzodioxatriazacycloheptadecin-7-carbonitrile was added to a mixture of Example 43A (270 mg, 0.52 mmol), 2-prop-2-inyoxytetrahydropyran (0.436 mL, 3.10 mmol) , triethylamine
(0.217 mL, 1.56 mmol) and (PPh3) 4Pd (180 mg, 0.156 mmol) in
DMF Cul (20 mg, 0.10 mmol), followed by the addition of N-Bu4NI (288 mg, 0.78 mmol). The reaction mixture was heated to 70 ° C
during the night, it cooled and concentrated. The residue was purified by flash chromatography eluting 9% ethyl acetate in dichloromethane to give the desired product (160 mg, 60%) creamy white solid. MS (ESI) m / z 510.02 (MH) "; 1 H NMR (500 MHz, DMSO-D6) d ppm 1.44-1.55 (m, 4H) 1.59-1.65 (m, 2H) 1.66-1.76 (m, 2H) 1.78 -1.83 (m, 2H) 1.90-1.96 (m, 2H) 3.48 (m, 1H) 3.76 (m, 1H) 4.21 (t, J = 4.99 Hz, 2H) 4.43-4.54 (m, 2H) 4.60 (d, J = 8.11 Hz, 2H) 4.85 (t, J = 2.96 Hz, 1H) 7.26 (s, 1H) 7.98 (s, 1H) 8.31 (s, 1H) 9.99 (s, 1H) 10.98 (s, 1H).
EXAMPLE 43C 18-Chloro-17- (3-hydroxyprop-1-ynyl) -2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15, 1,3,6-benzodioxatriazacycloheptadecin-7-carbonitrile A mixture of Example 43B (6 mg, 0.014 mmol) was heated,
HOAc (2 mL), THF (1 mL) and water (0.5 mL) at 45 ° C for 3 hours and concentrated. The residue was suspended in methanol, and the precipitates were collected by filtration. The desired product was obtained as a white solid in quantitative yield. MS (ESI) m / z 425.95 (M-H) '; 1H NMR (400 MHz, DMSO-D6) d ppm 1.54-1.67 (m, 2H) 1.74-1.83 (m, 2H) 1.85-1.98 (m, 2H) 4.19 (s, br, 2H) 4.35 (d, J = 5.83 Hz, 2H) 4.58 (s, br, 2H) 5.37 (t, J = 5.98 Hz, 1H) 7.26 (s, 1H) 7.94 (s, 1H) 8.31 (s, 1H) 10.01 (s, 1H) 10.99 ( s, 1H).
EXAMPLE 44 18-Chloro-2-oxo-17-T3- (teti rahi dro-2H- • pyran-2-yloxy) propyl II- 2.3 .11.12. , 13. , 14-hexahydro-1H, 10H -8,4-epiazeno-9,15,1,3,6-benzodioxatriazacyl loheptadec-7-carbonitrile A mixture of Example 43B (45 mg, 0.088 mmol) and P P was stirred. / C (5%, 20 mg) in THF (5 mL) under hydrogen aminosphere (2.812 kg / cm2) for 16 hours. The insoluble materials were filtered, and the filtrate was concentrated. The residue was purified by flash chromatography eluting with 9% ethyl acetate in dichloromethane to give the desired yield (36 mg, 80%). MS (ESI) m / z 513.93 (MH) "; 1H NMR (400 MHz, DMSO-D6) d ppm 1.38-1.53 (m, 4H) 1.56-1.65 (m, 3H) 1.71 (m, 1H) 1.77-1.86 (m, 4H) 1.88-1.98 (m, 2H) 2.65-2.77 (m, 2H) 3.31-3.45 (m, 2H) 3.62-3.78 (m, 2H) 4.17-4.21 (m, 2H) 4.54 (m, 1H ) 4.60 (,, J = 8.29 Hz, 2H) 7.08 (s, 1H) 7.97 (s, 1H) 8.17 (s, 1H) 9.88 (s, 1H) 10.87 (s, 1H).
EXAMPLE 45 18-CI gold-17- (3-h id roxi pro pil) -2-0X0-2,3,11,12, 13,14-hexah idro- 1H, 10H-8,4-epiazeno-9, 15,1,3,6-benzodioxatriazacycloheptadecin-7-carbonitrile A mixture of Example 44 (10 mg, 0.019 mmol), HOAc (4 mL), THF (2 mL) and water (1 mL) was heated to 45 °. C overnight and concentrated. The residue was purified by reverse phase HPLC to give the desired yield (7 mg, 85%). MS (ESI) m / z 430.07 (M-H) '; 1 H NMR (400 MHz, DMSO-D6) d ppm 1.59-1.65 (m, 2H)
1. 67-1.75 (m, 2H) 1.79-1.86 (m, 2H) 1.91-1.99 (m, 2H) 2.68 (í, J = 7.98 Hz, 2H) 3.42-3.47 (m, 2H) 4.19 (í, J = 4.91 Hz, 2H) 4.50 (í, J = 5.22Hz, 1H) 4.61 (t, J = 7.98 Hz, 2H) 7.07 (s, 1H) 7.99 (s, 1H) 8.16 (s, 1H) 9.89 (s, 1H) 10.90 (s, 1H).
EXAMPLE 46 18-Chloro-17- (2,3-dihydroxypropyl) -2-oxo-2,3,11,12,13,14-hexahydro-1 H, 10H-8,4-epiazeno-9,15 , 1,3,6-benzodioxatriazacicloheptadecin- 7-carbonitrilo
EXAMPLE 46A 17-Allyl-18-chloro-2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecin- 7- carbonitrile It was added to a mixture of Example 43A (50 mg, 0.096 mmol),
PdCI2 (PPh3) 2 (8.1 mg, 0.0115 mmole), Ph3P (15.1 mg, 0.058 mmole) and LiCl (32.6 mg, 0.77 mmole) in DMF (2 mL) ilobutadil (0.059 mL, 0.192 mmol). The reaction mixture was heated at 110 ° C for 1 hour and cooled. Aqueous saturated potassium fluoride solution (1 mL) was added. The mixture was stirred for 30 min and concentrated. The residue was purified by flash chromatography eluting with 9% ethyl acetate in dichloromethane to give the desired product (26 mg, 65%) creamy white solid. MS (ESI) m / z 411.98 (MH) "; 1 H NMR (400 MHz, DMSO-D6) d ppm 1.56-1.65 (m, 2H) 1.75-1.84 (m, 2H) 1.90-1.98 (m, 2H) 3.42 (d,
J = 6.14 Hz, 2H) 4.16 (í, J = 4.30 Hz, 2H) 4.60 (t, J = 7.98 Hz, 2H) 5.05-5.09 (m, 2H) 5.83-6.01 (m, 1H) 7.07 (s, 1H) 7.98 (s, 1H) 8.19 (s, 1H) 9.90 (s, 1H) 10.90 (s, 1H).
EXAMPLE 46B 18-Chloro-17- (2,3-di hydroxy propi I) -2-oxo-2,3, 11,12,13,14-hexah idro- 1H, 10H-8,4-e iazeno-9,15,1 , 3,6-benzodioxatriazacycloheptadecin-7-carbonitrile A mixture of Example 46A (10 mg, 0.024 mmol), THF (5 mL) and water (0.55 mL), and N-methylmorpholine-N-oxide (8.4 mg,
0. 072 mmol), followed by the addition of 2.5% (% by weight) of OsO4 in 2-mephyl-2-propanol (0.04 mL) at 0 ° C. The reaction mixture was stirred at room temperature overnight and concentrated. The residue was purified by HPLC eluting with the gradient from 0% -70% acetonitrile in 0.1% TFA aqueous solution. The desired production (9.3 mg, 85%) was obtained as a white solid. MS (ESI) m / z 445.99 (M-H) "; 1 H NMR (400 MHz, DMSO-D6) d ppm 1.56-1.66 (m,
2H) 1.78-1.86 (m, 2H) 1.90-2.00 (m, 2H) 2.54-2.62 (m, 2H) 2.89 (dd,
J = 13.96, 4.76 Hz, 2H) 3.70 (m, 1H) 4.17 (t, J = 4.91 Hz, 2H) 4.61 (t, J = 8.29 Hz, 2H) 7.10 (s, 1H) 8.00 (s, 1H) 8.16 (s, 1H) 9.90 (s, 1H)
. 90 (s, 1H).
EXAMPLE 47 18-Chloro-17- (3-hydroxy-3-methylbut-1-ynyl) -2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9, 15,1,3,6-benzodioxatriazacycloheptadecin-7-carbonitrile The desired product (22 mg, 50%) was prepared using a similar procedure described in Example 43B by suspending 2-prop-2-inloxytetrahydropyran with 2-methyl-buf. -3-in-2-oI. MS (ESI) m / z 454.03 (M-H) -; 1H NMR (500 MHz, DMSO-D6) d ppm 1.49 (s, 6 H) 1.60-1.66 (m, 2H) 1.79-1.84 (m, 2H) 1.91-1.97 (m, 2H) 4.21 (í, J = 4.88 Hz, 2H) 4.61 (í, J = 7.93 Hz, 2H) 5.50 (s, 1H) 7.17 (s, 1H) 8.00 (s, 1H) 8.31 (s, 1H) 9.99 (s, 1H) 11.01 (s, 1H) ).
EXAMPLE 48 18-Chloro-17- (3-htdrox_b ?? t-1-ynyl) -2-oxo-2,3,11,12,13,14-hexahydro-1 H, 10H-8,4-epiazeno- 9,15,1,3,6-benzodioxatriazacycloheptadecin-7-carbonitrile The desired product (25 mg, 60%) was prepared using a similar procedure described in Example 43B by substituting 2-prop-2-inloxytetrahydropyran with buí-3- in-2-ol MS (ESI) m / z 439.97 (M-H) -; 1H NMR (500 MHz, DMSO-D6) d ppm 1.41 (d, J = 6.71 Hz, 3H) 1.60-1.66 (m, 2H) 1.79-1.84 (m, 2H) 1.91-1.97 (m, 2H) 4.21 (i , J = 5.19 Hz, 2H) 4.59-4.66 (m, 3H) 5.51 (d, J = 5.19 Hz, 1H) 7.21 (s, 1H) 8.00 (s, 1H) 8.31 (s, 1H) 10.00 (s, 1H) 11.01 (s, 1H).
EXAMPLE 49 18-Chloro-17-y3- (diethylamino) prop-1-ynyl-2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1 , 3,6-benzodioxatriazacycloheptadecin-7-carbonitrile The desired product (66% yield) was prepared by using a similar procedure described in Example 43B substituting 2-prop-2-inloxy-yrahydropyran with diethylamino-2-propyne. MS (ESI) m / z 482.50 (M + H) +, 481.1 (MH) "; 1 H NMR (400 MHz, DMF-D7) d ppm 1.40 (λ, J = 7.21 Hz, 5 H) 1.72-1.79 (m , 2H) 1.90-1.96 (m, 2H) 2.00-2.09 (m, 2H) 3.48 (q, J = 7.21 Hz, 4H) 4.31 (í, J = 4.91 Hz, 2H) 4.53 (s, 2H) 4.75 (í , J = 7.98 Hz, 2H) 7.44 (s, 1H) 8.18 (s, 1H) 8.50 (s, 1H) 10.16 (s, 1H) 11.00 (s, 1H).
EXAMPLE 50 18-Chloro-17-r3- (dimethylamido) prop-1-in i p-2-oxo-2,3,11,12,13,14-hexahydro-1 H.10H-8,4-epiazeno-9 , 15.1, 3,6-benzodioxatriazacycloheptadecin-7-carbonitrile The desired yield (45% yield) was prepared by using a similar procedure described in Example 43B by suspending 2-prop-2-inloxytetrahydropyran with dimethylamino-2-propyne. MS (ESI) m / z 454.8 (M + H) +; 1 H NMR (500 MHz, DMSO-D.) D ppm 1.61-1.67 (m, 2H) 1.80-1.85 (m, 2H) 1.92-1.98 (m, 2H) 2.89 (s, 6 H) 4.23 (,, J = 4.88 Hz, 2H) 4.36 (s, 2H) 4.63 (í, J = 7.93 Hz, 2H) 7.37 (s, 1H) 8.01 (s, 1H) 8.37 (s, 1H) 10.05 (s, 1H) 11.05 (s, 1 HOUR).
EXAMPLE 51 18-Chloro-17- (d-methylamino) -2 -oxo -2, 3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1, 3 , 6-benzodioxatriacycloheptadecin-7-carbonitrile A mixture of formaldehyde (0.0345 mL, 0.463 mmol), 3 M H2SO4 (0.05) was added to a solution of Example 27E (36 mg, 0.0925 mmol) in THF (6 mL) at 0 ° C. mL) and THF (0.5 mL), followed by the addition of NaBH (11 mg, 0.28 mmol). The reaction mixture was stirred at 0 ° C for 3 hours. Sacred NaHCO3 was added to adjust the pH > 7. The precipitates were collected, washed with water completely, and purified by reverse phase HPLC eluting with the gradient from 0% -70% acetoniiril in 0.1% TFA aqueous solution. The desired product (33 mg, 86%) was obtained as a yellow solid. MS (ESI) m / z 415.35 (M-H) '; 1H NMR (400 MHz, DMSO-D6) d ppm 1.34-1.41 (m, 2H) 1.55-1.61 (m, 2H) 1.66.-1.76 (m, 2H) 2.49 (s, 6 H) 3.97 (i, J = 5.06 Hz, 2H) 4.37 (f, J = 7.98 Hz, 2H) 6.62 (s, 1H) 7.74 (s, 1H) 7.88 (s, 1H) 9.59 (s, 1H) 10.62 (s, 1H).
EXAMPLE 52 18-Chloro-17- (diethylamino) -2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1,3, 6-benzodioxatriazacycloheptadecin-7-carbonitrile To a solution of Example 27E (20 mg, 0.051 mmol) in THF (5 mL) at 0 ° C was added a mixture of acetylaldehyde (0.014 mL, 0.255 mmol), 3 M H2SO4 (0.034 mL). ) and THF (0.5 mL), followed by
addition of NaBH 4 (7.7 mg, 0.20 mmol). The reaction mixture was stirred at 0 ° C for 1 hour. Saturated NaHCO3 was added to adjust the pH > 7. The mixture was concentrated, and the precipitates were collected, washed with water completely, and dried to give the desired yield (22 mg, 97%) as a yellow solid. MS (DC1 / NH3) m / z 445.16 (M + H) +; 1H NMR (500 MHz, DMSO-D6) d ppm 0.96 (,, J = 7.02 Hz, 6 H) 1.57-1.64 (m, 2H) 1.79-1.84 (m, 2H) 1.92-1.99 (m, 2H) 3.06 ( q, J = 7.02 Hz, 4H) 4.20 (t, J = 4.88 Hz, 2H) 4.61 (i, J = 7.93 Hz, 2H) 6.89 (s, 1H) 7.98 (s, 1H) 8.15 (s, 1H) 9.83 (s, 1H) 10.90 (s, 1H).
EXAMPLE 53 18-Cory-2-oxo-17-piperidin-1-yl-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1,3, 6-Benzodioxatriazacycloheptadecin-7-carbonitrile The desired product (22 mg, 94%) was prepared using a similar procedure described in Example 52 by replacing the acetylaldehyde with glucaraldehyde. MS (DCI / NH3) m / z 457.18 (M + H) +; 1H NMR (500 MHz, DMSO-D6) d ppm 1.50-1.56 (m, 2H) 1.58-1.63 (m, 2H) 1.63-1.68 (m, 4H) 1.79-1.84 (m, 2H) 1.92-1.98 (m, 2H) 2.92 (t, J = 4.68 Hz, 4H) 4.21 (,, J = 4.99 Hz, 2H) 4.61 (,, J = 8.11 Hz, 2H) 6.82 (s, 1H) 7.98 (s, 1H) 8.13 (s) , 1H) 9.82 (s, 1H) 10.86 (s, 1H).
EXAMPLE 54 18-Chloro-17- (isobuylamino) -2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6 -benzodioxatriazacycloheptadecin-7-carbonitrile The desired yield (12.8 mg, 52%) was prepared by using a similar procedure described in Example 28 by replacing 3-pyridine carboxylaldehyde with isobuylaldehyde. MS (APCl) m / z 445.42 (M + H) +; 1H NMR (500 MHz, DMSO-D6) d ppm 0.92 (d, J = 6.41 Hz, 6 H) 1.54-1.61 (m, 2H) 1.78-1.83 (m, 2H) 1.87-1.99 (m, 3H) 2.99 ( i, J = 6.56 Hz, 2H) 4.18 (t, J = 5.19 Hz, 2H) 4.57 (l, J = 8.24 Hz, 2H) 5.08 (í, J = 5.95 Hz, 1H) 6.39 (s, 1H) 7.93 ( s, 1H) 7.97 (s, 1H) 9.68 (s, 1H) 10.78 (s, 1H).
EXAMPLE 55 17-Chloro-11,12-dihydroxy-2-bear-2,3,10,11,12,13-hexahydro-1H-8,4-epiazeno-9,14,1,3,6-benzodioxatriazacyclohexadecin- 7- carbonitrile
EXAMPLE 55A N-r6- (Allyloxy) -5-cyanopyrazin-2-ip-N '- (5-chloro-2-hydroxyl in Purea) The compound of the oligonucleotide was prepared using a similar procedure described in Example 88A, replacing Example 7F with Example 83B, MS (DCI) m / z 346.19 (M + H) +.
EXAMPLE 55B N-f2- (allyloxy) -5-chlorophenip-N'-f6- (allyloxy) -5-cyanopyrazin-2-ipurea It was added to a solution of Example 55A (456 mg, 1.32 mmol) in anhydrous hydroalide (18). mL) pyridylphosphine supported by polymer (659.5 mg, 1.98 mmol), di-butryl azodicarboxylate (455.5 mg, 1.98 mmol), and allyl alcohol (76.6 mg, 1.32 mmol). The reaction mixture was screened at room temperature for 5 hours. The solution was filtered, dried with silica gel powder (10 g), and purified by flash chromatography eluting with 20% ethyl acetate in hexanes (2 L) to give the title compound (140.8 mg, 28%). MS (ESI) m / z 385.95 (M + H) +; 1 H NMR (500 MHz, DMSO-De) d ppm 4.71 (d, J = 5.62 Hz, 2H) 4.95 (d, J = 5.30 Hz, 2H) 5.29-5.36 (m, 2H) 5.40-5.48 (m, 2H) 6.00-6.16 (m, 2H) 7.04-7.10 (m, 2H) 8.20 (d, J = 2.50 Hz, 1H) 8.88 (s, 1H) 9.05 (s, 1H) 10.71 (s, 1H).
EXAMPLE 55C 17-Chloro-2-oxo-2,3,10,13-tetrahydro-1H-8,4-epiazeno-9,14,1,3,6-benzodioxatriazacyclohexadecin-7-carbonitrile Example 55B was dissolved (140 mg, 0.36 mmole) in dichloromethane (200 mL). The 2nd Generation Grubbs Catalyst (46 mg, 0.054 mmol) was added. The solution was purged with N2 for 10 minutes, and heated at 40 ° C overnight. The reaction mixture was concentrated, and dried with silica gel powder (5 g). The residue was purified by instantaneous vaporization chromatography
eluting with 5% acetyl ether in dichloromethane (1L) and then with 20% ethanoyl acetate in dichloromethane (1L) to give the desired product (70 mg, 54%). MS (ESI) m / z 355.99 (MH) "; 1 H NMR (400 MHz, DMSO-D6) d ppm 4.71 (d, J = 3.38 Hz, 2H) 5.56 (d, J = 4.91 Hz, 2H) 5.85-5.89 (m, 2H) 7.12 (m, 1H) 7.18 (m, 1H) 7.98 (s, 1H) 8.31 (d, J = 2.45 Hz, 1H) 10.91 (s, 1H) 11.00 (s, 1H).
EXAMPLE 55D 17-Chloro-11,12-dihydroxy-2-oxo-2,3,10,11,12,13-hexahydro-1H-8,4-epiazeno-9,14,1,3,6-benzodioxatriazacyclohexadecin-7 carbonitrile Example 55C (70 mg, 0.20 mmol) was dissolved in teirahydrofuran (27 mL) and water (3 mL). 4-Methylmorpholine N-oxide (34.3 mg, 0.29 mmol) and OsO4 (2.5% in tert-butanol) (99.5 mg, 0.01 mmol) were added. The reaction ran at room temperature during the night. Then the solveníes were eliminated. The residue was dissolved in DMSO / meianol (1/1, 8 mL) and purified by HPLC to give the product of the tíulo (26.7 mg, 35%). MS (ESI) m / z 389.98 (MH) "; 1 H NMR (500 MHz, DMSO-D6) d ppm 4.00-4.09 (m, 2H) 4.17-4.31 (m, 3H) 5.19 (dd, J = 11.14, 4.12 Hz, 1H) 5.33 (dd, J = 16.63, 5.03 Hz, 2H) 7.11 (dd, J = 8.85, 2.44 Hz, 1H) 7.25 (d, J = 8.85 Hz, 1H) 8.00 (s, 1H) 8.33 (d , J = 2.44 Hz, 1H) 10.68 (s, 1H) 10.98 (s, 1H).
EXAMPLE 56 18-CI gold-17- (methylamino) -2-oxo-2,3, 11, 12, 13,14-hexahydro-1H, 10 H- 8,4-epiazeno-9,15,1,3 , 6-benzodioxatriazacycloheptadecin-7-carbonitrile The desired production (7.7 mg, 25%) was prepared using a similar procedure described in Example 28 by replacing the carboxylaldehyde of 3-pyridine with formaldehyde. MS (APCl) m / z 403.24 (M + H) +; 1H NMR (400 MHz, DMSO-D6) d ppm 1.54-1.62 (m, 2H) 1.78-1.85 (m, 2H) 1.92-2.00 (m, 2H) 2.78 (s, 3H) 4.21 (t, J = 5.22 Hz , 2H) 4.58 (f, J = 8.29 Hz, 2H) 5.33 (s, br, 1H) 6.35 (s, 1H) 7.94 (s, 1H) 7.97 (s, 1H) 9.69 (s, 1H) 10.77 (s, 1 HOUR).
EXAMPLE 57 14-Chloro-11-OXO-2.3.11, 12,18,18a-hexahydro-1 aH.10H-5, 9-epiazenooxirenofpr9,15,1,3,61benzodioxatriazacycloheptadecin-6-carbonitrile Example 7 was dissolved ( 100 mg, 0.27 mmol) in dichloromethane (25 mL). To this solution was added m-CPBA (70% concentration, 658 mg, 2.67 mmol). The reaction mixture was stirred at ambient temperature for 3 days. After the solvenie was eliminated. The mixture was dissolved in aceion (50 mL), and dried with silica gel powder (20 g). 5% ethyl acetate in dichloromethane (1L) and 20% ethyl acetate in dichloromethane (1 L) were used to run in flash chromatography to give the title compound (27.3 mg, 27%). MS (ESI) m / z 385.92 (M-H) "; 1H
NMR (400 MHz, DMSO-D6) d ppm 1.79 (m, 1H) 2.64 (m, 1H) 3.21 (m, 1H) 3.34 (m, 1H) 3.94 (t, J = 9.97 Hz, 1H) 4.45 (m, 1H) 4.79 (dd, j = 10.74, 4.30 Hz, 1H) 5.20 (m, 1H) 7.13 (dd, J = 8.75, 2.61Hz, 1H) 7.23 (d, J = 8.90 Hz, 1H) 7.99 (s, 1H 8.22 (d, J = 2.45 Hz, 1H) 10.46 (s, 1H) 10.99 (s, 1H).
EXAMPLE 58 18-Chloro-11,12- (cis) -di hydroxy-14-methyl-2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno- 9,15,1,3,6-benzodioxatriazacicloheptadecin-7-carbonitrilo
EXAMPLE 58A N-r6- (allyloxy) -5-cyanopyrazin-2-ip-N'-. { 5-chloro-2-r (1-methylbut-3-enyl) oxy-phenyl > urea Example 58A was synthesized using a similar procedure described in Example 55B by replacing the allyl alcohol with pen-4-en-2-ol (260 mg, 40%). MS (ESI) m / z 411.98 (M-H) '; 1H NMR (500 MHz, DMSO-De) d ppm 1.30 (d, J = 5.80 Hz, 3H) 1.95 (m, 1H) 2.38 (m, 1H) 4.61 (m, 1H) 4.96 (d, J = 5.19 Hz, 2H) 5.05-5.18 (m, 2H) 5.32-5.49 (m, 2H) 5.87 (m, 1H) 6.12 (m, 1H) 7.05 (dd, J = 8.70, 2.59 Hz, 1H) 7.14 (d, J = 8.85 Hz, 1H) 8.20 (d, J = 2.75 Hz, 1H) 8.82 (s, 1H) 8.96 (s, 1H) 10.80 (s, 1H).
EXAMPLE 58B (Cis) 18-chloro-14-methyl-2-oxo-2,3,13,14-tetrahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecin-7 carbonitrile Example 58B was synthesized using a similar procedure described in Example 55C replacing Example 55B with Example 58A (113.0 mg, 46%). Esío is the cis isomer. MS (ESI) m / z 383.94 (MH) "; 1 H NMR (500 MHz, DMSO-D6) d ppm 1.19 (d, J = 6.24 Hz, 3H) 2.35 (m, 1H) 2.56 (m, 1H) 4.86 ( m, 1H) 5.16 (d, J = 14.66 Hz, 1H) 5.53 (m, 1H) 5.63 (m, 1H) 5.73 (m, 1H) 7.11 (m, 1H) 7.16 (m, 1H) 8.02 (s, 1H) ) 8.05 (d, J = 2.50 Hz, 1H) 9.75 (s, 1H) 10.90 (s, 1H).
EXAMPLE 58C 18-Chloro-11.12-cis-dihydroxy-14-methyl-2-oxo-2,3,11,12,13,14-hexahydro-1 H, 10H-8,4-epiazeno-9,15,1 , 3,6-benzodioxatriazacicl or heptadecin-7-carbo nitrile Example 58 (16.2 mg, 22%) was synthesized using a similar procedure described in Example 55D replacing Example 55C with Example 58B. MS (ESI) m / z 417.92 (M-H) "; 1 H NMR (400 MHz, DMSO-D 6) d ppm 1.21 (d, J = 6.44 Hz, 3 H) 1.86 (m, 1 H) 1.98 (m, 1 H) 3.93 (m, 1 H) 4.21-4.32 (m, 2 H) 4.80 (d, J = 4.30 Hz, 1H) 4.88 (d, J = 7.67 Hz, 1H) 4.91-5.00 (m, 2H) 7.12 (m, 1H) 7.17 (m, 1H) 7.99 (s, 1H) 8.01 (d , J = 2.45 Hz, 1H) 9.90 (s, 1H) 10.91 (s, 1H).
EXAMPLE 59 18-Chloro-11.12-trans-dihydroxy-14-methyl-2-oxo-2,3,11,12, 13.1-hexahydro-1H, 10H-8,4-epiazeno-9,15,1,3 , 6- benzodioxatriazacicloheptadecin-7-carbonitrilo
EXAMPLE 59A (Trans) 18-chloro-14-methyl-2-oxo-2,3,13,14-tetrahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecin-7 - ca rbon itri I Example 59A was synthesized using a similar procedure described in Example 55C (75.1 mg, 31%). Esío was the trans isomer. MS (ESI) m / z 384.01 (MH) "; 1H NMR (500 MHz, DMSO-D6) d ppm 1.30 (d, J = 6.24 Hz, 3H) 2.20 (m, 1H) 2.46 (m, 1H) 4.67 ( m, 1H) 4.82 (m, 1H) 4.96 (d, J = 14.04 Hz, 1H) 5.58-5.67 (m, 2H) 7.13-7.19 (m, 2H) 7.66 (s, 1H) 7.98 (s, 1H) 9.12 (s, 1H) 10.83 (s, 1H).
EXAMPLE 59B 18-Chloro-11,12-trans-dihydroxy-14-methyl-2-oxo-2,3,11,12,13,14-hexahydro-1H.10H-8,4-epiazeno-9, 15, 1, 3,6-benzodioxatriazacycloheptadecin-7-carbonitrile Example 59 was synthesized using a similar procedure described in Example 55D by replacing Example 55C with the
Example 59A (45.1 mg, 75%). MS (ESI) m / z 417.95 (M-H) "; 1H NMR
(400 MHz, DMSO-D6) d ppm 1.17 (d, J = 5.83 Hz, 3H) 1.76 (m, 1H) 1.99 (m, 1H) 3.74 (m, 1H) 3.91-4.02 (m, 2H) 4.81 (m , 1H) 4.96 (dd,
J = 11.51, 1.99 Hz, 1H) 7.09-7.22 (m, 2H) 8.00 (s, 1H) 8.07 (d, J = 2.45 Hz, 1H) 10.05 (s, 1H) 10.94 (s, 1H).
EXAMPLE 60 18-Chloro-15-methyl-2-oxo-2,3,10,11,12,13,14,15-octahydro-1H-8,4-epiazeno-9,1,3,6,15- benzoxatetraazacycloheptadecin-7-carbonitrile
EXAMPLE 60A N-Allyl-N- (4-chloro-2-nitrophenyl) -N-methylamine 4-Chloro-1-fluoro-2-nitro-benzene (2.53 g, 14.41 mmol) was added dropwise in acetonitrile anhydrous (80 mL), allyl amyl melil (1.64 mL, 17.29 mmol) was stirred. The mixture was heated at 80 ° C overnight, concentrated with silica gel powder (18 g), and purified by flash chromatography eluting with 10% acetyl ether in hexanes (1 L) to give the Compound of the item (3.05 g, 93%). MS (DCI) m / z 227.09 (M + H) +; 1 H NMR (300 MHz, CDCl 3) d ppm 2.80 (s, 3 H) 3.76 (d, J = 5.43 Hz, 2 H) 5.16-5.29 (m, 2 H) 5.85 (m, 1 H) 7.00 (d, J = 9.16 Hz, 1H) 7.33 (dd, J = 8.99, 2.54 Hz, 1H) 7.74 (d, J = 2.71Hz, 1H).
EXAMPLE 60B N-Allyl-N- (2-amino-4-chlorophenyl) -N-methylamine Example 60A (3.05 g, 13.46 mmol), SnCl2.2H2O was heated
(15.18 g, 67.28 mmoles), were mixed with eryrylamine (56 mL, 403.69 mmol), and ethylene (140 mL), and were heated at 70 ° C for 2 hours. The reaction mixture was then cooled. The solution was filtered. The precipitate was washed with methanol (30 mLx3). The combined solution was dried with silica gel powder (15 g). 20% ethanoyl acetate in hexanes (1 L) was used to run in insipheral vaporization chromaphography to give the compound of the extract (1.61 g, 61%). MS (DCI) m / z 196.99 (M + H) +; 1 H NMR (300 MHz, CD 3 OD) d ppm 2.59 (s, 3 H) 3.42 (d, J = 6.44 Hz, 2 H) 5.08-5.29 (m, 2 H) 5.86 (m, 1 H) 6.58 (dd, J = 8.48, 2.37 Hz, 1H) 6.72 (d, J = 2.71Hz, 1H) 6.91 (d, J = 8.48 Hz, 1H).
EXAMPLE 60C N-. { 2-RALILE (Methylamino-1-5-chlorophenyl3-N'-R6- (but-3-enyloxy) -5-cyanopyrazin-2-ylurea) A mixture of Example 60B (0.863 g, 4.39 mmol), Example 7F (FIG. 1.36 g, 4.39 mmol) and anhydrous DMF (40 mL) 70 ° C overnight, the solveny was removed, and 20% ethyl acetate in hexanes (20 mL) was added, the precipitate was subjected to ulysonication, filtered was washed with 20% acetyl ether in hexanes (10 mLx3), and dried to give the title compound (1.2 g, 66%) MS (ESI) m / z 411.07 (MH) "; 1H NMR ( 500 MHz, DMSO-D6) d ppm 2.53-2.57 (m, 2H) 2.58 (s, 3H) 3.49 (d, J = 6.41Hz, 2H) 4.48 (í, J = 6.71Hz, 2H) 5.12 (d, J = 10.07 Hz, 2H) 5.14-5.22 (m, 2H) 5.77-5.93 (m, 2H) 7.07 (dd, J = 8.39.2.59 Hz, 1H) 7.24 (d, J = 8.54 Hz, 1H) 8.19
(d, J = 2.44 Hz, 1H) 8.90 (s, 1H) 9.27 (s, 1H) 10.90 (s, 1H).
EXAMPLE 60D 18-CI gold-15-methyl-2-oxo-2,3,10,11,14,15-hexahydro-1H-8, 4- epiazeno-9,1, 3,6,15 -benzoxatetraazacycloheptadecin-7-carbonitrile Example 60D was synthesized using a similar procedure described in Example 55C replacing Example 55B with Example 60C (0.79 g, 72%). MS (ESI) m / z 383.01 (MH) "; 1H NMR (500 MHz CD2CI2) d ppm 2.52 (s, 3H) 2.72 (q, J = 7.90 Hz, 2H) 3.55 (d, J = 6.86 Hz, 2H) 4.60-4.71 (m, 2H) 5.66 (m, 1H) 5.78 (m, 1H) 7.08-7.15 (m, 2H) 7.86 (s, 1H) 7.99 (d, J = 2.18 Hz, 1H) 8.26 (s, 1H) ) 10.39 (s, 1H).
EXAMPLE 60E 18-Chloro-15-methyl-2-oxo-2,3,10,11,12,13,14,15-octahydro-1H-8,4-epiazeno-9,1,3,6,15- benzoxatetraazacycloheptadecin-7-carbonitrile Example 60D (81.2 mg, 0.21 mmol) was dissolved in tetrahydrofuran (10 mL). 5% Pt / C (5 mg) was added to this solution. The reaction mixture was stirred under a hydrogen atmosphere (2.812 kg / cm2) at room temperature for 2 hours. The solution was filtered, and dried with silica gel powder (5 g). 10% ethanoyl acetate in dichloromethane (1L) was used to run in flash chromatography to give the title compound (69.4 mg,
85%). MS (ESI) m / z 384.79 (MH) "; 1 H NMR (400 MHz, DMSO-D6) d ppm 1.20-1.33 (m, 2H) 1.36-1.48 (m, 2H) 1.77-1.91 (m, 2H) 2.43 (s, 3H) 3.01 (t, J = 5.22 Hz, 2H) 4.49-4.64 (m, 2H) 7.15 (m, 1H) 7.23 (m, 1H) 7.99 (s, 1H) 8.01 (d, J = 2.45 Hz , 1H) 10.00 (s, 1H) 10.93 (s, 1H).
EXAMPLE 61 (Cis) 18-chloro-13-hydroxy-2-oxo-2,3,13,14-tetrahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacícloheptadecin-7 - carbonitrile
EXAMPLE 61A 2- (Tetrahydro-2H-pyran-2-yloxy) but-3-en-1-ol DL-2-hydroxy-3-butenoic acid meliléser (5 g, 43.06 mmol), 3.4- dihydro-2H-pyran (19.6 mL, 215.3 mmol), p-TsOH.H2O (40 mg, 0.22 mmol) and dichloromean (200 mL), and were stirred at ambient temperature for 3 hours. The solution was concentrated. The residue was dried, dissolved in THF (250 mL) at 0 ° C. LiAIH (3.27 g, 86.12 mmol) was added as a portion under N2. The reaction mixture was slowly quenched from 0 ° C to room temperature, stirred overnight and cooled to 0 ° C. H2O (5 mL) was added dropwise by syringe. The solvent was removed under reduced pressure. The residue was extracted with THF (500 mL). The solution was filtered, and dried with silica gel powder (20 g), and purified by flash chromatography eluting with 20% ethyl acetate in hexanes (2 L) to give the title compound.
íífulo (6.80 g, 89%). MS (DCI) m / z 177.44 (M + H) +; 1 H NMR (400 MHz, CDCl 3) d ppm 1.44-1.62 (m, 4 H) 1.71 (m, 1 H) 1.84 (m, 1 H) 3.40-3.62 (m, 3 H) 3.88 (m, 1 H) 4.16 (m, 1 H) 4.62-4.81 (m, 2H) 5.11-5.36 (m, 2H) 5.81 (m, 1H).
EXAMPLE 61B N-r6- (allyloxy) -5-cyanopyrazin-2-ip-N '- (5-chloro-2- 2- (tetrahydro-2H-pyran-2-yloxy) but-3-enyl.oxi phenyl) urea Example 61B was prepared using a similar procedure described in Example 55B by replacing the allyl alcohol with Example 61A (442.7 mg, 77%). MS (ESI) m / z 498.06 (MH) "; 1H NMR (300 MHz, DMSO-D6) d ppm 1.35-1.77 (m, 6 H) 3.39 (m, 1H) 3.76 (m, 1H) 4.10-4.25 ( m, 2H) 4.50 (m, 1H) 4.81 (m, 1H) 4.96 (d, J = 5.09 Hz, 2H) 5.15-5.52 (m, 4H) 5.78-6.20 (m, 2H) 7.04-7.22 (m, 2H 8.15 (d, J = 2.71Hz, 1H) 8.90 (s, 1H) 8.93 (s, 1H) 10.73 (s, 1H).
EXAMPLE 61C 18-Chloro-2-oxo-13- (tetrahydro-2H-pyran-2-yloxy) -2,3,13,14-tetrahydro-1H, 10H-8.4-epiazeno-9, 15, 1.3, 6- benzodioxatriazacycloheptadecin-7-carbonitrile Example 61C was synthesized using a similar procedure described in Example 55C replacing 55B with 61B (144.9 mg, 35%). This production is a mixture of cis and trans isomers. MS
(ESI) m / z 470.17 (MH) "; 1 H NMR (400 MHz, DMSO-D6) d ppm 1.32-1.79 (m, 6H) 3.45 (m, 1H) 3.76 (m, 1H) 4.03 (m, 1H) 4.17-4.46 (m,
H) 4.68 (m, 1H) 4.79-5.06 (m, 2H) 5.23-5.94 (m, 2H) 7.07-7.27 (m, H) 7.99 (s, 1H) 9.16 (s, 1H) 9.66 (s, 1H) 10.89 (s, 1H).
EXAMPLE 61D (Cis) 18-chloro-13-hydroxy-2-oxo-2,3,13,14-tetrahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecin-7 - carbonitrile Example 61C (21 mg, 0.04 mmol) was dissolved in THF (2 mL). Water (1 mL) and glacial acetic acid (4 mL) were added. The reaction mixture was stirred at ambient temperature overnight. The solvents were removed by a vacuum pump. The residue was dissolved in DMSO / meianol (1/1, 3 mL), and separated by HPLC to give the israns and cis isomers. The compound of the isolate was the cis Isomer (1.6 mg, 9%). MS (ESI) m / z 385.80 (MH) "; 1 H NMR (500 MHz, DMSO-De) d ppm 3.84 (t, J = 8.58 Hz, 1H) 4.24 (dd, J = 8.73.4.06 Hz, 1H) 4.59 (m, 1H) 5.38 (m, 1H) 5.46 (d, J = 4.68 Hz, 1H) 5.61 (m, 1H) 6.48 (s, 2H) 7.07-7.22 (m, 2H) 8.03 (s, 1H) 8.25 ( d, J = 2.50 Hz, 1H) 9.77 (s, 1H) 10.93 (s, 1H).
EXAMPLE 62 18-Chloro-11,12,13-trihydroxy-2-oxo-2,3,11,12,13,14-hesahydro-1H.10H-8,4-epiazeno-9,15,1, 3, 6-Benzodioxatriazacycloheptadecin-7-carbonitrile Example 61C (21 mg, 0.044 mmol) was oxidized using a similar procedure described in Example 55D. After the
Oxidation reaction, the solution was concentrated, and the residue was treated with a mixture of acetic acid, THF and water using a similar procedure described in Example 61 to give the title compound (6.3 mg, 34%). MS (ESI) m / z 420.01 (MH) "; H NMR (500 MHz, DMSO-D6) d ppm 3.74 (m, 1H) 3.88-4.03 (m, 2H) 4.12 (m, 1H) 4.21-4.34 (m , 2H) 4.65 (m, 1H) 5.06-5.20 (m, 3H) 7.10-7.27 (m, 2H) 8.00 (s, 1H) 8.27 (d, J = 2.50 Hz, 1H) 10.14 (s, 1H) 10.93 ( s, 1H).
EXAMPLE 63 18-Chloro-13-hydroxy-2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecin- 7- carbonitrile Example 61C (43 mg, 0.091 mmol) was hydrogenated using a similar procedure described in Example 60. The reaction solution was filtered, and concentrated. The residue was mixed with a mixture of acetic acid, THF and water using a similar procedure described in Example 61 to give the compound of the extract.
(2.7 mg, 8%). MS (ESI) m / z 387.96 (M-H) "; H NMR (500 MHz, DMSO-D6) d ppm 1.65 (m, 1H) 1.76 (m, 1H) 1.85 (m, 1H) 2.04 (m, 1H) 3.87
(m, 1H) 4.03 (dd, J = 10.45, 6.71Hz, 1H) 4.21 (dd, J = 10.61, 3.12Hz,
1H) 4.61 (t, J = 7.49 Hz, 1H) 5.03 (d, J = 4.37 Hz, 1H) 7.13 (m, 1H) 7.19
(m, 1H) 8.01 (s, 1H) 8.17 (d, J = 2.50 Hz, 1H) 10.03 (s, 1H) 10.94 (s,
1 HOUR).
EXAMPLE 64 (Trans, trans) 18-chloro-11,12,13-trihydroxy-2-oxo-2, 3,11, 12, 13,14-hexahydro-1H, 10H-8,4-epiazeno-9, 15,1,3,6-benzodioxatriazacicloheptadecin-7-carbonitrilo
EXAMPLE 64A (Trans) 18-chloro-13-hydroxy-2-oxo-2,3,13,14-tetrahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecin-7 carbonitrile Example 61C (200 mg, 0.42 mmol) was discarded using a similar procedure described in Example 61D. The HPLC separation gave the cis and frans isomers. The isomer of the ileum was trans (25.9 mg, 16%). MS (ESI) m / z 386.08 (MH) "; 1 H NMR (500 MHz, DMSO-D.) D ppm 3.97 (dd, J = 9.98, 6.55 Hz, 1H) 4.22 (dd, J = 9.98, 3.74 Hz, 1H) 4.31 (m, 1H) 5.25 (d, J = 5.30 Hz, 1H) 5.63 (m, 1H) 5.81 (m, 1H) 6.48 (s, 2H) 7.12-7.19 (m, 2H) 7.80 (d, J = 1.87 Hz, 1H) 8.02 (s, 1H) 9.16 (s, 1H) 10.85 (s, 1H.).
EXAMPLE 64B (Trans, trans) 18-chloro-11,12,13-trihydroxy-2-oxo-2,3,11,12,13,14-hexahydro-1 H, 10H-8,4-epiazeno-9,15 , 1,3,6-benzodioxatriazacycloheptadecin-7-carbonitrile Example 64A (23.2 mg, 0.06 mmol) was oxidized using a similar procedure described in Example 55D to give the title compound (7.4 mg, 29%). MS (ESI) m / z 419.96 (M-H) "; 1H
NMR (500 MHz, DMSO-D6) d ppm 3.72 (m, 1H) 3.90 (m, 1H) 4.00 (m, 1H) 4.11 (m, 1H) 4.30 (m, 1H) 4.61-4.68 (m, 2H) 4.91 -5.21 (m, 3H) 7.08-7.27 (m, 2H) 7.99 (s, 1H) 8.27 (d, J = 2.50 Hz, 1 H) 10.13 (s, 1H) 10.92 (s, 1H).
EXAMPLE 65 (Trans-cis) 18-chloro-11,12,13-trihydroxy-2-oxo-2,3, 1,12,13,14-hexahydro-1 H, 10H-8,4-epiazeno-9,15 , 1,3,6-benzodioxatriazacycloheptadecin-7-carbonitrile Example 65 (22.3 mg, 61%) was prepared using a similar procedure described in Example 55D by replacing Example 55C with Example 61D. MS (ESI) m / z 419.97 (MH) "; 1H NMR (300 MHz, DMSO-D6) d ppm 3.74 (m, 1H) 3.91-4.00 (m, _2H) 4.18-4.36 (m, 3H) 4.90 (dd) , J = 10.85, 2.37 Hz, 1H) 5.11 (dd, J = 5.26, 2.20 Hz, 2H) 5.18 (d, J = 4.75 Hz, 1H) 7.13-7.18 (m, 2H) 7.99-8.03 (m, 2H) 9.71 (s, 1H) 10.92 (s, 1H).
EXAMPLE 66 18-Bromo-2-oxo-2,3,11,14-tetrahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecin-7-carbonitrile
EXAMPLE 66A 1- (Allyloxy) -4-bromo-2-nitrobenzene To a mixture of anhydrous THF (200 mL) and 95% NaH (757 mg, 29.96 mmole) a 0 ° C under N2 allyl alcohol (2.04) was added. mL,
29. 96 mmoles) in the form of drops. After 0.5 hours, 4-bromo-1-fluoro-2-nitro-benzene (5.07 g, 23.04 mmol) was added in the form of drops. The reaction was heated from 0 ° C to ambient temperature under N2 overnight, and the inorganic salt was filtered. The filtrate was concentrated with silica gel powder (20 g), and purified by flash chromatography eluting with 10% ethyl acetate in hexanes (1 L) and 20% ethyl acetate in hexanes (1 L) to give the compound of the extract (5.06 g, 85%). MS (DCI) m / z 257.35 (M + H) +; 1 H NMR (300 MHz, CDCl 3) d ppm 4.65-4.70 (m, 2 H) 5.35 (m, 1 H) 5.48 (m, 1 H) 6.02 (m, 1 H) 6.97 (d, J = 9.16 Hz, 1 H) 7.61 (dd) , J = 8.99, 2.54 Hz, 1H) 7.97 (d, J = 2.37 Hz, 1H).
EXAMPLE 66B 2- (Allyloxy) -5-bromoaniline A mixture of Example 66A (5.06 g, 19.69 mmol), iron powder (11.02 g, 196.9 mmol), NH 4 C (0.53 g, 9.85 mmol), ethanol (160 mL) were heated. ), and water (40 mL) at 80 ° C last 6 hours. The solution was filtered, concentrated with silica gel powder (18 g), and purified by flash chromatography eluting with 10% ethyl acetate in hexanes (1L) to give the title compound (4.53 g, 97%). %). MS (DCI) m / z 227.91 (M + H) +; 1 H NMR (300 MHz, CDCl 3) d ppm 4.54 (d, J = 5.43 Hz, 2H) 5.29 (dd, J = 10.51, 1.36 Hz, 1H) 5.40 (dd, J = 17.46, 1.53 Hz, 1H) 6.09 (m , 1H) 6.65 (d, J = 8.48 Hz, 1H) 6.84 (m, 1H) 6.91 (d, J = 2.37 Hz, 1H).
EXAMPLE 66C N-f2- (allyloxy) -5-bromophenip-N'-r6- (but-3-enyloxy) -5-cyano irazin-2-illurea Example 66C (3.97 g, 100%) was prepared using a procedure similar described in Example 60C replacing Example 60B with Example 66B. MS (ESI) m / z 441.94 (MH) "; 1H NMR (300 MHz, DMSO-D6) d ppm 2.52-2.59 (m, 2H) 4.46 (t, J = 6.61 Hz, 2H) 4.71 (d, J = 5.42 Hz, 2H) 5.07-5.23 (m, 2H) 5.31 (dd, J = 10.51, 1.70 Hz, 1H) 5.43 (dd, J = 17.29, 1.70 Hz, 1H) 5.88 (m, 1H) 6.08 (m, 1H ) 7.03 (d, J = 8.81 Hz, 1H) 7.19 (dd, J = 8.65, 2.54 Hz, 1H) 8.32 (d, J = 2.37 Hz, 1H) 8.88 (s, 1H) 9.07 (s, 1H) 10.71 ( s, 1H).
EXAMPLE 66D 18-Bromo-2-oxo-2,3,11,14-tetrahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecin-7-carbonitrile Example 66C (1.22 g, 2.75 mmol) using a similar procedure described in Example 55C to give the title compound (0.67 g, 59%). MS (ESI) m / z 413.91 (MH) "; 1H NMR (500 MHz, DMSO-D6) d ppm 2.70 (q, J = 7.49 Hz, 2H) 4.63-4.71 (m, 4H) 6.01 (m, 1H) 6.08 (m, 1H) 7.16 (m, 1H) 7.23 (m, 1H) 7.97 (s, 1H) 8.23 (d, J = 2.50 Hz, 1H) 10.32 (s, 1H) 10.94 (s, 1H).
EXAMPLE 67 18-Bromo-12,13-dihydroxy-2-oxo-2,3,11, 12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6- benzodioxatriazacicloheptadecin-
7-Carbonitrile Example 66D (52 mg, 0.12 mmol) was oxidized using a similar procedure described in Example 55D to give the compound of the extract (41.2 mg, 79%). MS (ESI) m / z 447.86 (MH) "; 1H NMR (400 MHz, DMSO-D6) d ppm 1.92 (m, 1H) 2.33 (m, 1H) 3.75-3.87 (m, 2H) 4.07-4.17 (m , 2H) 4.60 (m, 1H) 4.70 (m, 1H) 4.90 (d, J = 4.91 Hz, 1H) 5.08 (d, J = 4.91 Hz, 1H) 7.13 (d, J = 8.90 Hz, 1H) 7.26 ( dd, J = 8.75, 2.61Hz, 1H) 7.99 (s, 1H) 8.28 (d, J = 2.45 Hz, 1H) 9.78 (s, 1H) 10.93 (s, 1H).
EXAMPLE 68 2-Oxo-18-r3- (tetrahydro-2H-pyran-2-yloxy) propin-2,3,11,14-tetrahydro-1H, 10H-8,4-epiazeno-9,15,1,3 , 6- benzodioxatriazacicloheptadecin-7-carbonitrilo
EXAMPLE 68A 1 - (Benzyloxy) -4-b-rom -2-nitrobenzene A mixture of 4-bromo-2-nifro-phenol (5.05 g, 23.16 mmole), benzyl bromide (4.12 mL, 34.73 mmole) and K2CO3 was stirred. (9.60 g, 69.48 mmol) in acetone (200 mL), and refluxed for 3 hours. The solution was filtered, dried with silica gel powder (20 g), and separated by flash chromatography eluting with 5% ethyl acetate in hexanes (1 L) and then with 20% ethanoyl ether hexanes (1 L) to give the title compound (6.84 g, 96%). MS (DCl) m / z 326.90 (M + NH 4) +;
H NMR (500 MHz, CD2Cl2) d ppm 5.21 (s, 2H) 7.06 (d, J = 9.05 Hz, 1H) 7.33-7.46 (m, 5 H) 7.63 (dd, J = 8.73, 2.50 Hz, 1H) 7.97 (d, J = 2.50 Hz, 1H).
EXAMPLE 68B 2- ( {3-r4- (Benzyloxy) -3-nitropheniHprop-2-ynyl} oxy) tetra idro-2H-pyran Example 68A (500 mg, 1.62 mmol), 2-prop-2 -inlyloxy-1-hydra-pyran (1.14 mL, 8.11 mmol), Pd (PPh3) 2 CI2 (171 mg, 0.24 mmol), Cul (2 mg, 0.011 mmol), PPh3 (320 mg, 1.22 mmol), frieylamine (1 mL) , and DMF (3 mL) were mixed and purged with N2. The mixture was heated at 120 ° C for 25 min. In a Smiih Symielizer. The Solvenis were eliminated by a vacuum pump. The residue was dissolved in aceion. The solution was dried with silica gel powder (10 g). 10% acetyl of acetyl in hexanes (2 L) was used to run in insannating vaporization chromatography to give the phylate compound (0.60 g, 100%). MS (DCl) m / z 385.10 (M + NH 4) +; 1H NMR (300 MHz, CD3OD) d ppm 1.45-1.92 (m, 6H) 3.48-3.60 (m, 2H) 3.88 (m, 1H) 4.45 (s, 1H) 4.46 (s, 1H) 5.29 (s, 2H) 7.29-7.42 (m, 4H) 7.43-7.48 (m, 2H) 7.61 (dd, J = 8.82, 2.03 Hz, 1H) 7.87 (d, J = 2.03 Hz, 1H).
EXAMPLE 68C 2-Amino-4-r3- (tetrahydro-2H-pyran-2-yloxy) propiphenol A mixture of Example 68B (1.19 g, 3.25 mmol) was stirred,
% Pd (OH) 2 / C (100 mg), and ethanol (50 mL), and heated at 50 ° C for 2 hours under H2 atmosphere (4.218 kg / cm2). The solution was filtered, dried with silica gel powder (8 g), and purified by flash chromatography eluting with 30% ethyl acetate in hexanes (1L) and then with 1% methanol in ethyl acetate. (1 L) to give the title compound (0.37 g, 45%). MS (DCl) m / z 252.05 (M + H) +; 1H NMR (300 MHz, CD3OD) d ppm 1.46-1.62 (m, 4H) 1.70 (m, 1H) 1.76-1.90 (m, 3H) 2.45-2.58 (m, 2H) 3.37 (m, 1H) 3.49 (m, 1H) 3.71 (m, 1H) 3.86 (m, 1H) 4.55 (t, J = 3.73 Hz, 1H) 6.41 (dd, J = 7.97.2.20 Hz, 1H) 6.59 (m, 1H) 6.61 (s, 1H) .
EXAMPLE 68D N-r6- (But-3-enyloxy) -5-cyanopyrazin-2-p-N'-. { 2-hydroxy-5-r3- (tetrahydro-2H-pyran-2-yloxy) propynyl urea Example 68C (0.37 g, 1.47 mmol) was coupled with Example
7F using a similar procedure described in Example 60C to give the compound of the extract (645.4 mg, 94%). MS (ESI) m / z 466.12 (MH) "; 1 H NMR (300 MHz, DMSO-D6) d ppm 1.36-1.55 (m, 4H) 1.62 (m, 1H) 1.69-1.85 (m, 3H) 2.52-2.60 (m, 2H) 3.40 (m, 1H) 3.63 (m, 1H) 3.74 (m, 1H) 3.98-4.05 (m, 3H) 4.45-4.57 (m, 3H) 5.06-5.25 (m, 2H) 5.89 (m , 1H) 6.72 (m, 1H) 6.79 (m, 1H) 7.93 (d, J = 2.03 Hz, 1H) 8.73 (s, 1H) 9.16 (s, 1H) 9.86 (s, 1H) 10.57 (s, 1H) .
EXAMPLE 68E N-. { 2- (allyloxy) -5-r3- (tetrahydro-2H-pyran-2-yloxy) propylphenyl > -N, -r6- (but-3-enyloxy) -5-cyanopyrazin-2-in? Rea Example 68E (200 mg, 51%) was synthesized using a similar procedure described in Example 55B replacing Example 55A with the Example 68D. MS (ESI) m / z 506.13 (MH) "; 1 H NMR (500 MHz, DMSO-D.) D ppm 1.39-1.50 (m, 4H) 1.62 (m, 1H) 1.69-1.85 (m, 3H) 2.52- 2.67 (m, 4H) 3.34 (m, 1H) 3.42 (m, 1H) 3.63 (m, 1H) 3.74 (m, 1H) 3.97 (m, 1H) 4.38 (m, 1H) 4.46 (t, J = 6.71 Hz , 1H) 4.54 (m, 1H) 4.66 (m, 1H) 5.04-5.25 (m, 2H) 5.21-5.46 (m, 2H) 5.87 (m, 1H) 6.10 (m, 1H) 6.85 (dd, J = 8.27 , 2.03 Hz, 1H) 6.96 (d, J = 8.42Hz, 1H) 7.97 (d, J = 2.18 Hz, 1H) 8.87 (s, 1H) 8.93 (s, 1H) 10.63 (s, 1H).
EXAMPLE 68F 2-Oxo-18-f3- (tetrahydro-2H-pyran-2-yl oxy) prop 1-2,3,11,14-tetrahydro-1 H, 10H-8, 4-epiazeno- 9,15,1,3,6-benzod-oxatriazacycloheptadecin-7-carbonitrile Example 68E (200 mg, 0.39 mmol) was cyclized using a similar procedure described in Example 55C to give the title compound (70 mg, 37% ). MS (ESI) m / z 478.00 (MH) "; 1H NMR (400 MHz, DMSO-D6) d ppm 1.35-1.54 (m, 4H) 1.63 (m, 1H) 1.68-1.85 (m, 3H) 2.54-2.63 (m, 2H) 2.71 (q, J = 7.26 Hz, 2H) 3.35 (m, 1H) 3.42 (m, 1H) 3.64 (m, 1H) 3.74 (m, 1H) 4.54 (m, 1H) 4.61-4.73 ( m, 4H) 5.99 (m, 1H) 6.10 (m, 1H) 6.90 (dd, J = 8.44, 1.99 Hz, 1H)
7. 08 (d, J = 8.29 Hz, 1H) 7.91 (d, J = 2.15 Hz, 1H) 7.98 (s, 1H) 10.26 (s, 1H) 10.85 (s, 1H).
EXAMPLE 69 2-Oxo-18-r2- (tetrahydro-2H-pyran-2-yloxy) ethoxy-2,3,11,14-tetrahydro-1H, 10H-8.4-epiazeno-9,15,1,3, 6- benzodioxatriazacicloheptadecin-7-carbonitrilo
EXAMPLE 69A Benzyl 2-Nitro-4-vinylphenyl ether A mixture of Example 68A (2.18 g, 7.08 mmol), Pd (PPh3) 4 (1.23 g, 1.06 mmol) and tribecyl-vinyl- (sprannose) (2.48 mL) was heated. 8.49 mmole) in DMF (200 mL) at 80 ° C during the night. The solvent was removed by a vacuum pump. The residue was dissolved in acetone (50 mL), and dried with silica gel powder (20 g). 10% ethyl acetate in hexanes (2 L) was used to run in insanitary vapor chromatography to give the compound of the title (1.69 g, 94%). MS (DCl) m / z 273.03 (M + NH 4) +; 1H NMR (500 MHz, CD2Cl2) d ppm 5.23 (s, 2H) 5.72 (d, J = 17.47 Hz, 1H) 6.67 (dd, J = 17.78, 10.92 Hz, 1H) 7.12 (d, J = 8.73 Hz, 1H ) 7.35 (m, 1H) 7.38-7.43 (m, 2H) 7.44-7.48 (m, 2H) 7.56 (dd, J = 8.73, 2.18 Hz, 1H) 7.87 (d, J = 2.18 Hz, 1H).
EXAMPLE 69B 2-r4- (Benzyloxy) -3-nitrophenyl-ethanol Example 69A (1.69 g, 6.62 mmol) was dissolved in anhydrous THF (60 mL). To this solution was added 9-BBN (0.5 M, 16 mL, 7.94 mmol). The reaction mixture was stirred under N2 at room temperature overnight. NaOH (0.32 g, 8.00 mmol) in H2O (2 mL) was added, followed by dropwise addition of 30% H2O2 (0.90 mL, 7.94 mmol). The mixture was stirred at room temperature for 3 hours. All solveníes were eliminated. To the residue was added acetyl ether (200 mL) and water (200 mL) for exiration. The organic phase was dried over MgSO4, and concentrated with silica gel powder (20 g). 20% acetyl in hexanes (1 L) and 60% acetyl in hexanes (1 L) were used to run in flash chromatography to give the composition of the extract (0.89 g, 63%). MS (DCl) m / z 291.04 (M + NH4) +; 1 H NMR (300 MHz, CDCl 3) d ppm 2.86 (,, J = 6.44 Hz, 2 H) 3.87 (,, J = 6.44 Hz, 2 H) 5.22 (s, 2 H) 7.06 (d, J = 8.48 Hz, 1 H) 7.29 -7.49 (m, 6 H) 7.74 (d, J = 2.37 Hz, 1H).
EXAMPLE 69C 2-. { 2-r 4 - (Benzyloxy) -3-nitrophenol ethoxy} tetrahydro-2H-pyran A mixture of Example 69B (0.89 g, 3.27 mmol), 3,4-dihydro-2H-pyran (1.49 mL, 16.34 mmol) and p-TsOH.H2O (5 mg) in dichloromethane was stirred (20 g. mL) at ambient temperature during the night. The reaction solution was dried with silica gel powder (15 g). HE
used 20% acetyl acetate in hexanes (1 L) to run in chroma- tography of instantaneous vaporization to give the title compound (1.06 g, 91%). MS (DCl) m / z 375.13 (M + NH 4) +; 1 H NMR (400 MHz, CDCl 3) d ppm 1.42-1.62 (m, 4 H) 1.68 (m, 1 H) 1.79 (m, 1 H) 2.88 (t, J = 6.60 Hz, 2 H) 3.45 (m, 1 H) 3.59 (m , 1H) 3.70 (m, 1H) 3.94 (m, 1H) 4.58 (i, J = 3.38 Hz, 1H) 5.21 (s, 2H) 7.03 (d, J = 8.59 Hz, 1H) 7.28-7.48 (m, 6 H) 7.77 (d, J = 2.15 Hz, 1H).
EXAMPLE 69D 2-A ino-4-r2- (tetrahydro-2H-pyran-2-yloxy) etinphenol Example 69C (1 g, 2.80 mmol) was reduced using a similar procedure described in Example 68C to give the title compound (512.1 mg, 77%). 2MS (DCl) m / z 238.04 (M + H) +; 1 H NMR (300 MHz, CD 3 OD) d ppm 1.40-1.59 (m, 4 H) 1.67 (m, 1 H) 1.81 (m, 1 H) 2.70 (,, J = 7.29 Hz, 2 H) 3.44 (m, 1 H) 3.54 (m , 1H) 3.71-3.88 (m, 2H) 4.57 (i, J = 3.56 Hz, 1H) 6.45 (dd, J = 8.14, 2.03 Hz, 1H) 6.60 (d, J = 8.14 Hz, 1H) 6.64 (d, J = 2.03 Hz, 1H).
EXAMPLE 69E N-r6- (but-3-enyloxy) -5-cyanopyrazin-2-in-N, -f2-hydroxy-5-r2- (tetrahydro-2H-pyran-2-yloxy) etinphenyl} urea Example 69D (512.1 mg, 2.16 mmol) was coupled with the
Example 7F using a similar procedure described in
Example 60C to give the title compound (864.8 mg, 88%). MS (ESI) m / z 452.08 (M-H) "; 1 H NMR (400 MHz, DMSO-D6) d ppm 1.33-
1. 52 (m, 4H) 1.58 (m, 1H) 1.72 (m, 1H) 2.54 (q, J = 6.44 Hz, 2H) 2.67-2.76 (m, 2H) 3.39 (m, 1H) 3.51 (m, 1H) 3.67 (m, 1H) 3.75 (m, 1H) 4.50 (i, J = 6.60 Hz, 2H) 4.56 (m, 1H) 5.05-5.22 (m, 2H) 5.88 (m, 1H) 6.71-6.81 (m, 2H) 7.95 (s, 1H) 8.71 (s, 1H) 9.15 (s, 1H) 9.90 (s, 1H) 10.54 (s, 1H).
EXAMPLE 69F N-f2- (allyloxy) -5-r2- (tetrahydro-2H-pyran-2-yloxy) ethenylphenyl} -N'-r6- (but-3-enyloxy) -5-cyanopyrazin-2-murea Example 69F (449.1 mg, 47%) was prepared using a similar procedure described in Example 55B. MS (ESI) m / z 492.08 (MH) "; 1 H NMR (500 MHz, DMSO-D6) d ppm 1.34-1.50 (m, 4H) 1.59 (m, 1H) 1.70 (m, 1H) 2.47 (m, 1H ) 2.55 (m, 1H) 2.74-2.86 (m, 2H) 3.39 (m, 1H) 3.55 (m, 1H) 3.65 (m, 1H) 3.78 (m, 1H) 3.98 (t, J = 4.84 Hz, 1H) 4.39 (t, J = 6.71 Hz, 1H) 4.46 (t, J = 6.55 Hz, 1H) 4.58 (m, 1H) 4.66 (m, 1H) 5.05-5.45 (m, 4H) 5.87 (m, 1H) 6.08 ( m, 1H) 6.89 (dd, J = 8.42.1.87 Hz, 1H) 7.09 (d, J = 8.73 Hz, 1H) 8.01 (d, J = 2.18 Hz, 1H) 8.86 (s, 1H) 8.94 (s, 1H ) 10.62 (s, 1H).
EXAMPLE 69G 2-OXQ-18-r2- (tetrahydro-2H-plran-2-i lox!) EthoxyT-2.3.11.14- tetrahydro-1H, 10H-8,4-epiazeno-9,15,1,3 , 6-benzodioxatriazacycloheptadecin-7-carbonitrile Example 69F (449 mg, 0.91 mmol) was cyclized using a similar procedure described in Example 55C to give the
Compound of the extract (126 mg, 30%). MS (ESI) m / z 464.03 (MH) "; 1 H NMR (500 MHz, DMSO-D6) d ppm 1.35-1.53 (m, 4H) 1.60 (m, 1H) 1.70 (m, 1H) 2.74-2.79 (m , 2H) 2.80-2.88 (m, 2H) 3.35-3.42 (m, 2H) 3.54 (m, 1H) 3.65 (m, 1H) 4.57 (m, 1H) 4.63-4.71 (m, 4H) 5.98 (m, 1H ) 6.10 (m, 1H) 6.92-7.00 (m, 2H) 7.96 (d, J = 2.14 Hz, 1H) 7.98 (s, 1H) 10.26 (s, 1H) 10.87 (s, 1H).
EXAMPLE 70 18- (3-Hydroxypropyl) -2-oxo-2,3,11,14-tetrahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecin-7-carbonitrile Example 68F (70 mg, 0.15 mmol) was removed by using a similar procedure described in Example 61 to give the compound of the extract (38 mg, 66%). MS (ESI) m / z 394.14 (MH) "; 1H NMR (400 MHz, DMSO-D6) d ppm 1.63-1.74 (m, 2H) 2.52-2.58 (m, 2H) 2.71 (q, J = 7.47 Hz, 2H) 3.38-3.46 (m, 2H) 4.43 (i, J = 5.52 Hz, 1H) 4.61-4.73 (m, 4H) 5.98 (m, 1H) 6.10 (m, 1H) 6.88 (dd, J = 8.44.1.99 Hz, 1H) 7.07 (d, J = 8.29 Hz, 1H) 7.89 (d, J = 1.84 Hz, 1H) 7.99 (s, 1H) 10.26 (s, 1H) 10.83 (s, 1H).
EXAMPLE 71 18- (2-Hydroxyethyl) -2-oxo-2,3,11,14-tetrahydro-1H, 10H-8,4-epiazeno- 9, 15, 1,3, 6-benzodioxatriazacicloheptadecin-7-carbo nitrile Example 69G (125 mg, 0.27 mmol) was discarded using a similar procedure described in Example 61 for
give the thioule compound (43.9 mg, 43%). MS (ESI) m / z 380.10 (MH) "; 1H NMR (400 MHz, DMSO-D6) d ppm 2.61-2.76 (m, 4H) 3.56 (t, J = 7.06 Hz, 2H) 4.59-4.73 (m, 4H) 5.98 (m, 1H) 6.10 (m, 1H) 6.91 (dd, j = 8.44, 1.99 Hz, 1H) 7.08 (d, J = 8.29 Hz, 1H) 7.90 (d, J = 1.84 Hz, 1H) 7.98 (s, 1H) 10.24 (s, 1H) 10.83 (s, 1H).
EXAMPLE 72 18-Bromo-2-oxo-2,3,11,12,13,14-hexahydro-1H.10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecin-7-carbonitrile The hydrogenated Example 66 (215 mg, 0.52 mmol) using a similar procedure described in Example 60 to give the title compound (80 mg, 37%). MS (ESI) m / z 417.91 (MH) "; 1 H NMR (400 MHz, DMSO-D.) D ppm 1.58-1.66 (m, 2H) 1.78-1.87 (m, 2H) 1.91-1.99 (m, 2H) 4.14-4.23 (m, 2H) 4.58-4.67 (m, 2H) 7.10 (d, J = 8.90 Hz, 1H) 7.25 (dd, J = 8.59, 2.45 Hz, 1H) 8.00 (s, 1H) 8.32 (d, J = 2.45 Hz, 1H) 9.94 (s, 1H) 10.93 (s, 1H).
EXAMPLE 73 18-H i droxi -2-0X0-2,3,11, 14-tetrah id ro-1H, 10 H-8,4-epiazen or- 9,15,1,3,6-benzodioxatriazacicloheptadecin-7 carbonitrile
EXAMPLE 73A 2- (2,5-Dimethoxyphenin-1H-isoindole-1,3 (2H) -dione 2.5-dimethoxyaniline (9.96 g, 65.00 mmol) and italic anhydride (10.11 g, 68.25 mmol) were mixed and heated to 185 ° C
last 15 minutes under N2. After the reaction mixture was cooled, acelline (50 mL) was added. The precipitate was sonicated, filtered, washed with ethyl acetate (10 mLX2), and dried to give the title compound (17.5 g, 95%). MS (ESI) m / z 283.91 (M + H) +; 1 H NMR (300 MHz, CDCl 3) d ppm 3.75 (s, 3 H) 3.79 (s, 3 H) 6.83 (,, J = 1.70 Hz, 1 H) 6.98 (d, J = 1.70 Hz, 2 H) 7.74-7.81 (m, 2H) 7.91-7.98 (m, 2H).
EXAMPLE 73B 2- (2.5-Dihydroxyphenyl) -1H-isoindol-1.3 (2 H) -dione Example 73A (17.5 g, 61.78 mmol) was dissolved in anhydrous dichloromethane (1 L). The solution was placed in a bath with dry ice for 0.5 hours. BBr3 (19.3 mL, 204.9 mmol) was added in the form of drops. The bath with dry ice was removed, and the reaction mixture was stirred for an additional 2 hours. It was then poured into ice water (2 L). The precipitate was filtered, washed with water (2 L), and dried to give the title compound (14.16 g, 90%). MS (ESI) m / z 253.95 (MH) "; 1H NMR (500 MHz, CD3OD) d ppm 6.65 (d, J = 2.81Hz, 1H) 6.78 (m, 1H) 6.83 (m, 1H) 7.84-7.88 ( m, 2H) 7.91-7.95 (m, 2H).
EXAMPLE 73C 2- (5- (rTer -butyl (diphenylsilyl-oxy) -2-hydroxyphenyl) -1H-isoindo [-1,3 (2H) -dione A mixture of Example 73B (5.31 g, 20.81 mmol) was heated.
3-buyldiphenylsilyl chloride (5.68 mL, 21.85 mmol), imidazole (2.83 g, 41.62 mmol) in anhydrous DMF (100 mL) at 50 ° C for 2 days. Solvency was eliminated by a vacuum pump. THF (200 mL) was added. The mixture was subjected to ulysonication. The suspension was filtered. The solution was dried with silica gel powder (20 g). 20% acetyl ether in hexanes (1 L) and 30% ethyl acetate in hexanes (1 L) were used to perform flash chromatography to give the compound of the extract (7 g, 68%). MS (APCl) m / z 492.19 (MH) "; 1 H NMR (500 MHz, CDCl 3) d ppm 1.10 (s, 9 H) 6.64 (dd, J = 8.73, 2.81 Hz, 1H) 6.78 (d, J = 8.73. Hz, 1H) 6.86 (d, J = 2.81 Hz, 1H) 7.34-7.45 (m, 6 H) 7.70-7.75 (m, 4H) 7.78 (dd, J = 5.46, 2.96 Hz, 2H) 7.92 (dd, J = 5.30, 3.12Hz, 2H).
EXAMPLE 73D 2- (2- (Allyloxy) -5-mer-butyl (diphenyl) -silyloxy}. Phenin-1H-isoindol-1,3 (2H) -dione A mixture of Example 73C (7 g, 14.2) was stirred. mmoles), allyl bromide (1.84 mL, 21.27 mmol) and K2CO3 (3.92 g, 28.36 mmol) in anhydrous acelline (200 mL), and refluxed overnight.The suspension was filtered, and dried with dry powder. silica gel (20 g) 15% ethyl acetate in hexanes (2 L) was used to run in insanitary vaporization chromatography to give the title compound (6.74 g, 89%) MS (DCl) m / z 551.13 (M + NH 4) +; 1 H NMR (300 MHz, CDCl 3) d ppm 1.09 (s, 9 H) 4.37-4.43 (m, 2H) 5.02-5.22 (m, 2H) 5.83 (m, 1H) 6.65-6.69 (m, 2H) 6.83 (d, J = 2.37 Hz, 1H) 7.34-7.47 (m,
6 H) 7.70-7.78 (m, 6 H) 7.89-7.94 (m, 2H).
EXAMPLE 73E 2- (Allyloxy) -5-. { rter-butyl (diphenyl) silyloxy} Aniline Example 73D (2.61 g, 4.89 mmol) was dissolved in meianol (100 mL). Hydrazine (20 mL) was added. The reaction was stirred at room temperature overnight. Solvenle and hydrazine were removed by a vacuum pump. The residue was dissolved in acetone (30 mL). The solution was dried with silica gel powder (15 g). 5% ethyl acetate in hexanes (2 L) was used to run in flash chromatography to give the title compound (0.72 g, 36%). MS (DCl) m / z 404.11 (M + H) +; 1H NMR (500 MHz, CDCl 3) d ppm 1.07 (s, 9H) 4.42 (d, J = 5.19 Hz, 2H) 5.22 (dd, J = 10.53.1.37 Hz, 1H) 5.34 (dd, J = 17.39, 1.53 Hz , 1H) 5.97-6.08 (m, 2H) 6.24 (d, J = 2.75 Hz, 1H) 6.49 (d, J = 8.85 Hz, 1H) 7.33-7.44 (m, 6 H) 7.71 (dd, J = 8.09, 1.37 Hz, 4H).
EXAMPLE 73F N- (2- (Allyloxy) -5-frter-butyl (diphenyl) silyloxyHenin, -6- (but-3-enyloxy) -5-cyanopyrazin-2-inurea Example 73E (724 mg, 1.75 mmole) with the
Example 7F using a similar procedure described in
Example 60C to give the title compound (957.1 mg, 88%). MS (ESI) m / z 618.36 (M-H) "; 1 H NMR (300 MHz, DMSO-D6) d ppm 1.04 (s,
9H) 2.52-2.59 (m, 2H) 4.45 (í, J = 6.61 Hz, 2H) 4.53 (d, J = 5.43 Hz, 2H) 5.06-5.44 (m, 4H) 5.78-6.11 (m, 2H) 6.21 ( dd, J = 8.99, 2.88 Hz, 1H) 6.76 (d, J = 8.82 Hz, 1H) 7.40-7.50 (m, 6 H) 7.68 (dd, J = 7.46, 1.70 Hz, 4H) 7.83 (d, J = 3.05 Hz, 1H) 8.83 (s, 1H) 8.90 (s, 1H) 10.64 (s, 1H).
EXAMPLE 73G 18-. { rTer-butyl (diphenyl) silinoxy-2-oxo-2,3,11,14-tetrahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecin-7-carbonitrile cyclized Example 73F (957.1 mg, 1.54 mmole) using a similar procedure described in Example 55C to give the title compound (516.6 mg, 57%). MS (ESI) m / z 590.28 (MH) "; 1 H NMR (400 MHz, DMSO-D.) D ppm 1.04 (s, 9 H) 2.66 (q, J = 7.16 Hz, 2H) 4.53 (d, J = 6.75 Hz, 2H) 4.67 (t, J = 7.21 Hz, 2H) 5.91-6.08 (m, 2H) 6.29 (dd, J = 8.90, 3.07 Hz, 1H) 6.88 (d, J = 8.90 Hz, 1H) 7.39- 7.52 (m, 6 H) 7.64-7.72 (m, 4H) 7.78 (d, J = 3.07 Hz, 1H) 7.95 (s, 1H) 10.20 (s, 1H) 10.81 (s, 1H).
EXAMPLE 73H 18-Hydroxy-2-oxo-2,3,11,14-tetrahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecin-7-carbonitrile Example 73G (0.52) was dissolved g, 0.87 mmol) in THF (10 mL).
To this solution TBAF (1.37 g, 5.24 mmol) was added. The reaction mixture was stirred at ambient temperature for 3 hours, and dried with silica gel powder (10 g). 20% of oil was used
ether in hexanes (1 L) and 1% methanol in ethyl acetate (1 L) to run on flash chromatography. The title compound was obtained (0.32 g, 100%). MS (ESI) m / z 352.06 (MH) "; 1H NMR (500 MHz, DMSO-D6) d ppm 2.68 (q, J = 7.42 Hz, 2H) 4.56 (d, J = 7.32 Hz, 2H) 4.68 (t , J = 7.48 Hz, 2H) 5.97 (m, 1H) 6.07 (m, 1H) 6.43 (dd, J = 8.70, 2.90 Hz, 1H) 6.96 (d, J = 8.85 Hz, 1H) 7.64 (d, J = 3.05 Hz, 1H) 7.96 (s, 1H) 9.03 (s, 1H) 10.21 (s, 1H) 10.86 (s, 1H).
EXAMPLE 74 18- (2-Hydroxyethin-2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8.4- epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecin-7-carbonitrile Example 71 was hydrogenated (20.6 mg, 0.05 mmol) using a similar procedure described in Example 60 to give the compound (11 mg, 53%) MS (ESI) m / z 382.19 (MH) "; 1H NMR (400 MHz, DMSO-D6) d ppm 1.54-1.64 (m, 2H) 1.75-1.85 (m, 2H) 1.88-2.01 (m, 2H) 2.66 (t, J = 7.06 Hz, 2H) 3.52-3.61 (m, 2H) 4.15 (t, J = 5.22 Hz, 2H) 4.53-4.66 (m, 3H) 6.92 (m, 1H) 7.01 (d, J = 8.29 Hz, 1H) 7.95 (d, J = 1.84 Hz, 1H) 7.99 (s, 1H) 9.86 (s, 1H) 10.79 (s, 1H).
EXAMPLE 75 18- (3-H i droxi prop i I) -2-oxo-2,3,11,12, 13,14-hexah id ro-1H, 10 H-8, 4- epiazeno-9,15, 1,3,6-benzodioxat riazacycloheptadecin-7-carbonitrile
Hydrogenation was carried out in Example 70 (20.6 mg, 0.05 mmol) using a similar procedure described in Example 60 to give the title compound (14.9 mg, 70%). MS (ESI) m / z 396.11 (MH) "; 1H NMR (400 MHz, DMSO-D6) d ppm 1.55-1.64 (m, 2H) 1.64-1.73 (m, 2H) 1.76-1.85 (m, 2H) 1.90 -2.00 (m, 2H) 2.52-2.58 (m, 2H) 3.41 (t, J = 6.44 Hz, 2H) 4.10-4.18 (m, 2H) 4.44 (m, 1H) 4.58-4.66 (m, 2H) 6.90 (m, 2H) dd, J = 8.59.2.15 Hz, 1H) 7.01 (d, J = 8.29 Hz, 1H) 7.94 (d, J = 1.84 Hz, 1H) 8.00 (s, 1H) 9.87 (s, 1H) 10.79 (s, 1H) ).
EXAMPLE 76 12,13-Dihydroxy-18- (2-hydroxyethyn-2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6 -benzodioxatriazacicloLeptadecin-7-carbonitrile Example 71 (17 mg, 0.04 mmol) was oxidized using a similar procedure described in Example 55D to give the title compound (13.9 mg, 75%) MS (ESI) m / z 414.21 ( MH) "; 1H NMR (400 MHz, DMSO-D6) d ppm 1.91 (m, 1H) 2.34 (m, 1H) 2.66 (t, J = 7.21 Hz, 2H) 3.53-3.61 (m, 2H) 3.76 (m , 1H) 3.84 (m, 1H) 4.05 (m, 1H) 4.13 (m, 1H) 4.54-4.62 (m, 2H) 4.68 (m, 1H) 4.85 (d, J = 5.22 Hz, 1H) 5.04 (d, J = 4.91 Hz, 1H) 6.94 (m, 1H) 7.04 (d, J = 7.98 Hz, 1H) 7.90 (d, J = 1.84 Hz, 1H) 8.00 (s, 1H) 9.71 (s, 1H) 10.79 (s) , 1 HOUR).
EXAMPLE 77 12,13-Dihydroxy-18- (3-hydroxypropion-2-oxo-2.3.11.12,13,14-hexahydro-1 H.10H-8,4-epiazeno-9, 15, 1.3.6- benzodioxatriazacycloheptadecin-7-carbonitrile Example 70 (23 mg, 0.06 mmol) was oxidized using a similar procedure described in Example 55D to give the title compound (12.3 mg, 49%) MS (ESI) m / z 428.19 (MH ); 1H NMR (400 MHz, DMSO-D6) d ppm 1.63-1.73 (m, 2H) 1.91 (m, 1H) 2.35 (m, 1H) 2.52-2.58 (m, 2H) 3.38-3.46 (m, 2H ) 3.77 (m, 1H) 3.84 (m, 1H) 4.06 (m, 1H) 4.13 (m, 1H) 4.42 (t, J = 5.06 Hz, 1H) 4.56-4.73 (m, 10.89 Hz, 2H) 4.85 (d) , J = 5.22 Hz, 1H) 5.04 (d, J = 5.22 Hz, 1H) 6.91 (dd, J = 8.44.1.99 Hz, 1H) 7.04 (d, J = 8.59 Hz, 1H) 7.90 (d, J = 1.84 Hz, 1H) 8.00 (s, 1H) 9.72 (s, 1H) 10.76 (s, 1H).
EXAMPLE 78 18-Chloro-13-methoxy-2-oxo-2.3.13.14-tetrahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecin-7-carbonitrile
EXAMPLE 78A 2-Methoxybut-3-en-1-ol Buadiene monoxide (3.26 g, 46.5 mmol) was dissolved in mefanol (30 mL). The solution was cooled in a bath with ice
0. 5 hours. A goya of concentrated H2SO4 was added. The bath with ice was removed, and the reaction was stirred at room temperature
during 3 hours. The reaction solution was dried with silica gel powder (20 g). 20% ethyl acetate in hexanes (1 L) was used to run in flash chromatography to give the title compound (1.16 g, 25%). MS (ESI) m / z 103.15 (M + H) +; 1 H NMR (300 MHz, CDCl 3) d ppm 3.35 (s, 3 H) 3.47-3.63 (m, 2 H) 3.72 (m, 1 H) 5.27-5.39 (m, 2 H) 5.68 (m, 1 H).
EXAMPLE 78B N-f6- (allyloxy) -5-cyanopyrazin-2-n-N'-. { 5-chloro-2-r (2-methoxybut-3-enyl) oxypihenyl > urea Example 78B (0.23 g, 36%) was prepared using a similar procedure described in Example 55B by replacing the allyl alcohol with Example 78A. MS (ESI) m / z 428.13 (M-H) '; 'H NMR (300 MHz, DMSO-D6) d ppm 3.28 (s, 3H) 4.11-4.15 (m, 2H) 4.95 (i, J = 1.53 Hz, 1H) 4.97 (t, J = 1.53 Hz, 1H) 5.25 -5.51 (m, 5 H) 5.87 (m, 1H) 6.12 (m, 1H) 7.07 (m, 1H) 7.14 (m, 1H) 8.18 (d, J = 2.37 Hz, 1H) 8.90 (s, 1H) 8.98 (s, 1H) 10.79 (s, 1H).
EXAMPLE 78C 18-Chloro-13-methoxy-2-oxo-2,3,13,14-tetrahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecin-7-carbonitrile cyclized Example 78B (0.23 g, 0.54 mmole) using a similar procedure described in Example 55C to give the compound of the extract (41.1 mg, 19%) with cis conformation. MS (ESI)
m / z 400.06 (M-H) -; H NMR (400 MHz, DMSO-D6) d ppm 3.39 (s, 3H) 3.96 (t, J = 8.29 Hz, 1H) 4.29-4.45 (m, 2H) 5.27-5.50 (m, 2H) 5.58 (s, 1H ) 5.84 (m, 1H) 7.17 (dd, J = 8.90.2.76 Hz, 1H) 7.28 (d, J = 8.90 Hz, 1H) 8.07 (s, 1H) 8.29 (d, J = 2.45 Hz, 1H) 9.76 ( s, 1H) 10.99 (s, 1H).
EXAMPLE 79 18-Chloro-11.12-dihydroxy-13-methoxy-2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1,3, 6- benzodioxatriazacycloheptadecin-7-carbonitrile Example 78C (35 mg, 0.087 mmol) was oxidized using a similar procedure described in Example 55D to give the title compound (12.9 mg, 34%). MS (ESI) m / z 434.09 (M-H) '; 1 H NMR (400 MHz, DMSO-D 6) d ppm 3.33 (s, 3 H) 3.61 (d, J = 7.36 Hz, 1 H) 3.81 (,, J = 6.14 Hz, 1 H) 4.08 (dd, J = 9.82, 2.76 Hz , 1H) 4.19 (í, J = 11.20 Hz, 1H) 4.29 (m, 1H) 4.36 (m, 1H) 4.92 (dd, J = 11.35, 2.45 Hz, 1H) 5.17 (d, J = 5.83 Hz, 1H) 5.20 (d, J = 5.52Hz, 1H) 7.05-7.24 (m, 2H) 7.85-8.10 (m, 2H) 9.64 (s, 1H) 10.89 (s, 1H).
EXAMPLE 80 (Trans) 18-chloro-11,12-dihydroxy-13-methoxy-2-oxo-2,3,11,12, 13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15, 1.3.6- benzodioxatriazacicloheptadecin-7-carbo nitrile
EXAMPLE 80A (Trans) 18-chloro-13-methoxy-2-oxo-2,3,13,14-tetrahydro-1H, 10H-8,4-
epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecin-7-carbonitrile The title compound has trans conformation and was prepared using the same procedure in Example 78 (108 mg, 50%). MS (ESI) m / z 400.11 (MH) "; 1H NMR (400 MHz, DMSO-D6) d ppm 3.32 (s, 3H) 3.66 (m, 1H) 4.02-4.16 (m, 2H) 4.20 (m, 1H ) 4.38 (dd, J = 10.28, 3.53 Hz, 1H) 5.06 (m, 1H) 5.66 (dd, J = 16.26.6.14 Hz, 1H) 5.97 (d, J = 15.96 Hz, 1H) 7.19-7.30 (m, 2H) 7.84 (d, J = 2.46 Hz, 1H) 8.07 (s, 1H) 9.23 (s, 1H) 10.93 (s, 1H).
EXAMPLE 80B 18-Chloro-11,12-trans-dihydroxy-13-methoxy-2-oxo-2,3,11,12,13,14-hexahydro-H, 10H-8,4-epiazeno-9,15,1, 3,6-benzodioxatriazacycloheptadecin-7-carbonitrile Example 80A (48 mg, 0.12 mmol) was used using a similar procedure described in Example 55D to give the title compound (22 mg, 42%). MS (ESI) m / z 434.24 (MH) "; 1H NMR (400 MHz, DMSO-D6) d ppm 3.32 (s, 3H) 3.57 (d, J = 7.06 Hz, 1H) 3.87 (d, J = 6.14 Hz , 1H) 4.05-4.17 (m, J = 9.82, 9.82 Hz, 2H) 4.36 (dd, J = 10.43, 7.67 Hz, 1H) 4.58 (m, 1H) 4.71 (m, 1H) 5.31 (m, 1H) 7.14 (dd, J = 8.75, 2.61Hz, 1H) 7.22 (m, 1H) 8.00 (s, 1H) 8.28 (d, J = 2.76 Hz, 1H) 10.14 (s, 1H) 10.95 (s, 1H).
EXAMPLE 81 18-Chloro-13-ethoxy-1, 12-cis-di-hydroxy-2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1 , 3,6-benzodioxatriazacycloheptadecin-7-carbonitrile EXAMPLE 81A 2-Ethoxybut-3-en-1-ol Example 81A (4.1 g, 75%) was synthesized using a similar procedure described in Example 78A replacing meianol with efanol. MS (ESI) m / z 117.12 (M + H) +; 1 H NMR (300 MHz, CDCl 3) d ppm 1.13-1.28 (m, 3H) 3.31-4.00 (m, 5H) 5.18-5.39 (m, 2H) 5.71 (m, 1H)
EXAMPLE 81B N-r6- (Allyloxy) -5-cyanopyrazin-2-iH-N '- (5-chloro-2-r (2-ethoxybut-3-enyl) oxylphenyl> urea Example 81B was prepared (179 mg , 27%) using a similar procedure described in Example 55B replacing alcohol with Example 81A MS (ESI) m / z 442.20 (MH) "; 1 H NMR (300 MHz, DMSO-D6) d ppm 0.96-1.22 (m, 3H) 3.11-3.43 (m, 3H) 3.51 (m, 1H) 3.96-4.25 (m, 2H) 4.96 (d, J = 5.43 Hz, 1H) 5.06-5.52 (m, 4H) 5.81-6.20 (m, 3H) m, 2H) 7.03-7.20 (m, 2H) 8.18 (d, J = 2.71 Hz, 1H) 8.89 (s, 1H) 8.99 (s, 1H) 10.78 (s, 1H)
EXAMPLE 81C (Cis) 18-chloro-13-ethoxy-2-oxo-2,3,13,14-tetrahydro-1H, 10H-8,4-
epiazene-9,15,1,3,6-benzodioxatriazacycloheptadecin-7-carbonitrile Example 81B (179 mg, 0.40 mmol) was cyclized using a similar procedure described in Example 55C to give the compound of the extract (cis isomer, 50 mg , 30%) and Example 82A (frans isomer). The analytical damages for the cis isomer is as follows: MS (ESI) m / z 414.10 (MH) "; 1 H NMR (400 MHz, DMSO-D.) D ppm 1.15 (t, J = 7.06 Hz, 3H) 3.46- 3.62 (m, 2H) 3.90 (i, J = 8.59 Hz, 1H) 4.31-4.43 (m, 2H) 5.34-5.41 (m, 2H) 5.54 (m, 1H) 5.75 (m, 1H) 7.12 (m, 1H 7.24 (d, J = 8.90 Hz, 1H) 8.01 (s, 1H) 8.25 (d, J = 2.76 Hz, 1H) 9.71 (s, 1H) 10.96 (s, 1H).
EXAMPLE 81D 18-Chloro-13-ethoxy-11,12-cis-dihydroxy-2-oxo-2,3,11,12,13,14-hexahydro-1 H, 10H-8,4-epiazeno-9,15 , 1,3,6-benzodioxatriazacycloheptadecin-7-carbonitrile Example 81 C (44.5 mg, 0.11 mmol) was oxidized using a similar procedure described in Example 55D to give the title compound (14.3 mg, 30%). MS (ESI) m / z 448.11 (MH) "; 1? NMR (400 MHz, DMSO-D6) d ppm 1.10 (i, J = 6.90 Hz, 3H) 3.47-3.58 (m, 2H) 3.71 (d, J = 7.06 Hz, 1H) 3.78 (í, J = 3.99 Hz, 1H) 4.03 (dd, J = 9.51, 2.76 Hz, 1H) 4.18 (m, 1H) 4.25-4.38 (m, 2H) 4.91 (dd, J = 11.51, 2.61 Hz, 1H) 5.17 (dd, J = 15.96, 5.52 Hz, 2H) 7.11-7.20 (m, 2H) 7.97 (d, J = 2.45 Hz, 1H) 7.99 (s, 1H) 9.62 (s, 1H) 10.89 (s, 1H)
EXAMPLE 82 18 -Cio ro-13-ethoxy -11,12-trans -di hi roxy -2-oxo-2,3, 11, 12, 13,14-hexahydro-1H, 10H-8,4-epiazeno-9 , 15, 1,3,6-benzodioxatriazacicloheptadecin-7-carbonitrilo
EXAMPLE 82A (Trans) 18-chloro-13-ethoxy-2-oxo-2,3,13,14-tetrahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecin-7 - carbonitrile The title compound (rans, 75 mg, 45%) was prepared using the same procedure described in Example 81C. MS (ESI) m / z 414.14 (MH) "; 1H NMR (400 MHz, DMSO-D6) d ppm 1.09 (,, J = 7.06 Hz, 3H) 3.39-3.56 (m, 2H) 4.00 (m, 1H) 4.11 (m, 1H) 4.33 (dd, J = 10.28, 3.84 Hz, 1H) 4.94-5.03 (m, 2H) 5.61 (dd, J = 16.26, 6.75 Hz, 1H) 5.90 (d, J = 16.26 Hz, 1H ) 7.15 (m, 1H) 7.21 (m, 1H) 7.78 (d, J = 2.15 Hz, 1H) 8.00 (s, 1H) 9.16 (s, 1H) 10.89 (s, 1H)
EXAMPLE 82B 18-Chloro-13-ethoxy-11,12-trans-dihydroxy-2-oxo-2,3,12,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1,3, 6- benzodioxatriazacicl or heptadecin-7-carbo nitrile Example 82A (43.4 mg, 0.10 mmol) was oxidized using a similar procedure described in Example 55D to give the title compound (16.2 mg, 34%). MS (ESI) m / z 448.09 (M-H) "; 1 H NMR (400 MHz, DMSO-D6) d ppm 1.12 (t, J = 6.90 Hz, 3H) 3.46-3.59
(m, 2H) 3.68 (d, J = 7.06 Hz, 1H) 3.85 (t, J = 5.06 Hz, 1H) 4.01-4.16 (m, 2H) 4.37 (dd, J = 10.13, 7.98 Hz, 1H) 4.56- 4.70 (m, 2H) 5.27 (d, J = 4.91 Hz, 1H) 5.34 (d, J = 5.22 Hz, 1H) 7.14 (dd, J = 8.90, 2.46 Hz, 1H) 7.22 (m, 1H) 8.00 (s) , 1H) 8.28 (d, J = 2.46 Hz, 1H) 10.14 (s, 1H) 10.95 (s, 1H)
EXAMPLE 83 (Cis) 18-nitro-2-oxo-2,3,13,14-tetrahydro-1H, 10H-8,4-epiazeno-9.15,1,3,6-benzodioxatriazacycloheptadecin-7-carbonitrile
EXAMPLE 83A 3- (Allyloxy) -5-aminopyrazine-2-carbonitrile Was injected into a suspension of 95% NaH (3.27 g, 129.36 mmol) in dioxane (300 mL) under N2 allyl alcohol allyl alcohol (8.8 mL, 129.36 mmol) . After the reaction was stirred for 20 minutes, Example 7D (10 g, 64.68 mmol) was added. The reaction mixture was stirred at 100 ° C overnight, cooled and filtered.
The precipitate was washed with ethyl acetate (100 mL × 10). The filtrate was concentrated with silica gel (20 g) and purified by insanitary vaporization chromatography eluting with 50% acetyl in hexanes (2 L) to give the title compound (8.2 g, 72%). MS
(DC1) m / z 176.99 (M + H) +; 1 H NMR (300 MHz, CDCl 3) d ppm 4.84-4.88
(m, 2H) 4.99 (s, 2H) 5.30 (m, 1H) 5.43 (m, 1H) 6.04 (m, 1H) 7.58 (s, 1H).
EXAMPLE 83B 6- (Allyloxy) -5-cyanopyrazin-2-ylcarbamate phenyl It was added to a mixture of phenyl chloroformate (15.86 mL, 126.59 mmol) and pyridine (7.96 mL, 98.46 mmol) in dichloromethane (150 mL) at 0 ° C under N2 atmosphere, Example 83A (12.39 g, 70.33 mmol) in anhydrous THF (50 mL) as drops. The reaction mixture was gradually warmed to room temperature, then stirred at ambient temperature for 0.5 hour, and diluted with ethyl acetate (1.5 L). The resulting suspension was washed with brine (200 mL × 5). The organic layer was dried over MgSO4 and evaporated. The residue was recrystallized from 20% ethyl acetate in hexanes (100 mL) to give the compound (12.94 g, 62%). MS (DCl) m / z 297.06 (M + H) +; 1 H NMR (300 MHz, CDCl 3) d ppm 4.92 (d, J = 5.43 Hz, 2H) 5.36 (dd, J = 10.51, 1.36 Hz, 1H) 5.48 (dd, J = 17.12, 1.53 Hz, 1H) 6.06 (m , 1H) 7.18-7.23 (m, 2H) 7.31 (t, J = 7.46 Hz, 1H) 7.39-7.49 (m, 2H) 7.60 (s, 1H) 9.00 (s, 1H).
EXAMPLE 83C N-r6- (allyloxy-5-cyanopyrazin-2-ip-N '- (2-hydroxy-5-nitrophenyl) urea 2-amino-4-nitro-phenol (1.38 g, 8.98 mmol) was coupled and the
Example 83B (2.66 g, 8.98 mmol) using a similar procedure described in Example 60C to give the title compound (3.1 g, 96%). MS (ESI) m / z 355.02 (MH) "; 1 H NMR (300 MHz, DMSO-De) d ppm 4.99 (d, J = 5.43 Hz, 2H) 5.35 (dd, J = 10.51, 1.36 Hz, 1H) 5.48 (m, 1H) 6.12 (m, 1H) 7.02 (d, J = 9.16 Hz, 1H) 7.89 (dd, J = 8.99,
2. 88 Hz, 1H) 8.80 (s, 1H) 9.05 (d, J = 3.05 Hz, 1H) 9.46 (s, 1H) 10.72 (s, 1H) 11.93 (s, 1H)
EXAMPLE 83D N-r6- (allyloxy) -5-cyanopyrazin-2-yn-N'-r2- (but-3-enyloxy) -5-nitrophenyl-urea The compound was prepared (209 mg, 10%) using a similar procedure described in Example 55B replacing the allyl alcohol with 1-bulenol and replacing Example 55A with Example 83C. MS (ESI) m / z 409.07 (MH) "; 1 H NMR (300 MHz, DMSO-De) d ppm 2.24-2.37 (m, 2H) 4.33 (t, J = 6.78 Hz, 2H) 4.90 (d, J = 5.42Hz, 2H) 5.00-5.52 (m, 4H) 5.73-6.21 (m, 2H) 7.40 (m, 1H) 7.99 (m, 1H) 8.84 (s, 1H) 8.98 (m, 1H) 9.07 (s, 1H) 10.80 (s, 1H)
EXAMPLE 83E (Cis) 18-nitro-2-oxo-2,3,13,14-tetrahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecin-7-carbonitrile Example was cyclized 83D (209 mg, 0.51 mmol) using a similar procedure described in Example 55C to give the compound of the isolate (cis isomer, 17.6 mg, 9%) and Example 102A (frans isomer, 13.5 mg, 8%). MS (ESI) m / z 381.16 (MH) "; 1 H NMR (400 MHz, DMSO-D.) D ppm 2.53-2.59 (m, 2H) 4.33 (f, J = 5.52 Hz, 2H) 5.37-5.42 (m , 2H) 5.64-5.75 (m, 2H) 7.37 (d, J = 9.21 Hz, 1H) 8.03 (dd, J = 9.05, 2.92 Hz, 1H) 8.05 (s, 1H) 9.16 (d, J = 2.76 Hz, 1H) 9.88 (s, 1H) 11.04 (s, 1H).
EXAMPLE 84 18-Ethoxy-2-oxo-2,3,11,14-tetrahydro-1H.10H-8,4-epiazeno-9,15,1,3,6-benzodioxatríazacicloheptadecin-7-carbonitrilo
EXAMPLE 84A 2-r2- (Allyloxy) -5-hydroxyphenin-1H-isoindole-1,3 (2H) -dione Example 73D (6.74 g, 12.60 mmol) was dissolved in THF (140 mL). TBAF (22.3 g, 85.2 mmol) was added. The reaction mixture was stirred at ambient temperature during the night. The solution was dried with silica gel powder (20 g). 20% ethyl acetate in hexanes (1 L) and 3% methanol in ethyl acetate (3 L) were used to run in insanitary vapor chromatography to give the compound of the title (1.99 g, 54%). MS (ESI) m / z 296.02 (M + H) +; 1H NMR (300 MHz, CD3OD) d ppm 4.52 (d, J = 5.43 Hz, 2H) 5.20 (dd, J = 10.51, 1.36 Hz, 1H) 5.34 (dd, J = 17.29, 1.36 Hz, 1H) 6.06 (m , 1H) 6.53 (dd, J = 8.82, 2.71Hz, 1H) 6.86 (d, J = 8.82 Hz, 1H) 7.51-7.77 (m, 4H) 7.94 (d, J = 6.78 Hz, 1H).
EXAMPLE 84B 2-r 2 - (Allyloxy) -5-ethoxy-phen-1H-isoindol-1,3 (2H) -dione A mixture of Example 84A (0.63 g, 2.13 mmol), iodoethane (0.68 mL, 8.52 mmol) was stirred. ) and K2CO3 (1.47 g, 10.65 mmol) in acetone (50 mL), and refluxed for 3 hours, and cooled. The solution was filtered, and dried with silica gel powder (10 g). 15% acetyl ether in hexanes (1 L) and 20%
acetyl in hexanes (1 L) to run in instantaneous vaporization chromatography. The title compound was obtained (320 mg, 46%). MS (DCl) m / z 324.07 (M + H) +; 1 H NMR (300 MHz, CDCl 3) d ppm 1.39 (,, J = 7.12 Hz, 3 H) 4.00 (q, J = 7.12 Hz, 2 H) 4.46-4.55 (m, 2 H) 5.07-5.30 (m, 2 H) 5.88 ( m, 1H) 6.82 (dd, J = 2.54, 0.85 Hz, 1H) 6.93-6.96 (m, 2H) 7.75-7.80 (tn, 2H) 7.94 (dd, J = 5.42, 3.05 Hz, 2H).
EXAMPLE 84C 2- (Allyloxy) -5-ethoxyaniline Example 84B (320 mg, 0.99 mmol) was dissolved in meianol
(20 mL). H2NNH2 (0.10 mL, 3 mmol) was added. The reaction mixture was agitated at room temperature for 3 hours. The solvents were removed by a vacuum pump. The residue was dissolved in acetone (10 mL). The solution was dried with silica gel powder (8 g). 15% ethyl acetate in hexanes (2 L) was used to run in instantaneous vaporization chromatography to give the title compound (167.2 mg, 88%). MS (APCl) m / z 194 (M + H) +; 1 H NMR (400 MHz, CDCl 3) d ppm 1.36 (t, J = 6.90 Hz, 3 H) 3.94 (q, J = 6.96 Hz, 2 H) 4.50 (d, J = 5.52 Hz, 2 H) 5.25 (dd, J = 10.43 , 1.53 Hz, 1H) 5.39 (dd, J = 17.18, 1.53 Hz, 1H) 6.06 (m, 1H) 6.26 (dd, J = 8.59, 2.76 Hz, 1H) 6.40 (d, J = 2.76 Hz, 1H) 6.71 (d, J = 8.90 Hz, 1H).
EXAMPLE 84D N-r2- (allyloxy) -5-ethoxyphenyl-N'-r6- (but-3-enyloxy) -5-cyanopyrazin-2-illurea Example 84C (167.2 mg, 0.87 mmol) was coupled and the Example 7F (268.2 mg, 0.87 mmol) using a similar procedure described in Example 60C to give the compound of the extract (332 mg, 93%). MS (ES) m / z 408.22 (MH) "; 1 H NMR (500 MHz, DMSO-D6) d ppm 1.31 (,, J = 7.02 Hz, 3H) 2.54 (q, J = 6.71 Hz, 2H) 3.95 (q , J = 7.02Hz, 2H) 4.46 (í, J = 6.71 Hz, 2H) 4.61 (d, J = 5.49 Hz, 2H) 5.11 (dd, J = 10.37, 1.53 Hz, 1H) 5.18 (dd, J = 17.24 , 1.68 Hz, 1H) 5.28 (dd, J = 10.53, 1.37 Hz, 1H) 5.41 (dd, J = 17.24,1.68 Hz, 1H) 5.88 (m, 1H) 6.07 (m, 1H) 6.56 (dd, J = 9.00, 2.90 Hz, 1H) 6.96 (d, J = 8.85 Hz, 1H) 7.78 (d, J = 2.75 Hz, 1H) 8.86 (s, 1H) 8.97 (s, 1H) 10.69 (s, 1H).
EXAMPLE 84E 18-Ethoxy-2-oxo-2,3,11,14-tetrahydro-1 H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecin-7-carbonitrile Example was cyclized 84D (332 mg, 0.81 mmol) using a similar procedure described in Example 55C to give the compound of the extract (192.5 mg, 62%). MS (EST) m / z 380.18 (M-H) "; 1H NMR (500 MHz, DMSO-D6) d ppm 1.31 (i, J = 6.87 Hz, 3H) 2.69 (q, J = 7.63 Hz, 2H) 3.95 (q, J = 6.92 Hz, 2H) 4.61 (d, J = 7.32 Hz, 2H) 4.69 (t, J = 7.32 Hz, 2H) 5.98 (m, 1H) 6.08 (m, 1H) 6.62 (dd, J = 9.00, 2.90 Hz, 1H) 7.07 (d, J = 8.85 Hz , 1H) 7.71 (d, J = 3.05 Hz, 1H) 7.98 (s, 1H) 10.26 (s, 1H) 10.88 (s, 1H).
EXAMPLE 85 18-CI oro-17- (eti I ami no) -2 -oxo -2, 3,11, 12, 13,14-hexah id ro-1H, 10 H- 8,4-epiazeno-9,15 , 1,3,6-benzodioxatriazacycloheptadecin-7-carbonitrile The desired yield was prepared (9.6 mg, 30%) using a similar procedure described in Example 28 by replacing the 3-pyridine carboxylaldehyde with acetylaldehyde. MS (APCl) m / z 417.29 (M + H) +; 1H NMR (400 MHz, DMSO-D6) d ppm 1.17 (I, J = 7.06 Hz, 3H) 1.54-1.60 (m, 2H) 1.76-1.83 (m, 2H) 1.90-1.98 (m, 2H) 3.14-3.22 (m, 2H) 4.18 (í, J = 5.06 Hz, 2H) 4.56 (t, J = 8.29 Hz, 2H) 5.02 (í, J = 5.68 Hz, 1H) 6.39 (s, 1H) 7.93 (s, 1H) 7.96 (s, 1H) 9.66 (s, 1H) 10.74 (s, 1H)
EXAMPLE 86 17- (Butylamino) -18-chloro-2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecin- 7- carbonitrile The desired production (12.8 mg, 52%) was prepared using a similar procedure described in Example 28 by replacing 3-pyridine carboxylaldehyde with buíiraldehyde. MS (APCl) m / z 445.64 (M + H) +; 1H NMR (400 MHz, DMSO-D6) d ppm 0.92 (t, J = 7.36 Hz, 3H) 1.31-1.42 (m, 2H) 1.51-1.63 (m, 4H) 1.78-1.84 (m, 2H) 1.92-2.00 (m, 2H) 3.15 (q, J = 6.44 Hz, 2H) 4.19 (í, J = 5.22 Hz, 2H) 4.58 (t, J = 7.67 Hz, 2H) 5.01 (í, J = 5.83 Hz, 1H) 6.40 (s, 1H) 7.94 (s, 1H) 7.97 (s, 1H) 9.68 (s, 1H) 10.77 (s, 1H).
EXAMPLE 87 17-Chloro-2-oxo-2,3,10,11,12,13-hexahydro-1H-8,4-epiazeno-9,14,1,3,6-benzodioxatriazacyclohexadecin-7-carbonitrile. mixture of palladium-carbon (5%, 2 mg) and Example 55C (10 mg, 0.028 mmol) in THF (25 mL) under a hydrogen atmosphere for 3 hours. The palladium-carbon was removed by filtration through Celite. The filtrate was concentrated, and the residue was washed with methanol and dried to give the title compound (7.5 mg, 75%). MS (ESI) m / z: 357.91 (MH) "; 1H NMR (500 MHz, DMSO-D6) d ppm 1.85-1.91 (m, 2H) 2.00-2.06 (m, 2H) 4.17 (,, J = 5.49 Hz , 2H) 4.75 (t, J = 7.32 Hz, 2H) 7.09 (dd, J = 8.85, 2.14 Hz, 1H) 7.18 (d, J = 8.54 Hz, 1H) 7.94 (s, 1H) 8.34 (s, 1H) 10.83 (s, 1H) 11.05 (s, 1H).
EXAMPLE 88 18-Chloro-14-methyl I -2 -oxo-2, 3,11,14-tetrahydro-1H, 10 H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecin-7 carbonitrile
EXAMPLE 88A N-r6- (but-3-enyloxy) -5-cyanopyrazin-2-ip-N '- (5-chloro-2-hydroxyphenipyrate) A solution of 2-amino-4-chlorophenol (1.39 g, 9.67 g) was heated mmoles) and Example 7F (2 g, 6.45 mmol) in NMP at 80 ° C for 24 hours, cooled and diluted with ethyl acetate (250 mL), the resulting mixture was washed with 10% HCl, and then The organic layer was dried over MgSO 4, concentrated and dried to give the
desired product (1.87 g, 80%). MS (DCl) m / z 377.07 (M + NH4)
EXAMPLE 88B N-f6- (but-3-enyloxy) -5-cyanopyrazin-2-n-N'-. { 5-Chloro-2-r (1-methylprop-2-eny-phenyl). Urea To a mixture of Example 88A (0.5 g, 1.39 mmol), triphenyl phosphine soporiated by polymer (927 mg, 2.78 mmol) and 3- buen-2-ol (0.481 mL, 5.56 mmol) in THF (20 mL) di-tert-builo azodicarboxylic acid (640.2 mg, 2.78 mmol) The reaction mixture was stirred overnight, and the insoluble material was removed by The filtrate was concentrated, and the residue was purified by flash chromatography eluting with 30% ethyl acetate in hexane The desired product was obtained (477 mg, 83%) MS (ESI) m / z 414.01 (M + H) +; 1H NMR (400 MHz, DMSO-D6) d ppm 1.45 (d, J = 6.44 Hz, 3H) 2.55 (q, J = 6.75 Hz, 2H) 4.46 (t, J = 6.75 Hz, 2H) 5.02 (m, 1H) 5.11 (m, 1H) 5.16-5.21 (m, 2H) 5.29 (d, J = 17.18 Hz, 1H) 5.83-5.98 (m, 2H) 7.02 (dd, J = 8.92, 2.45 Hz, 1H) 7.09 (d, J = 8.92.1H) 8.19 (d, J = 2.45 Hz, 1H) 8.88 (s, 1H) 8.94 (s, 1H) 10.76 (s, 1H).
EXAMPLE 88C 18-C lor o-14-meti I -2-0X0-2.3,11,14-tetrah id ro-1H, 10 H-8,4-epiazen or- 9,15,1,3,6-benzodioxatriazacycloheptadecin -7-Carbonitrile A mixture of Example 88B (270 mg, 0.65 mmol) and Grubbs Catalyst (2nd generation, 55 mg, 0.065 mmol) in CH2Cl2 was stirred.
(330 mL) at ambient temperature for 36 hours, and then DMSO (0.461 mL, 6.5 mmol) was added. The reaction mixture was further stirred for 24 hours. The residue was purified by flash chromatography eluting with 9% ethyl acetate in dichloromethane to give the desired product (158 mg, 63%). MS (DCI / NH3) m / z 386.1 (M + H) +; 1H NMR (500 MHz, DMSO-D6) d ppm 1.37 (d, J = 6.24 Hz, 3H) 2.42 (m, 1H) 2.49 (m, 1H) 4.34 (m, 1H) 4.74 (m, 1H) 4.95 (m 1H) 5.81 (dd, J = 15.91, 5.30 Hz, 1H) 5.98 (m, 1H) 7.17 (dd, J = 8.73, 2.81 Hz, 1H) 7.28 (d, J = 9.05 Hz, 1H) 7.85 (d, J = 2.50 Hz, 1H) 8.03 (s, 1H) 9.34 (s, 1H) 10.80 (s, 1H).
EXAMPLE 89 18-Bromo-16-fluoro-12,13-dihydroxy-2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1, 3,6-benzodioxatriazacicloheptadecin-7-carbonitrilo
EXAMPLE 89A 2- (Allyloxp-5-bromo-1-fluoro-3-nitrobenzene) A mixture of 4-bromo-o-fluoro-2-nifrophenol (2 g, 8.49 mmol), allyl bromide (0.88 mL, 10.07 g) was stirred. mmoles) and K2CO3 (2.34 g, 16.98 mmol) in DMF (20 mL) at 45 ° C overnight The inorganic salts were filtered, and the filtrate was concentrated to give the crude product, which was used directly for the next iapa without further purification MS (DCI / NH3) m / z 245.92 (M + H) +; 1 H NMR (400 MHz, DMSO-D6) d ppm 4.70 (d, J = 6.14 Hz, 2H) 5.27 (d,
J = 10.43 Hz, 1H) 5.37 (dd, J = 17.18, 1.53 Hz, 1H) 5.92-6.02 (m, 1H) 8.03-8.06 (m, 2H).
EXAMPLE 89B 2- (Allyloxy) -5-bromo-3-fluoroaniline A mixture of Example 89A (1.3 g, 4.71 mmol), tin chloride dihydrate (5.3 g, 23.5 mmol) and isopylamine (13.1 mL, 94.2 mmol) was heated. ) in eilanol (50 mL) at 70 ° C for 6 hours, cooled. The insoluble material was filtered and washed extensively with ethyl acetate. The combined filtrate was concentrated, and the residue was purified by insanitary vaporization chromatography eluting with 5% acetyl ether in dichloromethane to provide the desired yield (638 mg, 55%). MS (DCI / NH3) m / z 247.82 (M + H) +; 1H NMR (500 MHz, DMSO-D6) d ppm 4.41 (d, J = 5.93 Hz, 2H) 5.20 (dd, J = 10.45, 1.72Hz, 1H) 5.30 (dd, J = 17.31, 1.72 Hz, 1H) 5.43 (s, 2H) 6.03 (m, 1H) 6.56 (dd, J = 10.29, 2.50 Hz, 1H) 6.66 (dd, J = 2.34, 1.72 Hz, 1H).
EXAMPLE 89C N-r2- (allyloxy) -5-bromo-3-fluorophenin-N, -r6- (but-3-enyloxy) -5-cyanopyrazin-2-inurea A solution of Example 89B (103 mg, 0.42 g. mmoles) and Example 7F (130 mg, 0.42 mmol) in DMF at 80 ° C for 24 hours, cooled and concentrated. The residue was triturated with a mixture of hexane and ethyl acetate to give the desired product (110 mg,
56%). MS (ESI) m / z 461.95 (M-H) +, 464.0 (M + H) +; 1H NMR (500 MHz, DMSO-D.) D ppm 2.55 (q, J = 6.61 Hz, 2H) 4.47 (t, J = 6.71 Hz, 2H) 4.62 (d, J = 6.10 Hz, 2H) 5.12 (d, J = 10.37 Hz, 1H) 5.19 (dd, J = 17.24, 1.68 Hz, 1H) 5.28 (d, J = 10.07 Hz, 1H) 5.35 (dd, J = 17.24, 1.37 Hz, 1H) 5.88 (m, 1H) 6.06 (m, 1H) 7.30 (dd, J = 10.53, 2.29 Hz, 1H) 8.24 (d, J = 1.83 Hz, 1H) 8.89 (s, 1H) 9.22 (s, 1H) 10.69 (s, 1H).
EXAMPLE 89D 18-Bromo-16-fluoro-2-oxo-2,3,11,14-tetrahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecin-7-carbonitrile stirred a mixture of Example 89C (100 mg, 0.22 mmol) and Grubbs Catalyst (2nd generation, 18 mg, 0.022 mmol) in CH2Cl2 (150 mL) at ambient temperature for 6 hours and concentrated. The residue was purified by flash chromatography eluting with 9% ethyl acetate in dichloromethane to provide the desired yield (60 mg, 64%). MS (ESI) m / z 433.95 (MH) "; 1H NMR (500 MHz, DMSO-D6) d ppm 2.68 (q, J = 7.93 Hz, 2H) 4.59 (d, J = 7.32Hz, 2H) 4.65-4.69 (m, 2H) 6.02 (m, 1H) 6.09 (m, 1H) 7.38 (dd, J = 10.37.2.14 Hz, 1H) 8.02 (s, 1H) 8.28 (m, 1H) 10.25 (s, 1H) 11.06 ( s, 1H).
EXAMPLE 89E 18-Bromo-16-fluoro-12,13-dihydroxy-2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazen-9,15,1,3, 6- benzodioxatriazacycloheptadecin-7-carbonitrile Example 89D (20 mg, 0.046 mmol) and N-methylmorpholine-N-oxide (16 mg, 0.14 mmol) were dissolved in a mixture of THF (10 mL) and H 2 O (1.1 mL). The resulting mixture was brought with 2.5% (wt%) of OsO 4 in 2-meityl-2-propanol (0.08 mL) at 0 ° C. The reaction mixture was stirred at room temperature for 5 hours and concentrated. The white precipitates were collected by filtration and washed with water completely. The compound of the title (19.2 mg, 89%) was obfuscated as a white solid. MS (ESI) m / z: 467.40 (MH) "; 1H NMR (400 MHz, DMSO-D6) d ppm 1.94 (m, 1H) 2.20 (m, 1H) 3.76-3.88 (m, 2H) 4.07 (m, 1H) 4.24 (m, 1H) 4.62 (m, 1H) 4.75-4.83 (m, 2H) 5.01 (d, J = 5.22 Hz, 1H) 7.37 (dd, J = 11.05, 2.45 Hz, 1H) 8.00 (s, 1H) 8.20 (s, 1H) 10.09 (s, 1H) 11.00 (s, 1H)
EXAMPLE 90 19-Chloro-2-oxo-2,3,10,11,14,15-hexahydro-1H-8,4-epiazeno-9,16,1,3,6-benzodioxatriazacyclohectadecin-7-carbonitrile
EXAMPLE 90A 1- (But-3-enyloxp-4-chloro-2-nitrobenzene) It was added to a solution of 3-buten-ol (1.08 mL, 12.53 mmol) in THF (30 mL) at 0 ° C NaH (60 mL). %, 592 mg, 14.81 mmol).
The mixture was stirred for 30 minutes, and 4-chloro-1-fluoro-2-niiromobenzene (2 g, 11.39 mmol) in THF (5 mL) was added dropwise. The reaction mixture was further stirred at 0 ° C for 2 hours, monitored in ice water and extracted with ethyl acetate. The organic layer was dried over MgSO4 and concentrated to give the desired product (2.5 g, 97%). MS (DCI / NH3) m / z: 244.95 (M + H) +; 1H NMR (400 MHz, DMSO-D6) d ppm 2.47 (q, J = 6.55 Hz, 2H) 4.22 (i, J = 6.60 Hz, 2H) 5.08 (d, J = 10.13 Hz, 1H) 5.15 (dd, J = 17.18, 1.84 Hz, 1H) 5.80-5.91 (m.1H) 7.42 (d, J = 9.21 Hz, 1H) 7.70 (dd, J = 9.21, 2.76 Hz, 1H) 8.00 (d, J = 2.76 Hz, 1H )
EXAMPLE 90B 2- (But-3-enyloxp-5-chloroaniline) A mixture of Example 90A (1 g, 4.39 mmol), iron powder (2.46 g, 43.9 mmol) and NH 4 Cl (117 mg, 2.20 mmol) were heated in Ethanol (36 mL) and water (9 mL) at 80 ° C for 5 hours The insoluble material was filtered, and the filtrate was concentrated The residue was purified by insanitary vapor chromatography eluting with 50% dichloromethane in hexane to give the desired product (750 mg, 86%) as a yellow solid MS (APCl) m / z 198.25 (M + H) +; 1H
NMR (400 MHz, DMSO-D6) d ppm 2.47 (q, J = 6.85 Hz, 2H) 3.96 (t,
J = 6.60 Hz, 2H) 4.94 (s, 2H) 5.08 (d, J = 10.43 Hz, 1H) 5.16 (dd,
J = 17.18, 2.15 Hz, 1H) 5.92 (m, 1H) 6.47 (dd, J = 8.59, 2.76 Hz, 1H)
6. 64 (d, J = 2.76 Hz, 1H) 6.76 (d, J = 8.29 Hz, 1H)
EXAMPLE 90C N-r2- (but-3-enyloxP-5-chlorophenip-N'-r6- (but-3-Tnilox¡) -5- cyanopyrazin-2-ipurea A mixture of Example 90B (710 mg, 3.59 g. mmoles) and Example 7F (1.11 g, 3.59 mmol) in DMF (10 mL) at 80 ° C for 24 hours, the solvent was removed, and the residue was rinsed with ethyl ether to give the desired yield (1.32 g, 89%) .SM (ST) m / z 414.15 (M + H) +, 412.10 (MH) "; 1 H NMR (400 MHz, DMSO-De) d ppm 2.53-2.58 (m, 4H) 4.15 (t, J = 6.75 Hz, 2H) 4.46 (í, J = 6.60 Hz, 2H) 5.11 (t, J = 10.43 Hz, 2H) 5.18 (dd, J = 17.18, 1.23 Hz, 2H) 5.83-5.99 (m, 2H) 7.04 -7.12 (m, 2H) 8.19 (d, J = 2.45 Hz, 1H) 8.91 (s, 2H) 10.72 (s, 1H).
EXAMPLE 90D (Cis) 19-chloro-2-oxo-2,3,10,11,14,15-hexahydro-1H-8,4-epiazen-9,16,1,3,6-benzodioxatriazacyclohectadecin-7-carbonitrile y. (trans) 19-chloro-2-oxo-2,3,10.11, 14.15-hexahydro-1 H-8,4-epiazen-9,16,1,3,6-benzodioxatriazazacyclooctadecin-7-carbonitrile A mixture of Example 90C (500 mg, 1.21 mmol) and the Grubbs Catalyst (2nd generation, 151 mg, 0.18 mmol) in CH2Cl2 (600 mL) at room temperature overnight and concentrated. The residue was purified by flash chromatography eluting with 9% acetyl of ethyl or in dichloromethane to give the cis-forming product (231 mg, 50%) and the
Irans conformation production (58 mg, 12%). Analytical Dats for Example 90: MS (ESI) m / z 384.14 (MH) "; 1 H NMR (400 MHz, DMSO-De) d ppm 2.52-2.58 (m, 4H) 4.16 (t, J = 4.91 Hz, 2H ) 4.49 (d, J = 8.29 Hz, 2H) 5.55-5.67 (m, 2H) 7.14 (dd, J = 8.90, 2.45 Hz, 1H) 7.27 (d, J = 8.90 Hz, 1H) 7.96 (d, J = 2.45 Hz, 1H) 8.00 (s, 1H) 9.77 (s, 1H) 10.95 (s, 1H) Analytical Damage for Example 90D: MS (ESI) m / z 384.11 (MH) -; 1H NMR (400 MHz, DMSO-D6) d ppm 2.34-2.45 (m, 4H) 4.10 (t, J = 5.06 Hz, 2H) 4.56 (d, J = 4.91 Hz, 2H) 5.54-5.57 (m, 2H) 7.07 (d, J = 8.90 Hz, 1H) 7.19 (dd, J = 8.90.2.45 Hz, 1H) 7.73 (d, J =: 2.76 Hz, 1H) 8.00 (s, 1H) 9.02 (s, 1H) 10.87 (s, 1H)
EXAMPLE 91 (12R, 13S) -19-Chloro-12,13-cis-dihydroxy-2-oxo-2,3,10,11,12,13,14,15-octahydro-1H-8,4-epiazeno-9, 16,1,3-benzodioxadiazacyclooctadecin-7-carbonitrile The desired production (19.6 mg, 90%) was prepared using a similar procedure described in Example 3, replacing Example 1 with the cis product of Example 90D. MS (ESI) m / z 418.09 (M-H) -; 1H NMR (500 MHz, DMSO-D6) d ppm 1.83-1.91 (m, 3H) 2.04 (m, 1H) 3.58 (m, 1H) 3.71 (m, 1H) 4.01 (m, 1H) 4.22 (m, 1H) 4.46 (m, 1H) 4.61-4.68 (m, 3H) 7.15-7.19 (m, 2H) 7.86 (d, J = 1.53 Hz, 1H) 8.00 (s, 1H) 9.49 (s, 1H) 10.94 (s, 1H) )
EXAMPLE 92 (12R, 13S) -19-chloro-12,13-trans-dihydroxy-2-oxo-2,3,10,11,12,13,14,15-octahydro-1H-8,4-epiazeno- 9,16,1,3-benzodioxadiazacyclooctadecin-7-carbonitrile The desired product (20 mg, 92%) was prepared using a similar procedure described in Example 3 by replacing Example 1 with the production of Example 90D. MS (ESI) m / z 418.16 (M-H) -; 1H NMR (400 MHz, DMSO-D6) d ppm 1.73 (m, 1H) 1.84-2.00 (m, 2H) 2.23 (m, 1H) 3.38 (m, 1H) 3.53 (m, 1H) 4.00 (i, J = 7.36 Hz, 1H) 4.35 (í, J = 8.13 Hz, 1H) 4.59 (í, J = 8.13 Hz, 2H) 4.72 (dd, J = 6.44, 4.60 Hz, 2H) 7.17 (s, 2H) 7.88 (s, 1H) 8.01 (s, 1H) 9.55 (s, 1H) 10.92 (s, 1H)
EXAMPLE 93 19-chloro-2-oxo-2,3.10.11,12,13,14,15-octahydro-1H-8,4-e? Iazeno- 9,16,1,3,6-benzodioxatriazaciclooctadecin-7 carbonitrile A mixture of 5% palladium-carbon (5 mg, 0.0024 mmol) and Example 90 (40 mg, 0.10 mmol) in THF (50 mL) was stirred under a hydrogen atmosphere for 7 hours. The palladium-carbon was removed by filtration through Celite. The filtrate was concentrated, and the residue was washed with methanol. The compound of the particle was produced in quantitative yield. MS (ESI) m / z: 386.08 (MH) "; 1 H NMR (400 MHz, DMSO-De) d ppm 1.43-1.59 (m, 4H) 1.74-1.92 (m, 4H) 4.15 (s, 2H) 4.52 ( t, J = 6.90 Hz, 2H) 7.15 (s, 2H) 7.96 (s, 1H) 8.00 (s, 1H) 9.61 (s, 1H) 10.91 (s, 1H).
EXAMPLE 94 18-Meti I -2-oxo-2,3, 11,14-tetrahydro-1H, 10 H-8,4-ep i azen o- 9,15,1,3,6-benzodioxatriazacicloheptadecin-7 -carbonitrile
EXAMPLE 94A 1- (Allyloxp-4-methyl-2-nitrobenzene) It was added to a mixture of 4-methyl-2-nitro-phenol (1.50 g, 9.80 mmol) and K2CO3 (2.03 g, 14.7 mmol) in acetone (23 mL allyl bromide (1.24 ml, 14.7 mmol) The reaction mixture was stirred at room temperature overnight, then heated at 40 ° C for 6 hours, the inorganic salts were filtered and washed with acetone. The mixture was concentrated and the residue was purified by flash chromatography eluting with hexane / EtOAc (95: 5) to give 1.67 g (88%) of the desired product MS (DCI / NH3) m / z: 211.0 (M + NH4) +; H NMR (300 MHz, DMSO-D6) d ppm 2.30 (s, 3H) 4.67-4.75 (m, 2H) 5.27 (m, 1H) 5.42 (m, 1H) 5.97 (m, 1H) 7.24 (d, J = 8.48 Hz, 1H) 7.45 (dd, J = 8.65, 2.20 Hz, 1H) 7.69 (d, J = 2.37 Hz, 1H).
EXAMPLE 94B 2- (Allyloxy) -5-methylaniline A mixture of Example 94A (1.50 g, 7.76 mmol), Fe (4.35 g, 77.6 mmol), NH 4 Cl (0.208 g, 3.90 mmol), and H 2 O (5 mL) were heated. in EtOH (20ml) at 90 ° C for 6 hours. The reaction mixture was cooled and filtered through celite. The filtrate was concentrated and the
The residue was purified by chroma- tography of insannant vaporization eluting with hexane / ethyl ether (95: 5) to give 0.542 g (43%) of the desired product. MS (ESI) m / z: 163.8 (M + H) +; 1 H NMR (300 MHz, CD 3 OD) d ppm 2.17 (s, 3 H) 4.51 (ddd, J = 5.26, 1.53, 1.53 Hz, 2 H) 5.23 (m, 1 H) 5.39 (m, 1 H) 6.08 (m, 1 H) 6.47 (dd, J = 8.14, 1.70 Hz, 1H) 6.60 (d, J = 2.03 Hz, 1H) 6.69 (d, J = 8.14 Hz, 1H).
EXAMPLE 94C N-r2- (allyloxP-5-methylphenylH-N'-r6- (but-3-enyloxy-5-cyanopyrazin-2-Purea) Example 94B (0.2 g, 1.13 mmol) and Example 7F were heated ( 0.418 g, 1.35 mmol) in DMF (13 mL) at 75 ° C for 5 hours The reaction mixture was cooled, diluted with ethyl ether, and washed with 50% brine and water. MgSO 4 and concentrated The unpurified product was purified by flash chromatography eluting with hexane / ethyl acetate (7: 3 to 5: 5) to give 76.2 mg of the desired product MS (ESI) m / z: 380.0 ( M + H) +; 1 H NMR (300 MHz, CDCl 3) d ppm 2.35 (s, 3H) 2.56 (td, J = 6.44, 6.44 Hz, 2H) 4.48 (t, J = 6.61 Hz, 2H) 4.59 (d, J = 6.90 Hz, 2H) 5.06-5.19 (m, 2H) 5.25-5.39 (m, 2H) 5.83 (m, 1H) 5.99 (m, 1H) 6.83 (m, 1H) 6.92 (m, 1H) 7.89 (s) , 1H) 8.15 (s; 1H) 8.42 (s, 1H) 9.56 (s, 1H).
EXAMPLE 94D 18 - et i I -2 -oxo -2, 3,11, 14-tetrahydro-1 H, 10H-8,4-epiazeno- 9,15,1,3,6-benzodioxatriazacycloheptadecin-7-carbonitrile It was brought Example 94C (40 mg, 0.11 mmol) in CH2Cl2 (55 mL) was obtained with the Grubbs II (13.4 mg, 0.016 mmol). The reaction mixture was stirred at 40 ° C overnight. Solvent was evaporated and the residue was purified by flash chromatography eluting with hexane / ethyl ether / dichloromethane (7.5: 2: 0.5 to 6: 3: 1) to give 4.0 mg of the desired product. MS (ESI) m / z: 351.7 (M + H) +; 1H NMR (400 MHz, CDCl 3) d ppm 2.35 (s, 3H) 2.76 (id, J = 7.06, 7.06 Hz, 2H) 4.60 (d, J = 6.75 Hz, 2H) 4.76 (t, J = 7.36 Hz, 2H ) 5.98-6.13 (m, 2H) 6.82-6.95 (m, 2H) 7.93 (s, 1H) 7.98 (s, 1H) 9.40 (s, 1H) 10.43 (s, 1H).
EXAMPLE 95 18-Methyl-2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecin-7-carbonitrile added to a solution of Example 94D (21.2 mg, 0.0603 mmol) in THF (4 mL) 10% Pd / C (5.3 mg). The reaction mixture was agitated under hydrogen (a balloon was used) for 2.5 hours. Solvent was evaporated and the residue was evaporated with DMSO / MeOH (1: 1). The solid was filtered and washed with DMF, the filtrate was purified by reverse phase preparative HPLC to give 2.4 mg of the desired product. LC / MS (APCl) m / z: 354.7 (M + H) +; 1 H NMR (500 MHz, DMSO-De) d ppm 1.51-1.64 (m, 2H) 1.75 -1.85 (m, 2H) 1.89-
2. 01 (m, 2H) 2.25 (s, 3H) 4.14 (t, J = 5.03 Hz, 2H) 4.61 (i, J = 8.00 Hz, 2H) 6.88 (d, J = 8.24 Hz, 1H) 6.99 (d, J = 8.24 Hz, 1H) 7.91 (s, 1H) 7.99 (s, 1H) 9.85 (s, 1H) 10.83 (s, 1H).
EXAMPLE 96 16-bromo-18-methyl-2-oxo-2,3,11,14-tetrahydro-1H, 10H-8,4-epiazeno-9,15.1.3.6-benzodioxatriazacicloheptadecin-7-carbonitrile
EXAMPLE 96A 2- (allyloxp-1-bromo-5-methyl-3-nitrobenzene) A mixture of 2-bromo-4-methyl-6-niiophenol (7.00 g, 30.2 mmol), K2CO3 (6.26 g, 45.3 mmol) was added. in aceilone (105 mL) allyl bromide (3.80 mL, 45.3 mmol) The reaction mixture was agitated at room temperature overnight, then heated to 40 ° C. for 5 hours inorganic salts were filtered and washed with acetone. The filtrate was concentrated to give 7.74 g (94%) of the desired production MS (DCI / NH3) m / z: 289.0 (M + NH4) +; 1H NMR (300 MHz, CD3OD) d ppm 2.37 (s, 3H ) 4.61 (d, J = 6.10 Hz, 2H) 5.26 (dd, J = 10.51, 1.80 Hz, 1H) 5.39 (dd, J = 17.29, 1.80 Hz, 1H) 6.09 (m, 1H) 7.63 (s, 1H) 7.74 (s, 1H).
EXAMPLE 96B 2- (Allyloxy) -3-bromo-5-methylaniline A mixture of Example 96A (7.74 g, 28.5 mmol) was heated,
Fe (15.9 g, 285 mmol), NH 4 Cl (0.762 g, 14.3 mmol), and H 2 O (18.4 mL) in EOH (73 mL) at 90 ° C lasted 5 hours. The reaction mixture was cooled and filtered through celite. The reaction mixture was concentrated, evaporated with ethyl acetate, and washed with water and brine. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by flash chromatography eluting with hexane / ethyl acetate (95: 5) to give 4.62 g (67%) of the desired product. MS (ESI) m / z: 241.8 (M + H) +; 1H NMR (300 MHz, CDCl 3) d ppm 2.20 (s, 3H) 4.46 (ddd, J = 5.76, 1.36, 1.36 Hz, 2H) 5.25 (m, 1H) 5.45 (m, 1H) 6.13 (m, 1H) 6.51 (d, J = 2.03 Hz, 1H) 6.75 (d, J = 2.03 Hz, 1H).
EXAMPLE 96C N-.2- (allyloxy) -3-bromo-5-methylphen-N-r6- (but-3-enyloxp-5-cyanopyrazin-2-inurea Example 96B (3.75 g, 15.5 mmol) was heated and Example 7F (3.58 g, 11.5 mmoies) in DMF (100 mL) at 85 ° C overnight was cooled, diluted with ethyl acetate, and washed with 50% brine and water. The organic layer was dried over MgSO4 and concentrated.The unpurified product was purified by flash chromatography eluting with hexane / ethyl acetate / dichloromean (9: 1: 2 to 8: 1: 2) to give 2.55 g (48%). ) of the desired production MS (ESI) m / z: 457.9 (M + H) +; 1 H NMR (300 MHz, CDCl 3) d ppm 2.34 (s, 3H) 2.58 (id, J = 6.78, 6.78 Hz, 2H) 4.45 (d, J = 6.44 Hz, 2H) 4.54 (í, J = 6.95 Hz, 2H) 5.04-5.33 (m, 4H)
. 76-6.10 (m, 2H) 7.17 (s, 1H) 7.85 (s, 1H) 8.07 (s, 1H) 8.21 (s, 1H) 10.01 (s, 1H).
EXAMPLE 96D 16-Bromo-18-methyl I -2-oxo-2,3, 11,14-tetrahydro-1 H, 10 H-8, 4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecin-7 carbonitrile Example 96C (1.55 g, 3.38 mmol) in CH2Cl2 (1600 mL) was chartered with Grubbs II Catalyst (212 mg, 0.34 mmol). The reaction mixture was stirred at 40 ° C overnight. The solvent was evaporated and the residue was purified by flash chromatography eluting with dichloromethane / ethyl acetyle (95: 5 to 85:15) to give 1.05 g (72%) of the desired product. MS (ESI) m / z: 428.0 (M-H) +; 1 H NMR (300 MHz, CDCl 3) d ppm 2.35 (s, 3H) 2.74 (id, J = 8.36, 8.36 Hz, 2H) 4.48 (d, J = 7.46 Hz, 2H) 4.68-4.85 (m, 2H) 5.97 ( m, 1H) 6.22 (m, 1H) 7.18 (s, 1H) 7.91 (s, 1H) 8.09 (s, 1H) 8.80 (s, 1H) 10.34 (s, 1H).
EXAMPLE 97 16-Bromo-18-methyl-2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecin- 7- carbonitrile To a solution of Example 96D (36.1 mg, 0.0839 mmol) in THF (5 mL) was added 10% Pd / C (7.2 mg). The reaction mixture was stirred under hydrogen (a balloon was used) for 2.5 hours. The reaction mixture was diluted with MeOH and the calycalizer was filtered. He
The filtrate was concentrated and the residue was triturated with ether to give 23.1 mg (64%) of the desired product as a gray solid. MS (ESI) m / z: 430.1 (M-H) +; 1H NMR (300 MHz, DMSO-D6) d ppm 1.56-1.67 (m, 2H) 1.85-1.98 (m, 4H) 2.28 (s, 3H) 4.04 (t, J = 5.26 Hz, 2H) 4.85 (t, J = 6.95 Hz, 2H) 7.20 (d, J = 1.50 Hz, 1H) 8.00 (s, 1H) 8.03 (d, J = 1.36 Hz, 1H) 10.45 (s, 1H) 10.96 (s, 1H).
EXAMPLE 98 16- (3-Hydroxyprop-1-iniP-18-methyl I-2-OXO-2.3, 11, 12, 13, 14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1, 3,6-benzodioxatriazacycloheptadecin-7-carbonitrile A mixture of Example 97 (20.0 mg, 0.0463 mmol), Cul (2.0 mg), Pd (dppf) CI2.CH2Cl2 (3.8 mg), triethylamine (39 μL, 0.278 mmol) was heated. , and propargyl alcohol (16 μL, 0.278 mmol) in DMF (1 mL) in a microwave oven (Explorer from CEM Corp.) at 150 ° C for 65 minutes The unpurified product was purified by using reverse phase preparative HPLC. to give 2.0 mg of the desired product MS (DCI / NH3) m / z: 408.2 (M + H) +; 1H NMR (400 MHz, CD3OD) d ppm 1.67-1.76 (m, 2H) 1.97-2.09 (m, 4H) 2.27 (s, 3H) 4.26 (t, J = 4.80 Hz, 2H) 4.44 (s, 2H) 4.92 (í, J = 6.90 Hz, 2H) 6.96 (s, 1H) 7.89 (s, 1H) 8.05 ( s, 1H) 10.55 (s, 1H).
EXAMPLE 99 18-Chloro-2-oxo-2,3,11,14-tetrahydro-1H, 10H-8,4- epiazenopiomer2.3-b1f1,12,4,6,91-dioxatriazacycloheptadecin-7-carbonitrile
EXAMPLE 99A 2- (Allyloxp-5-chloro-3-nitropyridine) It was added to a mixture of 5-chloro-3-nitro-pyridin-2-ol (0.600 g, 3.4 mmol), DBAD (1.19 g, 5.16 mmol), pyridylphosphine-supported polymer (3 mmol / g, 1.70 g, 5.16 mmol) in THF (18 mL) allyl alcohol (0.42 mL, 6.12 mmol) The reaction mixture was stirred at room temperature overnight, filtered through The residue was purified by flash chromatography eluting with hexane / ethyl acetate (95: 5 to 1: 1) to give 0.120 g (15%) of the desired production MS (DCI / NH3). ) m / z: 214.9 (M + H) +; 1 H NMR (300 MHz, CDCl 3) d ppm 5.01 (ddd, J = 5.34, 1.40, 1.40 Hz, 2H) 5.32 (dd, J = 10.51, 1.36 Hz, 1H ) 5.49 (dd, J = 17.12.1.53 Hz, 1H) 6.06 (m, 1H) 8.28 (d, J = 2.37 Hz, 1H) 8.34 (d, J = 2.37 Hz, 1H).
EXAMPLE 99B 2- (Allyloxy) -5-chloropyridin-3-amine A mixture of Example 99A (0.120 g, 0.559 mmol), Fe (0.313 g, 5.59 mmol), NH4CI (0.0150 g, 0.28 mmol), and H2O was heated. (0.40 ml) in EtOH (1.4 mL) at 90 ° C for 5 hours. Mix
The reaction mixture was cooled and filtered through celite. The filtrate was concentrated, brought with oil, and washed with water and brine. The organic layer was dried over MgSO4 and concentrated. The unpurified product was purified by instantaneous vaporization chromatography eluting with hexane / ethyl acetate (9: 1) to give 23.3 mg (23%) of the desired product. LC / MS (APCl) m / z: 185.2 (M + H) +; 1 H NMR (300 MHz, CDCl 3) d ppm 2.97 (s, 2 H, brd) 4.87 (d, J = 5.43 Hz, 2 H) 5.26 (dd, J = 10.51, 1.02 Hz, 1 H) 5.38 (dd, J = 17.12, 1.53 Hz, 1H) 6.09 (m, 1H) 6.90 (d, J = 2.37 Hz, 1H) 7.49 (d, J = 2.03 Hz, 1H).
EXAMPLE 99C N-r2- (allyloxP-5-chloropyridin-3-ip-N'-r6- (but-3-enyloxp-5-cyanopyrazin-2-illurea) Example 99B (23.3 mg, 0.128 mmol) was heated and the Example 7F (47.5 mg, 0.153 mmol) in DMF (2 mL) at 85 ° C for 5 hours The reaction mixture was cooled, dilated with ethyl acetate, and washed with 50% brine and water. The organic was dried over MgSO4 and concentrated, the crude product was purified by flash chromatography eluting with hexane / ethyl acetate / dichloromean (8: 2: 1) to give 10.0 mg
(20%) of the desired production. MS (ESI) m / z: 401.2 (M + H) +; 1H NMR
(400 MHz, CDCI3) d ppm 2.59 (id, J = 6.44, 6.44 Hz, 2H) 4.51 (t,
J = 6.44 Hz, 2H) 4.95 (d, J = 5.52Hz, 2H) 5.04-5.22 (m, 2H) 5.24-5.42
(m, 2H) 5.84 (m, 1H) 6.05 (m, 1H) 7.86 (s, 1H) 8.12 (s, 1H) 8.26 (s, 1H) 8.50 (s, 1H) 9.59 (s, 1H).
EXAMPLE 99D 18-Chloro-2-oxo-2,3,11,14-tetrahydro-1H, 10H-8,4-epiazenopyridof2,3-bl ri, 12,4,6,91-dioxatriazacycloheptadecin-7-carbonitrile Example 99C was brought ( 9.0 mg, 0.022 mmol) in CH2Cl2 (8 mL) with the second generation Grubbs Catalyst (2.1 mg, 0.0034 mmol). The reaction mixture was stirred at 40 ° C overnight. The solvent was evaporated and the residue was purified by flash chromatography eluting with dichloromethane / methanol (9: 1) to give 2.9 mg (36%) of the desired product. MS (ESI) m / z: 371.1 (M-H) +; 'H NMR (400 MHz, CDCl 3) d ppm 2.68-2.95 (m, 2H) 4.73 (,, J = 7.82Hz, 2H) 5.01 (d, J = 7.06 Hz, 2H) 5.98 (m, 1H) 6.11 (m , 1H) 7.84 (s, 1H) 7.88 (s, 1H) 8.30 (s, 1H) 8.47 (s, 1H) 10.37 (s, 1H).
EXAMPLE 100 18-Chloro-17-hydroxy-2-oxo-2,3,11.12,13,14-hexahydro-1H, 10H-8,4-metheno-9,15,1,3-benzodioxadiazacycloheptadecin-7-carbonitri I'm
EXAMPLE 100A 2- (Methyl but-3-enyloxp-4-nitrobenzoate) 2-Hydroxy-4-nitrobenzoic acid was converted to the methylated ester a solution of the acid in methanol with a caylalitic amount of concentrated sulfuric acid. , 20.3 mmol) was dissolved in THF (100 mL), then the PPh3 soporide was added by polymer (20 g, 3 mmol / g PPh3, 60.0 mmol), 3-
buten-1-ol (2.2 mL, 1.8 g, 25.7 mmol), and di-tert-butylazodicarboxylane (5.4 g, 23.5 mmol). After stirring at room temperature during the night, more 3-buyen-1-ol (0.8 mL, 0.7 g, 9.7 mmol) and di-buylazodicarboxylate (2.0 g, 8.7 mmol) were added and the reaction was agitated on another day. environmental ambience. The reaction then was filtered through celite, the reaction was washed with EtOAc, and the filtrate was concentrated. The unpurified product was purified by column chromatography using 9/1 hexanes / EtOAc. The product (4.2 g, 84%) was recovered as very pale yellow solids. MS (DCI / NH3) m / z: 252 (M + H) +; 1 H NMR (300 MHz, DMSO-de) d ppm 2.46-2.55 (m, 2H), 3.83 (s, 3H), 4.24 (i, J = 6.4 Hz, 2H), 5.09 (m, 1H), 5.18 (m , 1H), 5.90 (m, 1H), 7.83-7.87 (m, 2H), 7.88 (s, 1H).
EXAMPLE 100B 2- (But-3-enyloxy) -4-nitrobenzamide The compound described in Example 100A was saponified by stirring in methanol and 4N NaOH at ambient temperature overnight. This acid (4.0 g, 16.7 mmol) was dissolved in DMF (35 mL), then HOBT (2.5 g, 18.5 mmol) and EDCl-HCl (3.5 g, 18.3 mmol) were added and stirred at ambient temperature for 75 min. Then NH4OH conc. (0.0 mL) and the reaction was stirred at room temperature for 4 days. Water (450 mL) was added, the resulting solids were filtered and dried to give the product (3.6 g, 90%) as white solids. MS (DCI / NH3) m / z: 237 (M + H) +;
1 H NMR (300 MHz, DMSO-d 6) d ppm 2.53-2.62 (m, 2H), 4.31 (t, J = 6.1Hz, 2H), 5.11 (m, 1H), 5.20 (m, 1H), 5.92 (m , 1H), 7.66 (br s, 1H), 7.85 (br s, 1H), 7.84-7.89 (m, 2H), 7.93 (m, 1H).
EXAMPLE 100C 2- (But-3-enyloxp-4-nitrobenzonitrile The compound described in Example 100B (3.6 g, 15.1 mmol) was stirred in THF (30 mL), cooled in a water bath with ice, then added trieylamine (0.3 mL, 4.6 g, 45.3 mmol) and the reaction was stirred for 10 min.It was then added anhydride of trifluoroacetic acid (3.2 mL, 4.8 g, 22.6 mmol) to gofas at more than 10 min. in cold under N2 for 50 min, then the bath was removed and the stirring continued for another 70 min, then the reaction was carried out on ice, then E2O2 and water was added, it was washed with the organic layer 2M Na2CO3 and brine. drying the organic layer over Na2SO, filtration and the production concentration (3.5 g, 100%) were recovered as yellow-brown solids MS (DCI / NH3) m / z: 236 (M + H + NH3) +; 1 H NMR (300 MHz, DMSO-de) d ppm 2.53-2.59 (m, 2H), 4.37 (,, J = 6.4 Hz, 2H), 5.12 (m, 1H), 5.21 (m, 1H), 5.90 (m , 1H), 7.90 (dd, J = 8.5 and 2.0 Hz, 1H), 7.99 (d, J = 2.0 Hz, 1H), 8.07 (d, J = 8.5 Hz, 1H).
EXAMPLE 100D 4-Amino-2- (but-3-enyloxy) benzonitrile The compound described in Example 100C (1.5 g,
6. 9 mmol) in THF (35 mL), then a solution of NH CI (0.41 g, 7.7 mmol) in water (17 mL) was added, followed by the addition of iron powder (1.9 g, 34.0 mmol). The reaction was heated to 85CC for 2.5 h. More NH4CI (0.57 g, 10.6 mmol) and iron powder (1.5 g, 26.9 mmol) were added and the heating continued for 2.5 h. The reaction then cooled to ambient air, filtered through celite, and concentrated. The residue was partitioned between EOAc and 2M Na2CO3, then the organic layer was washed with brine and dried over Na2SO4. After filtration and concentration, the product was recovered (1.3 g, 100%) as an orange syrup. MS (DCI / NHs) m / z: 206 (M + H + NH 3) +; 1 H NMR (300 MHz, DMSO-d 6) d ppm 2.44-2.53 (m, 2H), 4.02 (t, J = 6.8 Hz, 2H), 5.10 (m, 1H), 5.18 (m, 1H), 5.93 (m , 1H), 6.18 (dd, J = 8.5 and 2.0 Hz, 1H), 6.24 (d, J = 2.0 Hz, 1H), 7.22 (d, J = 8.5 Hz, 1H).
EXAMPLE 100E 3- (Phenyl but-3-enyloxp-4-cyanophenylcarbamate) The compound described in Example 100D (1.3 g, 6.9 mmol) was dissolved in CH 3 CN (20 mL), cooled to 0 ° C, then diisopropylethylamine was added. (1.3 mL, 0.96 g, 7.5 mmol) followed by the addition in phenyl chloroformia gofas (1.0 mL, 1.2 g, 7.7 mmol) The reaction was stirred cold for 1 h, during which time the layer chromatography The reaction was then poured onto ice, then E2O2 was added and the reaction was then poured into ice.
2M Na2CO3. The organic layer was washed with brine and dried over Na2SO4. After filtration and concentration the product (2.2 g, 100%) was recovered as orange solids and the next step was continued without purification. MS (DCI / NH3) m / z: 326 (M + H + NH3) +.
EXAMPLE 100F N- (2- (allyloxp-5-chloro-4-fr2- (trimethylsilylPethoxy-1-methoxy-phenyl-N'-r3- (but-3-enyloxy) -4-cyanophenurea urea The compound described in Example 100E (322 mg , 1.04 mmol) and the compound described in Example 10D (295 mg, 0.90 mmol) were dissolved in DMF (1.0 mL) and heated at 50 [deg.] C. overnight, the next day, the temperature was raised to 100 [deg.] C. The reaction was then cooled to ambient temperature and partitioned between water and EtOAc The organic layer was washed with brine and dried over Na2SO4 Unpurified material was purified by chromatography column using 65/35 hexanes / EtOAc to give the product (260 mg, 53%) MS (ESI) m / z: 544 and 546 (M + H) +; 1H NMR (300 MHz, DMSO-d6) d ppm 0.01 (s, 9H), 0.91 (t, J = 8.1 Hz, 2H), 2.51-2.59 (m, 2H), 3.78 (t, J = 8.1 Hz, 2H), 4.16 (t, J = 6.5 Hz, 2H), 4.69-4.73 (m, 2H), 5.13 (m, 1H), 5.21 (m, 1H), 5.29 (s, 2H), 5:34 (m, 1H), 5.47 (m, 1H), 5.92 (m, 1H), 6.10 (m, 1H), 6.99 (dd, J = 8.5 and 2.0 Hz, 1H), 7.01 (s, 1H), 7.51 (d, J = 2.0 Hz, 1H), 7.60 (d, J = 8.5 Hz, 1H), 8.14 (s, 1H), 8.28 (s, 1H), 9.81 (s, 1H).
EXAMPLE 100G 18-Chloro-17-hydroxy-2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-methano-9,15,1,3-benzodioxadiazacycloheptadecin-7 carbonitrile
The compound of the title compound described in Example 100F was prepared by the following sequence. 1) Cyclization as described in Example 1, but replacing the Hoyveda-Grubbs tracer by the second generation tracer and running the reaction in 1,2-dichloroethane at 85 ° C for 2 hours instead of dichloromean at 50 ° C for 1 hour. the night. 2) The reduction as described in Example 2 but substituting palladium on carbon for platinum on carbon and running the reaction in THF instead of THF-MeOH. 3) A deprotection of the phenol by stirring in MeOH-dioxane with a caylalicity of conc. HCl. at ambient temperature for 90 min., followed by purification using preparative HPLC. MS (DCI / NH3) m / z: 405 and 407 (M + H + NH3) +; 1 H NMR (400 MHz, DMSO-d 6) d ppm 1.52-1.59 (m, 2H), 1.75-1.81 (m, 2H), 1.81-1.89 (m, 2H), 4.01-4.07 (m, 2H), 4.30- 4.35 (m, 2H), 6.63 (s, 1H), 6.65 (d, J = 8.6 Hz, 1H), 7.28 (s, 1H), 7.60 (d, J = 8.6 Hz, 1H), 7.78 (s, 1H) ), 8.07 (s, 1H), 9.25 (s, 1H), 9.90 (s, 1H).
EXAMPLE 101 11,12-Cis-dihydroxy-18-nitro-2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6- benzodioxatriazacycloheptadecin-7-carbonitrile Example 83E (15 mg, 0.04 mmol) was oxidized using a
similar procedure described in Example 55D to give the title compound (3.9 mg, 24%). MS (ESI) m / z 415.12 (MH) "; 1 H NMR (500 MHz, DMSO-D6) d ppm 1.93 (m, 1H) 2.17 (m, 1H) 3.84 (m, 1H) 4.21 (m, 1H) 4.37 (,, J = 9.61 Hz, 1H) 4.52-4.64 (m, 2H) 4.77 (dd, J = 11.44, 2.90 Hz, 1H) 4.97 (d, J = 4.88 Hz, 1H) .5.17 (d, J = 5.19 Hz, 1H) 7.42 (d, J = 9.15 Hz, 1H) 8.02-8.12 (m, 2H) 9.10 (d, J = 2.75 Hz, 1H) 10.18 (s, 1H) 11.09 (s, 1H).
EXAMPLE 102 11,12-Trans-dihydroxy-18-nitro-2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1,3, 6-benzodioxatriazacicloheptadecin- 7-carbonitrilo
EXAMPLE 102A (Trans) 18-nitro-2-oxo-2,3,13,14-tetrahydro-1 H, 10H-8.4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecin-7-carbonitrile The desired product was prepared (13.5 mg, 8%) using the same procedure in Example 83. MS (ESI) m / z 381.19 (MH) "; 1H NMR (500 MHz, DMSO-D6) d ppm 2.39-2.47 (m, 2H) 4.41 (,, J = 5.63 Hz, 2H) 4.89-4.94 (m, 2H) 5.66 (m, 1H) 5.74 (m, 1H) 7.37 (d, J = 9.14 Hz, 1H) 8.02 (s, 1H) 8.07 (dd) , J = 9.14, 2.74 Hz, 1H) 8.70 (d, J = 2.74 Hz, 1H) 9.31 (s, 1H) 10.97 (s, 1H).
EXAMPLE 102B 11,12-Trans-Dihydroxy-18-nitro-2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6- benzodioxatriazacycloheptadecin-7-carbonitrile Example 102A (12.3 mg, 0.032 mmol) was oxidized using a similar procedure described in Example 55D to give the title compound (2.3 mg, 17%). MS (ESI) m / z 415.04 (MH) "; 1H NMR (500 MHz, DMSO-D6) S ppm 2.01 (q, J = 4.78 Hz, 2H) 3.58 (m, 1H) 4.04 (m, 1H) 4.42 ( t, J = 5.19 Hz, 2H) 4.52 (m, 1H) 4.76 (dd, J = 11.44, 2.29 Hz, 1H) 5.08 (d, J = 4.58 Hz, 1H) 5.16 (d, J = 5.19 Hz, 1H) 7.42 (d, J = 9.46 Hz, 1H) 7.97-8.08 (m, 2H) 9.12 (d, J = 3.05 Hz, 1H) 10.12 (s, 1H) 11.05 (s, 1H).
EXAMPLE 103 18-Ethoxy-2,13-d-hydroxy-2-oxo-2,3,11,12,13,14-hexahydro-1H.10H-8,4-epiazeno-9,15.1.3.6-benzodioxatriazacycloheptadecin- 7- carbonitrile Example 84C (58.2 mg, 0.15 mmol) was oxidized using a similar procedure described in Example 55D to give the title compound (10.1 mg, 16%). MS (ESI) m / z 414.21 (M-H) "; 1H
NMR (500 MHz, DMSO-D6) d ppm 1.37 (I, J = 7.02 Hz, 3H) 1.98 (m,
1H) 2.41 (m, 1H) 3.81-3.91 (m, 2H) 4.02 (q, J = 6.81 Hz, 2H) 4.07
4. 17 (m, 2H) 4.67 (m, 1H) 4.76 (m, 1H) 4.95 (d, J = 4.88 Hz, 1H)
. 12 (d, J = 5.19 Hz, 1H) 6.72 (dd ,, J = 9.00, 2.90 Hz, 1H) 7.10 (d, J = 9.15 Hz, 1H) 7.81 (d, J = 3.05 Hz, 1H) 8.05 (s) , 1H) 9.81 (s, 1H)
. 91 (s, 1H)
EXAMPLE 104 18-Methoxy-2-oxo-2,3,11,14-tetrahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecin-7-carbonitrile
EXAMPLE 104A 2-r2- (AilyloxP-5-methoxyfenp-1H-isoindole-1,3 (2H) -diopa A mixture of Example 84A (0.69 g, 2.34 mmol), iodomethane (0.58 mL, 9.34 mmol) was stirred. and K2CO3 (1.61 g, 11.68 mmol) in acetone (20 mL), and refluxed for 3 hours, cooled, the solution was filtered, dried with silica gel powder (10 g). % acetylation of ethyl in hexanes (2 L) to run in insannant vaporization chroma- ography The compound was obtained (377 mg, 52%) MS (APCl) m / z 310 (M + H) +.
EXAMPLE 104B 2- (Allyloxy) -5-methoxyaniline Example 104A (377 mg, 1.21 mmol) was dissolved in meianol (50 mL). H2NNH2 (0.114 mL, 3.65 mmol) was added. The reaction was run at room temperature for 3 hours. The solvents were removed by a vacuum pump. The residue was dissolved in aceine (20 mL). The solution was dried with silica gel powder (10 g). 15% ethyl acetate in hexanes (2 L) was used to run in insanitary vaporization chromatography to give the compound of
íííulo (210.6 mg, 97%). MS (DCl) m / z 180.03 (M + H) +; 1 H NMR (300 MHz, CDCl 3) d ppm 3.74 (s, 3 H) 4.53 (,, J = 1.36 Hz, 1 H) 4.55 (,, J = 1.53 Hz, 1 H) 5.24 (m, 1 H) 5.41 (m, 1 H) 6.08 (m, 1H) 6.43 (dd, J = 8.82, 2.71 Hz, 1H) 6.68 (d, J = 3.05 Hz, 1H) 6.78 (d, J = 8.82 Hz, 1H)
EXAMPLE 104C N-F2- (allyloxy) -5-methoxyphenn-N'-f6- (but-3-enyloxy) -5-cyanopyrazin-2-illurea Example 104B (210.5 mg, 1.17 mmol) was coupled and the Example 7F (364.1 mg, 1.17 mmol) using a similar procedure described in Example 60C to give the title compound (430.8 mg, 92%). MS (ESI) m / z 394.12 (MH) "; 1 H NMR (500 MHz, DMSO-De) d ppm 2.54 (q, J = 6.71 Hz, 2H) 3.70 (s, 3H) 4.46 (t, J = 6.56 Hz , 2H) 4.62 (d, J = 5.49 Hz, 2H) 5.12 (d, J = 10.37 Hz, 1H) 5.18 (dd, J = 17.24, 1.68 Hz, 1H) 5.28 (dd, J = 10.68, 1.22 Hz, 1H ) 5.41 (dd, J = 17.39, 1.53 Hz, 1H) 5.88 (m, 1H) 6.08 (m, 1H) 6.58 (dd, J = 9.15, 3.05 Hz, 1H) 6.98 (d, J = 9.15 Hz, 1H) 7.79 (d, J = 3.05 Hz, 1H) 8.88 (s, 1H) 8.99 (s, 1H) 10.69 (s, 1H)
EXAMPLE 104D 18-Methoxy-2-oxo-2,3,11,14-tetrahydro-1H, 10H-8,4-epiazeno-9,15,1, 3,6-benzodioxatriazacycloheptadecin-7-carbonitrile Example 104C was cyclized (430.8 mg, 1.09 mmol) using a similar procedure described in Example 55C to give the thioule compound (148.7 mg, 37%). MS (ESI) m / z 366.16 (M-H) ";
1H NMR (500 MHz, DMSO-D6) d ppm 2.69 (q, J = 7.53 Hz, 2H) 3.71 (s, 3H) 4.61 (d, J = 7.32 Hz, 2H) 4.68 (i, J = 7.48 Hz, 2H ) 5.98 (m, 1H) 6.08 (m, 1H) 6.63 (dd, J = 8.85, 3.05 Hz, 1H) 7.09 (d, J = 9.15 Hz, 1H) 7.72 (d, J = 3.05 Hz, 1H) 7.98 ( s, 1H) 10.27 (s, 1H) 10.87 (s, 1H)
EXAMPLE 105 2-Oxo-18-r2- (tetrahydro-2H-pyran-2-yloxypetox-2,3.11.14-tetrahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecin-7 -carbonitrile
EXAMPLE 105A 2-. { 2- (Allyloxy) -5-r2- (tetrahydro-2H-? -ran-2-yloxy) ethoxyphenyl > -1H- isoindol-1,3 (2H) -dione The mixture of Example 84A (0.69 g, 2.34 mmol), 2- (2-bromoeloxi) i.erahydro-2H-pyran (1.41 mL, 9.34 mmol) was refluxed and refluxed. K2CO3 (1.61 g, 11.68 mmol) in aceilone (20 mL) lasted overnight and was cooled. The solution was filtered, dried with silica gel powder (10 g). 20% ethyl acetate in hexanes (1 L) and 30% ethyl acetate in hexanes (1 L) were used to run in instantaneous vaporization chromatography. The compound of the title was obtained (265.3 mg, 27%). MS (APCl) m / z 424 (M + H) +.
EXAMPLE 105B 2- (Allyloxy) -5-f2 - (tetrahydro-2H-pyran-2-yloxy) ethoxylaniline Example 105A (265.3 mg, 0.63 mmol) was dissolved in
meianol (50 mL). H2NNH2 (0.12 mL, 3.60 mmol) was added. The reaction was stirred at room temperature for 3 hours. Then the solveníes were eliminated by means of a vacuum pump. The residue was dissolved in aceine (20 mL). The solution was dried with silica gel powder (10 g). 20% acetyl efflux in hexanes (2 L) was used to run in chroma- tography of insanitary vaporization to give the compound of the title (189.5 mg, 100%). MS (DCl) m / z 294.13 (M + H) +; 'H NMR (300 MHz, CDC13) 6 ppm 1.55-1.94 (m, 6 H) 3.73-3.82 (m, 2H) 3.98 (t, J = 4.75 Hz, 1H) 4.04-4.11 (m, 3H) 4.53 (d, J = 5.43 Hz, 2H) 4.70 (i, J = 3.56 Hz, 1H) 5.25 (m, 1H) 5.40 (m, 1H) 6.07 (m, 1H) 6.40 (dd, J = 8.82, 2.71 Hz, 1H) 6.61 (d, J = 2.71 Hz, 1H) 6.75 (d, J = 8.82 Hz, 1H).
EXAMPLE 105C N-. { 2- (allyloxp-5-r2- (tetrahydro-2H-pyran-2-yloxpetoxpfeniP-N'-r6- (but-3-enyloxy) -5-cyanopyrazin-2-inurea Example 105B was coupled (187.6 mg, 0.64 mmoles) and Example 7F (198.2 mg, 0.64 mmol) using a similar procedure described in Example 60C to give the title compound (263.9 mg, 81%) MS (ESI) m / z 508.36 (MH) "; NMR (500 MHz, DMSO-De) d ppm 1.41-1.55 (m, 4H) 1.63 (m, 1H) 1.75 (m, 1H) 2.54 (q, J = 6.51 Hz, 2H) 3.45 (m, 1H) 3.69 ( m, 1H) 3.79 (m, 1H) 3.90 (m, 1H) 3.97 (t, J = 6.71 Hz, 1H) 4.05 (i, J = 4.58 Hz, 2H) 4.46 (t, J = 6.71 Hz, 2H) 4.62 (d, J = 5.49 Hz, 1H) 4.65 (t, J = 3.51 Hz, 1H) 5.12 (d, J = 10.37 Hz, 1H) 5.18 (dd, J = 17.09, 1.83 Hz, 1H) 5.28 (dd, J = 10.53,
1. 37 Hz, 1H) 5.41 (dd, J = 17.24, 1.68 Hz, 1H) 5.88 (m, 1H) 6.08 (m, 1H) 6.60 (dd, J = 8.85, 3.05 Hz, 1H) 6.97 (d, J = 8.85 Hz, 1H) 7.81 (d, J = 3.05 Hz, 1H) 8.87 (s, 1H) 8.99 (s, 1H) 10.70 (s, 1H).
EXAMPLE 105D 2-Oxo-18-r2- (tetrahydro-2H-pyran-2-yloxypetoxy-2,3,11,14-tetrahydro-1H, 10H-8.4-epiazeno-9,15,1.3.6-benzodioxatriazacycloheptadecin- 7-Carbonitrile Example 105C (263.9 mg, 0.52 mmol) was cyclized using a similar procedure described in Example 55C to give the thioule compound (116.3 mg, 47%) MS (ESI) m / z 480.26 (MH).; 1H NMR (500 MHz, DMSO-D.) D ppm 1.40-1.54 (m, 4H) 1.64 (m, 1H) 1.72 (m, 1H) 2.70 (q, J = 7.53 Hz, 2H) 3.45 (m, 1H) 3.70 (m, 1H) 3.78 (m, 1H) 3.90 (m, 1H) 4.06 (i, J = 4.73 Hz, 2H) 4.62 (d, J = 7.02 Hz, 2H) 4.65 (i, J = 3.51 Hz, 1H ) 4.69 (i, J = 7.48 Hz, 2H) 5.98 (m, 1H) 6.08 (m, 1H) 6.66 (dd, J = 8.85, 3.05 Hz, 1H) 7.09 (d, J = 9.15 Hz, 1H) 7.74 ( d, J = 2.75 Hz, 1H) 7.98 (s, 1H) 10.27 (s, 1H) 10.88 (s, 1H)
EXAMPLE 106 12.13 -Dihydr oxy -18-methoxy -2 -oxo -2, 3,11, 12,13,14-hexahydro-1 H, 10H-8,4-epiazeno-9,15,1, 3,6-benzodioxatriazacycloheptadecin-7-carbonitrile Example 104D (55.2 mg, 0.15 mmol) was oxidized using a similar procedure described in Example 55D to give the title compound (20.8 mg, 34%). MS (ESI) m / z 400.11 (M-H) "; 1H
NMR (500 MHz, DMSO-D6) d ppm 1.91 (m, 1H) 2.33 (m, 1H) 3.71 (s, 3H) 3.75-3.85 (m, 2H) 3.99-4.12 (m, 2H) 4.61 (m, 1H ) 4.69 (m, 1H) 4.88 (d, J = 4.88 Hz, 1H) 5.05 (d, J = 5.19 Hz, 1H) 6.67 (dd, J = 9.15, 3.05 Hz, 1H) 7.06 (d, J = 9.15 Hz , 1H) 7.76 (d, J = 3.05 Hz, 1H) 7.99 (s, 1H) 9.75 (s, 1H) 10.85 (s, 1H)
EXAMPLE 107 18- (2-Hydroxyethoxy) -2-oxo-2,3,11,14-tetrahydro-1H.10H-8.4- epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecin-7-carbonitrile Example 105D was irradiated (100 mg, 0.21 mmol) with a mixture of acetic acid, THF and water using a similar procedure described in Example 61 to give the compound of the extract (60.5 mg, 73%). MS (ESI) m / z 396.01 (MH) "; H NMR (500 MHz, DMSO-D6) d ppm 2.70 (q, J = 7.43 Hz, 2H) 3.69 (q, J = 5.49 Hz, 2H) 3.91 (f , J = 5.03 Hz, 2H) 4.61 (d, J = 7.32 Hz, 2H) 4.69 (t, J = 7.48 Hz, 2H) 4.83 (f, J = 5.65 Hz, 1H) 5.98 (m, 1H) 6.08 (m , 1H) 6.64 (dd, J = 8.85.3.05 Hz, 1H) 7.08 (d, J = 9.15 Hz, 1H) 7.75 (d, J = 3.05 Hz, 1H) 7.97 (s, 1H) 10.27 (s, 1H) 10.89 (s, 1H)
EXAMPLE 108 18-f2- (Dimethylamino) ethoxyl-2-oxo-2,3.11.14-tetrahydro-1H.10H-8.4- epiazen or-9,15,1,3,6-benzodioxatriazacycloheptadecin-7-carbonitrile It was added to a solution of Example 73H (149.7 mg, 0.42
mmoles) in anhydrous tetrahydrofuran (5 mL) triphenylphosphine supported by the polymer (282 mg, 0.85 mmol), di-tert-butyl azodicarboxylate (195 mg, 0.85 mmol), and N, N-dimethylaminoetanolol (38.9 mg, 0.44 mmol) . The reaction mixture was shaken at room temperature overnight. The solution was filtered, concentrated, dissolved in DMSO / methanol (1/1, 3 mL), and separated by HPLC to give the title compound (4.3 mg, 2%). MS (ESI) m / z 423.25 (MH) "; 1 H NMR (400 MHz, DMSO-D.) D ppm 2.59-2.67 (m, 2H) 2.85 (s, 6 H) 3.35-3.41 (m, 2H) 4.35 (t, J = 6.75 Hz, 2H) 4.50 (d, J = 6.75 Hz, 2H) 4.55-4.67 (m, 2H) 5.86-6.08 (m, 2H) 6.42 (dd, J = 8.75, 2.92 Hz, 1H) 6.90 (d, J = 8.90 Hz, 1H) 7.59 (d, J = 3.07 Hz, 1H) 8.34 (s, 1H) 8.98 (s, 1H) 9.31 (s, 1H) 10.31 (s, 1H).
It will be evident for an experiment in the technique that the present invention was not limited to previous illus- trafied examples and that it can be represented in other specific forms without departing from the essential attributions of the same. It is therefore desired that the examples be considered in all respects as illustrative and non-restrictive, reference is made to the appended claims in lieu of the foregoing examples and all changes that would originate within the meaning and range of equivalence of the claims, therefore they are intended to cover.
Claims (9)
1. - A compound of the formula (I): or an israpeutically acceptable salt thereof, where it is an individual or double bond; A is selected from the group consisting of aryl and heeroaryl, wherein the aryl and the heteroaryl are optionally substituted with one, two, or substituent selected independently from the group consisting of alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, cyano, halogen, haloalkylsulfonyloxy haloalkoxy, heteroarylalkoxy, heterocycle, heteroaryloxyalkoxy, heteroaryloxyalkoxy, heteroaryloxyalkyl, heteroaryloxy-alkynyl, heteroarylcarbonylalkoxy, haloalkyl, hydroxyalkenyl, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, hydroxyalkyl, NRaRb, (NRaRb) alkoxy, (NRaR) alkyl, and (NRaR) alkynyl; R1 is selected from the group consisting of hydrogen, alkoxycarbonyl, alkyl, carboxy, cyano, halogen, and nifro; R2 and R3 are independently selected from the group that it consists of hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylsulfonyl, aryisulfonyl, halogen, hydroxy, and NRaRb; or R2 and R3, together with the atoms to which they are attached, form an epoxide; X1 and X2 are independently selected from the group consisting of CH and N; Y and Z are independently selected from the group consisting of CH2, O, and NRZ, wherein Rz is selected from the group consisting of hydrogen and alkyl; L1 and L2 are independently selected from the group consisting of a bond and alkylene; Ra and Rb are independently selected from the group consisting of hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkyl, arylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heteroarylsulfonyl, and (NRcRd) alkylcarbonyl; and R ° and Rd are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl.
2. A compound of the formula (II): or a therapeutically acceptable salt thereof, wherein it is an individual or double bond; R1 is selected from the group consisting of hydrogen, alkoxycarbonyl, alkyl, carboxy, cyano, halogen, and nitro; R2 and R3 are selected independently from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylsulfonyl, arylsulfonyl, halogen, hydroxy, and NRaRb; or R2 and R3, together with the atoms to which they are attached, form an epoxide; R 4 is selected from the group consisting of alkoxy, alkyl, cyano, halogen, heterocycloxy alkoxy, heteroaryloxyalkyl, hydroxy, hydroxy alkoxy, hydroxyalkyl, nitro, NR a R, and (NR a R b) alkoxy; R5 is selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonyl, alkylsulfonyl, ariisulfonilo, alkylsulfonyl, ariisulfonilo, carboxy, carboxyalkyl, haloalkylsulfonyloxy, heíeroarilalcoxi, heferoarilcarbonilalcoxi, heíerociclo, heíerocicloalcoxi, heíerociclooxialquilo, heíerociclooxialquinilo , hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, NRaRb, (NRaRb) alkoxy, (NRaRb) alkyl, (NRaR) alkynyl, (NRaRb) carbonyl, (NRaRb) carbonylalkoxy, and (NRaRb) carbonylalkyl; Y and Z are independently selected from the group consisting of CH2, O, and NRZ, wherein Rz is selected from the group consisting of hydrogen and alkyl; L1 and L2 are independently selected from the group consisting of a bond and alkylene; Ra and Rb are independently selected from the group consisting of hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkyl, arylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heteroarylsulfonyl, and (NRcRd) alkylcarbonyl; and Rc and R are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl.
3. The compound according to claim 2, wherein: R1 is selected from the group consisting of hydrogen and cyano; R2 and R3 are independently selected from the group consisting of hydrogen, alkoxy and hydroxy; R4 is halogen; R5 is hydrogen; Cast; Z is O; and L1 is CH2.
4. The compound according to claim 1, wherein L1 is CH2 and L2 is a bond.
5. The compound according to claim 1, wherein L1 is CH2 and L2 is CH2.
6. A compound selected from the group consisting of: 18-chloro-11,14-dihydro-1H, 10H-8,4-epiazeno-9,15,1,3,6- benzodioxatriazacycloheptadecin-2-one; 18-chloro-11,12,13,14-tetrahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxairiazacycloheptadeclin-2-one; 18-chloro-12,13-dihydroxy-11,12,13,14-eiehydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxairiazacyclohepcydecin-2-one; 17-chloro-10,13-dihydro-1H-8,4-epiazeno-9,14,1,3,6-benzodioxayriazacyclohexadecin-2-one; 17-chloro-10,11,12,13-teirahydro-1H-8,4-epiazeno-9,14,1,3,6-benzodioxaryriazacyclohexadecin-2-one; 17-chloro-11,12-dihydroxy-10,11,12,13-eiehydro-1H-8,4-epiazeno-9,14,1,3,6-benzodioxayriazacyclohexadecin-2-one; 18-chloro-2-oxo-2,3,11, 14-teirahydro-1 H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriacecyclohepcydecin-7-carbonyiiril; 18-chloro-2-oxo-2,3,11, 12,13,14-hexahydro-1 H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxayriazacyclohepfadecin-7-carbonyiyl; 18-chloro-12,13-dihydroxy-2-oxo-2,3,11, 12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1, 3,6-benzodioxairiazacycloheptadecin- 7-carbonitrile; 18-chloro-17-hydroxy-2-oxo-2,3,11, 12,13,14-hexahydro-1 H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxairiazacycloheptadecin-7 -carboniírilo; 18-chloro-17- (3-hydroxypropoxy) -2-oxo-2,3,11, 12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6- benzodioxayriazacíclohepíadecin-7-carbonitrilo; 18-chloro-17- (2,3-dihydroxypropoxy) -2-oxo-2I3,11,12,13,14- hexahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxayriazacycloheptadecin-7-carbonyiril; 18-chloro-17- (2-hydroxyethoxy) -2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6- benzodioxaryriazacycloheptadecin-7-carbonifril; 18-chloro-17- (2-meioxy-eioxy) -2-oxo-2, 3,11, 12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6 -benzodioxaryriazacyclohepdecycline-7-carboniiril; 18-chloro-17- [2- (2-meioxy-dioxy) ethoxy] -2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1 , 3,6-benzodioxatriazacyclohepíadecin-7-carbonitrilo; 18-chloro-17- [2- (dimethylamino) ethoxy] -2-oxo-2,3,11,12,13,14-hexahydro-1 H.10H-8, 4-epiazeno-9, 15, 1, 3,6-benzodioxayriazacycloheptadecin-7-carboniiril; 18-chloro-2-oxo-17- (2-piperidin-1-ylethoxy) -2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1, 3,6-benzodioxayriazacyclohepcydecin-7-carbonitrile; 18-chloro-2-oxo-17- (2-pyrrolidin-1-yloxy) -2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1, 3,6-benzodioxatriazacyclohepíadecin-7-carbonyiril; 18-chloro-17- (2-morpholin-4-ylethoxy) -2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1, 3,6-benzodioxayriazacyclohepcydecin-7-carboniiril; 18-chloro-17- (3-morpholin-4-ylpropoxy) -2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1, 3,6- benzo dioxairiazacycloheptadecin-7-carboniiril; 18-chloro-2-oxo-17- (pyrid i n-4-yl methoxy) -2, 3,11,12,13,14-hexahydro-1 H, 10H-8,4-epiazeno-9,15, 1, 3,6-benzodioxatriazacyclohepcydecin-7-carboniiril; 18-chloro-2-oxo-17- (pyridin-3-ylmefoxy) -2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1, 3, 6-benzodioxatriazacieloheptadecin-7-carbonitrile; 18-chloro-2-oxo-17- (pyridin-2-ylmethoxy) -2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1,3, 6-benzo dioxairiazacyclohepcydecin-7-carboniiril; 18-chloro-2-oxo-17- (2-oxo-2-pyridin-2-yleloxy) -2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9, 15,1,3,6-benzodioxatriazacyclohepíadecin-7-carbonyiril; 18-chloro-17- [2- (1H-imidazol-1-yl) eioxy] -2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9 , 15,1,3,6-benzodioxairiazazacycloheptadecin-7-carbonyiril; 18-chloro-17-isopropoxy-2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxayriazacycloheptadecin-7-carbonitrile; 17-amino-18-chloro-2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxairiazacyclohepcydecin-7-carbonyiiril; 17-amino-18-chloro-2-oxo-2,3,11,14-eeryhydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxayriazacyclohepcydecin-7-carbonyiyl; 18-chloro-2-oxo-17 - [(pyridin-3-ylmeiyl) amino] -2,3,11,12,13,14- hexahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacyclohepíadecin-7-carbonifril; 18-Chloro-2-oxo-17 - [(pyridin-4-ylmeiyl) amino] -2,3,11,12,13,14-hexahydro H, 10 H -8,4-epiazeno-9,15,1,3 , 6-benzo dioxairiazacyclohepcydecin-7-carboniiril; N- (18-chloro-7-cyano-2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacyclohepíadecin -17-yl) pyridine-2-carboxamide; N- (18-Chloro-7-cyano-2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxairiazacic Iohepíadecin -17-yl) pyridin-4-carboxamide; 2-chloro-N- (18-chloro-7-cyano-2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1,3 , 6-benzodioxatríazaciclohepíadecin-17-il) isonicoíinamida; N- (18-chloro-7-cyano-2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxaíriazacyclohepíadecin -17-yl) pyridine-3-carboxamide; N- (18-chloro-7-cyan 0-2-0X0-2, 3, 11, 12, 13,14-hexah id ro-1H, 10H-8,4-epiazeno-9,15,1,3, 6-benzodioxatriazacycloheptadecin-17-yl) acetamide; N- (18-chloro-7-cyano-2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1, 3,6-benzodioxayriazacycloheptadecin -17-yl) -2- (dimethylamino) acetylamide; N- (18-chloro-7-cyano-2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxaíriazacyclohepíadecin -17-il) -3- (cyclopenylamino) propanamide; 3-c I o ro- N- (18-cl or ro-7-ci an o-2-oxo-2,3,11, 12,13,14-hexahydro-1 H, 10H-8, 4-epiazeno -9,15,1,3,6-benzodioxa tria zaciclohept adecín-7-yl) propanamide; N- (18-chloro-7-cyano-2-oxo-2,3,11, 12,13,14-hexahydro-1 H, 1 OH- 8,4-epiazeno-9,15,1,3,6 ~ benzodioxaryriazacyclohepfadecin-17-yl) -3- [cyclohexyl (meityl) amino] propanamide; N- (18-chloro-7-cyano-2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxaíriazacyclohepíadecin -17-yl) mephsulfonamide; N- (18-chloro-7-cyano-2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazen-9,15,1,3,6-benzodioxatriazacícloheptadecin -17-yl) -6-morpholin-4-ylpyridin-3-sulfonamide; N- (18-chloro-7-cyano-2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacicloheptadecin -17-yl) -2,2,2-и fluoroethane-sulfonamide; N- (18-chloro-7-cyano-2-oxo-2,3,11, 12,13,14-hexahydro-1 H, 1 OH-8,4-epiazeno-9,15,1, 3,6 -benzodioxatriazacyclohepcydecin-17-yl) -4-fluorobenzenesulfonamide; N- (18-chloro-7-cyano-2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacyclohepíadecin -17-yl) -4- (trifluoromethoxy) benzenesulfonamide; 18-chloro-17- (3-hydroxyprop-1-ynyl) -2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4epiazene-9,15,1,3, 6-benzodioxatriazacyclohepíadecin-7-carbonitrilo; 18-chloro-7-cyano-2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxaíríazaciclohepíadecin-17- il-trifluoromethanesulfonate; 18-chloro-2-oxo-17- [3- (1-ehydro-2 H -pyran-2-yloxy) prop-1-ynyl-2,3,11,12,13,14-hexahydro-1H, 10H-8, 4-epiazeno-9,15,1,3,6-benzodioxatriazaciclohepíadecín-7-carboniírilo; 18-chloro-2-oxo-17- [3- (1-ehydro-2H-pyran-2-yloxy) propyl] -2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno -9,15,1,3,6-benzodioxatriazacyclohepcydecin-7-carbonitrile; 18-chloro-17- (3-hydroxypropyl) -2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6- benzodioxaryriazacyclohepcydecin-7-carbonylryl; 18-chloro-17- (2,3-dihydroxypropyl) -2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8, 4-epiazeno-9, 15, 1,3 , 6-benzodioxayriazacycloheptadecin-7-carboniiril; 17-allyl-18-chloro-2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxayriazacycloheptadecin-7 carboniiril; 18-Chloro-17- (3-hydroxy-3-methyl-1-yl) -2-oxo-2,3,11,12,13,14-hexahydro-1 H, 10H-8,4-e piazeno- 9, 15, 1,3,6-benzodioxafriazacyclohepíadecin-7-carboniírílo; 18-chloro-17- (3-hydroxybuí-1-ynyl) -2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1, 3,6-benzodioxatriazacycloheptadecin-7-carboniiril; 18-chloro-17- [3- (dieylamino) prop-1-ynyl] -2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epíazeno-9,15 , 1,3,6- benzodioxayriazacyclohepíadecin-7-carboniírílo; 18-chloro-17- [3- (dimethylamino) prop-1-ynyl] -2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15 , 1,3,6-benzodioxatriazaciclohepfadecin-7-carboniírilo; 18-chloro-17- (dimethylamino) -2-oxo-2,3,11, 12,13,14-hexahydro-1H, 10H-8,4-epíazeno-9,15,1,3,6-benzodioxatriazaciclohepíadecin- 7-carbonitrile; 18-chloro-17- (diethylamino) -2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epíazeno-9,15,1,3,6-benzodioxatriazacicloheptadecin- 7-carbonitrile; 18-chloro-2-oxo-17-piperidin-1-yl-2,3,11,12,13,14-hexahydro-1 H, 10H-8,4-epia zeno-9,15,1,3, 6-benzodioxa idioza cyclohepcydecin-7-carbonitrile; 18-chloro-17- (isobuylamino) -2-oxo-2,3,11, 12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1, 3,6-benzodioxairiazacyclohepíadecin- 7-carboniiril; 17-chloro-11,12-dihydroxy-2-oxo-2,3,10,11, 12,13-hexahydro-1 H-8,4-epiazeno-9,14,1,3,6-benzodioxatriazacyclohexadecine-7 -carbonitrile; 17-chloro-2-oxo-2,3,10,13-и-tetrahydro-1H-8,4-epiazeno-9,14,1,3,6-benzodioxayriazacyclohexadecin-7-carbonyiril; 18-chloro-17- (meitylamino) -2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxairiazacycloheptadecin- 7-carboniiril; 14-chloro-11-oxo-2,3,11,12,18,18a-hexahydro-1H, 10H-5,9- epiazenooxyrene [1] [9,15,1, 3,6] be nzodioxafriaza cyclohepiad ecin-6-carbonitrile; 18-chloro-11, 12-cis-d i hydroxy-14-methyl-l-2-oxo-2,3, 11, 12, 13,14-hexah id ro- 1 H, 1 O H-8.4 -epiazen 0-9,15,1,3,6-benzo dioxairiazacycloheptadecin-7-carbonyiril; (cis) 18-chloro-14-mei i-2-oxo-2,3, 13,14-teirah id ro-1H, 10 H-8, 4-epiazeno-9,15,1,3,6- benzodioxairylazacycloheptadecyn-7-carbonyiyl; 18-chloro-11,12-trans-dihydroxy-14-meityl-2-oxo-2,3,11,12,13,14-h, exahydro-1H, 10H-8,4-epiazen-9, 15, 1, 3,6-benzodioxayriazacyclohepcydecin-7-carboniiril; (rans) 18-chloro-14-methyl-2-oxo-2,3,13,14-tetrahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxaíriazaciclohepíadecin-7-carbonitrilo; 18-chloro-15-m eti l-2-oxo-2,3,10,11,12, 13,14, 15-octah id ro-1H-8,4-epiazeno-9,1,3,6, 15-benzoxateirazazacycloheptadecin-7-carbonitrile; (cis) 18-chloro-13-hydroxy-2-oxo-2,3,13,14-tetrahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxatríazacicIohepíadecin-7-carboniírilo; 18-chloro-11,12,13-dihydroxy-2-oxo-2,3,11, 12,13,14-hexahydro-1 H, 10H-8,4-epiazeno-9,15,1, 3,6 -benzodioxatriazacyclohepíadecin-7-carbonyiril; 18-chloro-13-hydroxy-2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxaíriazaciclohepíadecin-7- carbonitrile; (rans, rans) 18-chloro-11,12,13-dihydroxy-2-oxo- 2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxairiazacyclohepcydecin-7-carbonitrile; (cis, rans) 18-chloro-11,12,13-dihydroxy-2-oxo-2, 3,11, 12,13,14-hexahydro-1 H, 10H-8,4-epiaze no-9, 15 , 1,3,6-benzodioxayriazacyclohepcydecin-7-carbonitrile; 18-bromo-2-oxo-2,3,11,14-eiehydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacyclohepíadecin-7-carbonifrílo; 18-bromo-12,13-dihydroxy-2-oxo-2,3,11, 12,13,14-hexahydro-1 H, 10H-8,4-epiazeno-9,15,1, 3,6-benzodioxatriazacíclohepíadecin-7 -carboniírilo; 2-oxo-18- [3- (1-tetrahydro-2H-pyran-2-yloxy) propyl] -2,3,11,14-eeryhydro-1H, 10H-8,4-epiazeno-9,15,1,3 , 6-benzodioxayriazacyclohepcydecin-7-carbonyiyl; 2-oxo-18- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] -2,3,11,14-tetrahydro-1H, 10H-8,4-epiazeno-9, 15, 1, 3,6-benzodioxatriazacycloheptadecin-7-carboniyri; 18- (3-hydroxypropyl) -2-oxo-2,3,11,14-teirahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxayriazacycloheptadecin-7-carbonyiyl; 18- (2-hydroxyethyl) -2-oxo-2,3,11,14-tetrahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxayriazacycloheptadecin-7-carbonyiril; 18-bromo-2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazen or-9,15,1,6,6-benzodioxatriazacyclohepcydecin-7-carbonitrile; 18-hydroxy-2-oxo-2,3,11,14-tetrahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacyclohepíadecin-7-carbonitrile; 18- (2-hydroxyethyl) -2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4- epiazeno-9,15,1,3,6-benzodioxairiazacyclohepcydecin-7-carbonitrile; 18- (3-hydroxypropyl) -2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacyclohepíadecin-7 carboniiril; 12,13-d ih id rox¡-18- (2-h¡droxieti l) -2-oxo-2,3,11,12,13, 14-hexahydro-1H, 10H-8,4epiazeno-9,15 , 1,3,6-benzodioxalriazacyclohepcydecin-7-carbonitrile; 12,13-dihydroxy-18- (3-hydroxypropyl) -2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1,3, 6-benzodioxayriazacyclohepcydecin-7-carbonitrile; 18-chloro-13-methoxy-2-oxo-2,3,13,14-tetrahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxairiazacicloheptadecin-7-carbonyliryl; 18-chloro-11,12-dihydroxy-13-methoxy-2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1,3, 6-benzo dioxairiazacyclohepfadecin-7-carboniiril; 18-chloro-11,12-dihydroxy-13-meioxy-2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H8,4-epiazeno-9,15,1,3,6- benzodioxaryriazacycloheptadecin-7-carbonyiyl; 18-chloro-13-eioxy-11,12-cis-dihydroxy-2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1, 3,6-benzodioxatriazacyclohepíadecin-7-carbonyiril; (cis) 18-chloro-13-eoxy-2-oxo-2,3,13,14-tetrahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacicloheptadecin-7-carbonitrilo; 18-chloro-13-ethoxy-11,12-trans-dihydroxy-2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1, 3,6- benzodioxairiazacyclohepcydecin-7-charcoal; (cis) 18-nitro-2-oxo-2,3,13,14-teirahydro-1H, 10H-8,4-epiazeno-9, 15,1, 3,6-benzodioxayriazacyclohepcydecin-7-carbonylyl; 18-eioxy-2-oxo-2,3,11,14-teirahydro-1 H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxayriazacyclohepcydecin-7-carbonyiyl; 18-chloro-17- (erylamino) -2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacyclohepíadecin- 7-carboniiril; 17- (but i lamino) - 18-chloro-2-oxo-2,3,11, 12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6- benzodioxaryriazacyclohepcydecin-7-carbonyiyl; 17-chloro-2-oxo-2,3,10,11, 12,13-hexahydro-1 H-8,4-epiazeno-9,14,1,3,6-benzodioxayriazacyclohexadecine-7-carbonyiril; 18-chloro-14-meityl-2-oxo-2,3,11,14-tetrahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxayriazacyclohepfadecin-7-carbonyiril; 18-bromo-16-fIuoro-12,13-dihydroxy-2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1,3, 6-benzodioxafriazacycloheptadecin-7-carbonitrile; 18-bromo-16-fluoro-2-oxo-2,3,11, 14-teirahydro-1 H, 1 OH-8,4-epiazeno-9,15,1,3,6-benzodioxayriazacyclohepfadecin-7-carbonyiril; (cis) 19-chloro-2-oxo-2,3,10,11, 14,15-hexahydro-1 H-8,4-epiazeno-9,16,1, 3,6-benzodioxairiazacyclohexadecine-7-carbonyiril; (iorans) 19-chloro-2-oxo-2,3,10,11, 14,15-hexahydro-1 H-8,4-epiazeno-9,16,1,3,6-benzodioxairiazacyclohexane-7-carbonitrile; (12R.13 S) -19-chloro-12,13-cis-dihydroxy-2-oxo- 2,3,10,11,12,13,14,15-octahydro-1H-8,4-epiazeno-9,16,1,3-benzodioxadiazacycloocctadecine-7-carbonitrile; (12R.13 S) -19-chloro-12,13-trans-dihydroxy-2-oxo-2,3,10,11,12,13,14,15-octahydro-1H-8,4-epiazeno-9 , 16,1,3-benzo dioxa di aza c ic lo ocia dec ine-7- car bo nitrilo; 19-chloro-2-oxo-2,3,10,11,12,13,14,15-ociahidro-1H-8,4-epiazeno-9,16,1, 3,6-benzodioxatriazaciclooctadecine-7-carbonitrile; 18-meti 1-2-0X0-2.3, 11,14-tetrah id ro-1H, 10 H-8, 4-epiazeno-9,15,1, 3,6-benzodioxatriazacycloheptadecin-7-carbonitrile; 18-meti 1-2-0X0-2.3,11, 12,13,14-hexahydro-1 H, 10H-8,4-epiazeno-9,15,1, 3,6-benzodioxatriazacycloheptadecin-7-carbonitrile; 16-bromo-18-methyl-2-oxo-2,3,11,14-tetrahydro-1H, 10H-8, 4-epiazeno-9, 15,1, 3, 6-benzodioxatriazaciclohepíadecin -7 -carboniírilo; 16-bromo-18-meti I-2-OXO-2.3, 11, 12, 13,14-hexah id ro-1H, 10 H-8,4-epiazeno-9,15,1, 3,6-benzodioxatriazacyclohepíadecin- 7-carbonitrile; 16- (3-h id roxiprop-1 -i nil) -18-meti 1-2-0X0-2.3, 11, 12, 13,14-hexahydro-1H, 10H8,4-epíazeno-9,15, 1,3,6-benzodioxatriazacyclohepadecin-7-carbonyiril; 18-chloro-2-oxo-2,3,11,14-teirahydro-1H, 10H-8,4-epiazenopyrido [2,3, b] [1,12, 4,6,9] dioxairiazacycloheptadecin-7-carbonyloyl; 18-chloro-17-hydroxy-2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-methylene-9,15,1,3-benzodioxadiazacycloheptadecin-7-carbonitrile; 11,12-cis-dihydroxy-18-nitro-2-oxo-2,3,11, 12,13,14-hexahydro- 1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacyclohepcydecin-7-carbonyiiril; 11,12-trans-dihydroxy-18-niiro-2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1, 3,6- benzodioxatriazacycloheptadecin-7-carbonitrile; 18-ethoxy-12,13-dihydroxy-2-oxo-2,3,11, 12,13, 14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxairiazacycloheptadecin- 7-carboniiril; 18-methoxy-2-oxo-2, 3, 11,14-tetrahydro-1 H, 10 H-8,4-epiazeno-9, 15,1, 3,6-benzodioxa tria zacyclohepíadecin-7-carbonyiril; 2-oxo-18- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] -2,3,11,14-teirahydro-1H, 10H-8,4-epiazeno-9,15,1,3 , 6-benzodioxatriazacicloheptadecin-7-carbonyiril; 12,13-dihydroxy-18-meioxy-2-oxo-2,3,11,12,13,14-hexahydro-1H, 10H-8,4-epiazeno-9,15,1, 3,6-benzodioxatriazacicloheptadecin- 7-carbonitrile; 18- (2-h id roxietoxi) -2-oxo-2, 3, 11,14-tetrah id ro-1H, 1 OH-8,4-epiazeno-9,15,1, 3,6-benzodioxatriazaciclohepíadecin-7 -carbotiitrile; and 18- [2- (dimethylamino) ethoxy] -2-oxo-2,3,11,14-eeryhydro-1H, 10H-8,4-epiazeno-9,15,1,3,6-benzodioxayriazacycloheptadecin-7 carbonitrile.
7. A pharmaceutical composition comprising a compound of claim 1 or a therapeutically acceptable salt thereof, in combination with a carrier íerapéuíicamente acepiable.
8. A method for inhibiting protein kinases in a patient with the recognized need for said treatment, comprising administering to the patient a therapeutically acceptable amount of a compound of claim 1, or an epileuically acceptable salt thereof.
9. A method to eradicate cancer in a patient with the recognized need for said treatment, which comprises administering to the patient an epistemically acceptable amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US10/702,140 | 2003-11-05 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA06005033A true MXPA06005033A (en) | 2006-10-17 |
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