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Bridged bicyclic kallikrein inhibitors

09815853 · 2017-11-14

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Abstract

Provided herein are kallikrein modulating compounds, pharmaceutical compositions comprising the same, and uses thereof.

Claims

1. A compound of formula (I): ##STR00739## wherein: one of A and B is O and the other of A and B is a bond; ring C is phenyl, wherein ring C, in addition to —CR.sup.3R.sup.4—Z—X.sup.1—R.sup.1, is optionally substituted with one or two substituents independently selected from C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy, hydroxy, halo, haloC.sub.1-C.sub.6alkyl, haloC.sub.1-C.sub.6alkoxy, amino, C.sub.1-C.sub.6alkyl-amino, diC.sub.1-C.sub.6alkylamino, and cyano; R.sup.3 and R.sup.4 are independently hydrogen, fluoro, or C.sub.1-C.sub.6alkyl; or R.sup.3 and R.sup.4 together with the carbon they are attached form C═O, C═NR.sup.12 (wherein R.sup.12 is hydrogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy, or hydroxy), or C.sub.3-C.sub.6cycloalkyl, provided that when R.sup.3 and R.sup.4 together form C═NR.sup.12, then Z is NR.sup.13; Z is a bond, NR.sup.13, or CR.sup.14R.sup.15 wherein R.sup.13, R.sup.14, and R.sup.15 are independently hydrogen or C.sub.1-C.sub.6alkyl; X.sup.1 is bond, —C═NR.sup.8, CR.sup.16R.sup.17, O, or S(O).sub.q, wherein q is 0, 1, or 2, R.sup.8 is hydrogen OH, C.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.6alkyl, or C.sub.3-C.sub.8cycloalkyl, and R.sup.16 and R.sup.17 are independently hydrogen, deuterium, or C.sub.1-C.sub.6alkyl, or R.sup.16 and R.sup.17 together with the carbon atom they are attached form C.sub.3-C.sub.6cycloalkyl, C═NH, or C═O, provided that when R.sup.3 and R.sup.4 together form C═O, then X.sup.1 is not O; R.sup.1 is mono or bicyclic aryl, mono or bicyclic heteroaryl, C.sub.3-C.sub.6cycloalkyl, monocyclic heterocyclyl, or fused heterocyclyl, wherein each of the aforementioned ring(s) is optionally substituted with R.sup.e, R.sup.f or R.sup.g independently selected from C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, C.sub.3-C.sub.6cyclo-alkyl, C.sub.1-C.sub.6alkoxy, hydroxy, halo, haloC.sub.1-C.sub.6alkyl, haloC.sub.1-C.sub.6alkoxy, amino, C.sub.1-C.sub.6alkylamino, diC.sub.1-C.sub.6alkylamino, aminoC.sub.1-C.sub.6alkyl, aminocarbonyl, amidinoC.sub.1-C.sub.6alkyl, —C(═NR.sup.h)NHR.sup.i (wherein R.sup.h and R.sup.i are independently hydrogen, hydroxy, C.sub.1-C.sub.6alkoxy, benzyloxy, acyl, —C(O)OC.sub.1-C.sub.6alkyl, a natural or an unnatural amino acid residue, a dipeptidic residue, —CO(ethylene)SO.sub.2R.sup.u ((wherein R.sup.u is C.sub.1-C.sub.6alkyl, optionally substituted monocyclic heteroaryl, optionally substituted phenyl, or optionally substituted monocyclic heterocyclyl), or —CO(CH.sub.2).sub.2-3OR.sup.v (wherein R.sup.v is hydrogen, C.sub.1-C.sub.6alkoxyC.sub.1-3alkyl, or optionally substituted monocyclic heterocyclyl)), cyano, monocyclic heteroaryl (wherein the monocyclic heteroaryl is optionally substituted with one, two or three substituents independently selected from C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.6cycloalkyl, C.sub.1-C.sub.6alkoxy, hydroxy, halo, haloC.sub.1-C.sub.6alkyl, haloC.sub.1-C.sub.6alkoxy, amino, C.sub.1-C.sub.6alkylamino, diC.sub.1-C.sub.6alkylamino, and cyano) and monocyclic heterocyclyl (wherein the monocyclic heterocyclyl is optionally substituted with one, two or three substituents independently selected from C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.6cycloalkyl, C.sub.1-C.sub.6alkoxy, hydroxy, halo, haloC.sub.1-C.sub.6alkyl, haloC.sub.1-C.sub.6alkoxy, amino, C.sub.1-C.sub.6alkylamino, and diC.sub.1-C.sub.6alkylamino); R.sup.5 and R.sup.6 are hydrogen; R.sup.2 and R.sup.7 together with the atoms they are attached form ring D: ##STR00740## wherein ring D is phenyl; and R.sup.30 is C.sub.3-C.sub.6cycloalkyl, mono or bicyclic aryl, mono or bicyclic heteroaryl, monocyclic heterocyclyl, fused heterocyclyl, spiro heterocycloamino or bridged heterocycloamino, and wherein each of the aforementioned ring in R.sup.30, whether by itself or part of another group, is optionally substituted with R.sup.m, R.sup.n or R.sup.o independently selected from C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, C.sub.3-C.sub.6cycloalkyl, C.sub.3-C.sub.6cycloalkylC.sub.1-6alkoxy, C.sub.3-C.sub.6cycloalkylC.sub.1-6alkoxy, C.sub.1-C.sub.6alkoxy, hydroxy, halo, haloC.sub.1-C.sub.6alkyl, haloC.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.6alkylthio, C.sub.1-C.sub.6alkyl-sulfonyl, amino, C.sub.1-C.sub.6alkylamino, diC.sub.1-C.sub.6alkylamino, aminocarbonyl, acyl, aminoC.sub.1-C.sub.6alkyl, cyano, monocyclic heteroaryl (wherein the monocyclic heteroaryl is optionally substituted with one, two or three substituents independently selected from C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.6cycloalkyl, C.sub.1-C.sub.6alkoxy, hydroxy, halo, haloC.sub.1-C.sub.6alkyl, haloC.sub.1-C.sub.6alkoxy, amino, C.sub.1-C.sub.6alkylamino, diC.sub.1-C.sub.6alkylamino, and cyano), and monocyclic heterocyclyl (wherein the monocyclic heterocyclyl is optionally substituted with one, two or three substituents independently selected from C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.6cycloalkyl, C.sub.1-C.sub.6alkoxy, hydroxy, halo, haloC.sub.1-C.sub.6alkyl, haloC.sub.1-C.sub.6alkoxy, amino, C.sub.1-C.sub.6alkylamino, and diC.sub.1-C.sub.6alkylamino); R.sup.31 is hydrogen; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ring C is phenyl optionally substituted, in addition to —CR.sup.3R.sup.4—Z—X.sup.1—R.sup.1, with a substituent selected from C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy, hydroxy, and halo.

3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, having structure (I″) ##STR00741##

4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein R.sup.3 and R.sup.4 together with the carbon atom to which they are attached form C═O.

5. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein Z is NR.sup.13, and X.sup.1 is CR.sup.16R.sup.17 where R.sup.16 and R.sup.17 are independently hydrogen, deuterium, or C.sub.1-C.sub.6alkyl.

6. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein —(CR.sup.3R.sup.4)—Z—X.sup.1— is —CONHCH.sub.2—.

7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein R.sup.1 is phenyl optionally substituted with R.sup.e, R.sup.f, or R.sup.g independently selected from methyl, ethyl, isopropyl, n-propyl, cyclopropyl, methoxy, ethoxy, hydroxy, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, fluoro, chloro, amino, aminomethyl, —CONH.sub.2, —CONHCH.sub.3, tetrahydropyran-4-yl, 3,6-dihydro-2H-pyran-4-yl, 2,4-dihydrofuran-3-yl, tetrazol-1-yl, amidinoC.sub.1-C.sub.6alkyl, —C(═NR.sup.h)NHR.sup.i (where R.sup.h and R.sup.i are independently hydrogen, hydroxy, C.sub.1-C.sub.6alkoxy, acyl, —C(O)OC.sub.1-C.sub.6alkyl, a natural or an unnatural amino acid residue, —CO(ethylene)SO.sub.2R.sup.u (where R.sup.u is C.sub.1-C.sub.6alkyl, optionally substituted monocyclic heteroaryl, optionally substituted phenyl, or optionally substituted monocyclic heterocyclyl), or —CO(CH.sub.2).sub.2-3OR.sup.v (where R.sup.v is hydrogen, C.sub.1-C.sub.6alkoxyC.sub.1-3alkyl, or optionally substituted monocyclic heterocyclyl)), cyano, and 1,2,4-oxadiazol-5(4H)-one-3-yl.

8. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein R.sup.1 is phenyl optionally substituted with R.sup.e and R.sup.f independently selected from methyl, ethyl, isopropyl, n-propyl, cyclopropyl, methoxy, ethoxy, hydroxy, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, fluoro, chloro, —CONH.sub.2, —CONHCH.sub.3, tetrahydropyran-4-yl, 3,6-dihydro-2H-pyran-4-yl,2,4-dihydrofuran-3-yl, tetrazol-1-yl, and cyano wherein R.sup.e and R.sup.f are attached to the carbon atoms of the phenyl ring that are ortho to the carbon of the phenyl ring attached to X.sup.1, and is substituted with R.sup.g wherein R.sup.g is amino, aminomethyl, —C(═NR.sup.h)NHR.sup.i (where R.sup.h and R.sup.i are independently hydrogen, hydroxy, methoxy, ethoxy, methylcarbonyl, methoxycarbonyl, ethoxycarbonyl, a natural or an unnatural amino acid residue, —CO(ethylene)SO.sub.2R.sup.u (where R.sup.u is C.sub.1-C.sub.6alkyl, optionally substituted monocyclic heteroaryl, optionally substituted phenyl, or optionally substituted monocyclic heterocyclyl), or —CO(CH.sub.2).sub.2-3OR.sup.v (where R.sup.v is hydrogen, C.sub.1-C.sub.6alkoxyC.sub.1-3alkyl, or optionally substituted monocyclic heterocyclyl)), and 1,2,4-oxadiazol-5(4H)-one-3-yl and wherein R.sup.g is located at the carbon of the phenyl ring that is para to the carbon of the phenyl ring attached to X.sup.1.

9. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein R.sup.1 is mono or bicyclic heteroaryl optionally substituted with R.sup.e, R.sup.f or R.sup.g independently selected from C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, C.sub.3-C.sub.6cycloalkyl, C.sub.1-C.sub.6alkoxy, hydroxy, halo, haloC.sub.1-C.sub.6alkyl, haloC.sub.1-C.sub.6alkoxy, amino, C.sub.1-C.sub.6alkylamino, diC.sub.1-C.sub.6alkylamino, aminoC.sub.1-C.sub.6alkyl, aminocarbonyl, amidinoC.sub.1-C.sub.6alkyl, —C(═NR.sup.h)NHR.sup.i (where R.sup.h and R.sup.i are independently hydrogen, hydroxy, C.sub.1-C.sub.6alkoxy, acyl, —C(O)OC.sub.1-C.sub.6alkyl, a natural or an unnatural amino acid residue, a dipeptidic residue, —CO(ethylene)SO.sub.2R.sup.u (where R.sup.u is C.sub.1-C.sub.6alkyl, optionally substituted monocyclic heteroaryl, optionally substituted phenyl, or optionally substituted monocyclic heterocyclyl), or —CO(CH.sub.2).sub.2-3OR.sup.v (where R.sup.v is hydrogen, C.sub.1-C.sub.6alkoxyC.sub.1-3alkyl, or optionally substituted monocyclic heterocyclyl)), cyano, monocyclic heteroaryl (wherein the monocyclic heteroaryl is optionally substituted with one, two or three substituents independently selected from C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.6cycloalkyl, C.sub.1-C.sub.6alkoxy, hydroxy, halo, haloC.sub.1-C.sub.6alkyl, haloC.sub.1-C.sub.6alkoxy, amino, C.sub.1-C.sub.6alkylamino, diC.sub.1-C.sub.6alkylamino, and cyano), and monocyclic heterocyclyl (wherein the monocyclic heterocyclyl is optionally substituted with one, two or three substituents independently selected from C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.6cycloalkyl, C.sub.1-C.sub.6alkoxy, hydroxy, halo, haloC.sub.1-C.sub.6alkyl, haloC.sub.1-C.sub.6alkoxy, amino, C.sub.1-C.sub.6alkylamino, and diC.sub.1-C.sub.6alkylamino).

10. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein R.sup.1 is pyridinyl, pyrimidinyl, pyazinyl, pyridazinyl, isoquinolinyl, benzypyrazolyl, or benzisoxazolyl, optionally substituted with R.sup.e, R.sup.f, or R.sup.g independently selected from methyl, ethyl, isopropyl, n-propyl, cyclopropyl, methoxy, ethoxy, hydroxy, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, fluoro, chloro, amino, aminomethyl, —CONH.sub.2, —CONHCH.sub.3, tetrahydropyran-4-yl, 3,6-dihydro-2H-pyran4-yl, 2,4-dihydrofuran-3-yl, tetrazol-1-yl, amidinoC.sub.1-C.sub.6alkyl, —C(═NR.sup.h)NHR.sup.i (where R.sup.h and R.sup.i are independently hydrogen, hydroxy, C.sub.1-C.sub.6alkoxy, acyl, —C(O)OC.sub.1-C.sub.6alkyl, a natural or an unnatural amino acid residue, —CO(ethylene)SO.sub.2R.sup.u (where R.sup.u is C.sub.1-C.sub.6alkyl, optionally substituted monocyclic heteroaryl, optionally substituted phenyl, or optionally substituted monocyclic heterocyclyl), or —CO(CH.sub.2).sub.2-3OR (where R.sup.v is hydrogen, C.sub.1-C.sub.6alkoxyC.sub.1-3alkyl, or optionally substituted monocyclic heterocyclyl)), cyano, and 1,2,4-oxadiazol-5(4H)-one-3-yl.

11. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein R.sup.1 is pyridin-3-yl optionally substituted with R.sup.e and R.sup.f independently selected from methyl, ethyl, isopropyl, n-propyl, cyclopropyl, methoxy, ethoxy, hydroxy, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, fluoro, chloro, —CONH.sub.2, —CONHCH.sub.3, tetrahydropyran-4-yl, 3,6-dihydro-2H-pyran-4-yl, 2,4-dihydrofuran-3-yl, tetrazol-1-yl, and cyano and wherein R.sup.e and R.sup.f are attached to the C-2 and C-4 position of the pyridine-3-yl ring, and is substituted with R.sup.9 wherein R.sup.9 is amino, aminomethyl, —C(═NR.sup.h)NHR.sup.i (where R.sup.h and R.sup.i are independently hydrogen, hydroxy, methoxy, ethoxy, methylcarbonyl, methoxycarbonyl, ethoxycarbonyl, a natural or an unnatural amino acid residue, —CO(ethylene)SO.sub.2R.sup.u (where R.sup.u is C.sub.1-C.sub.6alkyl, optionally substituted monocyclic heteroaryl, optionally substituted phenyl, or optionally substituted monocyclic heterocyclyl), or —CO(CH.sub.2).sub.2-3OR.sup.v (where R.sup.v is hydrogen, C.sub.1-C.sub.6alkoxyC.sub.1-3alkyl, or optionally substituted monocyclic heterocyclyl)), or 1,2,4-oxadiazol-5(4H)-one-3-yl, and R.sup.9 is attached to the C-6 position of the pyridinyl ring.

12. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure below: ##STR00742##

13. A compound selected from: a mixture of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-12-phenyl-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide and N-[(6-amino-2,4-dimethyl-pyridin-3-yl)methyl]-1-phenyl-15-oxatetra-cyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; a mixture of (±)-N-[(6-amino-2,4 dimethylpyridin-3-yl)methyl]12-(4-fluorophenyl)-15-oxatetra-cyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide and (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-11-(4-fluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; a mixture of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-12-(6-methoxypyridin-3-yl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide and (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-11-(6-methoxypyridin-3-yl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; a mixture of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-12-(3,5-dimethyl-1,2-oxazol-4-yl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-dimethyl-1,2-oxazol-4-yl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; a mixture of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-12-{8-oxa-3-azabicyclo[3.2.1]octan-3-yl}-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide and (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-11-{8-oxa-3-azabicyclo[3.2.1]octan-3-yl}-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; a mixture of (±)-N-{[4-(aminomethyl)phenyl]methyl}-12-(4-fluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide and (±)-N-{[4-(aminomethyl)phenyl]methyl}-11-(4-fluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; a mixture of (±)-12-(4-fluorophenyl)-N-{[5-methoxy-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]methyl}-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide and (±)-11-(4-fluorophenyl)-N-{[5-methoxy-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]methyl}-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; a mixture of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-12-(3-fluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide and (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-11-(3-fluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide a mixture of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-12-(2-ethoxy-5-fluoropyridin-4-yl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide and (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-11-(2-ethoxy-5-fluoropyridin-4-yl)-15-oxatetra-cyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; a mixture of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)-methyl]-12-[5-fluoro-2-(propan-2-yloxy)pyridin-4-yl]-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide and (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-11-[5-fluoro-2-(propan-2-yloxy)pyridin-4-yl]-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; a mixture of (±)-N-[(6-chloro-2-fluoro-3-methoxyphenyl)methyl]-12-(furan-2-yl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; and (±)-N-[(6-chloro-2-fluoro-3-methoxyphenyl)methyl]-11-(furan-2-yl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; a mixture of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-12-(furan-2-yl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide and (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-11-(furan-2-yl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; a mixture of (±)-N-[(6-chloro-2-fluoro-3-methoxyphenyl)-methyl]-12-(3-fluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide and (±)-N-[(6-chloro-2-fluoro-3-methoxyphenyl)methyl]-11-(3-fluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; a mixture of (±)-{2-[12-(4-fluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carbonyl]-2,3-dihydro-1H-isoindol-5-yl}methanamine and (±)-{2-[11-(4-fluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carbonyl]-2,3-dihydro-1H-isoindol-5-yl}methanamine; a mixture of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)-methyl]-12-(2-fluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide and (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-11-(2-fluoro-phenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)-methyl]-12-(2-fluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide a mixture of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-12-(2-methoxyphenyl)-15-oxatetra-cyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide and (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-11-(2-methoxy-phenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; a mixture of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-12-(1H-1,3-benzodiazol-4-yl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide and (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-11-(1H-1,3-benzodiazol-4-yl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; a mixture of (±)-12-(1H-1,3-benzodiazol-4-yl)-N-[(6-chloro-2-fluoro-3-methoxyphenyl)methyl]-15-oxatetra-cyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide and (±)-11-(1H-1,3-benzodiazol-4-yl)-N-[(6-chloro-2-fluoro-3-methoxyphenyl)methyl]-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; a mixture of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-12-(1,3-benzoxazol-7-yl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide and (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-1-(1,3-benzoxazol-7-yl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide a mixture of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-12-(2-oxo-1,2-dihydropyridin-1-yl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide and (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-11-(2-oxo-1,2-dihydropyridin-1-yl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; a mixture of (±)-N-[(1-aminoisoquinolin-6-yl)methyl]-12-(2-fluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide and (±)-N-[(1-aminoisoquinolin-6-yl)methyl]-11-(2-fluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; a mixture of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-12-(4-fluoropyridin-3-yl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide and (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-11-(4-fluoropyridin-3-yl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; a mixture of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-12-(1,3-benzoxazol-4-yl)-15-oxatetra-cyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide and (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-11-(1,3-benzoxazol-4-yl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; a mixture of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-12-(2,6-difluorophenyl)-15-oxatetra-cyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide and (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-11-(2,6-difluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide a mixture of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-12-(2,4-difluorophenyl)-15-oxatetra-cyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide and (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-11-(2,4-difluoro-phenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; a mixture of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-12-(3-fluoropyridin-4-yl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide and (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-1-(3-fluoropyridin-4-yl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; a mixture of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-12-(3,5-difluorophenyl)-15-oxatetra-cyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide and (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-1-(3,5-difluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; a mixture of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-12-(2,3-difluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide and (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-1-(2,3-difluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; a mixture of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-12-(2-chlorophenyl)-15-oxatetra-cyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide and (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-11-(2-chloro-phenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; a mixture of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)-methyl]-12-(3,4-difluorophenyl)-15-oxatetra-cyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide and (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-11-(3,4-difluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; a mixture of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-12-[2-(trifluoromethyl)-phenyl]-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide and (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-1-[2-(trifluoromethyl)phenyl]-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; a mixture of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-12-(5-chloro-2-fluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide and (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-11-(5-chloro-2-fluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide a mixture of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-12-(2-fluoro-5-methylphenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide and (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-1-(2-fluoro-5-methylphenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; a mixture of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-12-(5-chlorothiophen-2-yl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide and (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-1-(5-chlorothiophen-2-yl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; a mixture of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)-methyl]-12-(4-benzoylpiperazin-1-yl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide and (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-11-(4-benzoylpiperazin-1-yl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-11-(4-benzoylpiperazin-1-yl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide a mixture of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)-methyl]-12-(2-fluoro-4-methoxyphenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide and (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-11-(2-fluoro-4-methoxyphenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; a mixture of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)-methyl]-12-(4-cyano-2-fluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide and (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-1-(4-cyano-2-fluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; a mixture of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-12-(2-cyano-4-fluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide and (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-11-(2-cyano-4-fluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)-methyl]-12-(2-cyano-4-fluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; a mixture of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)-methyl]-12-(2H-1,3-benzodioxol-4-yl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide a mixture of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)-methyl]-12-(2-carbamoylphenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide and (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-11-(2-carbamoylphenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; a mixture of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)-methyl]-12-(2-cyano-4-methyl-phenyl)-15-oxaetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide and (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-11-(2-cyano-4-methylphenyl)-15-oxateracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)-methyl]-12-(2-cyano-4-methylphenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; a mixture of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)-methyl]-12-(2-cyano-4-methoxy-phenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; a mixture of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-12-(pyridin-2-yl)-15-oxatetra-cyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide and (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-11-(pyridin-2-yl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (±)-N-[(6-amino-4-methoxy-2-methylpyridin-3-yl)methyl]-12-(2,4-difluorophenyl)-15-oxatetra-cyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; a mixture of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)-methyl]-12-(2,3-dihydro-1,4-benzodioxin-5-yl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide and (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-11-(2,3-dihydro-1,4-benzodioxin-5-yl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; a mixture of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)-methyl]-12-(2-cyanophenyl)-15-oxatetra-cyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide and (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-11-(2-cyanophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; a mixture of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)-methyl]-12-(2-cyano-6-methylphenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide and (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-11-(2-cyano-6-methylphenyl)-15-oxatetra-cyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; a mixture of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)-methyl]-12-[6-(cyclopropylmethoxy)pyridin-3-yl]-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-11-[6-(cyclopropylmethoxy)pyridin-3-yl]-15-oxatetra-cyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; a mixture of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)-methyl]-12-(6-methoxy-4-methylpyridin-3-yl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide and (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-11-(6-methoxy-4-methylpyridin-3-yl)-15-oxatetra-cyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; a mixture of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)-methyl]-12-(pyrimidin-2-yl)-15-oxatetra-cyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide and (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-1-(pyrimidin-2-yl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; a mixture of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)-methyl]-12-(2-methanesulfonylphenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide and (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-11-(2-methanesulfonylphenyl)-15-oxatetra-cyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; a mixture of (±)-N-[(6-amino-4-ethoxy-2-methylpyridin-3-yl)-methyl]-12-(2,4-difluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide and (±)-N-[(6-amino-4-ethoxy-2-methylpyridin-3-yl)methyl]-11-(2,4-difluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; a mixture of (±)-N-[(6-amino-4-ethoxy-2-methylpyridin-3-yl)methyl]-12-(2,3-difluorophenyl)-15-oxatetra-cyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide and (±)-N-[(6-amino-4-ethoxy-2-methylpyridin-3-yl)methyl]-11-(2,3-difluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (±)-12-(2,3-difluorophenyl)-N-[(6-fluoro-4-methyl-2,3-dihydro-1H-isoindol-5-yl)methyl]-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-12-(2,4-difluorophenyl)-15-oxatetra-cyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1S,8R)—N-[(6-amino-2,4-dimethylpyridin-3-yl)-methyl]-12-(2,4-difluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; a mixture of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)-methyl]-12-(5-methylfuran-2-yl)-15-oxatetra-cyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide and (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-1-(5-methylfuran-2-yl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; a mixture of (±)-N-{[4-(aminomethyl)-2,6-dimethylphenyl]-methyl}-12-(2-cyano-4-fluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide and (±)-N-{[4-(aminomethyl)-2,6-dimethylphenyl]methyl}-1-(2-cyano-4-fluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; a mixture of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)-methyl]-12-{2-oxa-6-azaspiro[3.3]heptan-6-yl}-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide and (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-11-{2-oxa-6-azaspiro[3.3]heptan-6-yl}-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (±)-12-(2,4-difluorophenyl)-N-[(6-fluoro-4-methyl-2,3-dihydro-1H-isoindol-5-yl)methyl]-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (±)-12-(2,4-difluorophenyl)-N-[(4,6-dimethyl-2,3-dihydro-1H-isoindol-5-yl)methyl]-15-oxatetra-cyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (±)-12-(2,3-difluorophenyl)-N-[(4,6-dimethyl-2,3-dihydro-1H-isoindol-5-yl)methyl]-15-oxatetra-cyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; a mixture of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)-methyl]-12-(3-oxomorpholin-4-yl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide and (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-1-(3-oxomorpholin-4-yl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-12-[2-fluoro-4-(trifluoromethyl)-phenyl]-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)-methyl]-12-(4-chloro-2-cyanophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)-methyl]-12-(2,3,4-trifluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (±)-N-[(6-amino-4-methoxy-2-methylpyridin-3-yl)methyl]-12-(2-cyano-4-methylphenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)-methyl]-12-(4-chloro-2,3-difluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; a mixture of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)-methyl]-12-(1,3-thiazol-2-yl)-15-oxatetra-cyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide and (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-1-(1,3-thiazol-2-yl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)-methyl]-12-(7-fluoro-2H-1,3-benzodioxol-4-yl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (±)-N-[(6-amino-4-methoxy-2-methylpyridin-3-yl)methyl]-12-(4-chloro-2,3-difluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)-methyl]-12-(3-fluoropyridin-2-yl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (±)-N-[(6-amino-4-ethoxy-2-methylpyridin-3-yl)-methyl]-12-(2-fluoro-6-methylphenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)-methyl]-12-(2-fluoro-6-methylphenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (±)-N-[(6-amino-4-methoxy-2-methylpyridin-3-yl)methyl]-12-(2-fluoro-6-methylphenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)-methyl]-12-(3,5-difluoropyridin-2-yl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)-methyl]-12-(2,3-difluoro-4-methylphenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)-methyl]-12-[2,3-difluoro-4-(trifluoromethyl)-phenyl]-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)-methyl]-12-[4-fluoro-3-(trifluoromethyl)-phenyl]-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)-methyl]-12-(1H-1,3-benzodiazol-5-yl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (±)-N-[(4,6-dimethyl-2,3-dihydro-1H-isoindol-5-yl)methyl]-12-(2-fluoro-6-methylphenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (±)-N-{[4-(aminomethyl)-2,6-dimethylphenyl]-methyl}-12-(4-chloro-2,3-difluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)-methyl]-12-(2-ethynylphenyl)-15-oxatetra-cyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (±)-12-(2,4-difluorophenyl)-N-{[5-methoxy-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]methyl}-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)-methyl]-12-(3-methanesulfonylphenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (±)-12-(2,4-difluorophenyl)-N-{[2-fluoro-3-methoxy-6-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-methyl}-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8R)—N-[(6-amino-2,4-dimethylpyridin-3-yl)-methyl]-11-(2-fluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (±)-N-[(4-chloro-6-methyl-2,3-dihydro-1H-isoindol-5-yl)methyl]-12-(2,4-difluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (±)-N-[(6-amino-4-ethyl-2-methylpyridin-3-yl)methyl]-12-(2,4-difluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (±)-N-[(6-amino-4-ethyl-2-methylpyridin-3-yl)methyl]-12-(2-cyano-4-methylphenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (±)-12-(2-cyano-4-methylphenyl)-N-[(4,6-dimethyl-2,3-dihydro-1H-isoindol-5-yl)methyl]-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-[(6-amino-4-ethyl-2-imethylpyridin-3-yl)methyl]-12-(2,4-trifluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-[(6-amino-4-ethyl-2-imethylpyridin-3-yl)methyl]-12-(chloro-2-cyano-4-methylphenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-[(6-amino-2,4-dimethylpyridin-3-yl)-methyl]-12-(2-cyano-4-methylphenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)-methyl]-12-(2,4-difluoro-6-methylphenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (±)-N-[(6-amino-4-ethyl-2-methylpyridin-3-yl)-methyl]-12-(2,4-difluoro-6-methylphenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (±)-12-(2-cyano-4-methylphenyl)-N-[(6-fluoro-4-methyl-2,3-dihydro-1H-isoindol-5-yl)methyl]-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-[(6-amino-2,4-dimethylpyridin-3-yl)-methyl]-12-(4-chloro-2,3-difluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)-methyl]-12-(2-chloro-4,6-difluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (±)-N-{[4-(aminomethyl)-2,6-dimethylphenyl]-methyl}-12-(2,4-difluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (±)-N-[(1-aminoisoquinolin-5-yl)methyl]-12-(2,4-difluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)-methyl]-12-(4-oxo-1,4-dihydropyridin-1-yl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (±)-N-[(6-amino-4-methoxy-2-methylpyridin-3-yl)methyl]-12-(2,4-difluoro-6-methylphenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (±)-N-[(6-amino-4-ethoxy-2-methylpyridin-3-yl)-methyl]-12-(2,4-difluoro-6-methylphenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (±)-N-[(1-aminoisoquinolin-7-yl)methyl]-12-(2,4-difluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (±)-N-[(1-aminoisoquinolin-4-yl)methyl]-12-(2,4-difluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)-methyl]-2-(2-cyano-5-methylphenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)-methyl]-12-(2-cyano-6-methylpyridin-3-yl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)-methyl]-12-[2-cyano-3-(trifluoromethyl)-phenyl]-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (±)-N-[(6-amino-2,5-dimethylpyridin-3-yl)-methyl]-12-(2,4-difluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)-methyl]-12-(4-methoxypyridin-3-yl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (±)-N-[(2-aminopyridin-4-yl)methyl]-12-(2,4-difluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)-methyl]-12-(2,4,5-trifluorophenyl)-15-oxatetra-cyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (±)-N-[(4-carbamimidoylphenyl)methyl]-12-(2,4-difluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; a mixture of (±)-N-[(4-carbamimidoylphenyl)methyl]-11-(2,4-difluorophenyl)-15-oxa-4-azatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-5-carboxamide and (±)-N-[(4-carbamimidoylphenyl)methyl]-12-(2,4-difluorophenyl)-15-oxa-4-azatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-5-carboxamide; (±)-N-[(6-amino-2-methyl-4-propylpyridin-3-yl)methyl]-12-(2,4-difluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide (±)-N-{[6-amino-2-methyl-4-(propan-2-yl)pyridin-3-yl]methyl}-12-(2,4-difluorophenyl)-15-oxatetra-cyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-[(6-amino-2,4-dimethylpyridin-3-yl)-methyl]-12-(4-chloro-2-fluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-[(1-aminoisoquinolin-5-yl)methyl]-12-(2-fluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-[(6-amino-2,4-dimethylpyridin-3-yl)-methyl]-12-(2-chloro-4-fluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-[(6-amino-2,4-dimethylpyridin-3-yl)-methyl]-12-(2-fluoro-6-methoxypyridin-3-yl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (±)-N-[(6-amino-4-cyclopropyl-2-methylpyridin-3-yl)methyl]-12-(2,4-difluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-[(2-amino-4,6-dimethylpyrimidin-5-yl)methyl]-12-(2,4-difluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-[(6-amino-4-ethyl-2-methylpyridin-3-yl)methyl]-12-(2,4-difluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1S,8R)—N-[(6-amino-2,4-dimethylpyridin-3-yl)-methyl]-12-(2-(methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)-5-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-[(4-carbamimidoylphenyl)methyl]-12-(2-fluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (±)-N-[(4-carbamimidoylphenyl)methyl]-12-phenyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-[(6-amino-4-chloro-2-methylpyridin-3-yl)methyl]-12-(2,4-difluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; 2-[(1R,8S)-12-{[(6-amino-2,4-dimethylpyridin-3-yl)methyl]carbamoyl}-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaen-4-yl]pyridin-1-ium-1-olate; (±)-12-(2,4-difluorophenyl)-N-({3-fluoro-4-[N′-hydroxycarbamimidoyl]phenyl}methyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide (±)-N-[(4-carbamimidoyl-3-fluorophenyl)methyl]-12-(2,4-difluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-[(4-carbamimidoyl-2,6-dimethyl-phenyl)methyl]-12-(2,4-difluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-[(3-carbamimidoylphenyl)methyl]-12-(2-fluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-[(4-carbamimidoylphenyl)methyl]-12-(4-fluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-[(4-carbamimidoylphenyl)methyl]-12-(2,4-difluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)-12-(2,4-difluorophenyl)-N-{[4-(N′-hydroxycarbamimidoyl)phenyl]methyl}-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)-12-(2-fluorophenyl)-N-{[4-(N′-hydroxycarbamimidoyl)phenyl]methyl}-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-[(3-amino-1,2-benzoxazol-6-yl)-methyl]-12-(2,4-difluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-[(3-amino-1H-indazol-6-yl)methyl]-12-(2,4-difluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-{[6-amino-2-methyl-4-(propan-2-yl)-pyridin-3-yl]methyl}-12-(2,4-difluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-[(4-carbamimidoyl-3-fluorophenyl)-methyl]-12-(2,4-difluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-[(6-amino-2,4-dimethylpyridin-3-yl)-methyl]-12-(2-methylpyridin-3-yl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0,.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-12-(2-methoxypyridin-3-yl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; 2-[(1R,8S)-12-{[(6-amino-2,4-dimethylpyridin-3-yl)methyl]carbamoyl}-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaen-4-yl]-5-fluoropyridin-1-ium-1-olate; (1R,8S)—N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-12-(4-methylpyridin-3-yl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-[(1-aminoisoquinolin-5-yl)methyl]-12-(2-cyano-4-methylphenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1S,8R)—N-[(4-carbamimidoylphenyl)methyl]-12-(5-chlorothiophen-2-yl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-[(6-amino-4-ethenyl-2-methylpyridin-3-yl)methyl]-12-(2,4-difluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-(4-aminobenzenecarboximidoyl)-12-(2,4-difluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-{[6-amino-4-(3,6-dihydro-2H-pyran-4-yl)-2-methylpyridin-3-yl]methyl}-12-(2,4-difluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-[(4-carbamimidoylphenyl)methyl]-12-(5-methylfuran-2-yl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)-12-(2,4-difluorophenyl)-N-{[4-(N′-methoxycarbamimidoyl)phenyl]methyl}-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-{[6-amino-2-methyl-4-(prop-1-en-2-yl)pyridin-3-yl]methyl}-12-(2,4-difluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1S,8R)—N-[(4-carbamimidoylphenyl)methyl]-12-{8-oxa-3-azabicyclo[3.2.1]octan-3-yl}-5-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1S,8R)—N-[(4-carbamimidoylphenyl)methyl]-12-(pyrrolidin-1-yl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-[(3-amino-1,2-benzoxazol-7-yl)-methyl]-12-(2-fluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)-12-(2-fluorophenyl)-N-{[4-(N′-methoxy-carbamimidoyl)phenyl]methyl}-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)-12-(4-fluorophenyl)-N-{[4-(N′-methoxy-carbamimidoyl)phenyl]methyl}-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-[(6-amino-4,5-dimethylpyridin-3-yl)methyl]-12-(2-fluorophenyl)-15-oxatetra-cyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-(4-carbamimidoylphenyl)-12-(2,4-difluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-(3-amino-1,2-benzoxazol-5-yl)-12-(2,4-difluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-{[6-amino-2-methyl-4-(trifluoro-methyl)pyridin-3-yl]methyl}-12-(2,4-difluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-{[6-amino-2-methyl-4-(oxan-4-yl)pyridin-3-yl]methyl}-12-(2,4-difluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-[(6-amino-2,4-diethylpyridin-3-yl)methyl]-12-(2,4-difluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1S,8R)-12-(5-chlorothiophen-2-yl)-N-({4-[N′-methoxycarbamimidoyl]phenyl}methyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-12-{imidazo[1,2-a]pyridin-2-yl}-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)-12-(2-fluorophenyl)-N-[(4-methoxy-phenyl)methyl]-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-({2,6-difluoro-4-[N′-methoxy-carbamimidoyl]phenyl}methyl)-12-(2,4-difluorophenyl)-5-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-[(4-carbamimidoyl-2,6-difluoro-phenyl)methyl]-12-(2,4-difluorophenyl)-[15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-[(6-amino-2,4-dicyclopropylpyridin-3-yl)methyl]-12-(2,4-difluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-(3-carbamimidoylphenyl)-methyl]-12-(2,4-difluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-[(4-carbamimidoylphenyl)methyl]-12-cyclopropyl-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-[(6-chloro-2-fluoro-3-methoxyphenyl)-methyl]-12-(2,4-difluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboximidamide; 4-[(1R,8S)-12-({[6-amino-2-methyl-4-(propan-2-yl)pyridin-3-yl]methyl}carbamoyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaen-4-yl]-3-fluoropyridin-1-ium-1-olate (1R,8S)—N-({2,6-difluoro-4-[N′-hydroxy-carbamimidoyl]phenyl}methyl)-12-(2,4-difluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-{[6-amino-4-(2,5-dihydrofuran-3-yl)-2-methylpyridin-3-yl]methyl}-12-(2,4-difluoro-phenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-[(6-carbamimidoylpyridin-3-yl)-methyl]-12-(2,4-difluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; ethyl N-[amino[4-({[(1R,8S)-12-(2,4-difluoro-phenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaen-4-yl]formamido}-methyl)-3,5-difluorophenyl]-methylidene]-carbamate; (1R,8S)-12-(2,4-difluorophenyl)-N-{[4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl]methyl}-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)-12-cyclopropyl-N-({4-[N′-methoxy-carbamimidoyl]phenyl}methyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; ethyl N-[amino[4-({[(1R,8S)-12-(2,4-difluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaen-4-yl]formamido}-methyl)phenyl]methylidene]carbamate; (1S,8R)—N-({2,6-difluoro-4-[N′-methoxy-carbamimidoyl]phenyl}methyl)-12-(1,3-thiazol-2-yl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1S,8R)—N-[(4-carbamimidoyl-2,6-difluoro-phenyl)methyl]-12-(1,3-thiazol-2-yl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1S,8R)-12-(5-chlorothiophen-2-yl)-N-{[4-(N′-hydroxycarbamimidoyl)phenyl]methyl}-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; 4-[(1R,8S)-12-{[(6-amino-4-cyclopropyl-2-methylpyridin-3-yl)methyl]carbamoyl}-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaen-4-yl]-3-fluoropyridin-1-ium-1-olate; (1R,8S)—N-[(4-carbamimidoyl-2,6-difluoro-phenyl)methyl]-12-cyclopropyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-12-(2,4-difluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboximidamide; (1R,8S)—N-(3-cyano-4-fluorophenyl)-12-(2,4-difluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboximidamide; (1S,8R)—N-[(4-carbamimidoyl-2,6-difluoro-phenyl)methyl]-12-(1H-pyrazol-1-yl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-(3-aminophenyl)-12-(2,4-difluoro-phenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-(4-aminophenyl)-12-(2,4-difluoro-phenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; 2-[(1R,8S)-12-({[6-amino-2-methyl-4-(propan-2-yl)pyridin-3-yl]methyl}carbamoyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaen-4-yl]-3-fluoropyridin-1-ium-1-olate; (1R,8S)—N-[(4-carbamimidoyl-2-fluorophenyl)-methyl]-12-(2-fluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-[(4-carbamimidoyl-2-fluorophenyl)-methyl]-12-(2,4-difluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-[(3-carbamoylphenyl)methyl]-12-(2,4-difluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; 2-[(1R,8S)-12-({[6-amino-2-methyl-4-(propan-2-yl)pyridin-3-yl]methyl}carbamoyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaen-4-yl]-5-fluoropyridin-1-ium-1-olate; (1R,8S)—N-[(1-amino-6-chloroisoquinolin-5-yl)methyl]-12-(2-fluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-[(1-amino-6-chloroisoquinolin-7-yl)methyl]-12-(2-fluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1S,8R)—N-[(4-carbamimidoyl-2,6-difluoro-phenyl)methyl]-12-(2H-1,2,3-triazol-2-yl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-[(1-amino-6-methylisoquinolin-5-yl)methyl]-12-(2-fluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-[(1-amino-6-methylisoquinolin-7-yl)methyl]-12-(2-fluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-[(4-carbamimidoyl-2-fluorophenyl)-methyl]-12-cyclopropyl-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-(6-aminopyridin-3-yl)-12-(2,4-difluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1S,8R)—N-[(4-carbamimidoylphenyl)methyl]-12-(1H-pyrazol-1-yl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-[(4-carbamimidoyl-2-methylphenyl)-methyl]-12-(2,4-difluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1S,8R)—N-[(4-carbamimidoylphenyl)methyl]-12-(3,3-difluoroazetidin-1-yl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-(4-aminopyridin-2-yl)-12-(2,4-difluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; a mixture of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-12-(2,4-difluorophenyl)-11-methyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9(14),10,12-hexaene-4-carboxamide and (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-11-(2,4-difluorophenyl)-12-methyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9(14),10,12-hexaene-4-carboxamide; (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)-methyl]-11,12-dicyclopropyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1S,8R)—N-[(4-carbamimidoyl-2-methylphenyl)-methyl]-12-(1H-pyrazol-1-yl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)-12-(2,4-difluorophenyl)-N-[(piperidin-4-yl)methyl]-15-oxatetracyclo-6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)-methyl]-11,12-diphenyl-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (±)-N-[(4-carbamimidoylphenyl)methyl]-11,12-dicyclopropyl-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-[(azetidin-3-yl)methyl]-12-(2,4-difluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)-12-(2,4-difluorophenyl)-N-[(3R)-pyrrolidin-3-yl]-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)-12-(2,4-difluorophenyl)-N-[(3S)-pyrrolidin-3-yl]-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-[(5-carbamimidoylpyridin-2-yl)methyl]-12-cyclopropyl-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-[(4-carbamimidoyl-2-fluorophenyl)-methyl]-12-(4-fluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)-12-(2,4-difluorophenyl)-N-{[4-(N′-methoxycarbamimidoyl)-2,6-dimethylphenyl]-methyl}-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-[(4-carbamimidoyl-2,6-dimethyl-phenyl)methyl]-12-cyclopropyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-[(5-carbamimidoylpyridin-2-yl)-methyl]-12-(2,4-difluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1S,8R)—N-[(4-carbamimidoyl-2,6-difluoro-phenyl)methyl]-12-(1,1-dioxo-1λ.sup.6-thiomorpholin-4-yl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1S,8R)—N-[(4-carbamimidoylphenyl)methyl]-12-(1,1-dioxo-1λ.sup.6-thiomorpholin-4-yl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-[(4-carbamimidoyl-3-methoxyphenyl)-methyl]-12-(2,4-difluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; a mixture of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-12-(4-fluorophenyl)-1,8-dimethyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide and (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-11-(4-fluorophenyl)-1,8-dimethyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-(azepan-4-yl)-12-(2,4-difluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)-12-(2,4-difluorophenyl)-N-(piperidin-4-yl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-(2-aminopyridin-4-yl)-12-(2,4-difluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; methyl N-[1-amino[4-({[(1R,8S)-12-(2,4-difluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaen-4-yl]formamido}-methyl)phenyl]-methylidene]carbamate; hexyl N-[1-amino[4-({[(1R,8S)-12-(2,4-difluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaen-4-yl]formamido}-methyl)phenyl]methylidene]carbamate; (1R,8S)-12-cyclopropyl-N-({2,6-difluoro-4-[N′-methoxycarbamimidoyl]phenyl}methyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; methyl N-[(1)-amino[4-({[(1R,8S)-12-cyclopropyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaen-4-yl]formamido}methyl)phenyl]methylidene]carbamate methyl N-[1-amino[4-({[(1R,8S)-12-cyclopropyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaen-4-yl]formamido}-methyl)-3,5-difluorophenyl]-methylidene]-carbamate; propyl N-[1-amino[4-({[(1R,8S)-12-(2,4-difluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaen-4-yl]formamido}-methyl)phenyl]methylidene]carbamate; (1S,8R)—N-({2,6-difluoro-4-[N′-methoxycarbamimidoyl]phenyl}methyl)-12-(1H-pyrazol-1-yl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-{[2-fluoro-4-(N′-hydroxy-carbamimidoyl)phenyl]methyl}-12-(2-fluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-{[2-fluoro-4-(N′-methoxy-carbamimidoyl)phenyl]methyl}-12-(2-fluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-({4-[(1)-amino({[benzoyl]-imino})methyl]phenyl}methyl)-12-(2,4-difluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)-12-(2,4-difluorophenyl)-N-{[4-(5,5-dimethyl-4,6-dioxo-1,4,5,6-tetrahydropyrimidin-2-yl)phenyl]methyl}-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)-12-cyclopropyl-N-{[2-fluoro-4-(N′-methoxycarbamimidoyl)phenyl]methyl}-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)-12-(2,4-difluorophenyl)-N-{[2-fluoro-4-(N′-hydroxycarbamimidoyl)phenyl]-methyl}-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1S,8R)—N-({4-[N′-methoxycarbamimidoyl]-phenyl}methyl)-12-(1H-pyrazol-1-yl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)-12-(2,4-difluorophenyl)-N-{[4-(N′-methoxycarbamimidoyl)-2-methylphenyl]-methyl}-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)-12-(2,4-difluorophenyl)-N-{[4-(N,N′-dihydroxycarbamimidoyl)phenyl]methyl}-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)-12-(2,4-difluorophenyl)-N-{[4-(N′-hydroxycarbamimidoyl)-2-methylphenyl]-methyl}-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-({4-[N′-(benzyloxy)carbamimidoyl]-phenyl}methyl)-12-(2,4-difluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; tert-butyl N-[1-amino[4-({[(1R,8S)-12-(2,4-difluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaen-4-yl]formamido}methyl)phenyl]-methylidene]carbamate; (1S,8R)—N-[(4-carbamimidoylphenyl)methyl]-12-(3,3-difluoroazetidin-1-yl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (±)-11,12-dicyclopropyl-N-({4-[N′-methoxy-carbamimidoyl]phenyl}methyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1S,8R)—N-({4-[N′-methoxycarbamimidoyl]-2-methylphenyl}methyl)-12-(1H-pyrazol-1-yl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)-12-cyclopropyl-N-{[4-(N-ethoxy-carbamimidoyl)phenyl]methyl}-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)-12-(2,4-difluorophenyl)-N-{[4-(N′-ethoxycarbamimidoyl)phenyl]methyl}-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1S,8R)-12-(3,3-difluoroazetidin-1-yl)-N-({4-[N′-methoxycarbamimidoyl]phenyl}methyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)-12-cyclopropyl-N-{[4-(N′-hydroxy-carbamimidoyl)phenyl]methyl}-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)-12-cyclopropyl-N-{[5-(N′-methoxy-carbamimidoyl)pyridin-2-yl]methyl}-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-({4-[N′-ethoxycarbamimidoyl]-phenyl}methyl)-12-(4-fluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; tert-butyl N-[1-amino[4-({[(1R,8S)-12-(4-fluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaen-4-yl]formamido}-methyl)phenyl]methylidene]carbamate; (1R,8S)—N-{[2-fluoro-4-(N′-methoxy-carbamimidoyl)phenyl]methyl}-12-(4-fluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)-12-cyclopropyl-N-{[4-(N′-methoxy-carbamimidoyl)-2,6-dimethylphenyl]methyl}-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)-12-(2,4-difluorophenyl)-N-({4-[N′-(propan-2-yloxy)carbamimidoyl]phenyl}-methyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)-12-(2,4-difluorophenyl)-N-{[6-(N′-methoxycarbamimidoyl)pyridin-3-yl]methyl}-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-6-fluoro-11-(4-fluorophenyl)-13-methyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9(14),10,12-hexaene-4-carboxamide; (1R,8S)—N-[(4-carbamimidoylphenyl)methyl]-11,12-dicyclopropyl-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1S,8R)—N-[(4-carbamimidoylphenyl)methyl]-11,12-dicyclopropyl-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1S,8R)-11,12-dicyclopropyl-N-({4-[N′-hydroxycarbamimidoyl]phenyl}methyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)-11,12-dicyclopropyl-N-({4-[N′-hydroxycarbamimidoyl]phenyl}methyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)-methyl]-6-fluoro-12-(4-fluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxamide; (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)-methyl]-6-fluoro-11-(4-fluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxamide; a mixture of (±)-N-[(4-carbamimidoylphenyl)methyl]-11-(2,4-difluorophenyl)-15-oxa-4-azatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-5-carboxamide and (±)-N-[(4-carbamimidoylphenyl)methyl]-12-(2,4-difluorophenyl)-15-oxa-4-azatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-5-carboxamide; (1S,8R)-11,12-dicyclopropyl-N-({4-[N′-methoxycarbamimidoyl]phenyl}methyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; a mixture of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-5-fluoro-12-(4-fluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxamide and (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-5-fluoro-11-(4-fluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxamide; (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)-methyl]-6-fluoro-11-(4-fluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxamide; and a mixture of (±)-N-[(4-carbamimidoylphenyl)methyl]-11-(2,4-difluorophenyl)-15-oxa-4-azatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-5-carboxamide and (±)-N-[(4-carbamimidoylphenyl)methyl]-12-(2,4-difluorophenyl)-15-oxa-4-azatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-5-carboxamide; or an individual regioisomer thereof; or an individual stereoisomer of any of the foregoing compounds; or an E or Z isomer thereof of any of the foregoing compounds; or a pharmaceutically acceptable salt of any of the foregoing compounds.

14. A compound selected from: (1R,8S)—N-[(4-carbamimidoylphenyl)methyl]-12-(2-fluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-[(4-carbamimidoylphenyl)methyl]-12-(4-fluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-[(4-carbamimidoylphenyl)methyl]-12-(2,4-difluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)-12-(2,4-difluorophenyl)-N-{[4-(N′-hydroxycarbamimidoyl)phenyl]methyl}-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)-12-(2-fluorophenyl)-N-{[4-(N′-hydroxycarbamimidoyl)phenyl]methyl}-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)-12-(2,4-difluorophenyl)-N-{[4-(N′-methoxycarbamimidoyl)phenyl]methyl}-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)-12-(2-fluorophenyl)-N-{[4-(N′-methoxycarbamimidoyl)phenyl]methyl}-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)-12-(4-fluorophenyl)-N-{[4-(N′-methoxycarbamimidoyl)phenyl]methyl}-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-[(4-carbamimidoyl-2-fluorophenyl)methyl]-12-(2-fluorophenyl)-15-oxatetra-cyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-[(4-carbamimidoyl-2-fluorophenyl)methyl]-12-(4-fluorophenyl)-15-oxatetra-cyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-{[2-fluoro-4-(N′-hydroxycarbamimidoyl)phenyl]methyl}-12-(2-fluoro-phenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-{[2-fluoro-4-(N′-methoxycarbamimidoyl)phenyl]methyl}-12-(2-fluoro-phenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)-12-(2,4-difluorophenyl)-N-{[4-(N′-ethoxycarbamimidoyl)phenyl]methyl}-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)—N-({4-[N′-ethoxycarbamimidoyl]phenyl}methyl)-12-(4-fluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; tert-butyl N-[1-amino[4-({[(1R,8S)-12-(4-fluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaen-4-yl]formamido}methyl)phenyl]-methylidene]carbamate; and (1R,8S)—N-{[2-fluoro-4-(N′-methoxycarbamimidoyl)phenyl]methyl}-12-(4-fluoro-phenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; or an E or Z isomer thereof; or a pharmaceutically acceptable salt of any of the foregoing compounds.

15. The compound of claim 13 selected from: (1S,8R)-11,12-dicyclopropyl-N-({4-[N′-methoxycarbamimidoyl]phenyl}methyl)-15-oxatetra-cyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1S,8R)-11,12-dicyclopropyl-N-({4-[N′-hydroxycarbamimidoyl]phenyl}methyl)-15-oxatetra-cyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1S,8R)—N-[(4-carbamimidoylphenyl)methyl]-11,12-dicyclopropyl-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)-12-cyclopropyl-N-{[4-(N′-hydroxycarbamimidoyl)phenyl]methyl}-15-oxatetra-cyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; (1R,8S)-12-cyclopropyl-N-{[4-(N-ethoxycarbamimidoyl)phenyl]methyl}-15-oxatetra-cyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; methyl N-[1-amino[4-({[(1R,8S)-12-cyclopropyl-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaen-4-yl]formamido}methyl)-phenyl]methylidene]carbamate; (1R,8S)-12-cyclopropyl-N-({4-[N′-methoxycarbamimidoyl]phenyl}methyl)-15-oxatetra-cyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; and (1R,8S)—N-[(4-carbamimidoylphenyl)methyl]-12-cyclopropyl-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide; or an E or Z isomer thereof; or a pharmaceutically acceptable salt of any of the foregoing compounds.

16. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

Description

EXAMPLES

Synthetic Procedures

Reference 1

Synthesis of 5-bromoisobenzofuran (INT-1)

(1) ##STR00611##

(2) Step 1:

(3) To a stirred solution of 5-bromo-2-benzofuran-1(3H)-one (12.60 g; 59.15 mmol; 1 eq.) in dichloromethane (591 mL) cooled to −78° C. was added DIBAL (59.15 ml; 1 mol/l; 59.15 mmol; 1 eq.) (1 M solution in toluene) dropwise and the mixture was stirred at −78° C. After 60 minutes, approximately 10% more DIBAL solution was added (6 mL) and the reaction left for additional 30 minutes. Before proceeding with the work up, celite was added to the reaction mix, followed up with addition of water (2.64 mL), then 15% NaOH (2.64 mL) and water (6.6 mL). The reaction mix was removed from bath and left to reach RT, then stirred at RT for 40 min before filtering it over celite. The filtered solution was dried over Na.sub.2SO.sub.4, filtered and concentrated to dryness to give 5-bromo-1,3-dihydro-2-benzofuran-1-ol as a white solid. Partial Yield: ˜10.0 g. The celite cake was transferred to a round bottom flask and stirred with DCM for 30 minutes, filtered and dried over Na.sub.2SO.sub.4; filtered again and concentrated to give additional 1.3 g of product and a total of 11.3 g were obtained (˜89% yield).

(4) Step 2:

(5) Sodium hydride (2.41 g; 60.16 mmol; 1.25 eq.) was suspended in THF (600 mL) and the mixture was cooled to 0° C. in an ice bath. A solution of 5-bromo-1,3-dihydro-2-benzofuran-1-ol (10.35 g; 48.13 mmol; 1 eq.) in THF (200 mL) was added slowly to the suspension and the resulting mixture was stirred for 30 minutes. Iodomethane (14.98 mL; 240.65 mmol; 5 eq.) was added over a 5 minute period and the mixture was allowed to warm to RT. After stirring overnight, the reaction mixture was quenched with ice water and extracted with diethyl ether. The aqueous layer was back extracted once and the combined organics were washed with brine, then dried over MgSO.sub.4, filtered and concentrated. The crude material was purified on a silica gel column using 0-10% EtOAc in heptane to give the desired product as clear oil which solidified under high vacuum to give 5-bromo-1-methoxy-1,3-dihydro-2-benzofuran 9.0 g (78%).

(6) Step 3:

(7) To a solution of 5-bromo-1-methoxy-1,3-dihydro-2-benzofuran (12.15 g; 53.04 mmol; 1 eq.) in diethyl ether (200 mL) cooled to 0° C. was added commercial 2M LDA solution in THF/heptane/ethylbenzene (79.56 mL; 2 mol/l; 159.12 mmol; 3 eq.) dropwise. The reaction mix turned progressively dark brown and the dark cloudy mixture was stirred at 0° C. After 15-20 minutes, the reaction mix was diluted with diethyl ether and quenched with saturated solution of NH.sub.4Cl. The organic layer was isolated and the aqueous layer was back extracted with ether. The combined organics were dried over Na.sub.2SO.sub.4, filtered and concentrated to give 5-bromoisobenzofuran (100%) which was used directly for the next reaction.

(8) Alternate Synthesis:

(9) Step 1:

(10) Into a 5-L 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 1,4-dibromo-2-fluorobenzene (600.0 g, 2.38 mol, 1.00 equiv) and furan (485.7 g, 7.14 mol, 3.00 equiv) in toluene (1.8 L) with stirring at ˜30° C., followed by the drop-wise addition of n-BuLi (2.5 mol/L; 952 mL, 2.38 mol, 1.00 equiv) over a period of 10 min at −30° C. The resulting solution was stirred for an additional 30 min at room temperature then it was quenched with water. The resulting mixture was extracted with ethyl acetate and washed with H.sub.2O. The organic layers were combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by a silica gel column eluting with ethyl acetate/petroleum ether (1:10) o deliver 336.0 g (1.51 mol, 63.3%) of (±) 4-bromo-11-oxatricyclo[6.2.1.0.sup.2,7]-undeca-2,4,6,9-tetraene as a yellow solid.

(11) Step 2:

(12) Into a 3-L 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of (±) 4-bromo-11-oxatricyclo[6.2.1.0.sup.2,7]undeca-2,4,6,9-tetraene (100.0 g, 448.3 mmol, 1.00 equiv) in dichloromethane (500 mL), followed by the addition of a solution of bis(pyridin-2-yl)-1,2,4,5-tetrazine (116.5 g, 493.2 mmol, 1.10 equiv) in dichloromethane (500 mL) dropwise with stirring at 0° C. over 5 min. The resulting solution was heated to reflux for 1 h then cooled to 0° C. and used directly in the synthesis of INT-3 below.

Reference 2

Synthesis of (5-(methoxycarbonyl)-2-(trimethylsilyl)phenyl)(phenyl)-iodonium triflate Salt (INT-2)

(13) ##STR00612##

(14) Step 1:

(15) In a screw-cap thick-wall reaction vessel, methyl 2-oxo-2H-pyran-5-carboxylate (4.00 g; 25.95 mmol; 1 eq.) and trimethyl[(trimethylsilyl)ethynyl]silane (13.27 g; 77.86 mmol; 3 eq.) were combined. The vessel was sealed and stirred in a metal sand bath at 200° C. After 24 h, the vessel was cooled, and the contents was adsorbed on to silica gel and purified by silica gel chromatography (ethyl acetate/hexanes gradient) to give methyl 3,4-bis(trimethylsilyl)benzoate (7.14 g) as a colorless oily residue.

(16) Step 2:

(17) In a round-bottom flask, (diacetoxyiodo)benzene (8.20 g; 25.45 mmol; 1 eq.) was dissolved in DCM (100 mL) and cooled in an ice bath. Trifluoromethanesulfonic acid (4.50 mL; 50.91 mmol; 2 eq.) was added slowly and the reaction was stirred for 30 m at 25° C. The reaction was then re-cooled in an ice bath and methyl 3,4-bis(trimethylsilyl)benzoate (7.14 g; 25.45 mmol; 1 eq.) dissolved in DCM (15 mL) was added. The reaction was stirred to 25° C. over 16 h. The solvent was evaporated and the residue was triturated and sonicated with diethyl ether (300 mL) to give (5-(methoxycarbonyl)-2-(trimethylsilyl)phenyl)(phenyl)iodonium trifluoromethanesulfonate (14.26 g) as a white solid.

Reference 3

Synthesis of (±) methyl 12-bromo-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate and (±) methyl 11-bromo-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (INT-3)

(18) ##STR00613##

(19) To a stirred solution of [5-(methoxycarbonyl)-2-(trimethylsilyl)phenyl]-(phenyl)iodanium trifluoromethanesulfonate (INT-2; 11.00 g; 19.63 mmol; 1 eq.) in dichloromethane (196 mL) at 0° C. was added a solution in ether of 5-bromo-2-benzofuran (INT-1, 10.44 g; 53 mmol; 2.7 eq.) over a 10 minute period. To this dark mixture was added tetrabutylammonium fluoride (25.52 mL; 1.00 mol/l; 25.52 mmol; 1.3 eq.) and the mixture was stirred at 0° C. LC/MS after 20 min showed formation of a single product (mass is consistent with desired product, Rt 1.03 min, MS+ 330/332. The mixture was diluted with water and extracted with DCM; the combined organics were dried over MgSO.sub.4, filtered and concentrated to afford a dark oil. The crude material was purified by column chromatography eluting with 0-15% EtOAc in hexanes to provide a mixture of the title compounds. Regioisomers could not be isolated. Yield: 5.45 g (83%).

Reference 4

Separation of (±) methyl 12-bromo-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (INT-3a) and (±) methyl 11-bromo-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (INT-3b)

(20) ##STR00614##

(21) Step 1:

(22) Sodium hydroxide (22.65 mL; 2.00 mol/L; 45.3 mmol; 15 eq.) was added to a solution of (±) methyl 12-bromo-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate and (±) methyl 11-bromo-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (1000 mg; 3.02 mmol; 1 eq.) in acetonitrile (15.1 mL) and methanol (15.1 mL). The mixture was heated at 60° C. for 20 minutes and then cooled to RT. Organic solvents were removed under reduced pressure and the aqueous layer was washed with ethyl ether.

(23) The aqueous layer was concentrated under reduced pressure to remove volatile organics. The remaining aqueous layer was cooled and kept at room temperature. White precipitates were collected by vacuum filtration and washed with small amount of cold water. After drying, (±) sodium 12-bromo-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (INT-5a) was obtained (0.4 g). The recrystallization process can be repeated until desired regioisomerical purity (e.g. 98%) was reached as analyzed by LC/MS. The filtrate contains (±) sodium 11-bromo-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (INT-5b).

(24) Step 2:

(25) To a mixture (±) sodium 12-bromo-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (INT-5a); 500 mg; 1.47 mmol; 1 eq.) and potassium carbonate (407 mg; 2.95 mmol; 2 eq.) in N,N-dimethylformamide (4.9 mL) was added iodomethane (0.18 mL; 2.95 mmol; 2 eq.). The mixture was heated to 50° C. for 1 h and cooled to RT. The reaction mixture was the diluted with water and extracted with ethyl ether. The combined organics were dried with MgSO.sub.4, filtered, and concentrated to afford (±) methyl 12-bromo-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (INT-3a) as a white solid (488 mg; 99%). This methyl ester can be used directly for subsequent reactions without further purification. MS (M+H).sup.+ found for C.sub.16H.sub.11BrO.sub.3: 331.2, 332. LC/MS conditions, Column: Phenomenex Kinetex F5, 150×4.6 mm; Solvent A: 0.1% TFA in Water; Solvent B: Acetonitrile; Flow Rate: 0.75 ml/min; 17 run time; 5-40% gradient solvent B.

Reference 5

Isolation of methyl (1S,8R)-12-bromo-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (INT-3a1), methyl (1R,8S)-12-bromo-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (INT-3a2), methyl (1R,8R)-11-bromo-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (INT-3b1) and methyl (1S,8S)-11-bromo-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (INT-3b2) and corresponding acids and salts thereof

(26) ##STR00615##

(27) By Chiral Separation:

(28) The racemic mixture of INT-3a (i.e., (±) methyl 12-bromo-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate) or INT-3b (i.e., (±) methyl 11-bromo-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate) can be separated into their enantiomerically pure components (INT-3a1 and INT-3a2 and INT-3b1 and INT-3b2 respectively) by chiral HPLC or SFC using commercial chiral columns such as DAICEL CHIRALCEL OJ-3, 50×4.6 mm, 3.0 μm under normal phase conditions (e.g., using hexane/EtOH or iPrOH) or Lux Amylose-2 column 5 uM 4.6×100 column under reverse phase conditions (e.g., water/acetonitrile, with 0.1% TFA or HCOOH). Similar conditions can be used for the separation of the corresponding carboxylic acids ((±) 12-bromo-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid designated INT-4a1 and INT-4a2 and (±)11-bromo-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid designated INT-4b1 and INT-4b2 respectively).

(29) By enzymatic resolution: lipase or esterase can also be used to selectively hydrolyze one of the enantiomers of the racemic mixture of esters INT-3a or INT-3b or selectively esterify of one of the enantiomers of the racemic mixture of acids INT-4a or INT-4b.

(30) Applying the conditions described above, INT-3a (200 mg) gave 75 mg of methyl (1S,8R)-12-bromo-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (INT-3a1) and 74 mg of methyl (1R,8S)-12-bromo-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (INT-3a2) after chiral HPLC separation.

(31) methyl (1S,8R)-12-bromo-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (INT-3a1): .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.98 (s, 1H), 7.82 (dd, J=7.5, 1.5 Hz, 1H), 7.50 (s, 1H), 7.39 (d, J=7.5 Hz, 1H), 7.28 (s, 1H), 7.21 (m, 2H), 6.09 (d, J=1.5 Hz, 2H), 3.90 (s, 3H). MS (M+H).sup.+ found for C.sub.16H.sub.11BrO.sub.3: 331.2, found 331.

(32) methyl (1R,8S)-12-bromo-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (INT-3a2): .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.98 (s, 1H), 7.83 (dd, J=7.5, 1.2 Hz, 1H), 7.50 (s, 1H), 7.40 (d, J=7.5 Hz, 1H), 7.28 (s, 1H), 7.21 (m, 2H), 6.09 (s, 2H), 3.90 (s, 3H). MS (M+H).sup.+ found for C.sub.16H.sub.11BrO.sub.3: 331.2, found 331.

(33) ##STR00616##

(34) By recrystallization: Another methodology to separate pure enantiomers from the racemic mixture of acids INT-4a (or INT-4b) involves the recrystallization of the salts of the racemic acid with a chiral amine such as (S)-1-phenylethan-1-amine or (R)-1-phenylethan-1-amine.

(35) Step 1:

(36) A mixture of (±) 12-bromo-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (INT-4a; 35.6 g, 112 mmol; 95% d.e) and (R)-1-phenylethanamine (13.6 g, 112 mmol) were dissolved in acetonitrile (2,265 mL) at 60° C. To this solution was added H.sub.2O (113.3 mL) until it became cloudy, then a few drops of acetonitrile were added to form a clear solution at 60° C. The mixture was then cooled slowly to room temperature overnight. The precipitate thus formed was collected by filtration and dried under vacuum to afford 13.9 g of (1R)-1-phenylethan-1-aminium (1S,8R)-12-bromo-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate as an off-white solid (with approximately 90% e.e.). The collected solids were treated with a small amount of water (˜120% by weight of solids) and stirred for 1 hr. The slurry was then filtered and the solids were dried to obtain 9.3 g of enantio-enriched (1R)-1-phenylethan-1-aminium (1S,8R)-12-bromo-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (95% e.e.). The mother liquor was recycled for reuse.

(37) Step 2:

(38) Into a 500-mL round-bottom flask, was placed a solution of (1R)-1-phenylethan-1-aminium (1S,8R)-12-bromo-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (15.3 g, 34.91 mmol, 1.00 equiv) in water (250 mL). The resulting solution was acidified by 1 M aqueous HCl to pH 4 with stirring. The resulting mixture was extracted with ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to afford 9.3 g (84%) of (1S,8R)-12-bromo-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid as a white solid.

Reference 6

Synthesis of tert-butyl (isobenzofuran-5-ylmethoxy)dimethylsilane (INT-5)

(39) ##STR00617##

(40) Step 1:

(41) 5-(Hydroxymethyl)isobenzofuran-1(3H)-one was synthesized from 1-oxo-1,3-dihydroisobenzofuran-5-carboxylic acid (97%, PharmaBlock R&D Co. Ltd) according to the procedure described by Spicer, J. A. et al. in Bioorg. Med. Chem., 2012, 20(3), 1319-1336.

(42) Step 2:

(43) A mixture of 5-(hydroxymethyl)isobenzofuran-1(3H)-one (400 mg; 2.44 mmol; 1 eq.), tert-butyl(chloro)dimethylsilane (477 mg; 3.17 mmol; 1.3 eq.) and 1H-imidazole (216 mg; 3.17 mmol; 1.3 eq.) in N,N-dimethylformamide (9 mL) was stirred at ambient temperature for 16 h. The mixture was then diluted with 1:1 toluene/EtOAc (50 mL) and washed with water. The organic phase was dried over MgSO.sub.4, filtered and concentrated. The crude material was purified by column chromatography on a 12 g ISCO Gold column eluting with 30% EtOAc in hexanes to provide 5-(((tert-butyldimethylsilyl)oxy)methyl)isobenzofuran-1(3H)-one as a white solid (500 mg; 73.7%).

(44) Step 3:

(45) To a stirred solution of 5-(((tert-butyldimethylsilyl)oxy)methyl)isobenzofuran-1(3H)-one (910 mg; 3.27 mmol; 1 eq.) in DCM (32.7 mL) cooled to −78° C. was added diisobutylaluminium hydride (1 M solution in DCM; 3.9 mL; 3.9 mmol; 1.2 eq.) drop-wise. The mixture was stirred at −78° C. and after 20 min it was quenched with 10% NaOH (10 mL), allowed to reach ambient temperature and then diluted with water. The organic layer was separated and the aqueous layer was extracted with DCM. The combined organics were dried over MgSO.sub.4, filtered and concentrated to give (S)-5-(((tert-butyldimethylsilyl)oxy)methyl)-1,3-dihydroisobenzofuran-1-ol and (R)-5-(((tert-butyldimethylsilyl)oxy)methyl)-1,3-dihydroisobenzofuran-1-ol. .sup.1H NMR of the crude material confirmed formation of the title compound in equilibrium with the corresponding open form aldehyde. This material was taken on without further purification.

(46) Step 4:

(47) (To a stirred solution of (S)-5-(((tert-butyldimethylsilyl)oxy)methyl)-1,3-dihydroisobenzo-furan-1-ol and (R)-5-(((tert-butyldimethylsilyl)oxy)methyl)-1,3-dihydroisobenzofuran-1-ol (916 mg; 3.27 mmol; 1 eq.) in THF (32.7 mL) cooled to 0° C. was added sodium hydride (157 mg; 6.53 mmol; 2 eq.) in one portion and the mixture was stirred at 0° C. for 15 min. Iodomethane (1 mL; 16.3 mmol; 5 eq.) was then added drop-wise and the mixture was allowed to warm to ambient temperature. The progress of the reaction was monitored by TLC (20% EtOAc in hexanes) and upon completion (˜36 h) the mixture was quenched and diluted with water and extracted with EtOAc. The combined organics were washed with brine, then dried over MgSO.sub.4, filtered and concentrated. The crude material was purified by column chromatography on a 24 g ISCO Gold column eluting with 10% EtOAc in hexanes to provide (S)-tert-butyl((1-methoxy-1,3-dihydroisobenzofuran-5-yl)methoxy)dimethylsilane and (R)-tert-butyl((1-methoxy-1,3-dihydroisobenzofuran-5-yl)methoxy)dimethylsilane as a clear oil (759 mg; 78.9% for the two steps).

(48) Step 5:

(49) To a solution of (S)-tert-butyl ((1-methoxy-1,3-dihydroisobenzofuran-5-yl)methoxy)-dimethylsilane and (R)-tert-butyl ((1-methoxy-1,3-dihydroisobenzofuran-5-yl)methoxy)-dimethylsilane (170 mg; 0.58 mmol; 1 eq.) in Et.sub.2O (1.92 mL) cooled to 0° C. was added freshly prepared LDA (1M solution in THF, 1.8 mL˜3 eq.) drop-wise. The dark cloudy mixture was stirred at 0° C. .sup.1H NMR of a small aliquot of the reacting mixture after 15 minutes confirmed formation of the desired product. The reacting mixture was then diluted with Et.sub.2O, washed with NH.sub.4Cl and water, dried over MgSO.sub.4 and filtered. This crude product solution was concentrated to ˜1 mL, kept at 0° C. and used in the next step without further purification.

Reference 7

Synthesis of tert-butyl (5-(aminomethyl)-4,6-dimethylpyridin-2-yl)carbamate

(50) ##STR00618##

(51) Step 1:

(52) Into a 500-mL three neck round-bottom flask, was placed polyphosphoric acid (PPA) (300 g). This was followed by the addition of (2E)-3-aminobut-2-enenitrile (30 g, 365.39 mmol, 1 eq.) at 100° C. The resulting solution was stirred for 3 h at 165° C. The reaction mixture was cooled to 90° C. and then quenched by the addition of water/ice. The pH value of the solution was adjusted to 9 with sodium hydroxide (10%). The resulting solution was extracted with ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum to give 12.4 g (23%) of 6-amino-2,4-dimethylpyridine-3-carbonitrile as a yellow solid.

(53) Step 2:

(54) Into a 500-mL round-bottom flask, was placed 6-amino-2,4-dimethylpyridine-3-carbonitrile (12.4 g, 84.25 mmol, 1 eq.), 4-dimethylaminopyridine (1.03 g, 8.43 mmol, 0.1 eq.), and tetrahydrofuran (100 mL). This was followed by the addition of a solution of Boc.sub.2O (55 g, 252 mmol, 3 eq.) in tetrahydrofuran (100 mL) dropwise with stirring. The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with H.sub.2O and extracted with ethyl acetate and the organic layers combined. The resulting mixture was washed with brine. The combined organics were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10) as eluent. This resulted in 13.2 g (45%) of tert-butyl N-[(tert-butoxy)carbonyl]-N-(5-cyano-4,6-dimethylpyridin-2-yl)carbamate as a light yellow solid.

(55) Step 3:

(56) Into a 250-mL round-bottom flask, was placed tert-butyl N-[(tert-butoxy)carbonyl]-N-(5-cyano-4,6-dimethylpyridin-2-yl)carbamate (7.1 g, 20.44 mmol, 1 eq.), methanol (70 mL), dichloromethane (20 mL). This was followed by the addition of H.sub.2O.sub.2 (2.69 mL, 1.5 eq.) dropwise with stirring. To this was added a solution of sodium hydroxide (1.228 g, 30.7 mmol, 1.5 eq.) in water (10 mL) dropwise with stirring. The resulting solution was stirred for 2 h at 0° C. in a water/ice bath. The reaction was then quenched by the addition of 10% Na.sub.2CO.sub.3 (100 mL). The resulting solution was extracted with ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:3) as eluent. This resulted in 3.8 g (75%) of tert-butyl N-(5-cyano-4,6-dimethylpyridin-2-yl)carbamate as a white solid.

(57) Step 4:

(58) Into a 100-mL round-bottom flask, was placed tert-butyl N-(5-cyano-4,6-dimethylpyridin-2-yl)carbamate (3.8 g, 15.37 mmol, 1 eq.), NH.sub.3/MeOH (10 mL), methanol (20 mL), and Raney-Ni (3.8 g). To the above, hydrogen was introduced. The resulting solution was stirred overnight at room temperature under 1 atm of hydrogen. The solids were filtered. The resulting mixture was concentrated under vacuum. This resulted in 3.2 g (83%) of tert-butyl N-[5-(aminomethyl)-4,6-dimethylpyridin-2-yl]carbamate as a white solid.

Reference 8

Synthesis of 5-(aminomethyl)-4,6-dimethylpyridin-2-amine (INT 6a)

(59) ##STR00619##

(60) Step 1:

(61) Into a 100-mL round-bottom flask was placed a solution of tert-butyl N-[5-(aminomethyl)-4,6-dimethylpyridin-2-yl]carbamate (2.51 g, 10 mmol, 1 eq.) in dichloromethane (52 mL) and then added TFA (2.7 mL) dropwise with stirring. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The crude product was purified by Combi-Flash with the following conditions: column C18, 20-45 um, 100 A, 120 g. Mobile phase: solvent A: water contains 0.05% TFA, solvent B: CH.sub.3CN. Gradient: 5-28%. Run time: 12 min. Flow rate: 80 mL/min. This resulted in 1.40 g (53%) of 5-(amino-methyl)-4,6-dimethylpyridin-2-amine in form of its corresponding trifluoroacetic acid salt as a light green solid.

(62) Alternative Route:

(63) Step 1:

(64) Into a 5000-mL round-bottom flask, was placed a mixture of tert-butyl N-[(tert-butoxy)carbonyl]-N-(5-cyano-4,6-dimethylpyridin-2-yl)carbamate (210 g, 0.605 mol, 1.00 equiv), methanol (3000 mL), ammonia (300 mL) and Raney-Ni (60 g). The solution was purged with hydrogen 3 times and stirred under an atmosphere of hydrogen overnight at room temperature. The solids were separated by filtration and the filtrate was concentrated under vacuum to afford 180 g (84.8%) of tert-butyl N-[5-(aminomethyl)-4,6-dimethylpyridin-2-yl]-N-[(tert-butoxy)carbonyl]carbamate (INT-6b).

(65) Step 2:

(66) Into a 5000-mL 3-necked round-bottom flask, was placed a solution of tert-butyl N-[5-(aminomethyl)-4,6-dimethylpyridin-2-yl]carbamate (130.0 g, 517.26 mmol, 1.00 equiv) in dioxane (3000 mL) and the solution was sparged with hydrogen chloride (gas) with stirring until the solution was saturated. The resulting mixture was stirred for 16 h at room temperature then it was concentrated under vacuum. The residue was washed with of ether and dried to afford 90.0 g (69%) of 5-(aminomethyl)-4,6-dimethylpyridin-2-amine (also may be called 5-(azaniumyl-methyl)-4,6-dimethylpyridin-2-aminium) dichloride (INT-6a) as a white solid. LCMS (ES) [M+1].sup.+ m/z 152.0.

Reference 9

Synthesis of 4-(aminomethyl)-N′-methoxybenzimidamide dihydrochloride (INT-7)

(67) ##STR00620##

(68) Step 1:

(69) Into a 20-L 4-necked round-bottom flask, was placed a mixture of tert-butyl N-[(tert-butoxy)carbonyl]carbamate (1113 g, 5.12 mol, 1.00 equiv), THF (10 L), 4-(bromomethyl)-benzonitrile (1000 g, 5.10 mol, 1.00 equiv), Cs.sub.2CO.sub.3 (1672 g, 5.13 mol, 1.00 equiv) and LiI (34.0 g, 255 mmol, 0.05 equiv). The resulting mixture was stirred for 12 h at 70° C., then it was cooled to room temperature and filtered. The filtrate was diluted with EtOAc (10 L), washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated to dryness. The crude product was washed with ethyl acetate/petroleum(1/2) and the solids were collected by filtration to afford 820 g (48%) of tert-butyl N-[(tert-butoxy)carbonyl]-N-[(4-cyanophenyl)-methyl]carbamate as a white solid.

(70) Step 2:

(71) Into a 10-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a mixture of tert-butyl N-[(tert-butoxy)carbonyl]-N-[(4-cyanophenyl)methyl]carbamate (600 g, 1.81 mol, 1.00 equiv) in ethanol (4.2 L) and the temperature was gradually raised to 55° C. After almost complete dissolution, trimethylamine (TEA; 876 mL, 3.50 equiv) was added, then a solution of O-methylhydroxylamine hydrochloride (435 g, 5.21 mol. 2.00 equiv) in water (1.02 L) was added dropwise with stirring over 50 min. Mercaptoacetic acid (126 mL, 5.21 mol, 1.00 equiv) was then added and the resulting solution was stirred for 21 h at 90° C. The mixture was then concentrated under vacuum, diluted with H.sub.2O and extracted with n-BuOAc. The organic phase was further washed with saturated aq. K.sub.2CO.sub.3, dried over anhydrous sodium sulfate and concentrated under vacuum by half. This was followed by addition of 800 mL of ethanol. The mixture containing tert-butyl N-[(tert-butoxy)carbonyl]-N-([4-[N-methoxycarbamimidoyl]phenyl]-methyl)carbamate was directly used in the next step.

(72) Step 3:

(73) Into a 10-L 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen at room temperature, was placed a mixture of tert-butyl N-[(tert-butoxy)carbonyl]-N-([4-[N-methoxycarbamimidoyl]phenyl]methyl)carbamate (600 g, 1.58 mol, 1.00 equiv), n-BuOAc (3.0 L) and ethanol (500 mL) followed by concentrated hydrogen chloride aqueous solution (527 mL, 6.32 mol, 4.00 equiv) slowly. The resulting mixture was stirred for 4 h at 35° C., then it was cooled to 0° C. and aged for 1 h. The solids thus formed were collected by filtration. The filter cake was washed with n-BuOAc/ethanol (24/7) and dried under vacuum to afford 336 g (84%) of the title compound (INT-7) as a brown solid. LC-MS (ES) [M−2HCl+1].sup.+ m/z: 180.1

Reference 10

Synthesis of 4-(aminomethyl)-N′-hydroxybenzimidamide hydrochloride chloride (INT-8)

(74) ##STR00621##

(75) Step 1:

(76) Into a 1-L round-bottom flask, was placed a mixture of tert-butyl N-[(tert-butoxy)carbonyl]-N-[(4-cyanophenyl)methyl]carbamate (40.0 g, 120.34 mmol, 1.00 equiv), methanol (500 mL), potassium carbonate (33.1 g, 239.49 mmol, 2.00 equiv) and NH.sub.2OH.HCl (16.7 g, 240.28 mmol, 2.00 equiv). The resulting solution was stirred for 3 h at 70° C. and concentrated under vacuum. The residue was diluted with 600 mL of EtOAc, washed with 3×200 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to afford 27.0 g (61%) of tert-butyl N-[(tert-butoxy)carbonyl]-N-([4-[N-hydroxycarbamimidoyl]-phenyl]methyl)carbamate as a white solid.

(77) Step 2:

(78) Into a 500-mL round-bottom flask, was placed a mixture of tert-butyl N-[(tert-butoxy)carbonyl]-N-[[4-(N-hydroxycarbamimidoyl)phenyl]methyl]carbamate (27.0 g, 73.97 mmol, 1.00 equiv) in dichloromethane (300 mL), followed by dioxane (150 mL) which was freshly saturated with hydrochloride (gas). The resulting solution was stirred for 16 h at room temperature. The solids were collected by filtration and dried to afford 11.088 g (64%) of the title compound (INT-8) as a white solid. LCMS (ES) [M+1].sup.+ m/z: 166.0.

Reference 11

Synthesis of 4-(aminomethyl)-3,5-difluoro-N′-hydroxybenzimidamide dichloride (INT-9)

(79) ##STR00622##

(80) Step 1:

(81) Into a 1-L round-bottom flask, was placed a solution of 4-bromo-2,6-difluorobenzaldehyde (43.0 g, 195.45 mmol, 1.00 equiv) in methanol (500 mL) with stirring at 0° C. Sodium borohydride (NaBH.sub.4; 7.4 g, 195.45 mmol, 1.00 equiv) was then added in portions and the resulting mixture was stirred for 10 min at 0° C. and then concentrated under vacuum. The residue was diluted with EtOAc, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum to afford 43.0 g of (4-bromo-2,6-difluorophenyl)methanol as a white solid.

(82) Step 2:

(83) Into a 1-L round-bottom flask, was placed a solution of (4-bromo-2,6-difluorophenyl)methanol (43.0 g, 193.69 mmol, 1.00 equiv) in dichloromethane (600 mL) with stirring at 0° C. Thionyl chloride (46.1 g, 387.38 mmol, 2.00 equiv) was then added dropwise and the resulting mixture was stirred for 16 h at room temperature, then it was concentrated under vacuum to afford 46 g of 5-bromo-2-(chloromethyl)-1,3-difluorobenzene as yellow oil. Step 3: Into a 1-L round-bottom flask, was placed a solution of ammonia (300 mL) and dioxane (300 mL) and 5-bromo-2-(chloromethyl)-1,3-difluorobenzene (46.0 g, 190.08 mmol, 1.00 equiv) in dioxane (50 mL) was added dropwise with stirring over 1 h. The resulting mixture was stirred for 16 h at room temperature then it was concentrated under vacuum to afford 47.0 g of (4-bromo-2,6-difluorophenyl)methanamine as a white crude solid.

(84) Step 4:

(85) Into a 1-L round-bottom flask, was placed a solution of (4-bromo-2,6-difluorophenyl)methanamine (47.0 g, 212.67 mmol, 1.00 equiv), dichloromethane (600 mL), methanol (60 mL), Boc.sub.2O (139.1 g, 638.01 mmol, 3.00 equiv) and 4-dimethylaminopyridine (2.6 g, 21.27 mmol, 0.10 equiv). The resulting mixture was stirred for 1 h at room temperature then it was concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1/4) to afford 24.0 g (35%) of tert-butyl N-[(4-bromo-2,6-difluorophenyl)methyl]carbamate as white solid.

(86) Step 5:

(87) Into a 500-mL round-bottom flask, was placed a mixture of tert-butyl N-[(4-bromo-2,6-difluorophenyl)methyl]carbamate (24.0 g, 74.77 mmol, 1.00 equiv), N,N-dimethylformamide (300 mL), water (3 mL), Zn(CN).sub.2 (10.50 g, 89.72 mmol, 1.20 equiv), tris(dibenzylideneacetone)dipalladium, chloroform complex (Pd.sub.2(dba).sub.3.CHCl.sub.3; 3.87 g, 3.74 mmol, 0.05 equiv) and 1,1′-bis(diphenylphosphino)ferrocene (dppf, 4.97 g, 8.97 mmol, 0.12 equiv). The resulting mixture was stirred for 1 h at 120° C. under N.sub.2. After concentration, the residue was diluted with EtOAc, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1/4) to afford 20.0 g (100%) of tert-butyl N-[(4-cyano-2,6-difluorophenyl)methyl]carbamate as white solid.

(88) Step 6:

(89) Into a 250-mL round-bottom flask, was placed a mixture of tert-utyl N-[(4-cyano-2,6-difluorophenyl)methyl]carbamate (11.0 g, 41.04 mmol, 1.00 equiv), methanol (150 mL), potassium carbonate (8.50 g, 61.56 mmol, 1.50 equiv) and NH.sub.2OH.HCl (5.71 g, 82.08 mmol, 2.00 equiv). The resulting mixture was stirred for 1 h at 60° C. and concentrated under vacuum. The residue was diluted with EtOAc, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1/1) to afford 10.2 g (83%) of tert-butyl N-([2,6-difluoro-4-[N-hydroxycarbamimidoyl]phenyl]methyl)carbamate as a yellow solid.

(90) Step 7:

(91) Into a 250-mL round-bottom flask, was placed a mixture of tert-butyl N-([2,6-difluoro-4-[N-hydroxycarbamimidoyl]phenyl]methyl)carbamate (4.50 g, 14.95 mmol, 1.00 equiv) in dichloromethane (30 mL), followed by dioxane (100 mL) which was freshly saturated with hydrochloride (gas). The resulting mixture was stirred for 2 h at room temperature. The solids were collected by filtration to afford 2.65 g (65%) of the title compound (INT-9) as a white solid. LC-MS (ESI) m/z: calculated for C.sub.8H.sub.11C.sub.12F.sub.2N.sub.3O: 273.02. found: 202 [M-2HCl+H].sup.+. Rt: 0.96 min.

Reference 12

Synthesis of 4-(aminomethyl)-3,5-difluorobenzimidamide dihydrochloride (INT-10)

(92) ##STR00623##

(93) Step 1:

(94) Into a 250-mL round-bottom flask, was placed a mixture of tert-butyl N-([2,6-difluoro-4-[N-hydroxycarbamimidoyl]phenyl]methyl)carbamate (5.70 g, 18.94 mmol, 1.00 equiv), AcOH (80 mL), HCOONH.sub.4 (6.00 g, 94.7 mmol, 5.00 equiv) and 5% Pd on C (2.00 g). The resulting mixture was stirred for 1 h at 120° C. The solids were collected by filtration and the filtrate was concentrated under vacuum. The residue was dissolved in H.sub.2O and the pH of the solution was adjusted to 9 with sodium hydroxide aqueous solution. To this mixture was added methanol (100 mL), Boc.sub.2O (8.26 g, 37.88 mmol, 2.00 equiv) and 4-dimethylamino-pyridine (231 mg, 1.89 mmol, 0.10 equiv) and the resulting mixture was stirred for 1 h at room temperature then it was concentrated under vacuum. The residue was diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was suspended in 10 mL of EtOAc and stirred for 10 min. The solid was collected by filtration and dried to afford 2.50 g (46%) of tert-butyl N-[(4-carbamimidoyl-2,6-difluorophenyl) methyl]carbamate as white solid.

(95) Step 2:

(96) Into a 50-mL round-bottom flask, was placed a solution of tert-butyl N-[(4-carbamimidoyl-2,6-difluorophenyl)methyl]carbamate (2.50 g, 8.77 mmol, 1.00 equiv) in dichloromethane (20 mL), followed by dioxane (10 mL) which was freshly saturated with hydrochloride (gas) and the resulting mixture was stirred for 0.5 h at room temperature. The solids were collected by filtration and dried to afford 1.36 g (60%) of the title compound (INT-10) as an off-white solid. LC-MS (ESI) m/z: calculated for C.sub.8H.sub.11C.sub.12F.sub.2N.sub.3: 257.03. found: 186 [M-2HCl+H].sup.+. Rt: 0.58 min.

Reference 13

Synthesis of 4-(aminomethyl)-3,5-difluoro-N′-methoxybenzimidamide hydrochloride (INT-11)

(97) ##STR00624##

(98) Step 1:

(99) Into a 250-mL round-bottom flask, was placed a mixture of tert-butyl N-[(4-cyano-2,6-difluorophenyl)methyl]carbamate (7.70 g, 28.70 mmol, 1.00 equiv), methoxylamine hydrochloride (4.7 g, 57.32 mmol, 2.00 equiv), 2-sulfanylacetic acid (2.64 g, 28.66 mmol, 1.00 equiv), TEA (5.8 g, 57.32 mmol, 2.00 equiv) in ethanol (120 mL). The resulting mixture was stirred for 16 hours at 90° C. then it was concentrated. The residue was purified by column flash chromatography eluting with ethyl acetate/petroleum ether (1/10) to afford 5.80 g (64%) of tert-butyl N-([2,6-difluoro-4-[N′-methoxycarbamimidoyl]phenyl]methyl)carbamate as a light yellow solid.

(100) Step 2:

(101) Into an 100-mL round-bottom flask, was placed tert-butyl N-([2,6-difluoro-4-[N′-ethoxycarbamimidoyl]phenyl]methyl)carbamate (4.00 g, 12.69 mmol, 1.00 equiv) with stirring followed by a solution of 4 N HCl in dioxane (50 mL). The resulting mixture was stirred for 1 hour at room temperature. The solids were collected by filtration and dried to afford 2.1607 g (79%) of the title compound as a white solid. LC-MS (ESI) m/z: calculated for C.sub.9H.sub.11F.sub.2N.sub.3O: 215.09. found: 216[M+H].sup.+. Rt: 1.339 min.

Example 1

Synthesis of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-12-[(1H-pyrazol-1-yl)methyl]-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide and (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-11-[(1H-pyrazol-1-yl)methyl]-15-oxatetracyclo-[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11, 13-hexaene-4-carboxamide

(102) ##STR00625##

(103) Step 1:

(104) To a stirred solution of (5-(methoxycarbonyl)-2-(trimethylsilyl)phenyl)(phenyl)iodonium trifluoromethanesulfonate (INT-2), 100 mg; 0.18 mmol; 1 eq.) in DCM (1.8 mL) at 0° C. was added tert-butyl (isobenzofuran-5-ylmethoxy)dimethylsilane (INT-5, 151 mg; 0.58 mmol; 3.22 eq.) as a solution in Et.sub.2O prepared as described above. To this orange mixture was added tetrabutylammonium fluoride (1M solution in THF; 0.23 mL; 0.23 mmol; 1.3 eq.) and the mixture was stirred at 0° C. for 30 min. The mixture was then diluted with water and extracted with DCM; the combined organics were dried over MgSO.sub.4, filtered and concentrated to afford a dark oil. The crude material was purified by column chromatography on a 12 g ISCO Gold column eluting with 10% EtOAc in hexanes to provide methyl (9S,10R)-7-(((tert-butyldimethylsilyl)oxy)-methyl)-9,10-dihydro-9,10-epoxyanthracene-2-carboxylate, methyl (9R,10S)-7-(((tert-butyldimethylsilyl)oxy)methyl)-9,10-dihydro-9,10-epoxyanthracene-2-carboxylate, methyl (9S,10S)-6-(((tert-butyldimethylsilyl)oxy)methyl)-9,10-dihydro-9,10-epoxyanthracene-2-carboxylate and methyl (9R,10R)-6-(((tert-butyldimethylsilyl)oxy)-methyl)-9,10-dihydro-9,10-epoxyanthracene-2-carboxylate (59 mg; 83%).

(105) Step 2:

(106) To a stirred solution of methyl (9S,10R)-7-(((tert-butyldimethylsilyl)oxy)methyl)-9,10-dihydro-9,10-epoxyanthracene-2-carboxylate, methyl (9R,10S)-7-(((tert-butyldimethylsilyl)oxy)methyl)-9,10-dihydro-9,10-epoxyanthracene-2-carboxylate, methyl (9S,10S)-6-(((tert-butyldimethylsilyl)oxy)methyl)-9,10-dihydro-9,10-epoxyanthracene-2-carboxylate and methyl (9R,10R)-6-(((tert-butyldimethylsilyl)oxy)-methyl)-9,10-dihydro-9,10-epoxyanthracene-2-carboxylate (55 mg; 0.14 mmol; 1 eq.) in THF (1.4 mL) at ambient temperature was added tetrabutylammonium fluoride (1M in THF; 0.18 mL; 0.18 mmol; 1.3 eq.) and the mixture was stirred at ambient temperature for 30 min. The mixture was then quenched with sat. NH.sub.4Cl and diluted with water, then extracted with EtOAc; the combined organics were dried over MgSO.sub.4, filtered and concentrated. The crude material was purified by column chromatography on a 4 g ISCO Gold column eluting with 30% EtOAc in hexanes to provide methyl (9S,10R)-7-(hydroxymethyl)-9,10-dihydro-9,10-epoxyanthracene-2-carboxylate, methyl (9R,10S)-7-(hydroxymethyl)-9,10-dihydro-9,10-epoxyanthracene-2-carboxylate, methyl (9S,10S)-6-(hydroxymethyl)-9,10-dihydro-9,10-epoxyanthracene-2-carboxylate, and methyl (9R,10R)-6-(hydroxymethyl)-9,10-dihydro-9,10-epoxyanthracene-2-carboxylate (36 mg; 92%).

(107) Step 3:

(108) To a stirred solution of methyl (9S,10R)-7-(hydroxymethyl)-9,10-dihydro-9,10-epoxyanthracene-2-carboxylate, methyl (9R,10S)-7-(hydroxymethyl)-9,10-dihydro-9,10-epoxyanthracene-2-carboxylate, methyl (9S,10S)-6-(hydroxymethyl)-9,10-dihydro-9,10-epoxyanthracene-2-carboxylate and methyl (9R,10R)-6-(hydroxymethyl)-9,10-dihydro-9,10-epoxyanthracene-2-carboxylate (35 mg; 0.12 mmol; 1 eq.) in DCM (0.62 mL) cooled to 0° C. was added Hunig's base (0.03 mL; 0.15 mmol; 1.2 eq.) followed by methanesulfonyl chloride (0.01 mL; 0.14 mmol; 1.1 eq.) and the mixture was stirred at 0° C. After 1 h the mixture was diluted with DCM, washed with sat. NH.sub.4Cl and brine, dried over Na.sub.2SO.sub.4, filtered and concentrated.

(109) To a mixture of methyl (9S,10R)-7-(methylsulfonyloxymethyl)-9,10-dihydro-9,10-epoxyanthracene-2-carboxylate, methyl (9R,10S)-7-(methylsulfonyloxymethyl)-9,10-dihydro-9,10-epoxyanthracene-2-carboxylate, methyl (9S,10S)-6-(methylsulfonyloxymethyl)-9,10-dihydro-9,10-epoxyanthracene-2-carboxylate and methyl (9R,10R)-6-(methylsulfonyloxy-methyl)-9,10-dihydro-9,10-epoxyanthracene-2-carboxylate, 1H-pyrazole (10.1 mg; 0.15 mmol; 1.2 eq.) and cesium carbonate (60.6 mg; 0.19 mmol; 1.5 eq.) in N,N-dimethylformamide (1.24 mL) was stirred at ambient temperature overnight. The mixture was then diluted with 20 mL 1:1 EtOAc/PhMe washed once with water (20 mL), dried over MgSO.sub.4, filtered and concentrated. The residue was purified by column chromatography on a 12 G ISCO Gold column eluting with 20% and 40% EtOAc in hexanes. This material was resubjected to the reaction conditions adding 1 eq. of NaI. After 12 h, the reaction mixture was worked up and the crude material was purified as described above to afford methyl (9S,10R)-7-((1H-pyrazol-1-yl)methyl)-9,10-dihydro-9,10-epoxyanthracene-2-carboxylate, methyl (9R,10S)-7-((1H-pyrazol-1-yl)methyl)-9,10-dihydro-9,10-epoxyanthracene-2-carboxylate, methyl (9S,10S)-6-((1H-pyrazol-1-yl)methyl)-9,10-dihydro-9,10-epoxyanthracene-2-carboxylate and methyl (9R,10R)-6-((1H-pyrazol-1-yl)methyl)-9,10-dihydro-9,10-epoxyanthracene-2-carboxylate (19 mg; 50%).

(110) Step 4:

(111) To a stirred solution of methyl (9S,10R)-7-((1H-pyrazol-1-yl)methyl)-9,10-dihydro-9,10-epoxyanthracene-2-carboxylate and methyl (9R,10S)-7-((1H-pyrazol-1-yl)methyl)-9,10-dihydro-9,10-epoxyanthracene-2-carboxylate and methyl (9S,10S)-6-((1H-pyrazol-1-yl)methyl)-9,10-dihydro-9,10-epoxyanthracene-2-carboxylate and methyl (9R,10R)-6-((1H-pyrazol-1-yl)methyl)-9,10-dihydro-9,10-epoxyanthracene-2-carboxylate (19 mg; 0.06 mmol; 1 eq.) in THF (0.6 mL) and methanol (0.3 mL) was added 1N lithium hydroxide (0.3 mL; 0.3 mmol; 5 eq.) and the mixture was stirred at ambient temperature for 2.5 h. The mixture was then quenched with 1N HCl (0.6 mL), extracted with EtOAc, dried over MgSO.sub.4, filtered and concentrated. The crude material was dried under high vacuum for 30 min to give (9S,10R)-7-((1H-pyrazol-1-yl)methyl)-9,10-dihydro-9,10-epoxyanthracene-2-carboxylic acid, (9R,10S)-7-((1H-pyrazol-1-yl)methyl)-9,10-dihydro-9,10-epoxyanthracene-2-carboxylic acid, (9S,10S)-6-((1H-pyrazol-1-yl)methyl)-9,10-dihydro-9,10-epoxyanthracene-2-carboxylic acid, and (9R,10R)-6-((1H-pyrazol-1-yl)methyl)-9,10-dihydro-9,10-epoxyanthracene-2-carboxylic acid which was then taken on to the next step without further purification.

(112) Step 5:

(113) To a stirred solution of (9S,10R)-7-((1H-pyrazol-1-yl)methyl)-9,10-dihydro-9,10-epoxyanthracene-2-carboxylic acid, (9R,10S)-7-((1H-pyrazol-1-yl)methyl)-9,10-dihydro-9,10-epoxyanthracene-2-carboxylic acid and (9S,10S)-6-((1H-pyrazol-1-yl)methyl)-9,10-dihydro-9,10-epoxyanthracene-2-carboxylic acid, (9R,10R)-6-((1H-pyrazol-1-yl)methyl)-9,10-dihydro-9,10-epoxyanthracene-2-carboxylic acid (18 mg; 0.06 mmol; 1 eq.) and 5-(aminomethyl)-4,6-dimethylpyridin-2-amine (INT6a, 9.4 mg; 0.06 mmol; 1.1 eq.) (previously azeotroped together with 1 mL PhMe for 30 min) in N,N-dimethylformamide (0.6 mL) at ambient temperature was added Hunig's base (0.03 mL; 0.17 mmol; 3 eq.) followed by HATU (21.5 mg; 0.06 mmol; 1 eq.). The orange mixture was stirred for 20 min. then it was diluted with 1 mL water (clear solution turned cloudy) and directly purified via R-Phase preparative HPLC (13 min. method at 28 mL/min eluting with a gradient of 95-0% water (containing 0.1% formic acid) in acetonitrile) affording the title compounds as a white powder (7.9 mg; 31% for the two steps). MS ES+ m/z=452.11 (M+H).sup.+.

Example 2

Synthesis of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-12-[(1H-pyrazol-1-yl)methyl]-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(114) ##STR00626##

(115) (±)-N-[(6-Amino-2,4-dimethylpyidin-3-yl)methyl]-12-[(1H-pyrazol-1-yl))methyl]-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide and (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-11-[(1H-pyrazol-1-yl)methyl]-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide (Example 1; 25 mg) was purified via R-Phase preparative HPLC (Rt=24.0 min, see conditions below) affording title compounds as the less polar eluting component (10.4 mg).

(116) LC/MS Conditions:

(117) column used: Waters, XSelect CSH Prep C18, 250×19 mm Solvent A: 0.1% Formic Acid in Water; Solvent B: Acetonitrile; 30 min run, Flow Rate: 29 ml/min

(118) TABLE-US-00002 Time (min) A % B % 0 100 0 1.0 100 0 4.0 91 9 26.0 77 23 27.0 50 50 28.5 50 50 29.0 100 0

Example 3

Synthesis of (±)N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-11-(1H-pyrazol-1-ylmethyl)-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(119) ##STR00627##

(120) ((±)-N-[(6-Amino-2,4-dimethylpyridin-3-yl)methyl]-12-[(1H-pyrazol-1-yl)methyl]-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide and (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-11-[(1H-pyrazol-1-yl)methyl]-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide (Example 1; 25 mg) was purified via R-Phase preparative HPLC (Rt=23.5 min, see conditions for Example 2) affording the title compounds as the more polar eluting component (11.5 mg).

Example 4

Synthesis of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-12-[(4-methyl-1H-pyrazol-1-yl)methyl]-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide and (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-11-[(4-methyl-1H-pyrazol-1-yl)methyl]-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(121) ##STR00628##

(122) Step 1:

(123) A stirred suspension of a mixture of INT-3 (100 mg; 0.30 mmol; 1 eq.), methylboronic acid (36.2 mg; 0.6 mmol; 2 eq.), cesium carbonate (246 mg; 0.75 mmol; 2.5 eq.) and 1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (22 mg; 0.03 mmol; 0.1 eq.) in 1,4-dioxane (12.1 mL) and methanol (3.4 mL) was heated to 80° C. After 1 h, the reacting mixture was cooled to ambient temperature, filtered with additional MeOH and concentrated. The brown residue was purified by column chromatography on a 24 g ISCO Gold column eluting with 10% EtOAc in heptane to provide a mixture of (±) methyl 12-methyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4, 6,9,11,13-hexaene-4-carboxylate and (±) methyl 11-methyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (68 mg; 85%).

(124) Step 2:

(125) To a mixture of (±) methyl 12-methyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate and (±) methyl 11-methyl-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (68 mg; 0.26 mmol; 1 eq.), and N-bromosuccinimide (47.7 mg; 0.27 mmol; 1.05 eq.) in carbon tetrachloride (2.6 mL) was added AIBN (2.1 mg; 0.01 mmol; 0.05 eq.). The resulting mixture was heated to 75° C. for 2 h. The reacting mixture was then cooled to ambient temperature, diluted with DCM, washed with sat. NaHCO.sub.3, dried over MgSO.sub.4, filtered and concentrated. The crude material was purified by column chromatography on a 12 g ISCO Gold column eluting with 10% EtOAc in heptane to provide a mixture of (±) methyl 12-(bromomethyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate and (±) methyl 11-(bromomethyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (67 mg; 76%).

(126) Step 3:

(127) To a stirred solution of a mixture of (±) methyl 12-(bromomethyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate and (±) methyl 11-(bromomethyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (67.00 mg; 0.19 mmol; 1.00 eq.) and 4-methyl-1H-pyrazole (0.03 mL; 0.39 mmol; 2 eq.) in N,N-dimethylformamide (1.9 mL) was added cesium carbonate (126.5 mg; 0.39 mmol; 2 eq.). The mixture was stirred at ambient temperature overnight then it was diluted with EtOAc, washed with water, dried over MgSO.sub.4, filtered and concentrated. The crude material was purified by column chromatography on a 4 g ISCO Gold column eluting with 10 and 40% EtOAc in heptane to provide a mixture of (±) methyl 12-[(4-methyl-1H-pyrazol-1-yl)methyl]-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate and (±) methyl 11-[(4-methyl-1H-pyrazol-1-yl)methyl]-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (52 mg; 77%).

(128) Step 4:

(129) (±) Methyl 12-[(4-methyl-1H-pyrazol-1-yl)methyl]-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate and (±) methyl 11-[(4-methyl-1H-pyrazol-1-yl)methyl]-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate was converted to (±) 12-[(4-methyl-1H-pyrazol-1-yl)methyl]-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid and (±) 11-[(4-methyl-1H-pyrazol-1-yl)methyl]-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid according to the procedure described for Example 1, Step 4 and the crude material was converted to the title compounds following the procedure described for Example 1, Step 5. The reaction mixture was diluted with 0.8 mL water and directly purified via R-Phase prep HPLC (13 min. method at 28 mL/min eluting with a gradient of 95-0% water (containing 0.1% formic acid) in acetonitrile) affording the title compounds as a white powder (10 mg; 29%). MS ES+m/z=466.05 (M+H).sup.+.

Example 5

Synthesis of (±)N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-12-(2-fluorophenyl)-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(130) ##STR00629##

(131) Step 1:

(132) To a solution of methyl 7-bromo-9,10-dihydro-9,10-epoxyanthracene-2-carboxylate (50 mg; 0.15 mmol; 1 eq.) and (2-fluorophenyl)boronic acid (25 mg; 0.18 mmol) in p-dioxane (1.2 mL) was added 1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium (II) (11.05 mg; 0.015 mmol) and sodium carbonate (32 mg; 0.3 mmol) in water (0.4 mL). After heating at 90° C. for 1 h, the mixture was cooled and diluted with EtOAc, organic layer was washed with water, brine, dried and concentrated to give crude product, which was purified by column chromatography (Hexanes/EtOAc=3:1) to give methyl 7-(2-fluorophenyl)-9,10-dihydro-9,10-epoxyanthracene-2-carboxylate (45 mg).

(133) Step 2:

(134) To a solution of methyl 7-(2-fluorophenyl)-9,10-dihydro-9,10-epoxyanthracene-2-carboxylate (45 mg, 0.13 mmol) in THF (1 mL) and MeOH (0.5 mL) was added a solution of LiOH (7 mg, 0.3 mmol) in water (0.5 mL), after stirred at ambient temperature for 2 h, the mixture was added 1N HCl to pH=3, and the acidified mixture was concentrated to dryness to give 7-(2-fluorophenyl)-9,10-dihydro-9,10-epoxyanthracene-2-carboxylic acid, which was used for next step without further purification.

(135) Step 3:

(136) To a solution of above crude 7-(2-fluorophenyl)-9,10-dihydro-9,10-epoxyanthracene-2-carboxylic acid and 5-(aminomethyl)-4,6-dimethylpyridin-2-amine (34 mg; 0.23 mmol) in DMF (1 mL) was added diisopropylethylamine (0.1 mL, 0.6 mmol) and HATU-1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (63 mg; 0.17 mmol), after stirred for 30 min at ambient temperature, it was diluted with water and was purified by column to give the title compounds (42 mg). MS: (M+H).sup.+ found for C.sub.29H.sub.24FN.sub.3O.sub.2: 466.5.

Example 6

Synthesis of (±)N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-12-(2,4-difluorophenyl)-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(137) ##STR00630##

(138) Step 1:

(139) To a solution of methyl 6- and 7-bromo-9,10-dihydro-9,10-epoxyanthracene-2-carboxylate (INT-3, 50 mg; 0.15 mmol; 1 eq., regioisomer mixtures) and 2,4-difluorophenyl-boronic acid (29 mg; 0.18 mol; 1.2 eq.) in dioxane (1.2 mL) was added 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (11 mg; 0.015 mol; 0.1 eq.) and sodium carbonate (32 mg; 0.3 mol; 2 eq.) in water (0.4 mL). After heating at 90° C. for 1 hr, the reaction mixture was diluted with EtOAc and brine, aqueous layer was separated and extracted with EtOAc, and organic layers were combined, dried and concentrated to give crude product, which was purified by column (Hexanes/EtOAc=4:1) to give methyl 6- and 7-(2,4-difluorophenyl)-9,10-dihydro-9,10-epoxyanthracene-2-carboxylate (36 mg).

(140) Step 2:

(141) A mixture of methyl 6- and 7-(2,4-difluorophenyl)-9,10-dihydro-9,10-epoxyanthracene-2-carboxylate was dissolved in THF (1 mL) and MeOH (0.5 mL) and lithium hydroxide (7 mg; 0.3 mmol; 2 eq.) in water (0.5 mL) was added. After stirring at room temperature for 2 h, the reaction mixture was acidified with 1N HCl and lyophilized to give a mixture of 6- and 7-(2,4-difluorophenyl)-9,10-dihydro-9,10-epoxyanthracene-2-carboxylic acid as crude product. The regioisomers were separated by HPLC.

(142) Step 3:

(143) To crude 7-(2,4-difluorophenyl)-9,10-dihydro-9,10-epoxyanthracene-2-carboxylic acid in DMF (1.5 mL) was added 5-(aminomethyl)-4,6-dimethylpyridin-2-amine (46 mg; 0.3 mmol; 2 eq.) and Hunig's base (0.11 mL; 0.6 mmol; 4 eq.) followed by HATU (63 mg; 0.17 mmol; 1.1 eq.). After stirring for 20 min at room temperature the mixture was diluted with water and CH.sub.3CN and was purified by preparatory HPLC to give the title compound (29 mg). MS: (M+H).sup.+ found for C.sub.29H.sub.23F.sub.2N.sub.3O.sub.2: 484.2

Example 7

Synthesis of (1R,8S)—N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-12-(2,4-difluorophenyl)-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(144) ##STR00631##

(145) Step 1:

(146) To a solution of (1S,8R)-12-bromo-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate INT-3a1(75 mg; 0.23 mmol; 1 eq.) in dioxane (1.5 mL) was added 2,4-difluoropheny-lboronic acid (43 mg; 0.27 mmol; 1.2 eq.) and 1,1′-bis(diphenylphosphino)-ferrocene]-dichloropalladichloropalladium(II) (17 mg; 0.02 mmol; 0.1 eq.) followed by sodium carbonate (48 mg; 0.45 mmol; 2 eq.) in water (0.5 mL). After stirring for 1.5 hr at approx. 90° C., the reaction mixture was cooled and diluted with EtOAc and brine, aqueous layer was separated and extracted with EtOAc, and organic layers were combined, dried and concentrated to give crude product, which was purified by column (Hexanes/EtOAc=4:1) to give methyl (1R,8S)-12-(2,4-difluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (57 mg, 69%).

(147) Step 2:

(148) To a solution of methyl (1R,8S)-12-(2,4-difluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (55 mg; 0.15 mmol; 1 eq.) in THF (1 mL) and MeOH (0.5 mL) was added lithium hydroxide (7 mg; 0.3 mmol; 2 eq.) in water (0.5 mL). After stirring for 3 h, the reaction mixture was acidified by 1N HCl to pH=3 and the mixture were lyophilized to give (1R,8S)-12-(2,4-difluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid as crude product.

(149) Step 3:

(150) To (1R,8S)-12-(2,4-difluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid in DMF (1.5 mL) was added 5-(aminomethyl)-4,6-dimethylpyridin-2-amine (46 mg; 0.3 mmol; 2 eq.) and Hunig's base (0.11 mL; 0.6 mmol; 4 eq.) followed by HATU (63 mg; 0.17 mmol; 1.1 eq.). After stirring for 20 min at room temperature the mixture was purified by preparatory HPLC to give the title compound (73 mg, 100%). MS: (M+H).sup.+ found for C.sub.29H.sub.23F.sub.2N.sub.3O.sub.2: 484.2

Example 8

Synthesis of (±)N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-12-(1,3-benzoxazol-4-yl)-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide and (±)N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-11-(1,3-benzoxazol-4-yl)-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(151) ##STR00632##

(152) Step 1:

(153) Yttrium tris(trifluoromethanesulfonate) (35.64 mg; 0.07 mmol; 0.05 eq.) and (diethoxymethoxy)ethane (2.2 mL; 13.3 mmol; 10 eq.) were combined. To this mixture was added a solution of 2-amino-3-bromophenol (0.25 g; 1.33 mmol; 1 eq.) in pyridine (215 μL; 2.66 mmol; 2 eq.) and DMSO (1 mL). The reaction mixture was stirred in a heat block at 70° C. for 4 h. After cooling the reaction mixture was taken up in ethyl acetate and water. The phases were separated, the aqueous phase was extracted with ethyl acetate, the combined organic phases were washed with water and brine, and then dried over sodium sulfate. After evaporation of solvent, the residue was purified by silica gel chromatography (ethyl acetate/hexanes gradient) to give 4-bromobenzo[d]-oxazole (0.19 g) as an off-white crystalline solid.

(154) Step 2:

(155) 4-Bromo-1,3-benzoxazole (320 mg; 1.62 mmol; 1 eq.) (g-cxy-000589) was dissolved in 1,4-dioxane (5 mL) and the solution was purged with argon gas. 4,4,4′,4′,5,5,5′,5′-Octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1026 mg; 4.04 mmol; 2.5 eq.), tricyclohexylphosphane (32 mg; 0.11 mmol; 0.07 eq.), potassium acetate (476 mg; 4.85 mmol; 3 eq.) and tris(dibenzylideneacetone)dipalladium(0) (74 mg; 0.08 mmol; 0.05 eq.) were added and the reaction mixture was sealed and stirred in a heat block at 90° C. After 2 h, the reaction mixture was cooled and taken up in ethyl acetate and ammonium chloride solution. The phases were separated, the aqueous phase was extracted with more ethyl acetate and the combined organic phases were dried over sodium sulfate. After evaporation of solvent the residue was purified by silica gel chromatography (methanol/DCM gradient) to give 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole (0.29 g) as an oil.

(156) Step 3:

(157) 4-(Tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzoxazole (110 mg; 0.42 mmol; 1.1 eq.) and a mixture of methyl 6-bromo-9,10-dihydro-9,10-epoxyanthracene-2-carboxylate/methyl 7-bromo-9,10-dihydro-9,10-epoxyanthracene-2-carboxylate (127 mg; 0.38 mmol; 1 eq.) were dissolved in 1,4-dioxane (2.5 mL) and sodium carbonate solution (0.44 mL; 2.60 mol/l; 1.15 mmol; 3 eq.) The solution was purged with argon gas. 1,1′-bis(diphenyl-phosphino)ferrocene]dichloropalladium(II) (28 mg; 0.04 mmol; 0.1 eq.) was added, the reaction was sealed and stirred in a heat block at 90° C. for 1.5 h. The cooled mixture was taken up in ethyl acetate and sodium bicarbonate solution. The phases were separated, the aqueous phase was extracted with more ethyl acetate and the combined organic phases were washed with brine. After drying over sodium sulfate and evaporation of solvent the residue was purified by silica gel chromatography (ethyl acetate/hexanes gradient) to give a mixture of methyl 6-(benzo[d]oxazol-4-yl)-9,10-dihydro-9,10-epoxyanthracene-2-carboxylate/methyl 7-(benzo[d]oxazol-4-yl)-9,10-dihydro-9,10-epoxyanthracene-2-carboxylate (0.1 g) as a colorless film.

(158) Step 4:

(159) A mixture of methyl 6-(benzo[d]oxazol-4-yl)-9,10-dihydro-9,10-epoxyanthracene-2-carboxylate and methyl 7-(benzo[d]oxazol-4-yl)-9,10-dihydro-9,10-epoxyanthracene-2-carboxylate (mixture of stereoisomers, 100 mg; 0.27 mmol; 1 eq.) was dissolved in THF (2.7 mL) and methanol (0.9 mL) and cooled in an ice bath. Lithium hydroxide (32 mg; 1.35 mmol; 5 eq.) dissolved in water (1.3 mL) was added dropwise and the reaction was then stirred at 25° C. After 2.5 h, water, ethyl acetate and 1 M HCl to adjust the pH to 4 were added. The mixture was partitioned into ammonium chloride solution and ethyl acetate, and the phases were separated and the aqueous phase was extracted with more ethyl acetate. The combined organic phases were washed with brine and dried over sodium sulfate. Evaporation of solvent gave a mixture of 6-(benzo[d]oxazol-4-yl)-9,10-dihydro-9,10-epoxyanthracene-2-carboxylic acid and 7-(benzo[d]oxazol-4-yl)-9,10-dihydro-9,10-epoxyanthracene-2-carboxylic acid which was used directly in the next step.

(160) Step 5:

(161) A mixture of 6-(benzo[d]oxazol-4-yl)-9,10-dihydro-9,10-epoxyanthracene-2-carboxylic acid and 7-(benzo[d]oxazol-4-yl)-9,10-dihydro-9,10-epoxyanthracene-2-carboxylic acid (mixture of stereoisomers, 96 mg; 0.27 mmol; 1 eq.) was dissolved in DMF (6 mL). Hunig's base-ethylbis(propan-2-yl)amine (376 μL; 2.16 mmol; 8 eq.), 5-(azaniumylmethyl)-4,6-dimethylpyridin-2-aminium ditrifluoroacetate (180 mg; 0.3 mmol; 1.1 eq.), then HATU-hexafluoro-5-phosphanuide 1-[(dimethylamino)(dimethyliminiumyl)methyl]-1H-[1,2,3]triazolo[4,5-b]pyridin-3-ium-3-olate (205 mg; 0.54 mmol; 2 eq.) were added and the reaction mixture was stirred at 25° C. After 16 h, the reaction mixture was warmed to 50° C. in a heat block for 2.5 h then cooled and taken up in water, sodium bicarbonate solution and ethyl acetate. The phases were separated and the aqueous phase was extracted with more ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate and evaporated to a residue which was purified by reverse phase chromatography (acetonitrile gradient with 0.1% aqueous formic acid, Waters XSelect CSH column) to give a mixture of the title compounds (14 mg) as a white solid. MS (M+H).sup.+ found for C.sub.30H.sub.24N.sub.4O.sub.3: 489.4.

Example 9

Synthesis of (±)N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-12-(2-cyano-4-methylphenyl)-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(162) ##STR00633##

(163) Step 1:

(164) (5-Methyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (59 mg; 0.24 mmol; 1 eq.), methyl (±) 7-bromo-9,10-dihydro-9,10-epoxyanthracene-2-carboxylate (INT-3a, 80 mg; 0.24 mmol; 1 eq.) and potassium carbonate (67 mg; 0.48 mmol; 2 eq.) were dissolved THF (1.2 mL) and water (0.6 mL). The solution was purged with Ar gas and [1,1′-bis(di-t-butyl-phosphino)ferrocene]palladium (II) dichloride (7.9 mg; 0.01 mmol; 0.05 eq.) was added and the reaction was sealed and stirred in a heat block at 60° C. for 7 h. The cooled mixture was partitioned into ethyl acetate and sodium bicarbonate solution, and the phases were separated. The aqueous phase was extracted with more ethyl acetate, the combined organics were washed brine, and dried over sodium sulfate. After evaporation the residue was purified by silica gel chromatography (ethyl acetate/hexanes gradient) to give methyl (±)7-(2-cyano-4-methylphenyl)-9,10-dihydro-9,10-epoxyanthracene-2-carboxylate (77 mg) as a colorless film.

(165) Step 2:

(166) Methyl (±)7-(2-cyano-4-methylphenyl)-9,10-dihydro-9,10-epoxyanthracene-2-carboxylate (77 mg; 0.21 mmol; 1 eq.) was dissolved in THF (2 mL) and methanol (0.7 mL). Lithium hydroxide (anhydrous) (25.1 mg; 1.05 mmol; 5 eq.) in water (1 mL) was added dropwise and the mixture was stirred at 25° C. for 4 h. Dilute aqueous HCl and water were added to adjust the pH to <4. Ethyl acetate and aqueous ammonium chloride solution were added, the phases were separated, and the aqueous phase was extracted with more ethyl acetate. The combined organic phases were washed with brine and dried over sodium sulfate. The solution was evaporated to 0.06 g of (±)7-(2-cyano-4-methylphenyl)-9,10-dihydro-9,10-epoxyanthracene-2-carboxylic acid as a white solid, which was used directly in the next step.

(167) Step 3:

(168) (±) 7-(2-Cyano-4-methylphenyl)-9,10-dihydro-9,10-epoxyanthracene-2-carboxylic acid (74 mg; 0.21 mmol; 1 eq.) was dissolved in DMF (2 mL). Hunig's base-ethylbis(propan-2-yl)amine (292 μL; 1.68 mmol; 8 eq.), 5-(azaniumylmethyl)-4,6-dimethyl-pyridin-2-aminium ditrifluoroacetate (amine-la, 159 mg; 0.31 mmol; 1.5 eq.), then 1-[bis(dimethylamino)-methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (159 mg; 0.42 mmol; 2 eq.) were added and the reaction was stirred at 25° C. for 14 h. The reaction mixture was then partitioned into sodium bicarbonate solution and ethyl acetate. The phases were separated and the aqueous phase was extracted with more ethyl acetate. The combined organic phases were washed with brine and dried over sodium sulfate. After evaporation the residue was purified by reverse phase chromatography (acetonitrile gradient with 0.1% aqueous formic acid, Waters XSelect CSH column) to give the title compound (50 mg) as a white solid. MS: (M+H).sup.+ found for C.sub.31H.sub.26N.sub.4O.sub.2: 487.4.

Example 10

Synthesis of (±)N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-12-[(pyrrolidin-1-yl)methyl]-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide and (±)N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-11-[(pyrrolidin-1-yl)methyl]-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(169) ##STR00634##

(170) Step 1:

(171) A stirred suspension of (±) methyl 12-bromo-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate and (±) methyl 11-bromo-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (INT-3; 100.00 mg; 0.30 mmol; 1.00 eq.), methylboronic acid (36.2 mg; 0.60 mmol; 2.00 eq.), cesium carbonate (246.0 mg; 0.75 mmol; 2.50 eq.) and 1,1′-bis(diphenylphosphino)-ferrocene]-dichloropalladium(II) (Pd(dppf)Cl.sub.2; 22.1 mg; 0.03 mmol; 0.10 eq.) in 1,4-dioxane (12.1 ml) and methanol (3.4 ml) was heated to 80° C. LC/MS analysis after 1 h showed complete conversion to a mixture of the desired product (major) and the de-brominated starting material (minor). The reacting mixture was cooled to RT, filtered with additional MeOH and concentrated. The brown residue was purified by column chromatography (24 G ISCO Gold) eluting with 10% EtOAc in heptane to provide a mixture of (±) methyl 12-methyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate, (±) methyl 11-methyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate and (±) methyl 15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (68 mg; 85%).

(172) Step 2:

(173) To a mixture of (±) methyl 12-methyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate, (±) methyl 11-methyl-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate and (±) methyl 15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (50.0 mg; 0.19 mmol; 1.00 eq.), and N-bromosuccinimide (NBS; 33.4 mg; 0.19 mmol; 1.00 eq.) in carbon tetrachloride (1.9 ml) was added 2,2′-azobis(2-methylpropionitrile) (AIBN; 1.5 mg; 0.01 mmol; 0.05 eq.). The resulting mixture was heated to 75° C. and after 3 h more N-bromosuccinimide (0.5 eq.) was added and the temperature was increased to 82° C. LC/MS after 4 h showed complete conversion of the starting material. The reacting mixture was cooled to RT, diluted with DCM, washed with sat. NaHCO.sub.3, dried over MgSO.sub.4, filtered and concentrated. The residue was purified by column chromatography (12 G ISCO Gold) eluting with 10% EtOAc in heptane to provide an inseparable mixture of (±) methyl 12-(bromomethyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate and (±) methyl 11-(bromomethyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (1:1; minor component) and (±) methyl 12-(dibromomethyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate and (±) methyl 11-(dibromomethyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (1:1; major component); (60 mg).

(174) Step 3:

(175) To a stirred solution of (±) methyl 12-(bromomethyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate, (±) methyl 11-(bromomethyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate, (±) methyl 12-(dibromomethyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate and (±) methyl 11-(dibromomethyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (60.0 mg; 0.17 mmol; 1.00 eq.) and, 1H-pyrazole (23.7 mg; 0.35 mmol; 2.00 eq.) in N,N-dimethylformamide (1.7 ml) was added cesium carbonate (113.3 mg; 0.35 mmol; 2.00 eq.). The mixture was stirred at RT for 10 min then it was diluted with EtOAc, washed with water, dried over MgSO.sub.4, filtered and concentrated. The residue was purified by column chromatography (4 G ISCO Gold) eluting with a gradient of 0-10% (7 min) and 10-40% (8 min) EtOAc in heptane to provide a mixture of (±) methyl 12-(dibromomethyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate and (±) methyl 11-(dibromomethyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (30 mg).

(176) Step 4:

(177) A solution of (±) methyl 12-(dibromomethyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate and (±) methyl 11-(dibromomethyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (47.0 mg; 0.11 mmol; 1.00 eq.) in tetrahydrofuran (0.3 ml) was cooled to 0° C. and Hunig's base-ethylbis(propan-2-yl)amine (DIEA; 0.02 ml; 0.12 mmol; 1.05 eq.) was added drop-wise, followed by diethoxyphosphinous acid (0.01 ml; 0.12 mmol; 1.05 eq.). The mixture was stirred at room temperature. On observing no reaction after overnight stirring the mixture was quenched with 0.2 mL of water and it was extracted with EtOAc. The organic layer was washed with sat. aq. NH.sub.4Cl and brine then dried over MgSO.sub.4, filtered and concentrated. The residue was treated with NaI in DMF and heated to 80° C. LC/MS analysis after 1 h showed complete conversion of the starting material. The black mixture was cooled to RT, diluted with brine, extracted with EtOAc, dried over MgSO.sub.4, filtered and concentrated. The residue was purified by column chromatography (4 G ISCO Gold) eluting with 10% EtOAc in heptane to provide a mixture of (±) methyl 12-formyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate and (±) methyl 11-formyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (20.0 mg; 64%).

(178) Step 5:

(179) A solution of (±) methyl 12-formyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate and (±) methyl 11-formyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (20.0 mg; 0.07 mmol; 1.00 eq.) in tetrahydrofuran (0.7 ml) at RT was added pyrrolidine (0.01 ml; 0.09 mmol; 1.20 eq.). After 10 min, sodium cyanoborohydride (1.4 mg; 0.02 mmol; 0.30 eq.) was added and the mixture was stirred at RT. On observing no reaction after overnight stirring, acetic acid (few drops) was added and LC/MS analysis after a few minutes showed complete conversion of the starting material. The mixture was quenched with sat. NaHCO.sub.3, diluted with water and extracted with EtOAc. The combined organics were dried over MgSO.sub.4, filtered and concentrated. The residue was purified by column chromatography (4 G ISCO Gold) eluting with 100% EtOAC to provide (±) methyl 12-(pyrrolidin-1-ylmethyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate and (±) methyl 11-(pyrrolidin-1-ylmethyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (12.8 mg; 54%).

(180) Step 6:

(181) To a stirred solution of (±) methyl 12-(pyrrolidin-1-ylmethyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate and (±) methyl 11-(pyrrolidin-1-ylmethyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (12.0 mg; 0.04 mmol; 1.00 eq.) in 0.4 mL THF and 0.2 mL of MeOH at RT was added 0.2 mL of 1M LiOH. The mixture was stirred at RT for 2.5 h then it was quenched with 0.4 mL 1N HCl, extracted with EtOAc, dried over MgSO.sub.4, filtered and concentrated to give the corresponding acid compounds.

(182) Step 7:

(183) To a mixture of 12-(pyrrolidin-1-ylmethyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid and (±) methyl 11-(pyrrolidin-1-ylmethyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid and 5-(aminomethyl)-4,6-dimethylpyridin-2-amine (5.9 mg; 0.04 mmol; 1.10 eq.) (previously azeotroped with 0.8 mL PhMe for 1.5 h) in N,N-dimethylformamide (0.4 ml) at RT was added Hunig's base (0.02 ml; 0.11 mmol; 3.00 eq.) followed by (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) (HATU; 13.6 mg; 0.04 mmol; 1.00 eq.). After 15 minutes, the reacting mixture was diluted with 0.4 mL water (clear solution turned cloudy) and directly purified via R-Phase prep. HPLC (gradient 0% to 75% MeCN with 0.1% formic acid in water with 0.1% formic acid) to obtain the title compounds. MS: (M+H).sup.+ found for C.sub.28H.sub.30N.sub.4O.sub.2: 455.1. (4.0 mg).

Example 11

Synthesis of (1R,8S)—N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-12-[(4-fluoro-1H-pyrazol-1-yl)methyl]-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(184) ##STR00635##

(185) Step 1:

(186) A stirred suspension of methyl (1S,8R)-12-bromo-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (INT-3a1; 480.00 mg; 1.45 mmol; 1.00 eq.), methylboronic acid (173.53 mg; 2.90 mmol; 2.00 eq.), cesium carbonate (1180.65 mg; 3.62 mmol; 2.50 eq.) and 1,1′-bis(diphenylphosphino)ferrocene]dichloro palladium(II) (106.06 mg; 0.14 mmol; 0.10 eq.) in 1,4-dioxane (57.98 ml) and methanol (16.10 ml) was heated to 80° C. After 1 h the reacting mixture was cooled to RT, filtered with additional MeOH and concentrated. The brown residue was purified by column chromatography (40 G ISCO Gold) eluting with 10% EtOAc in heptane to provide the desired methyl (1R,8S)-12-methyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate contaminated by inseparable methyl (1R,8S) 15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (320 mg).

(187) Step 2:

(188) To a stirred suspension of methyl (1R,8S)-12-methyl-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate and methyl (1R,8S) 15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (320.00 mg; 1.20 mmol; 1.00 eq.), and N-bromosuccinimide (224.58 mg; 1.26 mmol; 1.05 eq.) in carbon tetrachloride (12.02 ml) was added AIBN (9.87 mg; 0.06 mmol; 0.05 eq.). The resulting mixture was heated to 75° C. After 3 h the reacting mixture was cooled to RT diluted with DCM, washed with sat. NaHCO.sub.3, dried over MgSO.sub.4, filtered and concentrated. The crude material was purified by column chromatography (12 G ISCO Gold) eluting with 10% EtOAc in heptane to provide methyl (1S,8R)-12-(bromomethyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate contaminated by inseparable methyl (1S,8R)-12-(dibromomethyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (273 mg).

(189) Step 3:

(190) To a stirred solution of methyl (1S,8R)-12-(bromomethyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate and methyl (1S,8R)-12-(dibromomethyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (50.00 mg; 0.14 mmol; 1.00 eq.) and 4-fluoro-1H-pyrazole (24.93 mg; 0.29 mmol; 2.00 eq.) in N,N-dimethylformamide (1.45 ml) was added cesium carbonate (94.39 mg; 0.29 mmol; 2.00 eq.). The mixture was stirred at RT overnight then it was diluted with EtOAc, washed with water, dried over MgSO.sub.4, filtered and concentrated. The crude material was purified by column chromatography (12 G ISCO Gold) eluting with a gradient of 0-10% (7 minutes) then 10-40% (8 minutes) EtOAc in heptane to provide methyl (1R,8S)-12-[(4-fluoro-1H-pyrazol-1-yl)methyl]-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (34.9 mg).

(191) Step 4:

(192) To a stirred solution of methyl (1R,8S)-12-[(4-fluoro-1H-pyrazol-1-yl)methyl]-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (35.00 mg; 0.10 mmol; 1.00 eq.) in 0.8 mL THF and 0.4 mL of MeOH at RT was added 0.4 mL of 1M LiOH. The mixture was stirred at RT for 2 h then it was quenched with 0.8 mL 1N HCl, extracted with EtOAc, dried over MgSO.sub.4, filtered and concentrated.

(193) Step 5:

(194) To a mixture of (1R,8S)-12-[(4-fluoro-1H-pyrazol-1-yl)methyl]-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid and 5-(aminomethyl)-4,6-dimethylpyridin-2-amine (30.21 mg; 0.20 mmol; 2.00 eq.) (previously azeotroped with 0.8 mL PhMe) in N,N-dimethylformamide (1.00 ml) at RT was added Hunig's base (0.14 ml; 0.80 mmol; 8.00 eq.) followed by HATU (37.99 mg; 0.10 mmol; 1.00 eq). After 1 h the reacting mixture was diluted with 1 mL water (clear solution turned cloudy) and directly purified via R-Phase prep HPLC (gradient 0% to 75% MeCN with 0.1% formic acid in water with 0.1% formic acid). The fractions containing the product were collected, combined and lyophilized to afford the title compound. MS: (M+H).sup.+ found for C.sub.27H.sub.24FN.sub.5O.sub.2: 470.1. (34.2 mg).

Example 12

Synthesis of (1R,8S)—N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-12-[(4-methyl-1H-pyrazol-1-yl)methyl]-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(195) ##STR00636##

(196) Step 1:

(197) To a stirred solution of methyl (1S,8R)-12-(bromomethyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate and methyl (1S,8R)-12-(dibromomethyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (Example 11, Steps 1-2; 182.00 mg; 0.53 mmol; 1.00 eq.) and 4-methyl-1H-pyrazole (0.08 ml; 1.05 mmol; 2.00 eq.) in N,N-dimethylformamide (5.27 ml) was added cesium carbonate (343.58 mg; 1.05 mmol; 2.00 eq.). The mixture was stirred at RT then it was diluted with EtOAc, washed with water, dried over MgSO.sub.4, filtered and concentrated. The crude material was purified by column chromatography (4 G ISCO Gold) eluting with a gradient of 0-10% (7 minutes) then 10-40% (8 minutes) EtOAc in heptane to provide methyl (1R,8S)-12-[(4-methyl-1H-pyrazol-1-yl)methyl]-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (153 mg).

(198) Step 2:

(199) To a stirred solution of methyl (1R,8S)-12-[(4-methyl-1H-pyrazol-1-yl)methyl]-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (153.00 mg; 0.44 mmol; 1.00 eq.) in 3.2 mL THF and 1.6 mL of MeOH at RT was added 1.6 mL of 1M LiOH. The mixture was stirred at RT for 2 h then it was quenched with 3.2 mL 1N HCl, extracted with EtOAc, dried over MgSO4, filtered and concentrated.

(200) Step 3:

(201) To a mixture of (1R,8S)-12-[(4-methyl-1H-pyrazol-1-yl)methyl]-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (153.00 mg; 0.44 mmol; 1.00 eq.) and 5-(aminomethyl)-4,6-dimethylpyridin-2-amine (133.58 mg; 0.88 mmol; 2.00 eq.) (previously azeotroped with 2 mL PhMe) in N,N-dimethylformamide (4.42 ml) at RT was added Hunig's base (0.62 ml; 3.53 mmol; 8.00 eq.) followed by HATU (167.95 mg; 0.44 mmol; 1.00 eq.). After 1 h the reacting mixture was diluted with 4.5 mL water (clear solution turned cloudy) and directly purified via R-Phase prep HPLC (gradient 0% to 75% MeCN with 0.1% formic acid in water with 0.1% formic acid; 4 injections 2.1 mL each). The fractions containing the product from the four runs were collected, combined and lyophilized to afford (1R,8S)—N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-12-[(4-methyl-1H-pyrazol-1-yl)methyl]-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide. MS: (M+H).sup.+ found for C.sub.28H.sub.27N.sub.5O.sub.2: 466.2. (77.2 mg).

Example 13

Synthesis of (1R,8R)—N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-11-(3-fluorophenoxy)-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(202) ##STR00637##

(203) Step 1:

(204) A mixture of methyl (1R,8R)-11-bromo-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (INT-3b1; 59.00 mg; 0.18 mmol; 1.00 eq.), 3-fluorophenol (0.02 ml; 0.23 mmol; 1.30 eq.), copper(I) bromide (3.83 mg; 0.03 mmol; 0.15 eq.), 2,4-pentanedione (3.66 μL; 0.04 mmol; 0.20 eq.) and potassium carbonate (31.96 mg; 0.23 mmol; 1.30 eq.) in N,N-dimethylformamide (0.59 ml) at RT (the mixture started turning dark and cloudy but no reaction was detected by LC/MS) was evacuated and back-filled with Argon (from a balloon) and the mixture was heated to 120° C. under Argon. After 4 h the mixture was allowed to reach RT, and directly injected onto a 12 G ISCO Gold column and purified eluting with 10% EtOAc in heptane. The semi pure methyl (1R,8R)-11-(3-fluorophenoxy)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate thus obtained was taken on without further purification (54.9 mg).

(205) Step 2:

(206) To a stirred solution of methyl (1R,8R)-11-(3-fluorophenoxy)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (50.00 mg; 0.14 mmol; 1.00 eq.) in 1.0 mL THF and 0.5 mL of MeOH at RT was added 0.5 mL of 1M LiOH. The mixture was stirred at RT for 2 h then it was quenched with 1.0 mL 1N HCl, extracted with EtOAc, dried over MgSO4, filtered and concentrated.

(207) Step 3:

(208) To a mixture of (1R,8R)-1-(3-fluorophenoxy)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid and 5-(aminomethyl)-4,6-dimethylpyridin-2-amine (41.73 mg; 0.28 mmol; 2.00 eq.) (previously azeotroped with 1 mL PhMe for 1 h) in N,N-dimethylformamide (1.38 ml) at RT was added Hunig's base (0.19 ml; 1.10 mmol; 8.00 eq.) followed by HATU (52.47 mg; 0.14 mmol; 1.00 eq.). After 1 h the reacting mixture was diluted with 1.5 mL water (clear solution turned cloudy) and 0.5 mL MeOH and directly purified via R-Phase prep HPLC (gradient 0% to 75% MeCN with 0.1% formic acid in water with 0.1% formic acid; 2 injections 1.4 mL each). The fractions containing the product from the two runs were collected, combined and lyophilized to afford (1R,8R)—N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-11-(3-fluorophenoxy)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide. MS: (M+H).sup.+ found for C.sub.29H.sub.24FN.sub.3O.sub.3: 482.1. (26.3 mg).

Example 14

Synthesis of (1R,8S)—N-[(4-carbamimidoylphenyl)methyl]-12-cyclopropyl-15-oxatetracyclo-[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(209) ##STR00638##

(210) Step 1:

(211) A stirred suspension of (1S,8R)-12-bromo-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (INT-4a1; 100.00 mg; 0.32 mmol; 1.00 eq.), cyclopropylboronic acid (54.17 mg; 0.63 mmol; 2.00 eq.), cesium carbonate (256.85 mg; 0.79 mmol; 2.50 eq.) and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (23.07 mg; 0.03 mmol; 0.10 eq.) in 1,4-dioxane (1.58 ml) and methanol (0.53 ml) was heated to 80° C. After 2 h the reacting mixture was cooled to RT, diluted with EtOAc and water and acidified with 1N HCl. The organic phase was separated dried over MgSO.sub.4, filtered and concentrated. The oily orange residue was taken up in Et.sub.2O and filtered. The clear yellow filtrate was concentrated to provide a yellowish solid. This material was taken on without further purification (34 mg).

(212) Step 2:

(213) To a mixture of (1R,8S)-12-cyclopropyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (34.00 mg; 0.12 mmol; 1.00 eq.) in N,N-dimethylformamide (1.22 ml) at RT was added Hunig's base (0.04 ml; 0.24 mmol; 2.00 eq.) followed by 1H-1,2,3-benzotriazol-1-ol hydrate (HOBt; 28.06 mg; 0.18 mmol; 1.50 eq.) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (EDC; 46.84 mg; 0.24 mmol; 2.00 eq.). After stirring for 5 min 4-(aminomethyl)benzene-1-carboximidamide (27.34 mg; 0.18 mmol; 1.50 eq.) was added and the resulting mixture was stirred at RT. After 3.5 h the mixture was diluted with 1.3 mL water and directly purified by R-Phase prep HPLC (gradient 0% to 75% MeCN with 0.1% formic acid in water with 0.1% formic acid; 2 injections 1.2 mL each). The fractions containing the product from the two runs were collected, combined and lyophilized to afford the title compound. MS: (M+H).sup.+ found for C.sub.26H.sub.23N.sub.3O.sub.2: 410.1. (19.7 mg).

Example 15

Synthesis of (1R,8S)—N-[(4-carbamimidoyl-2,6-difluorophenyl)methyl]-12-(prop-1-en-2-yl)-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(214) ##STR00639##

(215) Step 1:

(216) A stirred solution of sodium (1S,8R)-12-bromo-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (INT-5a1; 150.00 mg; 0.44 mmol; 1.00 eq.), potassium trifluoro(prop-1-en-2-yl)boranuide (104.73 mg; 0.71 mmol; 1.60 eq.), triethylamine (0.14 ml; 0.97 mmol; 2.20 eq.) and 1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (6.47 mg; 0.01 mmol; 0.02 eq.) in 1-butanol (7.37 ml) was heated to 80° C. under nitrogen. After 5.5 h the reacting mixture was cooled to RT, filtered, diluted with water, acidified with 1N HCl and extracted with EtOAc. The organic phase was dried over MgSO.sub.4, filtered and concentrated to give an orange oil which turned into a solid under high vacuum. This material was taken up in Et.sub.2O and filtered; the clear yellow filtrate was concentrated to provide a yellowish solid which was dried under high vacuum. This material was taken on without further purification (59 mg).

(217) Step 2:

(218) To a mixture of (1R,8S)-12-(prop-1-en-2-yl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (9.00 mg; 0.03 mmol; 1.00 eq.) and 4-(aminomethyl)-3,5-difluorobenzimidamide dichloride (INT-10; 16.69 mg; 0.06 mmol; 2.00 eq.) in N,N-dimethylformamide (0.32 ml) at RT was added Hunig's base (0.05 ml; 0.26 mmol; 8.00 eq.) followed by HATU (12.30 mg; 0.03 mmol; 1.00 eq.). After 30 min the reacting mixture was diluted with 0.4 mL water and 0.3 mL MeCN and directly purified by R-Phase prep HPLC (gradient 0% to 75% MeCN with 0.1% formic acid in water with 0.1% formic acid). The fractions containing the product were collected, combined and lyophilized to afford the title compound. MS: (M+H).sup.+ found for C.sub.26H.sub.21F.sub.2N.sub.3O.sub.2: 446.1. (6.3 mg).

Example 16

Synthesis of (1R,8S)—N-[(4-carbamimidoyl-2,6-difluorophenyl)methyl]-12-(3,3,3-trifluoropropyl)-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(219) ##STR00640##

(220) Step 1:

(221) A stirred solution of (1S,8R)-12-bromo-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14-pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (INT-4a1; 76.00 mg; 0.24 mmol; 1.00 eq.), potassium trifluoro(3,3,3-trifluoropropyl)boranuide (97.76 mg; 0.48 mmol; 2.00 eq.), cesium carbonate (351.37 mg; 1.08 mmol; 4.50 eq.) and 1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (2.63 mg; 0.00 mmol; 0.02 eq.) in toluene (3.69 ml) and water (1.20 ml) was heated to 90° C. under nitrogen for 3 h. The mixture was then stirred at RT overnight then again at 90° C. for 7 h. The mixture was then diluted with EtOAc and water and acidified with 1N HCl, extracted with EtOAc then dried over MgSO.sub.4, filtered and concentrated. The residue was taken up in Et.sub.2O, filtered and concentrated. The resulting yellow crude solid was taken on without further purification (40 mg).

(222) Step 2:

(223) To a mixture of the crude material from step 1 (40.00 mg; 0.12 mmol; 1.00 eq.) in N,N-dimethylformamide (1.20 ml) at RT was added Hunig's base (0.04 ml; 0.24 mmol; 2.00 eq.) followed by 1H-1,2,3-benzotriazol-1-ol hydrate (27.49 mg; 0.18 mmol; 1.50 eq.) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (45.88 mg; 0.24 mmol; 2.00 eq.) After stirring for 5 min, 4-(aminomethyl)-3,5-difluorobenzimidamide dichloride (INT-10; 46.32 mg; 0.18 mmol; 1.50 eq.) was added and the resulting mixture was stirred at RT. After 4 h the mixture was directly purified by R-Phase prep HPLC (gradient 0% to 75% MeCN with 0.1% formic acid in water with 0.1% formic acid; 2 injections 0.8 mL each). The fractions containing the product from the two runs were collected, combined and lyophilized to afford (1R,8S)—N-[(4-carbamimidoyl-2,6-difluorophenyl)methyl]-12-(3,3,3-trifluoropropyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide. MS: (M+H).sup.+ found for C.sub.26H.sub.20F.sub.5N.sub.3O.sub.2: 502.1. (10.2 mg).

Example 17

Synthesis of (1R,8S)—N-[(4-carbamimidoyl-2,6-difluorophenyl)methyl]-12-(propan-2-yl)-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(224) ##STR00641##

(225) Step 1:

(226) To a solution of (1R,8S)-12-(prop-1-en-2-yl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (54.00 mg; 0.19 mmol; 1.00 eq.) in methanol (3.88 ml) was added platinum (IV) oxide (4.41 mg; 0.02 mmol; 0.10 eq.). The reaction mixture was stirred under an atmosphere of hydrogen (from a balloon after 3 cycles of evacuation/backfilling) at room temperature. After 3 h the reaction mixture was filtered through a syringe filter with additional MeOH and concentrated. This material was taken on to the next step without further purification (54 mg).

(227) Step 2:

(228) To a mixture of the crude material from step 1 (54.00 mg; 0.19 mmol; 1.00 eq.) in N,N-dimethylformamide (1.93 ml) at RT was added Hunig's base (0.07 ml; 0.39 mmol; 2.00 eq.) followed by 1H-1,2,3-benzotriazol-1-ol hydrate (44.25 mg; 0.29 mmol; 1.50 eq.) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (73.86 mg; 0.39 mmol; 2.00 eq.). After stirring for 5 min 4-(aminomethyl)-3,5-difluorobenzimidamide dichloride (INT-10; 74.58 mg; 0.29 mmol; 1.50 eq.) was added and the resulting mixture was stirred at RT. After 2.5 h the mixture was directly purified by R-Phase prep HPLC (gradient 0% to 75% MeCN with 0.1% formic acid in water with 0.1% formic acid; 3 injections 0.7 mL each). The fractions containing the product from the two runs were collected, combined and lyophilized to afford the title compound. MS: (M+H).sup.+ found for C.sub.26H.sub.23F.sub.2N.sub.3O.sub.2: 448.1. (23 mg).

Example 18

Synthesis of (1S,8R)—N-[(4-carbamimidoylphenyl)methyl]-12-(3,3-difluoroazetidin-1-yl)-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(229) ##STR00642##

(230) Step 1:

(231) A mixture of sodium (1S,8R)-12-bromo-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (INT-5a1; 95.00 mg; 0.28 mmol; 1.00 eq.), 3,3-difluoroazetidin-1-ium chloride (54.43 mg; 0.42 mmol; 1.50 eq.), Pd.sub.2(dba).sub.3 (12.83 mg; 0.01 mmol; 0.05 eq.), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos; 13.35 mg; 0.03 mmol; 0.10 eq.), and cesium carbonate (365.10 mg; 1.12 mmol; 4.00 eq.) in N,N-dimethylformamide (1.00 ml) was heated to 120° C. under an atmosphere of Argon. After 1 h the mixture was diluted with water and extracted with ethyl acetate. The organic phase contained only an insignificant amount of desired product. The aqueous phase was acidified with 1N HCl and extracted with EtOAc. The combined organics were dried over MgSO.sub.4, filtered and concentrated. The oily residue was taken up in Et.sub.2O, filtered and concentrated to afford an orange solid. This material was taken up again in Et.sub.2O and the insoluble light yellow material was separated, air dried and taken on to the next step without further purification (40 mg).

(232) Step 2:

(233) To a mixture of crude (1S,8R)-12-(3,3-difluoroazetidin-1-yl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (40.00 mg; 0.12 mmol; 1.00 eq.) in N,N-dimethylformamide (1.21 ml) at RT was added Hunig's base (0.06 ml; 0.36 mmol; 3.00 eq.) followed by 1H-1,2,3-benzotriazol-1-ol hydrate (27.90 mg; 0.18 mmol; 1.50 eq.) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (46.57 mg; 0.24 mmol; 2.00 eq.). After 5 min, 4-(aminomethyl)benzimidamide dichloride (40.47 mg; 0.18 mmol; 1.50 eq.) was added and the resulting mixture was stirred at RT. After 3.5 h the mixture was filtered through a syringe filter and directly purified by R-Phase prep HPLC (gradient 0% to 75% MeCN with 0.1% formic acid in water with 0.1% formic acid; 2 injections 0.7 mL each). The fractions containing the product from the two runs were collected, combined and lyophilized to afford the title compound. MS: (M+H).sup.+ found for C.sub.26H.sub.22F.sub.2N.sub.4O.sub.2: 461.1. (34.1 mg; 26% over the two steps).

Example 19

Synthesis of (1S,8R)-12-(3,3-difluoroazetidin-1-yl)-N-({4-N′-methoxycarbamimidoyl]phenyl}-methyl)-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(234) ##STR00643##

(235) To a mixture of (1S,8R)-12-(3,3-difluoroazetidin-1-yl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (20.00 mg; 0.06 mmol; 1.00 eq.) in N,N-dimethylformamide (0.61 ml) at RT was added Hunig's base (0.03 ml; 0.18 mmol; 3.00 eq.) followed by 1H-1,2,3-benzotriazol-1-ol hydrate (13.95 mg; 0.09 mmol; 1.50 eq.) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (23.29 mg; 0.12 mmol; 2.00 eq.). After 5 min, 4-(aminomethyl)-N′-methoxybenzimidamide dihydrochloride (INT-7; 19.65 mg; 0.09 mmol; 1.50 eq.) was added an the resulting mixture was stirred at RT. After 6 h the mixture was directly purified by R-Phase prep HPLC (gradient 0% to 75% MeCN with 0.1% formic acid in water with 0.1% formic acid). The fractions containing the product were collected, combined and lyophilized to afford the title compound. MS: (M+H).sup.+ found for C.sub.27H.sub.24F.sub.2N.sub.4O.sub.3: 491.1. (18.1 mg; 61%).

Example 20

Synthesis of (1R,8S)—N-({4-[N′-methoxycarbamimidoyl]phenyl}methyl)-12-(propan-2-yl)-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(236) ##STR00644##

(237) To a mixture of (1R,8S)-12-(propan-2-yl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (40.00 mg; 0.14 mmol; 1.00 eq.) in N,N-dimethylformamide (1.43 ml) at RT was added Hunig's base (0.07 ml; 0.43 mmol; 3.00 eq.) followed by 1H-1,2,3-benzotriazol-1-ol hydrate (32.78 mg; 0.21 mmol; 1.50 eq.) and N-[3-(dimethylamino)-propyl]-N′-ethylcarbodiimide hydrochloride (54.71 mg; 0.29 mmol; 2.00 eq.). After stirring for 5 min 4-(aminomethyl)-N′-methoxybenzimidamide dihydrochloride (INT-7; 46.16 mg; 0.21 mmol; 1.50 eq.) was added and the resulting mixture was stirred at RT. After 2 h the mixture was directly purified by R-Phase prep HPLC (gradient 0% to 75% MeCN with 0.1% formic acid in water with 0.1% formic acid). The fractions containing the product were collected, combined and lyophilized to afford the title compound. MS: (M+H).sup.+ found for C.sub.27H.sub.27N.sub.3O.sub.3: 442.1. (25 mg; 40%).

Example 21

Synthesis of (1S,8R)—N-[(4-carbamimidoylphenyl)methyl]-12-(pyrrolidin-1-yl)-15-oxatetra-cyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(238) ##STR00645##

(239) Step 1:

(240) Combined methyl (1S,8R)-12-bromo-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (INT-3a1; 280 mgs, 0.9 mmol), pyrrolidine (90 mgs, 1.3 mmol), Pd.sub.2(dba).sub.3 (38 mgs, 0.04 mmol), XPhos (40 mgs, 0.08), and cesium carbonate (826 mgs, 2.5 mmol) in DMF (2 mL) in a microwave vial. The reaction mixture was heated in a microwave at 120° C. for 1 hour. The reaction mixture was filtered thru a short plug of Celite. The resulting solution was diluted with water and extracted with ethyl acetate. The combined organics was dried over magnesium sulfate, filtered and evaporated to provide crude methyl (1S,8R)-12-(pyrrolidin-1-yl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (270 mgs).

(241) Step 2:

(242) To a solution of methyl (1S,8R)-12-(pyrrolidin-1-yl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (270 mgs, 0.8 mmol) in methanol (10 mL) was added 2M NaOH (1.7 mL). The reaction was heated to 60° C. for 1 hour. The reaction was cooled to room temperature, concentrated and purified by prep HPLC (gradient 0% to 75% MeCN with 0.1% formic acid in water with 0.1% formic acid) to afford (1S,8R)-12-(pyrrolidin-1-yl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (100 mgs).

(243) Step 3:

(244) To a solution of (1S,8R)-12-(pyrrolidin-1-yl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (100 mgs, 0.3 mmol) in Hunig's base (0.17 mL, 1.0 mmol) and DMF (2 mL) was added HATU (124 mgs, 0.3 mmol). 4-(aminomethyl)benzene-1-carboximidamide dihydrochloride (72 mgs, 0.3 mmol) was added to the reaction mixture and stirred for 15 minutes. The residue was purified by prep HPLC (gradient 0% to 75% MeCN with 0.1% formic acid in water with 0.1% formic acid) to afford the title compound (7 mgs). MS: (M+H).sup.+ found for C.sub.27H.sub.26N.sub.4O.sub.2: 439.1.

Example 22

Synthesis (1R,8S)—N-[(6-carbamimidoylpyridin-3-yl)methyl]-12-(2,4-difluorophenyl)-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(245) ##STR00646##

(246) Step 1:

(247) Combined 5-(bromomethyl)pyridine-2-carbonitrile (200 mgs) and 7 N ammonia in methanol (2 mL) in a capped reaction vial. The reaction mixture was heated at 65° C. for 2 hours. The reaction was cooled cool to rt and the solvents were evaporated. The residue was purified using prep HPLC (100% water) to afford 5-(aminomethyl)pyridine-2-carboximidamide (31 mgs).

(248) Step 2:

(249) To a solution of (1R,8S)-12-(2,4-difluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (Example 7, Steps 1-2; 47 mgs, 0.1 mmol) and Hunig's base (0.07 mL, 0.4 mmol) in DMA (2 mL) was added HATU (50 mgs, 0.1 mmol). 5-(Aminomethyl)pyridine-2-carboximidamide (20 mg, 0.1 mmol) was added to the reaction mixture and stirred for 15 minutes. The mixture was purified by prep HPLC (gradient 0% to 75% MeCN with 0.1% formic acid in water with 0.1% formic acid) to afford the title compound (3 mgs). MS: (M+H).sup.+ found for C.sub.28H.sub.20F.sub.2N.sub.4O.sub.2: 483.1.

Example 23

Synthesis (1R,8S)-12-cyclopropyl-N-({4-[N′-methoxycarbamimidoyl]phenyl}methyl)-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(250) ##STR00647##

(251) Step 1:

(252) To a solution of (1S,8R)-12-bromo-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (INT-4a1; 230 mgs, 0.7 mmol) and Hunig's base (0.63 mL, 3.6 mmol) in dimethylacetamide (DMA; 3 mL), was added HATU (275 mgs, 0.7 mmol). 4-(Aminomethyl)-N′-methoxybenzene-1-carboximidamide dihydrochloride (INT-7; 181 mgs, 0.7 mmol) was added to the reaction. The reaction was stirred for 15 minutes. The reaction mixture was purified by prep HPLC (gradient 0% to 75% MeCN with 0.1% formic acid in water with 0.1% formic acid) to afford (1S,8R)-12-bromo-N-({4-[N′-methoxycarbamimidoyl]phenyl}-methyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide (200 mgs).

(253) Step 2:

(254) A solution of (1S,8R)-12-bromo-N-({4-[N′-methoxycarbamimidoyl]-phenyl}-methyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide (200 mgs, 0.4 mmol), cyclopropylboronic acid (90 mgs, 1.1 mmol), Pd(dppf).sub.2Cl.sub.2 (17 mgs, 0.02 mmol), and 2M potassium carbonate (0.63 mL) in DMF (3 mL) was sealed in a microwave vial. The reaction mixture was heated to 100° C. for 30 minutes. The reaction mixture was filtered, concentrated and purified by prep HPLC (gradient 0% to 75% MeCN with 0.1% formic acid in water with 0.1% formic acid) to afford the title compound (41 mgs). MS: (M+H).sup.+ found for C.sub.27H.sub.25N.sub.3O.sub.3: 440.1

Example 24

Synthesis of (1R,8S)—N-[(4-carbamimidoyl-2,6-difluorophenyl)methyl]-12-cyclopropyl-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(255) ##STR00648##

(256) To a solution of (1R,8S)-12-cyclopropyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (Example 14, Step 1; 40 mgs, 0.1 mmol) and Hunig's base (0.13 mL, 0.7 mmol) in N-methyl-2-pyrrolidone (NMP; 2 mL) was added HATU (55 mgs, 0.1 mmol). To the resulting reaction mixture, 4-(aminomethyl)-3,5-difluorobenzimidamide dihydrochloride (INT-10; 37 mgs, 0.1 mmol) was added. The reaction was stirred for 15 minutes and the purified by prep HPLC (gradient 0% to 75% MeCN with 0.1% formic acid in water with 0.1% formic acid) to afford the title compound. (23 mgs). MS: (M+H).sup.+ found for C.sub.26H.sub.21F.sub.2N.sub.3O.sub.2: 446.2 (M+1).

Example 25

Synthesis of (1R,8S)-12-cyclopropyl-N-{[2,6-difluoro-4-(N-methoxycarbamimidoyl)phenyl]methyl})-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(257) ##STR00649##

(258) The title compound was prepared as described in Example 24, but using 4-(amino-methyl)-3,5-difluoro-N′-methoxybenzimidamide (INT-11) instead of 4-(aminomethyl)-3,5-difluorobenzene-1-carboximidamide dihydrochloride. MS: (M+H).sup.+ found for C.sub.27H.sub.23F.sub.2N.sub.3O.sub.3: 476.1.

Example 26

Synthesis of {amino[4-({[(1R,8S)-12-(2,4-difluorophenyl)-15-oxatetracyclo[6.6.1.02,7.09,14]-pentadeca-2,4,6,9,11,13-hexaen-4-yl]formamido}methyl)phenyl]methylidene}amino (2S)-2-amino-3-methylbutanoate

(259) ##STR00650##

(260) To a solution of (1R,8S)-12-(2,4-difluorophenyl)-N-({4-[N′-hydroxycarbamimidoyl]-phenyl}methyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide (Example 7; 140 mgs, 0.3 mmol) and Hunig's base (0.1 mL, 0.6 mmol) in NMP (5 mL) was added 2,5-dioxopyrrolidin-1-yl (2S)-2-{[(tert-butoxy)carbonyl]-amino}-3-methylbutanoate (88 mgs, 0.3 mmol). The reaction was stirred for 4 hours. Purified by prep HPLC (gradient 0% to 75% MeCN with 0.1% formic acid in water with 0.1% formic acid) to afford the title compound (35 mgs). MS: (M+H).sup.+ found for C.sub.34H.sub.30F.sub.2N.sub.4O.sub.4: 597.1.

Example 27

Synthesis of (1R,8S)-12-(2,4-difluorophenyl)-N-{[6-(N′-methoxycarbamimidoyl)-pyridin-3-yl]methyl}-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(261) ##STR00651##

(262) Step 1:

(263) To a solution of tert-butyl N-[(6-cyanopyridin-3-yl)methyl]carbamate (130 mgs, 0.6 mmol), thioglycolic acd (0.08 mL, 1.1 mmol), and Hunig's base (0.39 mL, 2.2 mmol) was added O-methylhydroxylamine hydrochloride (140 mgs, 1.7 mmol) in 2-propanol (2 mL) into a capped reaction vial. The reaction mixture was heated at 80° C. overnight. The reaction was cooled to room temperature, diluted reaction with water and extracted with ethyl acetate. The combined organics, dried with MgSO.sub.4, filtered, concentrated and purified by Combiflash silica gel column using 5% MeOH in DCM to afford tert-butyl N-{[6-(N-methoxycarbamimidoyl)-pyridin-3-yl]methyl}carbamate (109 mgs). The resulting product was treated with 4M HCl in dioxanes (3 mL). After stirred for 2 hours the reaction mixture was concentrated to afford 5-(aminomethyl)-N-methoxypyridine-2-carboximidamide dihydrochloride (107 mgs).

(264) Step 2:

(265) To a solution of (1R,8S)-12-(2,4-difluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (Example 7, Step 1-2; 150 mgs, 0.4 mmol) and Hunig's base (0.3 mL, 1.7 mmol) in NMP (3 mL) was added HATU (163 mgs, 0.4 mmol). 5-(Aminomethyl)-N-methoxypyridine-2-carboximidamide dihydrochloride (107 mgs, 0.4 mmol) was added to the reaction mixture. The reaction mixture was stirred for 15 minutes and purified by prep HPLC (gradient 0% to 75% MeCN with 0.1% formic acid in water with 0.1% formic acid) to afford the title compound (119 mgs). MS: (M+H).sup.+ found for C.sub.29H.sub.22F.sub.2N.sub.4O.sub.3: 513.3.

Example 28

Synthesis of (1R,8S)-12-(2,4-difluorophenyl)-N-{[4-(N′-methoxycarbamimidoyl)phenyl]methyl}-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(266) ##STR00652##

(267) The title compound was prepared as in Example 45, step 8, but substituting 4-(aminomethyl)-3,5-dimethylbenzene-1-carboximidamide with {4-(aminomethyl)-N′-methoxybenzimidamide dihydrochloride (INT-7). MS (ESI, pos. ion) m/z: 512.2 (M+1).

Example 29

Synthesis of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-12-(phenylsulfanyl)-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide and (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-11-(phenylsulfanyl)-15-oxatetracyclo-[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(268) ##STR00653##

(269) Step 1:

(270) A solution of diacetoxypalladium (2.03 mg; 0.01 mmol; 0.05 eq.) and (R)-1-[(SP)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine (5.02 mg; 0.01 mmol; 0.05 eq.) in dimethoxyethane (DME; 0.5 mL) was stirred for 15 min and the mixture was then added (±)-methyl 12-bromo-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate and (±)-methyl 11-bromo-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (INT-3; 60.00 mg; 0.18 mmol; 1.00 eq.), phenyl hydrosulfide (21.96 mg; 0.20 mmol; 1.10 eq.), and (tert-butoxy)sodium (19.15 mg; 0.20 mmol; 1.10 eq.). The reaction mixture was heated at 100° C. for 3 h. The reaction mixture was cooled and diluted with EtOAc and dilute HCl solution. The organic layer was separated and the aqueous layer was further extracted with EtOAc. The organic layers were combined, dried and concentrated to give crude product, which was purified by column chromatography (Hexanes/EtOAc (0.3% AcOH)=3:1) to give inseparable mixture of (±)-12-(phenylsulfanyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid and (±)-11-(phenylsulfanyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (40 mg).

(271) Step 2:

(272) To a suspension of a mixture of (±)-12-(phenylsulfanyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid and (±)-11-(phenylsulfanyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (40.00 mg; 0.12 mmol; 1.00 eq.) and 5-(aminomethyl)-4,6-dimethylpyridin-2-amine (34.92 mg; 0.23 mmol; 2.00 eq.) in DMF (1 mL) was added Hunig's base (0.06 ml; 0.35 mmol; 3.00 eq.) and HATU (48.30 mg; 0.13 mmol; 1.10 eq.). After stirring for 15 min, the reaction mixture was diluted with water and AcCN and purified by preparative HPLC to give the title compounds. MS: (M+H).sup.+ found for C.sub.29H.sub.25N.sub.3O.sub.2S: 480.1.

Example 30

Synthesis of (1R,8 S)—N-[(4-carbamimidoyl-3-fluorophenyl)methyl]-12-(2,4-difluorophenyl)-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(273) ##STR00654##

(274) Step 1:

(275) To a solution of tert-butyl N-[(4-cyano-3-fluorophenyl)methyl]carbamate (0.50 g; 2.00 mmol; 1.00 eq.) in MeOH (10 mL) was added hydroxylamine (0.20 g; 5.99 mmol; 3.00 eq.) and sodium carbonate (0.64 g; 5.99 mmol; 3.00 eq.). The mixture was heated at 80° C. for 4 h, then cooled and diluted with EtOAc and water. The organic layer was separated, dried and concentrated to give tert-butyl N-({3-fluoro-4-[N′-hydroxy-carbamimidoyl]phenyl}methyl)-carbamate (0.60 g).

(276) Step 2:

(277) To a solution of tert-butyl N-({3-fluoro-4-[N′-hydroxy-carbamimidoyl]-phenyl}methyl)carbamate (500.00 mg; 1.76 mmol; 1.00 eq.) in AcOH (40 mL) was added acetic anhydride (0.18 ml; 1.85 mmol; 1.05 eq.) followed by Pd/C (180.00 mg; 1.69 mmol; 0.96 eq.) and the reaction mixture was put on Parr shaker and charged with H.sub.2 (68 psi). After 4 h, the reaction mixture t was filtered and the filtrate was concentrated to give tert-butyl N-[(4-carbamimidoyl-3-fluorophenyl)methyl]carbamate, which was added with 4N HCl (4 mL) at room temperature and was stirred further for 1 h, after which the mixture was concentrated to give 4-(aminomethyl)-2-fluorobenzimidamide as HCl salt (410 mg).

(278) Step 3:

(279) To a solution of (1R,8S)-12-(2,4-difluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9(14),10,12-hexaene-4-carboxylic acid (Example 7, Step 1-2; 60.00 mg; 0.17 mmol; 1.00 eq.) and 4-(aminomethyl)-2-fluorobenzimidamide HCl salt (44.86 mg; 0.19 mmol; 1.10 eq.) in DMF (1 mL) at rt was added diisopropylethylamine (0.15 ml; 0.86 mmol; 5.00 eq.) followed by HATU (71.64 mg; 0.19 mmol; 1.10 eq.). Ater stirring the reaction mixture at ambient temperature for 30 min, the reaction mixture was then diluted with water and AcCN and was purified by preparatory HPLC to give the title compound (25 mg). MS: (M+H).sup.+ found for C.sub.29H.sub.20F.sub.3N.sub.3O.sub.2: 500.1.

Example 31

Synthesis of (1R,8S)—N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-12-benzyl-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(280) ##STR00655##

(281) Step 1:

(282) To a solution of methyl (1S,8R)-12-bromo-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (INT-3a1; 75.00 mg; 0.23 mmol; 1.00 eq.) in THF (1 mL) was added 1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (16.57 mg; 0.02 mmol; 0.10 eq.) followed by benzyl(bromo)zinc (1.36 ml; 0.50 mol/l; 0.68 mmol; 3.00 eq.). The mixture was flushed with N.sub.2, sealed and heated at 60° C. for 15 h. The reaction mixture was diluted with EtOAc and water and the organic layer was separated. The aqueous layer was further extracted with EtOAc, the organic layers were combined, dried over MgSO4 and concentrated to give crude product, which was purified by column chromatography (Hexanes/EtOAc=65:35) to give methyl (1R,8S)-12-benzyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (68 mg).

(283) Step 2:

(284) To a solution of methyl (1R,8S)-12-benzyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (66.00 mg; 0.19 mmol; 1.00 eq.) in THF (1 mL) was added MeOH (0.5 mL) and water (0.5 mL). Lithium hydroxide (23.08 mg; 0.96 mmol; 5.00 eq.) was added and after stirring for 4 hr at room temperature, the reaction mixture was diluted with 1N HCl and lyophilized to give crude acid, which was dissolved in DMF (1 mL). 5-(Aminomethyl)-4,6-dimethylpyridin-2-amine (58.30 mg; 0.39 mmol; 2.00 eq.) was added, followed by Hunig's base (0.10 ml; 0.58 mmol; 3.00 eq.) and HATU (80.62 mg; 0.21 mmol; 1.10 eq.) and the reaction mixture was stirred further until the reaction was complete. The mixture as diluted with water and AcCN and purified by preparatory HPLC to give the title compound. MS: (M+H).sup.+ found for C.sub.30H.sub.27N.sub.3O.sub.2: 462.1.

Example 32

Synthesis of (1R,8S)—N-[(4-carbamimidoyl-2,6-difluorophenyl)methyl]-12-(2,4-difluorophenyl)-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(285) ##STR00656##

(286) To a solution of (1R,8S)-12-(2,4-difluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (Example 7, Steps 1-2; 50.00 mg; 0.14 mmol; 1.00 eq.) in DMF (1 mL) was added 4-(aminomethyl)-3,5-difluorobenzene-1-carboximidamide dihydrochloride (INT-10; 29.07 mg; 0.16 mmol; 1.10 eq.) and diisopropylethylamine (0.12 ml; 0.71 mmol; 5.00 eq.) followed by HATU (56.98 mg; 0.15 mmol; 1.05 eq.). After stirring for 15 min, the reaction mixture was diluted with water and MeCN and purified by preparatory HPLC to the title compound (42 mg). MS: (M+H).sup.+ found for C.sub.29H.sub.19F.sub.4N.sub.3O.sub.2: 518.1.

Example 33

Synthesis of (1S,8R)—N-({2,6-difluoro-4-[N′-methoxycarbamimidoyl]phenyl}-methyl)-12-(1,3-thiazol-2-yl)-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(287) ##STR00657##

(288) Step 1:

(289) To a solution of methyl (1S,8R)-12-bromo-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (INT-3a1; 120.00 mg; 0.36 mmol; 1.00 eq.) and 2-(tributylstannyl)-1,3-thiazole (271.17 mg; 0.72 mmol; 2.00 eq.) in DMF (1.2 mL) was added bis(triphenylphosphine)dichloropalladium (25.43 mg; 0.04 mmol; 0.10 eq.). After heating at 95 degree for 2 h, the reaction mixture was cooled down and purified by column chromatography (Hexanes/EtOAc=65:35) to give methyl (1S,8R)-12-(1,3-thiazol-2-yl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate. The product was dissolved in THF (2 mL) and MeOH (1 mL) and water (1 mL) were added, followed by lithium hydroxyde (17.36 mg; 0.72 mmol; 2.00 eq.). After stirring at room temperature for 2 h, the mixture was acidified by 1N HCl and then lyophilized to give (1S,8R)-12-(1,3-thiazol-2-yl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (45 mg).

(290) Step 2:

(291) To a solution of (1S,8R)-12-(1,3-thiazol-2-yl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (45.00 mg; 0.14 mmol; 1.00 eq.) and 4-(aminomethyl)-3,5-difluoro-N′-methoxybenzene-1-carboximidamide (INT-11; 60.27 mg; 0.28 mmol; 2.00 eq.) in DMF (1.5 mL) was added diisopropylethylamine (0.10 ml; 0.56 mmol; 4.00 eq.) followed by HATU (58.57 mg; 0.15 mmol; 1.10 eq.). After stirring at room temperature for 30 min, the reaction mixture was diluted with water and MeCN and was purified by preparatory HPLC to the title compound (30 mg). MS: (M+H).sup.+ found for C.sub.27H.sub.20F.sub.2N.sub.4O.sub.3S: 519.0.

Example 34

Synthesis of (1S,8R)—N-[(4-carbamimidoyl-2,6-difluorophenyl)methyl]-12-(1,3-thiazol-2-yl)-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(292) ##STR00658##

(293) To a solution of (1S,8R)-12-(1,3-thiazol-2-yl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (Example 33, Step 1; 45.00 mg; 0.14 mmol; 1.00 eq.) and 4-(aminomethyl)-3,5-difluorobenzene-1-carboximidamide (INT-10; 51.86 mg; 0.28 mmol; 2.00 eq.) in DMF (1.5 mL) was added diisopropylethylamine (0.10 ml; 0.56 mmol; 4.00 eq.) followed by HATU (58.57 mg; 0.15 mmol; 1.10 eq.). After stirring for 30 min, the reaction mixture was diluted with water and MeCN and purified by preparatory HPLC to give the title compound (26 mg). (M+H).sup.+ found for C.sub.26H.sub.18F.sub.2N.sub.4O.sub.2S: 489.1.

Example 35

Synthesis of (1S,8R)—N-[(4-carbamimidoyl-2,6-difluorophenyl)methyl]-12-(1H-pyrazol-1-yl)-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(294) ##STR00659##

(295) Step 1:

(296) To a solution of (1S,8R)-12-bromo-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (INT-4a1; 100.00 mg; 0.32 mmol; 1.00 eq.) in DMF (1 mL) was added 1H-pyrazole (42.93 mg; 0.63 mmol; 2.00 eq.) followed by potassium phosphate (tribasic) (133.87 mg; 0.63 mmol; 2.00 eq.), copper iodide (12.01 mg; 0.06 mmol; 0.20 eq.) and (1S,2S)—N˜1˜,N˜2˜-dimethyl-1,2-cyclohexanediamine (17.94 mg; 0.13 mmol; 0.40 eq.). The reaction mixture was degassed for 2 min, sealed and heated at 110 degree for 15 h. The reaction mixture was diluted with water and EtOAc, the aqueous layer was acidified to pH=3 and then extracted with EtOAc. The organic layers were combined, dried over MgSO.sub.4 and was concentrated to give desired crude product, which was tritrirated to give (1S,8R)-12-(1H-pyrazol-1-yl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (50 mg).

(297) Step 2:

(298) To a solution of (1S,8R)-12-(1H-pyrazol-1-yl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (10.00 mg; 0.03 mmol; 1.00 eq.) and 4-(aminomethyl)-3,5-difluorobenzene-1-carboximidamide dihydrochloride (INT-10; 12.17 mg; 0.07 mmol; 2.00 eq.) in DMF (1.5 mL) was added Hunig's base (0.02 ml; 0.13 mmol; 4.00 eq.) followed by HATU (13.74 mg; 0.04 mmol; 1.10 eq.). After stirred for 30 min, it was diluted with water and MeCN and was purified by preparatory HPLC to give the title compound (11 mg). MS: (M+H).sup.+ found for C.sub.26H.sub.19F.sub.2N.sub.5O.sub.2: 472.2.

Example 36

Synthesis of (1S,8R)—N-[(4-carbamimidoyl-2-methylphenyl)methyl]-12-(1H-pyrazol-1-yl)-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(299) ##STR00660##

(300) To a solution of (1S,8R)-12-(1H-pyrazol-1-yl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (Example 35, Step 1; 9.00 mg; 0.03 mmol; 1.00 eq.) in DMF (0.6 mL) was added 1H-1,2,3-benzotriazol-1-ol hydrate (9.06 mg; 0.06 mmol; 2.00 eq.) and Hunig's base (0.02 ml; 0.12 mmol; 4.00 eq.) followed by 3-{[(ethylimino)methylene]-amino}-N,N,N-trimethyl-1-propanaminium iodide (17.58 mg; 0.06 mmol; 2.00 eq.), then it was added 4-(aminomethyl)-3-methylbenzene-1-carboximidamide (Example 48, Steps 1-5; 9.65 mg; 0.06 mmol; 2.00 eq.) and stirred overnight. The reaction mixture was diluted with water and MeCN and was purified by preparatory HPLC to give the title compound (4.5 mg). MS: (M+H).sup.+ found for C.sub.27H.sub.23N.sub.5O.sub.2: 450.1.

Example 37

Synthesis of (1S,8R)—N-({2,6-difluoro-4-[N′-methoxycarbamimidoyl]-phenyl}methyl)-12-(1H-pyrazol-1-yl)-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(301) ##STR00661##

(302) To a solution of (1S,8R)-12-(1H-pyrazol-1-yl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (Example 35, Step 1; 40.00 mg; 0.13 mmol; 1.00 eq.) and 4-(aminomethyl)-3,5-difluoro-N′-methoxybenzene-1-carboximidamide (INT-11; 56.58 mg; 0.26 mmol; 2.00 eq.) in DMF (1.5 mL) was added diisopropylethylamine (0.09 ml; 0.53 mmol; 4.00 eq.), followed by HATU (54.98 mg; 0.14 mmol; 1.10 eq.). After stirring for 30 min, the reaction mixture was diluted with water and MeCN and was purified by preparatory HPLC to give the title compound (38 mg). MS: (M+H).sup.+ found for C.sub.27H.sub.21F.sub.2N.sub.5O.sub.3: 502.1.

Example 38

Synthesis of (1S,8R)—N-({4-[N′-methoxycarbamimidoyl]phenyl}methyl)-12-(1H-pyrazol-1-yl)-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(303) ##STR00662##

(304) To a solution of (1S,8R)-12-(1H-pyrazol-1-yl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (Example 35, Step 1; 39.00 mg; 0.13 mmol; 1.00 eq.) and 4-(aminomethyl)-N′-methoxybenzimidamide dihydrochloride (INT-7; 45.94 mg; 0.26 mmol; 2.00 eq.) in DMF (1 mL) was added diisopropylethylamine (0.09 ml; 0.51 mmol; 4.00 eq.), followed by HATU (53.60 mg; 0.14 mmol; 1.10 eq.). After stirring for 10 min, the reaction mixture was diluted with water and was purified by preparatory HPLC to give the title compound (31 mg). MS: (M+H).sup.+ found for C.sub.27H.sub.23N.sub.5O.sub.3: 466.1.

Example 39

Synthesis of (1S,8R)—N-({4-[N′-methoxycarbamimidoyl]-2-methylphenyl}methyl)-12-(1H-pyrazol-1-yl)-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(305) ##STR00663##

(306) To a solution of (1S,8R)-12-(1H-pyrazol-1-yl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (Example 35, Step 1; 38.00 mg; 0.12 mmol; 1.00 eq.) in DMF (1 mL) was added 4-(aminomethyl)-N′-methoxy-3-methylbenzene-1-carboximidamide (Example 49, Steps 1-2; 48.26 mg; 0.25 mmol; 2.00 eq.) and diisopropylethylamine (0.09 ml; 0.50 mmol; 4.00 eq.), followed by HATU (52.23 mg; 0.14 mmol; 1.10 eq.). After stirring overnight, the reaction mixture was diluted with water and MeCN and was purified by preparatory HPLC to give the title compound (42 mg). MS: (M+H).sup.+ found for C.sub.28H.sub.25N.sub.5O.sub.3: 480.1.

Example 40

Synthesis of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-11-methyl-10-phenyl-11-azatricyclo[6.2.1.02,7]undeca-2,4,6,9-tetraene-4-carboxamide and (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-11-methyl-9-phenyl-11-azatricyclo[6.2.1.02,7]undeca-2,4,6,9-tetraene-4-carboxamide

(307) ##STR00664##

(308) Step 1:

(309) 3-Bromo-1-(triisopropylsilyl)-1H-pyrrole (0.15 g, 0.50 mmol) was dissolved in toluene (2.6 ml) and methanol (0.9 ml), and purged with Ar gas. Phenylboronic acid (63.5 mg, 0.52 mmol), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (18.15 mg, 0.02 mmol) and then sodium carbonate (0.56 ml, 2.65 M aq. solution, 1.49 mmol) were added. The reaction vessel was sealed and stirred in a heat block at 80° C. for 2.75 h, then to 25° C. over 16 h. More bis(diphenylphosphino)ferrocene]dichloropalladium(II) (9 mg, 0.01 mmol) was added and the reaction was heated at 80° C. for 7 h, then cooled and taken up in DCM and water. The phases were separated, the aqueous phase was extracted once with DCM, and the combined organics were washed with saturated sodium chloride solution. After drying over sodium sulfate, filtration and evaporation, the resulting residue was purified by silica gel chromatography (ethyl acetate/hexanes gradient) to give 3-phenyl-1-[tris(propan-2-yl)silyl]-1H-pyrrole as a colored oil (100 mg).

(310) Step 2:

(311) 3-Phenyl-1-[tris(propan-2-yl)silyl]-1H-pyrrole (100 mg, 0.18 mmol, 55% pure) was dissolved in THF (1 ml). Tetrabutylammonium fluoride (0.55 ml, 1 M THF solution, 0.55 mmol) was then added and the reaction was stirred for 1 h. The solution was evaporated carefully and the residue was dissolved in diethyl ether and water. The phases were separated and the aqueous phase was extracted once with more ether. The combined organics were washed with water and then saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated. The resulting residue was purified by silica gel chromatography (ethyl acetate/hexanes gradient) to give crude 3-phenyl-1H-pyrrole (100 mg).

(312) Step 3:

(313) 3-Phenyl-1H-pyrrole (100 mg, 0.14 mmol, 20% pure) was dissolved in DMSO (1 ml) and cyclohexane (1 ml). 18-Crown-6 (4.4 mg, 0.02 mmol) and potassium tert-butoxide (19.6 mg, 0.17 mmol) were added and then iodomethane (26 ul, 0.42 mmol) was added in portions over 10 m. After 1.5 h, water and diethyl ether were added and the phases were separated. The aqueous phase was extracted once more with ether, the combined organics were washed with saturated sodium chloride solution and dried over sodium sulfate. Filtration and evaporated gave a residue which was purified by silica gel chromatography (ethyl acetate/hexanes gradient) to give 1-methyl-3-phenyl-1H-pyrrole (45 mg).

(314) Step 4: [5-(Methoxycarbonyl)-2-(trimethylsilyl)phenyl](phenyl)iodanium trifluoromethanesulfonate (50 mg, 0.09 mmol) was added to a solution of 1-methyl-3-phenyl-1H-pyrrole (21 mg, 0.13 mmol) in DCM (1 ml) at 0° C. Tetrabutylammonium fluoride (0.12 ml 1 M THF solution, 0.12 mmol) was then added slowly at 0° C. After 30 m, water and more DCM were added, and the phases were separated. The aqueous phase was extracted twice more with DCM. The combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated to a residue. The residue was purified by silica gel chromatography (ethyl acetate/dichloromethane gradient) to give a mixture of (±)-methyl 11-methyl-10-phenyl-11-azatricyclo[6.2.1.0.sup.2,7]undeca-2,4,6,9-tetraene-4-carboxylate and (±)-methyl 11-methyl-9-phenyl-11-azatricyclo[6.2.1.0.sup.2,7]undeca-2,4,6,9-tetraene-4-carboxylate (35 mg).

(315) Step 5:

(316) A mixture of (±)-methyl 11-methyl-10-phenyl-11-azatricyclo[6.2.1.0.sup.2,7]undeca-2,4,6,9-tetraene-4-carboxylate and (±)-methyl 11-methyl-9-phenyl-11-azatricyclo[6.2.1.0.sup.2,7]-undeca-2,4,6,9-tetraene-4-carboxylate (35 mg, 0.12 mmol) was dissolved in THF (3 ml) and methanol (0.8 ml). The solution was cooled in an ice bath and lithium hydroxide (11.5 mg, 0.48 mmol) in water (2 ml) was added. The reaction was stirred at 25° C. for 17 h. More lithium hydroxide (6 mg, 0.24 mmol) in water (1 ml) was added and the reaction was stirred for 3 h more, then warmed to 50° C. After 3.5 h the reaction was cooled, saturated sodium chloride solution and ethyl acetate were added, and the pH was adjusted to 5-6 using aqueous HCl. The phases were separated, the aqueous phase was extracted five times more with warm ethyl acetate and the combined organics were dried over sodium sulfate. Filtration and evaporation gave a crude mixture of (±)-11-methyl-10-phenyl-11-azatricyclo[6.2.1.0.sup.2,7]undeca-2,4,6,9-tetraene-4-carboxylic acid and (±)-11-methyl-9-phenyl-11-azatricyclo[6.2.1.0.sup.2,7]undeca-2,4,6,9-tetraene-4-carboxylic acid (74 mg).

(317) Step 6:

(318) A mixture of (±)-11-methyl-10-phenyl-11-azatricyclo[6.2.1.0.sup.2,7]undeca-2,4,6,9-tetraene-4-carboxylic acid and (±)-11-methyl-9-phenyl-11-azatricyclo-[6.2.1.0.sup.2,7]undeca-2,4,6,9-tetraene-4-carboxylic acid (33 mg, 0.012 mmol) was dissolved in DMF (1.2 ml). Ethyl bis(propan-2-yl)amine (83 ul, 0.48 mmol), 5-(aminomethyl)-4,6-dimethylpyridin-2-amine (27 mg, 0.18 mmol), and then hexafluoro-λ.sup.5-phosphanuide 1-[bis(dimethylamino)methyl-iumyl]-1H-[1,2,3]triazolo[4,5-b]pyridin-3-ium-3-olate (90 mg, 0.24 mmol) were added. After 16 h, aqueous sodium bicarbonate solution and ethyl acetate were added. The phases were separated and the aqueous phase was extracted with ethyl acetate twice more. The combined organic phases were washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration and evaporation, the residue was purified by reverse phase chromatography (acetonitrile gradient with 0.1% aqueous formic acid, Waters XSelect CSH C18 column) to give the title compounds as a white solid (5.8 mg, 11%). MS: (M+H).sup.+ found for C.sub.26H.sub.2N.sub.4O: 411.2.

Example 41

Synthesis of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-12-(4-benzoylpiperazin-1-yl)-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide and (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-11-(4-benzoylpiperazin-1-yl)-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(319) ##STR00665##

(320) Step 1:

(321) Tert-butyl 1-piperazinecarboxylate (1 g, 5.37 mmol) was dissolved in DCM (18 ml). Triethylamine (1.5 ml, 10.74 mmol) was added and the solution was cooled in an ice bath. Benzoyl chloride (0.65 ml, 5.64 mmol) (diluted with DCM (0.3 ml)) was added dropwise and the reaction was stirred to 25° C. After 3 h, water and DCM were added, the phases were separated and the aqueous phase was extracted twice more with DCM. The combined organics were washed with brine, dried over sodium sulfate, filtered and evaporated to a white solid. Purification of this solid by silica gel chromatography (ethyl acetate/heptanes gradient) gave tert-butyl 4-benzoylpiperazine-1-carboxylate as a white solid (1.53 g, 98%).

(322) Step 2:

(323) Tert-butyl 4-benzoylpiperazine-1-carboxylate (1 g; 3.44 mmol) was dissolved in DCM (8 ml) and cooled in an ice bath. Trifluoroacetic acid (5.3 ml, 69 mmol) was added slowly. The reaction was stirred at 25° C. for 2.5 h and then evaporated. The residue was taken up in ethyl acetate and saturated sodium bicarbonate solution, the phases were separated and the aqueous phase was extracted five times with ethyl acetate. The combined organics were dried over sodium sulfate, filtered and evaporated to a glassy residue of 1-benzoylpiperazine (0.83 g).

(324) Step 3:

(325) {1-[2-(diphenylphosphanyl)naphthalen-1-yl]naphthalen-2-yl}-diphenylphosphane (28 mg, 0.05 mmol) and palladium acetate (10.2 mg, 0.05 mmol) were combined in toluene (1.5 ml), purged with Ar gas and stirred at 25° C. for 1 h. A mixture of methyl 12-bromo-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate and methyl 11-bromo-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (INT-3; 100 mg, 0.30 mmol) was dissolved in toluene (1 ml). 1-Benzoylpiperazine (99.6 mg, 0.39 mmol) dissolved in toluene (1 ml) and THF (1.5 ml) was added and the solution was purged with Ar gas. The bromoester and piperazine solution was then combined with the palladium mixture and sodium 2-methyl-2-propanolate (40.6 mg, 0.42 mmol) was added. The reaction mixture was sealed and stirred in a heat block at 80° C. for 1.5 h. After cooling, the mixture was taken up in ethyl acetate and aqueous sodium bicarbonate solution. The phases were separated, the aqueous phase was extracted twice more with ethyl acetate and the combined organics were washed with saturated sodium chloride solution. After drying over sodium sulfate, filtration and evaporation the residue was purified by silica gel chromatography (ethyl acetate/DCM gradient) giving a mixture of (±)-methyl 12-(4-benzoylpiperazin-1-yl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate and (±)-methyl 11-(4-benzoylpiperazin-1-yl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate as a faintly colored film (0.07 g, 52%).

(326) Step 4:

(327) Following Example 40, step 5, but substituting a mixture of (±)-methyl 11-methyl-10-phenyl-11-azatricyclo[6.2.1.0.sup.2,7]undeca-2,4,6,9-tetraene-4-carboxylate and (±)-methyl 11-methyl-9-phenyl-11-azatricyclo[6.2.1.0.sup.2,7]undeca-2,4,6,9-tetraene-4-carboxylate with a mixture of (±)-methyl 12-(4-benzoylpiperazin-1-yl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate and (±)-methyl 11-(4-benzoylpiperazin-1-yl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate gave a mixture of (±)-12-(4-benzoylpiperazin-1-yl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid and (±)-11-(4-benzoylpiperazin-1-yl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid.

(328) Step 5:

(329) The title compounds were prepared as in Example 40, step 6, but substituting a mixture of (±)-11-methyl-10-phenyl-11-azatricyclo[6.2.1.0.sup.2,7]undeca-2,4,6,9-tetraene-4-carboxylic acid and (±)-11-methyl-9-phenyl-11-azatricyclo[6.2.1.0.sup.2,7]undeca-2,4,6,9-tetraene-4-carboxylic acid with a mixture of (±)-12-(4-benzoylpiperazin-1-yl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid and (±)-11-(4-benzoyl-piperazin-1-yl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid. MS: (M+H).sup.+ found for C.sub.34H.sub.33N.sub.5O.sub.3: 560.3.

Example 42

Synthesis of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-12-(2-cyano-4-fluorophenyl)-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(330) ##STR00666##

(331) Step 1:

(332) ((2-Cyano-4-fluorophenyl)boronic acid (46 mg, 0.28 mmol), (±)-methyl 12-bromo-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (INT-3a; 80 mg, 0.24 mmol) and potassium carbonate (67 mg, 0.48 mmol) were dissolved in THF (1.2 ml) and water (0.6 ml). The solution was purged with Ar gas and then [1,1′-bis(di-t-butylphosphino)-ferrocene]palladium (II) dichloride (8 mg, 0.01 mmol) was added. The reaction vessel was sealed and stirred in a heat block at 60° C. After 8 h, the mixture was cooled and partitioned into ethyl acetate and sodium bicarbonate solution. The phases were separated, the aqueous phase was extracted twice more with ethyl acetate and the combined organics were washed with saturated sodium chloride solution. After drying over sodium sulfate, filtration and evaporation, the residue was purified by silica gel chromatography (ethyl acetate/hexanes gradient) to give (±)-methyl 12-(2-cyano-4-fluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (80 mg, 89%).

(333) Step 2:

(334) Following Example 40, step 5, but substituting a mixture of methyl 11-methyl-10-phenyl-11-azatricyclo[6.2.1.0.sup.2,7]undeca-2,4,6,9-tetraene-4-carboxylate and methyl 11-methyl-9-phenyl-11-azatricyclo[6.2.1.0.sup.2,7]undeca-2,4,6,9-tetraene-4-carboxylate with (±)-methyl 12-(2-cyano-4-fluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate gave (±)-12-(2-cyano-4-fluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid.

(335) Step 3:

(336) The title compound was prepared as in Example 40, step 6, but substituting a mixture of (±)-11-methyl-10-phenyl-11-azatricyclo[6.2.1.0.sup.2,7]undeca-2,4,6,9-tetraene-4-carboxylic acid and (±)-11-methyl-9-phenyl-11-azatricyclo[6.2.1.0.sup.2,7]undeca-2,4,6,9-tetraene-4-carboxylic acid with (±)-12-(2-cyano-4-fluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid. MS: (M+H).sup.+ found for C.sub.30H.sub.23FN.sub.4O.sub.2: 491.1.

Example 43

Synthesis of (1R,8S)—N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-12-(4-chloro-2,3-difluoro-phenyl)-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(337) ##STR00667##

(338) Step 1:

(339) ((4-Chloro-2,3-difluorophenyl)boronic acid (47 mg, 0.24 mmol) and methyl (1S,8R)-12-bromo-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (INT-3a1; 73.7 mg, 0.22 mmol) were dissolved in 1,4-dioxane (1.5 ml) and sodium carbonate (0.26 ml, 2.60 M aqueous solution, 0.67 mmol). The solution was purged with Ar gas and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (16.3 mg, 0.02 mmol) was added. The reaction was stirred in a heat block at 90° C. for 4 h then cooled, diluted with ethyl acetate, filtered through Celite and rinsed through with more ethyl acetate. After evaporation, the residue was purified by silica gel chromatography (ethyl acetate/hexanes gradient) to give methyl (1R,8S)-12-(4-chloro-2,3-difluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (0.08 g, 89%).

(340) Step 2:

(341) Following Example 40, step 5, but substituting a mixture of (±)-methyl 11-methyl-10-phenyl-11-azatricyclo[6.2.1.0.sup.2,7]undeca-2,4,6,9-tetraene-4-carboxylate and (±)-methyl 11-methyl-9-phenyl-11-azatricyclo[6.2.1.0.sup.2,7]undeca-2,4,6,9-tetraene-4-carboxylate with methyl (1R,8S)-12-(4-chloro-2,3-difluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate gave (1R,8S)-12-(4-chloro-2,3-difluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid.

(342) Step 3:

(343) The title compound was prepared as in Example 40, step 6, but substituting a mixture of (±)-11-methyl-10-phenyl-11-azatricyclo[6.2.1.0.sup.2,7]undeca-2,4,6,9-tetraene-4-carboxylic acid and (±)-11-methyl-9-phenyl-11-azatricyclo[6.2.1.0.sup.2,7]undeca-2,4,6,9-tetraene-4-carboxylic acid with (1R,8S)-12-(4-chloro-2,3-difluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid. MS: (M+H).sup.+ found for C.sub.29H.sub.22ClF.sub.2N.sub.3O.sub.2: 518.1.

Example 44

Synthesis of (1R,8S)—N-[(4-carbamimidoylphenyl)methyl]-12-(2-fluorophenyl)-15-oxatetracyclo-[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(344) ##STR00668##

(345) Step 1:

(346) (2-Fluorophenylboronic acid (27 mg, 0.19 mmol) and sodium (1S,8R)-12-bromo-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (INT-5a1; 60 mg, 0.18 mmol) were dissolved in 1,4-dioxane (1.4 ml) and sodium carbonate solution (0.2 ml, 2.6 M aq. solution, 0.53 mmol). The solution was purged with Ar gas and then 1,1′-bis(diphenyl-phosphino)ferrocene]dichloropalladium(II) (13 mg, 0.02 mmol) was added. The reaction was heated in a microwave reactor at 90° C. for 45 m. The cooled reaction was taken up in ethyl acetate and ammonium chloride solution, and the pH was adjusted to <3 with aqueous HCl. The phases were separated, the aqueous phase was extracted twice more with ethyl acetate, and the combined organics were washed with saturated sodium chloride solution. After drying over sodium sulfate, filtration and evaporation, the residue was purified by silica gel chromatography (methanol/DCM gradient) to give (1R,8S)-12-(2-fluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid as a tan solid (59 mg, 100%).

(347) Step 2:

(348) The title compound was prepared as in Example 40, step 6, but substituting a mixture of (±)-11-methyl-10-phenyl-11-azatricyclo[6.2.1.0.sup.2,7]undeca-2,4,6,9-tetraene-4-carboxylic acid and (±)-11-methyl-9-phenyl-11-azatricyclo[6.2.1.0.sup.2,7]undeca-2,4,6,9-tetraene-4-carboxylic acid with (1R,8S)-12-(2-fluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid. MS: (M+H).sup.+ found for C.sub.29H.sub.23FN.sub.3O.sub.2: 464.2.

Example 45

Synthesis of (1R,8S)—N-[(4-carbamimidoyl-2,6-dimethylphenyl)methyl]-12-(2,4-difluoro-phenyl)-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(349) ##STR00669##

(350) Step 1:

(351) 4-Bromo-3,5-dimethylbenzonitrile (0.5 g, 2.38 mmol) was dissolved in THF (12 ml). The solution was cooled in a dry ice/diethyl ether bath. N-butyllithium (1.05 ml 2.50 M solution in hexanes, 2.62 mmol) was added slowly over 30 m. Dry N,N-dimethylformamide (0.26 ml, 3.3 mmol) was then added slowly and the reaction allowed to warm slowly. After 1 h the reaction appeared complete (LC/MS, TLC) and by 2 h with the temperature at −30° C., the reaction was neutralized by addition of an aqueous saturated sodium chloride solution. The mixture was taken up in ethyl acetate and water, the phases were separated, the aqueous phase was extracted once more with ethyl acetate, and the combined organics were washed with more saturated sodium chloride solution. After drying over sodium sulfate, filtration and evaporation, the residue was purified by silica gel chromatography (ethyl acetate/hexanes gradient) to give 4-formyl-3,5-dimethylbenzonitrile as a white solid (0.18 g, 47%).

(352) Step 2:

(353) 4-Formyl-3,5-dimethylbenzonitrile (0.18 g, 1.13 mmol) was dissolved in THF (12 ml) and the solution was stirred in an ice bath. Sodium borohydride (43 mg, 1.13 mmol) and then dry methanol (1.1 ml) were added. The reaction was stirred to 25° C. and after 2 h the reaction was diluted with ethyl acetate. The solution was washed with water three times, washed with saturated sodium chloride solution and dried over sodium sulfate. Filtration and evaporation gave 4-(hydroxymethyl)-3,5-dimethylbenzonitrile as a white solid (0.16 g, 89%).

(354) Step 3:

(355) 4-(Hydroxymethyl)-3,5-dimethylbenzonitrile (0.16 g 1 mmol) was dissolved in dichloromethane (10 ml) and the solution was cooled in an ice bath. Triethylamine (0.21 ml, 1.50 mmol) was added, followed by slow addition of methanesulfonyl chloride (0.09 ml, 1.20 mmol). The reaction was stirred to 25° C., and after 2.5 h the reaction solution was washed with water and saturated sodium chloride solution. The organics were dried over sodium sulfate, filtered and evaporated to give (4-cyano-2,6-dimethylphenyl)methyl methanesulfonate as a white solid (0.2 g).

(356) Step 4:

(357) (4-Cyano-2,6-dimethylphenyl)methyl methanesulfonate (0.2 g 0.84 mmol) was dissolved in DMF (4 ml). Sodium azide (109 mg, 1.67 mmol) was added and the reaction was stirred in heat block at 30° C. After 2.5 h, the reaction was taken up in water and diethyl ether. The phases were separated and the aqueous phase was extracted twice more with ether. The combined organics were washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated to give a crude solid of 4-(azidomethyl)-3,5-dimethyl-benzonitrile (0.37 g).

(358) Step 5:

(359) In a screw-cap tube, absolute ethanol (6 ml) was cooled in an ice bath. Acetyl chloride (6.1 ml, 86 mmol) was added slowly in portions. 4-(Azidomethyl)-3,5-dimethylbenzonitrile (0.16 g, 0.86 mmol) suspended in ethanol (4 ml) was added at 0° C. The tube was sealed and stirred at 4° C. for 72 h. The reaction solution was then evaporated, co-evaporated from ethanol and then taken up in ammonia/methanol solution (14 ml of 7M methanol solution). After 22 h, the solution was evaporated and the residue taken up in ethyl acetate and water. The phases were separated and the aqueous phase was extracted once more with ethyl acetate. The combined organics were washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated to give a crude solid of 4-(azidomethyl)-3,5-dimethylbenzene-1-carboximidamide (0.34 g).

(360) Step 6:

(361) 10% Palladium (44.51 mg, 0.04 mmol) on carbon was combined with 4-(azidomethyl)-3,5-dimethylbenzene-1-carboximidamide (0.17 g, 0.84 mmol) in absolute ethanol (8 ml) and flushed w/H.sub.2 gas. After 4 h, the mixture was purged w/N.sub.2 gas, filtered through Celite, rinsed through with more ethanol and evaporated to a crude residue of 4-(aminomethyl)-3,5-dimethylbenzene-1-carboximidamide (0.28 g).

(362) Step 7:

(363) Following the procedure of Example 44, Step 1, but substituting 2-fluorophenyl-boronic acid with 2,4-difluorophenylboronic acid gave (1R,8S)-12-(2,4-difluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid as a brownish residue.

(364) Step 8:

(365) (1R,8S)-12-(2,4-difluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (63 mg, 0.18 mmol) was dissolved in DMF (1 ml). Ethyl bis(propan-2-yl)amine (63 ul, 0.36 mmol), hydroxybenzotriazole (37 mg, 0.27 mmol) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide (56 mg, 0.36 mol) were added and the solution was stirred for 5 m. Crude 4-(aminomethyl)-3,5-dimethylbenzene-1-carboximidamide (66 mg, 0.20 mmol) in DMF (0.5 ml) was then added and the mixture stirred for 14 h. The reaction mixture was taken up in water and ethyl acetate, the phases were separated and the aqueous phase was extracted twice more with ethyl acetate. The combined organics were washed with water and saturated sodium chloride solution, and dried over sodium sulfate. After filtration and evaporation the residue was purified by reverse phase chromatography (acetonitrile gradient with 0.1% aqueous formic acid, Waters XSelect CSH C18 column) to give the title compound as a white solid (28 mg, 30%). MS: (M+H).sup.+ found for C.sub.31H.sub.25F.sub.2N.sub.3O.sub.2: 510.2.

Example 46

Synthesis of (1R,8S)-12-(2,4-difluorophenyl)-N-{[4-(N′-hydroxy-carbamimidoyl)phenyl]methyl)}-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(366) ##STR00670##

(367) The title compound was prepared as in Example 45, step 8, but substituting 4-(amino-methyl)-3,5-dimethylbenzene-1-carboximidamide with 4-(aminomethyl)-N′-hydroxybenzene-1-carboximidamide (INT-8). MS: (M+H).sup.+ found for C.sub.29H.sub.21F.sub.2N.sub.3O.sub.3: 498.2.

Example 47

Synthesis of (1R,8S)-12-(2-fluorophenyl)-N-{[4-(N′-hydroxycarbamimidoyl)phenyl]methyl}-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(368) ##STR00671##

(369) The title compound was prepared as in Example 45, Step 8, but substituting 4-(aminomethyl)-3,5-dimethylbenzene-1-carboximidamide with 4-(aminomethyl)-N′-hydroxybenzene-1-carboximidamide (INT-8), and substituting (1R,8S)-12-(2,4-difluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid with (1R,8S)-12-(2-fluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (Example 44, Step 1). MS: (M+H).sup.+ found for C.sub.29H.sub.22FN.sub.3O.sub.3: 480.2.

Example 48

Synthesis of (1R,8S)—N-[(4-carbamimidoyl-2-methylphenyl)methyl]-12-(2,4-difluoro-phenyl)-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(370) ##STR00672##

(371) Step 1:

(372) 4-(Hydroxymethyl)-3-methylbenzonitrile (1 g, 6.79 mmol) was dissolved in dichloromethane (34 ml), and the resulting turbid solution was then cooled in an ice bath. Triethylamine (1.4 ml, 10.2 mmol) and then methanesulfonyl chloride (0.63 ml, 8.15 mmol) were added slowly. After 3 h, the reaction mixture was diluted with more DCM, washed with water and then a saturated sodium chloride solution. The organic phases was dried over sodium sulfate, filtered and evaporated to a residue of (4-cyano-2-methylphenyl)methyl methanesulfonate (1.6 g).

(373) Step 2:

(374) 4-Cyano-2-methylphenyl)methyl methanesulfonate (1.53 g, 6.79 mmol) was dissolved in DMF (20 ml). Sodium azide (883 mg, 13.58 mmol) was added and the mixture was stirred in a heat block at 30° C. After 2 h, water and diethyl ether were added. The phases were separated, the aqueous phase was extracted twice more with ether, the combined organics were washed with water and a saturated sodium chloride solution, and then dried over sodium sulfate. Filtration and evaporation gave 4-(azidomethyl)-3-methylbenzonitrile as a yellowish liquid (1.18 g).

(375) Step 3:

(376) 4-(Azidomethyl)-3-methylbenzonitrile (0.18 g, 1.05 mmol) was dissolved in dry methanol (3.5 ml). Triethylamine (0.44 ml 3.14 mmol) and then hydroxylamine hydrochloride (0.22 g, 3.14 mmol) were added, and the mixture was stirred in a heat block at 50° C. After 2.5 h, the reaction mixture was evaporated and taken up in ethyl acetate, saturated sodium bicarbonate and sodium chloride solutions. The phases were separated, the aqueous phase was extracted twice more with ethyl acetate. The combined organics were dried over sodium sulfate, filtered and evaporated to give 4-(azidomethyl)-N′-hydroxy-3-methylbenzene-1-carboximidamide as a colorless glass (0.22 g).

(377) Step 4:

(378) 4-(Azidomethyl)-N′-hydroxy-3-methylbenzene-1-carboximidamide (0.10 g, 0.49 mmol) was dissolved in acetic acid (5 ml) with palladium on carbon (10%) (31 mg, 0.03 mmol). Acetic anhydride (92 ul, 0.97 mmol) was added and the vessel was charged with H.sub.2 gas. After 14 h, the reaction mixture was filtered through Celite and evaporated. The resulting residue was co-evaporated from toluene to give N-[(4-carbamimidoyl-2-methylphenyl)methyl]acetamide as a white solid (0.139 g).

(379) Step 5:

(380) N-[(4-carbamimidoyl-2-methylphenyl)methyl]acetamide (78 mg, 0.27 mmol) was dissolved in isopropanol (3 ml) and 3M HCl (3 ml). The reaction was stirred in a heat block at 90° C. for 5 h, reduced to 65° C. for 16 h and then at 90° C. for 1 h more. The solution was then partly evaporated and freeze-dried to give [4-(azaniumylmethyl)-3-methylphenyl](imino)-methanaminium dichloride as a yellowish solid (65 mg).

(381) Step 6:

(382) The title compound was prepared as in Example 45, Step 8, but substituting 4-(aminomethyl)-3,5-dimethylbenzene-1-carboximidamide with [4-(azaniumylmethyl)-3-methylphenyl](imino)methanaminium dichloride. MS: (M+H).sup.+ found for C.sub.30H.sub.23F.sub.2N.sub.3O.sub.2: 496.4.

Example 49

Synthesis of (1R,8S)-12-(2,4-difluorophenyl)-N-{[4-(N′-methoxycarbamimidoyl)-2-methylphenyl]methyl}-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(383) ##STR00673##

(384) Step 1:

(385) Absolute ethanol (22 ml) was cooled in an ice bath. Acetyl chloride (22 ml, 308 mmol) was added slowly in portions. 4-(Azidomethyl)-3-methylbenzonitrile (Example 48, Step 2; 0.53 g, 3.08 mmol) was added and the reaction sealed and stirred at 4° C. for 72 h. The reaction solution was then evaporated to dryness and co-evaporated from ethanol to a white solid. The solid was dissolved in dry methanol (6 ml), and triethylamine (1.7 ml, 12.3 mmol) and then O-methyl hydroxylamine hydrochloride (0.26 g, 3.08 mmol) were added. After 23 h, the reaction solution was evaporated and taken up in ethyl acetate and water. The phases were separated and the aqueous phase was extracted once with ethyl acetate. The combined organics were washed with a saturated sodium chloride solution and dried over sodium sulfate. Filtration and evaporation gave 4-(azidomethyl)-N′-methoxy-3-methylbenzene-1-carboximidamide as an oil (0.43 g).

(386) Step 2:

(387) Platinum (IV) oxide (71 mg, 0.31 mmol) was combined with 4-(azidomethyl)-N′-methoxy-3-methylbenzene-1-carboximidamide (0.43 g, 1.96 mmol) in ethanol (10 ml). The reaction vessel was charged with H.sub.2 gas and stirred for 2 h. The mixture was then filtered through Celite, rinsed with ethanol and evaporated. Co-evaporation from toluene gave 4-(aminomethyl)-N′-methoxy-3-methylbenzene-1-carboximidamide as a colorless oil (0.39 g).

(388) Step 3:

(389) The title compound was prepared as in Example 45, Step 8, but substituting 4-(aminomethyl)-3,5-dimethylbenzene-1-carboximidamide with 4-(aminomethyl)-N′-methoxy-3-methylbenzene-1-carboximidamide. MS: (M+H).sup.+ found for C.sub.31H.sub.25F.sub.2N.sub.3O.sub.3: 526.2.

Example 50

Synthesis of (1R,8S)-12-(2,4-difluorophenyl)-N-{[4-(N′-hydroxycarbamimidoyl)-2-methylphenyl]methyl}-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(390) ##STR00674##

(391) Step 1:

(392) Platinum (IV) oxide (17.7 mg, 0.08 mmol) was combined with 4-(azidomethyl)-N′-hydroxy-3-methylbenzene-1-carboximidamide (Example 48, Step 3; 100 mg, 0.49 mmol) in ethanol (3 ml). The vessel was charged with H.sub.2 gas and stirred for 1.5 h. The reaction mixture was then filtered through Celite, rinsed with ethanol, evaporated and co-evaporated from toluene to give 4-(aminomethyl)-N′-hydroxy-3-methylbenzene-1-carboximidamide as a hygroscopic solid. (90 mg). MS (ESI, pos. ion) m/z: 180.0 (M+1).

(393) Step 2:

(394) The title compound was prepared as in Example 44, Step 8, but substituting 4-(aminomethyl)-3,5-dimethylbenzene-1-carboximidamide with 4-(aminomethyl)-N′-hydroxy-3-methylbenzene-1-carboximidamide. MS: (M+H).sup.+ found for C.sub.30H.sub.23F.sub.2N.sub.3O.sub.3: 512.3.

Example 51

Synthesis of (1R,8S)-12-cyclopropyl-N-{[4-(N′-hydroxycarbamimidoyl)phenyl]methyl}-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(395) ##STR00675##

(396) The title compound was prepared as in Example 44, Step 8, but substituting 4-(amino-methyl)-3,5-dimethylbenzene-1-carboximidamide with 4-(aminomethyl)-N′-hydroxybenzene-1-carboximidamide (INT-8), and substituting (1R,8S)-12-(2,4-difluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid with (1R,8S)-12-cyclopropyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (Example 14, Step 1). MS: (M+H).sup.+ found for C.sub.26H.sub.23N.sub.3O.sub.3: 426.2.

Example 52

Synthesis of (1R,8S)-12-cyclopropyl-N-{[5-(N′-methoxycarbamimidoyl)pyridin-2-yl]-methyl}-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(397) ##STR00676##

(398) Step 1:

(399) 5-Cyano-2-methylpyridine (1.025 g, 8.68 mmol) was dissolved in carbon tetrachloride (50 ml). N-bromosuccinimide (1.7 g, 9.54 mmol) and benzoyl peroxide (75%, 140 mg, 0.43 mmol) were added, and the mixture was heated to reflux in a heat block at 86° C. After 17 h, the reaction was filtered, rinsed with DCM and evaporated. The residue was purified by silica gel chromatography (ethyl acetate/hexanes gradient) to give 6-(bromomethyl)pyridine-3-carbonitrile as a brownish oil (0.69 g, 40%).

(400) Step 2:

(401) Absolute ethanol (30 ml) was cooled in an ice bath. Acetyl chloride (25 ml, 350 mmol) was added slowly in portions. At 0° C., 6-(bromomethyl)pyridine-3-carbonitrile (0.69 g, 3.5 mmol) in ethanol was added. The vessel was sealed and stirred at 4° C. for 65 h. The reaction mixture was evaporated to a slight yellowish solid, a mixture of products which was used directly in the next step.

(402) Step 3:

(403) The crude mixture from Step 2 was dissolved in dry methanol (7 ml) and triethylamine (1 ml), and was cooled in an ice bath. O-methyl hydroxylamine hydrochloride (0.29 g, 3.5 mmol) was added and the reaction was stirred to 25° C. After 15 h, the reaction mixture was evaporated. The residue was taken up in ethyl acetate and water, the phases were separated and the aqueous phase was extracted once with ethyl acetate. The combined organics were washed with a saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated to a solid. The solid was purified by silica gel chromatography (ethyl acetate/hexanes gradient) to give 6-(chloromethyl)-N′-methoxypyridine-3-carboximidamide as an oily residue (0.07 g, 10%).

(404) Step 4:

(405) 6-(Chloromethyl)-N′-methoxypyridine-3-carboximidamide (65 mg; 0.33 mmol) was dissolved in DMF (1 ml). Sodium azide (42 mg, 0.65 mmol) was added and the reaction mixture was stirred at 27° C. After 18 h, the mixture was taken up in ethyl acetate and water. The phases were separated, the aqueous phase was extracted twice more with ethyl acetate, and the combined organics were washed with water and a saturated sodium chloride solution. The solution was dried over sodium sulfate, filtered, and evaporated to give 6-(azidomethyl)-N′-methoxypyridine-3-carboximidamide as a yellowish oil (0.16 g).

(406) Step 5:

(407) Platinum (IV) oxide (12 mg, 0.05 mmol) was combined with 6-(azidomethyl)-N′-methoxypyridine-3-carboximidamide (67 mg, 0.32 mmol) in ethanol (3 ml). The vessel was charged with H.sub.2 gas and stirred for 1 h. The mixture was filtered through Celite, rinsed with ethanol and evaporated. Co-evaporation from toluene gave 6-(aminomethyl)-N′-methoxy-pyridine-3-carboximidamide as a brownish oil (60 mg).

(408) Step 6:

(409) The title compound was prepared as in Example 51, but substituting 4-(aminomethyl)-N′-hydroxybenzene-1-carboximidamide with 6-(aminomethyl)-N′-methoxy-pyridine-3-carboximidamide. MS: (M+H).sup.+ found for C.sub.26H.sub.24N.sub.4O.sub.3: 441.2.

Example 53

Synthesis of (1R,8S)—N-[(5-carbamimidoylpyridin-2-yl)methyl]-12-cyclopropyl-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(410) ##STR00677##

(411) Step 1:

(412) 6-(Bromomethyl)pyridine-3-carbonitrile (680 mg, 3.45 mmol) was dissolved in THF (70 ml). The solution was stirred in an ice bath and sodium hydride (60%, 0.17 g, 4.14 mmol) was added. Di(tert-butyl) imidodicarbonate (0.82 g, 3.8 mmol) was then added in portions and the reaction was stirred to 25° C. After 5 h, the reaction was taken up in ethyl acetate and aqueous sodium bicarbonate solution. The phases were separated and the aqueous phase was extracted once with ethyl acetate. The combined organics were washed with a saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography (ethyl acetate/hexanes gradient) to give tert-butyl N-[(tert-butoxy)carbonyl]-N-[(5-cyanopyridin-2-yl)methyl]carbamate (1.2 g).

(413) Step 2:

(414) Tert-butyl N-[(tert-butoxy)carbonyl]-N-[(5-cyanopyridin-2-yl)methyl]carbamate (0.19 g, 0.57 mmol) was dissolved in dry methanol (2 ml). Triethylamine (0.24 ml, 1.7 mmol) and then hydroxylamine hydrochloride (0.12 g, 1.7 mmol) were added. The reaction was stirred in a heat block at 40° C. for 5 h. Solvent was evaporated and the residue was taken up in ethyl acetate and a saturated sodium bicarbonate and sodium chloride solution. The phases were separated, the aqueous phase was extracted twice more with ethyl acetate, the combined organics were washed with a saturated sodium chloride solution and dried over sodium sulfate. After filtration and evaporation, a white solid of tert-butyl N-[(tert-butoxy)carbonyl]-N-{[5-(N′-hydroxycarbamimidoyl)pyridin-2-yl]methyl}carbamate was obtained (0.22 g).

(415) Step 3:

(416) Tert-butyl N-[(tert-butoxy)carbonyl]-N-{[5-(N′-hydroxycarbamimidoyl)pyridin-2-yl]methyl}carbamate (0.21 g, 0.57 mmol) was dissolved in acetic acid (5 ml) with palladium on carbon (10%) (37 mg, 0.03 mmol). Acetic anhydride (108 ul, 1.15 mmol) was added and the vessel was charged with H.sub.2 gas. After 4 h, the mixture was purged with N.sub.2 gas, filtered through Celite, rinsed with ethyl acetate and evaporated to give tert-butyl N-[(tert-butoxy)carbonyl]-N-[(5-carbamimidoylpyridin-2-yl)methyl]carbamate (0.45 g), which was used directly in the next step.

(417) Step 4:

(418) Tert-butyl N-[(tert-butoxy)carbonyl]-N-[(5-carbamimidoylpyridin-2-yl)methyl]-carbamate (0.20 g, 0.57 mmol) was mixed with hydrochloric acid (1.4 ml, 4 M 1,4-dioxane solution, 5.7 mmol). The mixture was diluted with DCM (1.5 ml) and more 4M HCl/dioxane (1.5 ml). After stirring for 1.5 h, the reaction was evaporated, and co-evaporated from toluene, leaving an off-white solid of [6-(azaniumylmethyl)pyridin-3-yl](imino)methanaminium dichloride (0.15 g). MS (ESI, pos. ion) m/z: 150.9 (M+1).

(419) Step 5:

(420) The title compound was prepared as in Example 51, but substituting 4-(aminomethyl)-N′-hydroxybenzene-1-carboximidamide with [6-(azaniumylmethyl)pyridin-3-yl](imino)methanaminium dichloride. MS: (M+H).sup.+ found for C.sub.25H.sub.22N.sub.4O.sub.2: 411.2.

Example 54

Synthesis of (1R,8S)-12-(2,4-difluorophenyl)-N-{[4-(N′-methoxycarbamimidoyl)-2,6-dimethylphenyl]methyl}-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(421) ##STR00678##

(422) Step 1:

(423) Into a 1-L round-bottom flask, was placed a mixture of 4-bromo-3,5-dimethylbenzonitrile (10.00 g, 47.62 mmol, 1.00 equiv), dioxane (400 mL), water (40 mL), Cs.sub.2CO.sub.3 (62.06 g, 190.48 mmol, 4.00 equiv), potassium tert-butyl N-[(difluoroboranyl)methyl]carbamate fluoride (22.57 g, 95.24 mmol, 2.00 equiv) and (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (3.sup.rd generation XPhos precatalyst; 2.01 g, 2.381 mmol, 0.05 equiv). The resulting solution was stirred for 16 h at 110° C. under nitrogen then it was cooled to RT and concentrated. The residue was diluted with 500 mL of EtOAc, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with acetate/petroleum ether (1/4) to afford 10.70 g (86%) of tert-butyl N-[(4-cyano-2,6-dimethylphenyl)methyl]carbamate as an off-white solid.

(424) Step 2:

(425) Into a 500-mL round-bottom flask, was placed a mixture of tert-butyl N-[(4-cyano-2,6-dimethylphenyl)methyl]carbamate (3.50 g, 13.46 mmol, 1.00 equiv), ethanol (200 mL), TEA (6.80 g, 67.30 mmol, 5.00 equiv), O-methylhydroxylamine hydrochloride (5.59 g, 67.30 mmol, 5.00 equiv) and 2-sulfanylacetic acid (3.10 g, 33.65 mmol, 2.50 equiv). The resulting mixture was stirred for 2 days at 90° C. then it was cooled and concentrated under vacuum. The residue was diluted with 100 mL of EtOAc, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1/4) to afford 1.81 g (44%) of tert-butyl N-([4-N-methoxycarbamimidoyl]-2,6-dimethylphenyl]methyl)-carbamate as a light yellow solid.

(426) Step 3:

(427) Into a 50-mL round-bottom flask, was placed a solution of tert-butyl N-([4-[N-methoxycarbamimidoyl]-2,6-dimethylphenyl]methyl)carbamate (1.50 g, 4.88 mmol, 1.00 equiv) in dichloromethane (20 mL) followed by dioxane (5 mL) which was freshly saturated with hydrochloride (gas). The resulting mixture was stirred for 16 h at room temperature then the solids were collected by filtration to afford 1.08 g (79%) of 4-(aminomethyl)-N-methoxy-3,5-dimethylbenzene-1-carboximidamide hydrochloride as an off-white solid.

(428) Step 4:

(429) The title compound was prepared as in Example 45, Step 8, but substituting 4-(aminomethyl)-3,5-dimethylbenzene-1-carboximidamide with 4-(aminomethyl)-N-methoxy-3,5-dimethylbenzene-1-carboximidamide hydrochloride.

Example 55

Synthesis of (1R,8S)-12-cyclopropyl-N-{[4-(N′-methoxycarbamimidoyl)-2,6-dimethylphenyl]-methyl}-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(430) ##STR00679##

(431) The title compound was prepared as in Example 51, but substituting 4-(amino-methyl)-N′-hydroxybenzene-1-carboximidamide with 4-(aminomethyl)-N-methoxy-3,5-dimethylbenzene-1-carboximidamide hydrochloride (Example 54, Steps 1-3). MS: (M+H).sup.+ found for C.sub.29H.sub.29N.sub.3O.sub.3: 468.5.

Example 56

Synthesis of (1R,8S)—N-[(4-carbamimidoyl-2,6-dimethylphenyl)methyl]-12-cyclopropyl-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(432) ##STR00680##

(433) The title compound was prepared as in Example 351, but substituting 4-(amino-methyl)-N′-hydroxybenzene-1-carboximidamide with [4-(azaniumylmethyl)-3,5-dimethyl-phenyl](imino)methanaminium dichloride (Example 45, Step 1-6). MS: (M+H).sup.+ found for C.sub.28H.sub.27N.sub.3O.sub.2: 438.2.

Example 57

Synthesis of (1R,8S)—N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-12-(4-chloro-2-cyanophenyl)-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(434) ##STR00681##

(435) Step 1:

(436) A stirred suspension of methyl (1S,8R)-12-bromo-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (85.00 mg; 0.26 mmol), (4-chloro-2-cyanophenyl)boronic acid (55.87 mg; 0.31 mmol), cesium carbonate (209.07 mg; 0.64 mmol) and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (18.78 mg; 0.03 mmol) in 1,4-dioxane (10.27 ml) and methanol (2.85 ml) was heated to 80° C. for 1 h. The reacting mixture was cooled to ambient temperature, filtered over celite and concentrated. The brown residue was purified by flash chromatography (Hexanes/EtOAc=3:1) to provide methyl (1R,8S)-12-(4-chloro-2-cyanophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate as a colorless foam (80 mg).

(437) Step 2:

(438) To a stirred solution of methyl (1R,8S)-12-(4-chloro-2-cyanophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (80.00 mg; 0.21 mmol) in tetrahydrofuran (2.40 ml) and methanol (1.20 ml) was added lithium hydroxide (0.52 ml; 2.00 mol/l). The mixture was stirred at ambient temperature for 4 h. The solvent was removed under vacuum and the residue was taken in small amounts of water. The solution was acidified with 3N HCl and extracted 3 times with EtOAc. The combined organics were dried over MgSO.sub.4, filtered and concentrated. The crude (1R,8S)-12-(4-chloro-2-cyanophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid was used in the next step without further purification.

(439) Step 3:

(440) To a stirred solution of (1R,8S)-12-(4-chloro-2-cyanophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (53.00 mg; 0.14 mmol) and 5-(aminomethyl)-4,6-dimethylpyridin-2-amine (34.96 mg; 0.16 mmol) in N,N-dimethylformamide (1.42 ml) at ambient temperature was added diisopropylethylamine (0.25 ml; 1.42 mmol) followed by HATU (53.91 mg; 0.14 mmol). The reaction mix was concentrated to dryness, then dissolved in water/acetonitrile and purified by prep HPLC. The fractions containing the product were partially concentrated, freeze and lyophilized to give the title compound (51 mg). MS: (M+H).sup.+ found for C.sub.30H.sub.23ClN.sub.4O.sub.2: 507.

Example 58

Synthesis of (1R,8S)—N-[(1-aminoisoquinolin-5-yl)methyl]-12-(2-fluorophenyl)-5-oxatetra-cyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(441) ##STR00682##

(442) Step 1:

(443) Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 5-bromoisoquinoline (15.3 g, 73.54 mmol, 1.00 equiv) in dichloromethane (300 mL), then 3-chlorobenzene-1-carboperoxoic acid (m-CPBA; 17.4 g, 80%/W, 80.89 mmol, 1.10 equiv) was added in portions. The resulting solution was stirred overnight at 45° C. The reaction was then cooled to RT, quenched by the addition of 200 mL of saturated aqueous Na.sub.2S.sub.2O.sub.3 solution and the separated water layer was extracted with dichloromethane. The combined organic layer was washed with 2N aqueous sodium hydroxide aqueous solution, 200 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to deliver 16.5 g (100%) of 5-bromoisoquinolin-2-ium-2-olate as a yellow solid.

(444) Step 2:

(445) Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 5-bromoisoquinolin-2-ium-2-olate (16.5 g, 73.64 mmol, 1.00 equiv) and POCl.sub.3 (27.1 g, 176.74 mmol, 2.40 equiv) in dichloromethane (300 mL). The resulting mixture was stirred overnight at 45° C. then it was cooled to RT and concentrated. The residue was treated cautiously with 500 mL of icy water and extracted with 3×500 mL of dichloromethane. The combined organic layer was washed with 500 mL of saturated sodium bicarbonate aqueous solution, 500 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to deliver 17.5 g (98%) of 5-bromo-1-chloroisoquinoline as a yellow solid.

(446) Step 3:

(447) Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a mixture of 5-bromo-1-chloroisoquinoline (17.5 g, 72.16 mmol, 1.00 equiv), AcNH.sub.2 (85.8 g, 1.45 mol, 20.15 equiv) and potassium carbonate (49.0 g, 354.53 mmol, 4.91 equiv). The mixture was stirred for 3 h at 180° C. then it was cooled to RT and poured into 2000 mL of water with stirring. The solids were collected by filtration to provide 12.0 g (75%) of 5-bromoisoquinolin-1-amine as a brown solid.

(448) Step 4:

(449) Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a mixture of 5-bromoisoquinolin-1-amine (8.20 g, 36.76 mmol, 1.00 equiv), N,N-dimethylformamide (120 mL), Zn(CN).sub.2 (8.60 g, 73.50 mmol, 2.00 equiv) and Pd(PPh.sub.3).sub.4 (8.30 g, 7.18 mmol, 0.20 equiv). The resulting mixture was stirred overnight at 130° C. The solids were separated by filtration and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1/1) to afford 9.40 g of 1-aminoisoquinoline-5-carbonitrile as a red solid.

(450) Step 5:

(451) Into a 250-mL round-bottom flask, was placed a mixture of 1-aminoisoquinoline-5-carbonitrile (3.3 g, 19.51 mmol, 1.00 equiv), methanol (100 mL), NH.sub.3.H.sub.2O (20.0 mL) and Raney-Ni (5.60 g). The mixture was degassed, purged with H.sub.2 5 times and stirred overnight at room temperature under an atmosphere of H.sub.2. After filtration through a pad of Celite, the filtrate was concentrated under vacuum to deliver 3.39 g (100%, crude) of 5-(aminomethyl)isoquinolin-1-amine as brown oil.

(452) Step 6:

(453) Into a 250-mL round-bottom flask, was placed a solution of 5-(aminomethyl)isoquinolin-1-amine (3.40 g, 19.63 mmol, 1.00 equiv), MeOH (100 mL) and Boc.sub.2O (5.10 g, 23.37 mmol, 1.20 equiv). The mixture was stirred for 0.5 h at room temperature. After the concentration, the residue was purified by silica gel column chromatography eluting with dichloromethane/methanol (20/1) to afford 4.70 g (88%) of tert-butyl N-[(1-aminoisoquinolin-5-yl)methyl]carbamate as a light yellow solid.

(454) Step 7:

(455) Into a 100-mL 3-necked round-bottom flask, was placed a solution of tert-butyl N-[(1-aminoisoquinolin-5-yl)methyl]carbamate (4.7 g, 17.20 mmol, 1.00 equiv) in dichloromethane (50 mL) with stirring at 0° C. The solution was then sparged with HCl (gas) to saturation and the resulting mixture was stirred for 1 h at 0° C. The solids were collected by filtration to provide 5.20 g of 5-(aminomethyl)isoquinolin-1-amine hydrochloride as a yellow solid.

(456) Step 8:

(457) To a stirred solution of (1R,8S)-12-(2-fluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (Example 44, Step 1; 60.00 mg; 0.18 mmol) and 5-(aminomethyl)isoquinolin-1-amine hydrochloride (37.86 mg; 0.18 mmol) in N,N-dimethylformamide (1.81 ml) was added diisopropylethylamine (0.32 ml; 1.81 mmol) followed by HATU (68.65 mg; 0.18 mmol) and the resulting mix was stirred at ambient temperature for 30 min. The reaction mix was concentrated and the residue was taken in acetonitrile/water and purified by prep HPLC. The fractions containing the product were partially concentrated, freeze and lyophilized to give the title compound (49.6 mg). MS: (M+H).sup.+ found for C.sub.31H.sub.22FN.sub.3O.sub.2: 488.1.

Example 59

Synthesis of (1R,8S)—N-[(4-carbamimidoylphenyl)methyl]-12-(4-fluorophenyl)-15-oxatetra-cyclo-[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(458) ##STR00683##

(459) Step 1:

(460) A stirred suspension of sodium (1S,8R)-12-bromo-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (120.00 mg; 0.35 mmol), 4-fluorophenylboronic acid (54.46 mg; 0.39 mmol), sodium carbonate (0.53 ml; 2.00 mol/l) and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (25.89 mg; 0.04 mmol) in 1,2-dimethoxyethane (1.20 ml) was purged with nitrogen and the vial was sealed and heated to 80° C. for 60 min. The reacting mixture was cooled to r.t., filtered and concentrated. The brown residue was dissolved/suspended in water and acidified with 3N HCl. The aqueous layer was extracted three times with EtOAc and the combined organics were dried over Na.sub.2SO.sub.4, filtered and concentrated. The corresponding (1R,8S)-12-(4-fluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid was used in the next step without further purification.

(461) Step 2:

(462) To a stirred solution of (1R,8S)-12-(4-fluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (50.00 mg; 0.15 mmol) and 4-(aminomethyl)benzene-1-carboximidamide (36.76 mg; 0.17 mmol) in N,N-dimethylformamide (1.50 ml) at r.t. was added diisopropylethylamine (0.26 ml; 1.50 mmol) followed by HATU (57.21 mg; 0.15 mmol) and the reaction mixture was stirred at ambient temperature for 15 min. The reaction mixture was concentrated and the residue was taken in acetonitrile/water and purified by prep HPLC. The fractions containing the product were partially concentrated, freeze and lyophilized to give the title compound (70 mg). MS: (M+H).sup.+ found for C.sub.29H.sub.22FN.sub.3O.sub.2: 464.1.

Example 60

Synthesis of (1R,8S)—N-[(1-aminoisoquinolin-5-yl)methyl]-12-(2-cyano-4-methylphenyl)-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(463) ##STR00684##

(464) Step 1:

(465) A stirred suspension of sodium (1S,8R)-12-bromo-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (70.00 mg; 0.21 mmol), 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (60.22 mg; 0.25 mmol), cesium carbonate (168.14 mg; 0.52 mmol) and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (15.10 mg; 0.02 mmol) in 1,4-dioxane (8.26 ml) and methanol (2.29 ml) was stirred at ambient temperature for 1 h. The reacting mixture was filtered and concentrated. The crude was dissolved in 1 ml of water, acidified with 3N HCl and extracted 3 times with EtOAc. The combined organics were dried over Na.sub.2SO.sub.4, filtered and concentrated. The crude (1R,8S)-12-(2-cyano-4-methylphenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid was used in the next step without further purification.

(466) Step 2:

(467) To a stirred solution of (1R,8S)-12-(2-cyano-4-methylphenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (50.00 mg; 0.14 mmol) and 5-(aminomethyl)isoquinolin-1-amine hydrochloride (29.67 mg; 0.14 mmol) in N,N-dimethylformamide (1.41 ml) at r.t. was added diisopropylethylamine (0.25 ml; 1.41 mmol) followed by HATU (53.80 mg; 0.14 mmol) and the mix was left stirring at ambient temperature for 30 min. The reaction mix was concentrated and the residue was taken in acetonitrile/water and purified by prep HPLC. The fractions containing the product were partially concentrated, freeze and lyophilized to give the title compound (72 mg). MS: (M+H).sup.+ found for C.sub.33H.sub.24N.sub.4O.sub.2: 509.0.

Example 61

Synthesis of (1S,8R)—N-[(4-carbamimidoylphenyl)methyl]-12-(5-chlorothiophen-2-yl)-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(468) ##STR00685##

(469) Step 1:

(470) A suspension of sodium (1S,8R)-12-bromo-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (70.00 mg; 0.21 mmol), (5-chlorothiophen-2-yl)boronic acid (40.23 mg; 0.25 mmol), sodium carbonate (0.52 ml; 2.00 mol/l; 1.03 mmol) in 1,2-dimethoxyethane (2.10 ml) was purged with nitrogen. 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (15.10 mg; 0.02 mmol) was added to the mixture and the vessel purged once again with nitrogen. The vial was sealed and heated to 80° C. for 90 min. The reacting mixture was cooled to r.t., filtered and concentrated. The crude was dissolved in 1 ml of water, acidified with 3N HCl and extracted 3 times with EtOAc. The combined organics were dried over Na.sub.2SO.sub.4, filtered and concentrated to give crude (1S,8R)-12-(5-chlorothiophen-2-yl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid which was used in the next step without further purification.

(471) Step 2:

(472) To a stirred solution of (1S,8R)-12-(5-chlorothiophen-2-yl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (70.00 mg; 0.20 mmol) and 4-(aminomethyl)benzenecarboximidamide dihydrochloride (48.20 mg; 0.22 mmol) in N,N-dimethylformamide (1.97 ml) was added diisopropylethylamine (0.34 ml; 1.97 mmol) followed by HATU (75.02 mg; 0.20 mmol) and the reaction mix stirred for 15 min at ambient temperature. The reaction mix was concentrated and the residue was taken in acetonitrile/water and purified by prep HPLC. The fractions containing the product were partially concentrated, freeze and lyophilized to give the title compound (24 mg). MS: (M+H).sup.+ found for C.sub.27H.sub.20ClN.sub.3O.sub.2S: 486.

Example 62

Synthesis of (1S,8R)—N-[(4-carbamimidoylphenyl)methyl]-12-(3-fluorophenoxy)-15-oxatetra-cyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(473) ##STR00686##

(474) Step 1:

(475) A flask containing a mixture of (1S,8R)-12-bromo-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (110.00 mg; 0.35 mmol), 3-fluorophenol (0.04 ml; 0.45 mmol), copper (I) bromide (7.46 mg; 0.05 mmol), 2,4-pentanedione (0.01 ml; 0.07 mmol) and potassium carbonate (62.23 mg; 0.45 mmol) in N,N-dimethylformamide (1.16 ml) was evacuated and back-filled with Argon and the mixture was heated to 130° C. for 48 h. The mixture was allowed to reach RT, and was directly injected onto a silica gel column for purification by flash chromatography (Hexanes/EtOAc=1:1, then DCM/MeOH=90:10) to give the corresponding (1S,8R)-12-(3-fluorophenoxy)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (25 mg).

(476) Step 2:

(477) To a stirred solution of (1S,8R)-12-(3-fluorophenoxy)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (25.00 mg; 0.07 mmol) and 4-(aminomethyl)benzene-1-carboximidamide dihydrochloride (17.54 mg; 0.08 mmol) in N,N-dimethylformamide (0.72 ml) at r.t. was added diisopropylethylamine (0.13 ml; 0.72 mmol) followed by HATU (27.29 mg; 0.07 mmol) and the reaction mix was stirred at ambient temperature for 15 minutes. The reaction mix was concentrated and the residue was taken in acetonitrile/water and purified by prep HPLC. The fractions containing the product were partially concentrated, freeze and lyophilized to give the title compound (13.7 mg). MS: (M+H).sup.+ found for C.sub.29H.sub.22FN.sub.3O.sub.3: 480.1.

Example 63

Synthesis of (1S,8R)-12-(5-chlorothiophen-2-yl)-N-{[4-(N′-hydroxycarbamimidoyl)phenyl]-methyl}-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(478) ##STR00687##

(479) Step 1:

(480) A suspension of sodium (1S,8R)-12-bromo-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate, INT-5a1 (400.00 mg; 1.18 mmol), (5-chlorothiophen-2-yl)boronic acid (229.87 mg; 1.42 mmol), sodium carbonate (2.95 ml; 2.00 mol/l) in 1,2-dimethoxyethane (12.00 ml) was purged with nitrogen. 1,1′-bis(diphenyl-phosphino)-ferrocene]dichloropalladium(II) (86.31 mg; 0.12 mmol) was added to the reaction mix and the vessel purged once again with nitrogen. The vial was sealed and heated to 80° C. for 90 min. Additional 1.2 equivalents (5-chlorothiophen-2-yl)boronic acid were added, followed by bis(diphenylphosphino)ferrocene]dichloropalladium(II). After 1 h reaction was cooled to ambient temperature and concentrated. The crude was suspended in water, treated with 3N HCl and extracted with EtOAc. The combined organics were washed with brine and dried over Na.sub.2SO.sub.4. The crude (1S,8R)-12-(5-chlorothiophen-2-yl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid was used in the next step without further purification.

(481) Step 2:

(482) (1S,8R)-12-(5-Chlorothiophen-2-yl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (65.00 mg; 0.18 mmol) was dissolved in N,N-dimethylformamide (1.10 ml). Diisopropylethylamine (0.25 ml; 1.47 mmol) was added to the solution followed by hydroxybenzotriazole (37.13 mg; 0.27 mmol) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (70.24 mg; 0.37 mmol) and the reaction mix was stirred for 10 min. A solution of 4-(aminomethyl)-N′-hydroxybenzene-1-carboximidamide (INT-8) (50.17 mg; 0.21 mmol) in 1 ml of DMF which was pretreated with 2.5 eq of diisopropylethylamine was added to the reaction flask and the reaction mix was stirred for 2 h. The solvent was removed under vacuum and the residue was taken in DMSO and acetonitrile. The solids in suspension were removed by filtration and the crude filtrate purified by prep HPLC. The fractions containing the product were partially concentrated freeze and lyophilized to give the title compound (21.4 mg). MS: (M+H).sup.+ found for C.sub.27H.sub.20ClN.sub.3O.sub.3S: 502.

Example 64

Synthesis of (1R,8S)—N-[(4-carbamimidoyl-2-fluorophenyl)methyl]-12-(2-fluorophenyl)-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(483) ##STR00688##

(484) Step 1:

(485) To a cooled solution of 4-(bromomethyl)-3-fluorobenzonitrile (4.00 g; 18.69 mmol in tetrahydrofuran (400.00 ml) was added sodium hydride (0.90 g; 22.43 mmol). Tert-butyl N-[(tert-butoxy)carbonyl]carbamate (4.47 g; 20.56 mmol) was added portion wise and the reaction mixture was stirred for 5 h. It was then diluted with EtOAc, washed with water and brine and dried over Na.sub.2SO.sub.4. The crude was purified by flash chromatography (Heptane/EtOAc=3:1) to give tert-butyl N-[(tert-butoxy)carbonyl]-N-[(4-cyano-2-fluorophenyl)methyl]carbamate (4.1 g).

(486) Step 2:

(487) To a solution of tert-butyl N-[(tert-butoxy)carbonyl]-N-[(4-cyano-2-fluoro-phenyl)methyl]carbamate (3.00 g; 8.56 mmol) in methanol (30.00 ml) was added hydroxylamine hydrochloride (0.89 g; 12.84 mmol) and diisopropylethylamine (2.24 ml; 12.84 mmol). The mixture was stirred at RT until complete dissolution and then heated under reflux for 16 h. The solvent was removed under vacuum and the residue was partitioned in EtOAc/water. The organic layer was isolated and washed with NaHCO.sub.3 solution and brine and dried over Na.sub.2SO.sub.4 before being evaporated under reduced pressure to give tert-butyl N-[(tert-butoxy)carbonyl]-N-{[2-fluoro-4-(N′-hydroxycarbamimidoyl)phenyl]methyl}-carbamate (3.1 g) which was used in the next step without further purification.

(488) Step 3:

(489) To a solution of tert-butyl N-[(tert-butoxy)carbonyl]-N-{[2-fluoro-4-(N′-hydroxycarbamimidoyl)phenyl]methyl}carbamate (1.0 g; 2.61 mmol) in acetic acid (70.00 ml) was added acetic anhydride (0.26 ml; 2.74 mmol) followed by palladium on carbon (Pd/C) (277.56 mg; 0.26 mmol) and the mix was hydrogenated at 65 psi for 3 h. The catalyst was removed by filtration over celite and the filtrate was concentrated to give tert-butyl N-[(tert-butoxy)carbonyl]-N-[(4-carbamimidoyl-2-fluorophenyl)methyl]carbamate (870 mg) which was used in the next step without further purification.

(490) Step 4:

(491) 4 N Hydrochloric acid (4.63 ml; 4.00 mol/l; 18.51 mmol) in dioxane was added to a suspension of tert-butyl N-[(tert-butoxy)carbonyl]-N-[(4-carbamimidoyl-2-fluorophenyl)-methyl]carbamate (850.00 mg; 2.31 mmol) and the reaction mixture was stirred at RT for 5 h. The solvent was partially removed under vacuum and the solid 4-(aminomethyl)-3-fluorobenzene-1-carboximidamide dihydrochloride that appeared was removed by filtration and dried overnight under high vacuum (420 mg).

(492) Step 5:

(493) (1R,8S)-12-(2-fluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (Example 44, Step 1; 70.00 mg; 0.21 mmol) and 4-(aminomethyl)-3-fluorobenzene-1-carboximidamide dihydrochloride (55.63 mg; 0.23 mmol) were dissolved in N,N-dimethylformamide (0.70 ml) and the reaction mixture was cooled to −78° C. HATU (88.10 mg; 0.23 mmol) was added to the mixture followed by diisopropylethylamine (0.15 ml; 0.84 mmol) and after 5 minutes the reaction flask was removed from the bath and stirred for 20 min. The reaction mixture was cooled in an ice bath and water was added drop wise to it. The precipitate was removed by filtration and the solid was dissolved in DMSO and purified on the prep HPLC. The fractions containing the product were partially concentrated, freeze and lyophilized to give the title compound (57.3 mg). MS: (M+H).sup.+ found for C.sub.30H.sub.23F.sub.2N.sub.3O.sub.3: 482.1.

Example 65

Synthesis of (1R,8S)—N-[(4-carbamimidoyl-2-fluorophenyl)methyl]-12-(2,4-difluorophenyl)-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(494) ##STR00689##

(495) (1R,8S)-12-(2,4-Difluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (Example 7, Steps 1-2; 70.00 mg; 0.20 mmol) and 4-(aminomethyl)-3-fluorobenzene-1-carboximidamide dihydrochloride (Example 64, Step 1-4; 57.57 mg; 0.24 mmol) were dissolved in N,N-dimethylformamide (0.70 ml) and the mixture was cooled to −78° C. HATU (83.58 mg; 0.22 mmol) was added followed by N,N-dimethylformamide (0.70 ml) and the reaction mixture was stirred 5 min. The flask was removed from the bath and was left stirred for 20 min at ambient temperature. Water was added drop wise to the reaction mixture and the precipitate formed was removed by filtration. This crude was dissolved in DMSO and purified by prep HPLC and the fractions containing the product were partially concentrated, freeze and lyophilized to give the title compound (37.2 mg). MS: (M+H).sup.+ found for C.sub.29H.sub.20F.sub.3N.sub.3O.sub.2: 500.0.

Example 66

Synthesis of (1R,8S)—N-[(4-carbamimidoyl-2-fluorophenyl)methyl]-12-cyclopropyl-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(496) ##STR00690##

(497) (1R,8S)-12-cyclopropyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (Example 14, Step 1; 25.70 mg; 0.09 mmol) and 4-(aminomethyl)-3-fluorobenzene-1-carboximidamide dihydrochloride (Example 64, Step 1-4; 26.61 mg; 0.11 mmol) were dissolved in N,N-dimethylformamide (0.26 ml) and the reaction mixture was cooled to 0° C. (1H-1,2,3-benzotriazol-1-yloxy)[tri(1-pyrrolidinyl)]phosphonium hexafluorophosphate (57.67 mg; 0.11 mmol) and diisopropylethylamine (0.06 ml; 0.37 mmol) were added and the reaction mix was stirred at 0° C. for 20 min. Water was added slowly to the reaction mixture and the precipitate that appeared was removed by filtration. The crude was dissolved in DMSO and purified on the prep HPLC. The fractions containing the title compound were concentrated and then suspended in acetonitrile/water, freeze and lyophilized. MS: (M+H).sup.+ found for C.sub.26H.sub.22FN.sub.3O.sub.2: 427.8.

Example 67

Synthesis of (1R,8S)—N-[(4-carbamimidoyl-2-fluorophenyl)methyl]-12-(4-fluorophenyl)-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(498) ##STR00691##

(499) (1R,8S)-12-(4-fluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (Example 59, Step 1; 30.00 mg; 0.09 mmol) and 4-(aminomethyl)-3-fluorobenzene-1-carboximidamide dihydrochloride (Example 64, Step 1-4; 23.84 mg; 0.10 mmol) were dissolved in N,N-dimethylformamide (0.30 ml) and the reaction mixture was cooled to −78° C. HATU (37.76 mg; 0.10 mmol) was added to the mixture followed by diisopropylethylamine (0.06 ml; 0.36 mmol) and after 5 minutes the reaction flask was removed from the bath and left to reach RT. After 10 min the reaction mixture was cooled in an ice bath and water was added drop wise to it. The precipitate was removed by filtration and the solid was dissolved in DMSO and purified on prep HPLC. The fractions containing the product were partially concentrated, freeze and lyophilized to give the title compound (27.10 mg). MS: (M+H).sup.+ found for C.sub.29H.sub.21F.sub.2N.sub.3O.sub.2: 427.8.

Example 68

Synthesis of (1R,8S)—N-{[2-fluoro-4-(N′-methoxycarbamimidoyl)phenyl]methyl}-12-(2-fluoro-phenyl)-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(500) ##STR00692##

(501) Step 1:

(502) To a solution of tert-butyl N-[(tert-butoxy)carbonyl]-N-[(4-cyano-2-fluoro-phenyl)methyl]carbamate (Example 64, Step 1; 1.0 g; 2.85 mmol) suspended in ethanol (7.00 ml) were added triethylamine (1.39 ml; 9.99 mmol) and a 30% W/W solution of O-methylhydroxylamine hydrochloride (476.72 mg; 5.71 mmol), followed by the addition of thioglycolic acid (0.20 ml; 2.85 mmol). The resulting mixture was stirred overnight at 87° C. Approximately 0.7 eq. O-methylhydroxylamine hydrochloride were added followed by one more equivalent of triethylamine and the reaction was stirred for an additional 4 h. The solvent was removed under vacuum and the residue partitioned in EtOAc/water. The organic layer was isolated and the aqueous phase extracted 2 more times with EtOAc. The combined organics were washed with brine, filtered and concentrated. The crude was purified by flash chromatography (heptane/EtOAc=3:1) to give tert-butyl N-[(tert-butoxy)carbonyl]-N-({2-fluoro-4-[N′-methoxycarbamimidoyl]phenyl}methyl)carbamate (350 mg).

(503) Step 2:

(504) Hydrochloric acid (0.29 ml; 12.00 mol/l) was added drop wise to a solution of tert-butyl N-[(tert-butoxy)carbonyl]-N-({2-fluoro-4-[N′-methoxycarbamimidoyl]phenyl}-methyl)carbamate (350.00 mg; 0.88 mmol) in ethanol (1.40 ml) and ethyl acetate (1.40 ml) and the suspension was heated to 35° C. for 3 h. The mixture was cooled to 0° C. and kept at that temperature for 30 min. The precipitate was removed by filtration and the crystals washed with a mixture of EtOAc and EtOH followed by EtOAc. The solid was dried under vacuum to give 4-(aminomethyl)-3-fluoro-N′-methoxybenzene-1-carboximidamide dihydrochloride (198 mg).

(505) Step 3:

(506) (1R,8S)-12-(2-fluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (Example 44, Step 1; 75.00 mg; 0.23 mmol) was dissolved in N,N-dimethylformamide (0.75 ml). Diisopropylethylamine (0.31 ml; 1.81 mmol), hydroxybenzotriazole (45.74 mg; 0.34 mmol) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (86.53 mg; 0.45 mmol) were added to the solution and the reaction mixture was stirred for 10 min. A solution of 4-(aminomethyl)-3-fluoro-N′-methoxybenzene-1-carboximidamide dihydrochloride (67.06 mg; 0.25 mmol) in 2 ml of DMF which was pretreated with 2.5 eq of diisorpopylethylamine was added to the reaction flask and the reaction mix was left stirring at ambient temperature for 4 h. The reaction mix was cooled to 0° C. and water was added drop wise to it and the precipitate that formed was removed by filtration. The solid was dissolved in DCM/MeOH and loaded onto silica gel and purified by flash chromatography (Heptanes/EtOAc=2:3) to give the title compound (64 mg). MS: (M+H).sup.+ found for C.sub.30H.sub.23F.sub.2N.sub.3O.sub.3: 511.9.

Example 69

Synthesis of (1R,8S)—N-{[2-fluoro-4-(N′-hydroxycarbamimidoyl)phenyl]methyl}-12-(2-fluorophenyl)-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(507) ##STR00693##

(508) Step 1:

(509) 4 N Hydrochloric acid (6.26 ml; 4.00 mol/l) in dioxane was added to a suspension of tert-butyl N-[(tert-butoxy)carbonyl]-N-{[2-fluoro-4-(N′-hydroxycarbamimidoyl)-phenyl]methyl}carbamate (Example 64, Steps 1-2; 1.2 g; 3.13 mmol) in water (2.40 ml) and the reaction mixture was stirred at RT for 5 h. The solvent was removed under vacuum and the residue was dissolved in water and concentrated once again to give 4-(aminomethyl)-3-fluoro-N′-hydroxybenzene-1-carboximidamide dihydrochloride.

(510) Step 2:

(511) (1R,8S)-12-(2-Fluorophenyl)-15 oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (Example 44, Step 1; 82.00 mg; 0.25 mmol) was dissolved in N,N-dimethylformamide (0.82 ml). Diisopropylethylamine (0.34 ml; 1.97 mmol), hydroxybenzotriazole (50.01 mg; 0.37 mmol) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (94.60 mg; 0.49 mmol) were added to the solution and the reaction mixture was stirred 10 m. A solution of 4-(aminomethyl)-3-fluoro-N′-hydroxybenzene-1-carboximidamide dihydrochloride (69.51 mg; 0.27 mmol) in 2 ml of DMF that was pretreated with 2.5 eq of diisopropylethylamine was added to the reaction flask and the reaction mixture was left stirring at ambient temperature for 1 h. The reaction mixture was cooled to 0° C. and water was added drop wise to it. The brown precipitate was removed by filtration. The crude product was dissolved in DCM/MeOH and adsorbed on silica gel. It was then purified by flash chromatography (DCM/MeOH=9:1). The fractions containing the product were concentrated and then taken in acetonitrile/water, freeze and lyophilized to the title compound (58 mg). MS: (M+H).sup.+ found for C.sub.29H.sub.21F.sub.2N.sub.3O.sub.3: 498.0.

Example 70

Synthesis of (1R,8S)-12-cyclopropyl-N-{[2-fluoro-4-(N′-methoxy-carbamimidoyl)phenyl]-methyl}-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(512) ##STR00694##

(513) (1R,8S)-12-cyclopropyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (Example 14, Step 1; 48.00 mg; 0.17 mmol) and 4-(aminomethyl)-3-fluoro-N′-methoxybenzene-1-carboximidamide dihydrochloride (Example 68, Steps 1-2; 55.91 mg; 0.21 mmol) were dissolved in N,N-dimethylformamide (0.48 ml) and the mixture was cooled to 0° C. (1H-1,2,3-benzotriazol-1-yloxy)[tri(1-pyrrolidinyl)]-phosphonium hexafluorophosphate was added followed by diisopropylethylamine (0.12 ml; 0.69 mmol) and the reaction mix stirred 5 min. The flask was removed from the bath and was left to reach RT. After 10 min. water was added slowly to the reaction mix and the precipitate formed was removed by filtration. The solid was dissolved in DCM and purified by flash chromatography (Heptane/EtOAc=2:3) followed by a second purification by prep HPLC. The fractions containing the product were partially concentrated, freeze and lyophilized to give the title compound (19.2 mg). MS: (M+H).sup.+ found for C.sub.27H.sub.24FN.sub.3O.sub.3: 457.6.

Example 71

Synthesis of (1R,8S)-12-(2,4-difluorophenyl)-N-{[2-fluoro-4-(N′-hydroxycarbamimidoyl)phenyl]methyl}-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(514) ##STR00695##

(515) (1R,8S)-12-(2,4-Difluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (Example 7, Step 1-2; 30.00 mg; 0.09 mmol) was dissolved in N,N-dimethylformamide (0.30 ml). N-[3-(Dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (19.70 mg; 0.10 mmol), diisopropylethylamine (0.06 ml; 0.34 mmol) and hydroxybenzotriazole (13.89 mg; 0.10 mmol) were added to the reaction mix and stirred 10 min. A solution of 4-(aminomethyl)-3-fluoro-N′-hydroxybenzene-1-carboximidamide dihydrochloride (Example 69, Step 1; 26.3 mg, 0.1 mmol) in 1 ml of DMF, pretreated with 2 eq of diisopropylethylamine was added to the reaction flask and the reaction mis was left stirring at ambient temperature for 2 h. The flask was cooled to 0° C. and water was added drop wise to it. The precipitate was removed by filtration and the solid was dissolved in DCM and purified by flash chromatography (DCM/MeOH=9:1). The fractions containing the product were concentrated to dryness and then suspended in acetonitrile/water, freeze and lyophilized to give the title compound (25.8 mg). MS: (M+H).sup.+ found for C.sub.29H.sub.20F.sub.3N.sub.3O.sub.3: 516.1.

Example 72

Synthesis of (1R,8S)—N-({4-[N′-ethoxycarbamimidoyl]phenyl}methyl)-12-(4-fluorophenyl)-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(516) ##STR00696##

(517) Step 1:

(518) Tert-butyl N-[(4-cyanophenyl)methyl]carbamate (2.00 g; 8.61 mmol) was suspended in ethanol (14.00 ml). Triethylamine (4.20 ml; 30.14 mmol) and a 30% W/W solution of O-ethylhydroxylamine hydrochloride (1.68 g; 17.22 mmol) were added to the mix, followed by the addition of thioglycolic acid (0.60 ml; 8.61 mmol). The resulting mixture was stirred for 24 h at 90° C. The solvent was removed under vacuum and the residue was partitioned in EtOAc/water. The organic layer was isolated and the aqueous phase extracted 2 times; the combined organics were washed with brine, filtered and concentrated. The crude was purified by flash chromatography (Heptane/EtOAc=3:1) to give tert-butyl N-({4-[N′-ethoxy-carbamimidoyl]phenyl}methyl)carbamate (1.0 g).

(519) Step 2:

(520) Hydrochloric acid (1.14 ml; 12.00 mol/l; 13.64 mmol) was added drop wise to a solution tert-butyl N-({4-[N′-ethoxycarbamimidoyl]phenyl}methyl)carbamate (1.0 g; 3.41 mmol) in ethanol (4.00 ml) and ethyl acetate (4.00 ml) and the suspension was heated to 35° C. for 3 h. Additional 0.5 ml of HCl were added and the reaction mixture was left stirring overnight ambient temperature. The solvent was removed under vacuum and the remaining solid was dried under high vacuum to give 4-(aminomethyl)-N′-ethoxybenzene-1-carboximidamide dihydrochloride (907 mg).

(521) Step 3:

(522) (1R,8S)-12-(4-fluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (Example 59, Step 1; 60.00 mg; 0.18 mmol) and 4-(aminomethyl)-N′-ethoxybenzene-1-carboximidamide dihydrochloride (57.67 mg; 0.22 mmol) were dissolved in N,N-dimethylformamide (1.81 ml). Diisopropylethylamine (0.32 ml; 1.81 mmol) and HATU (68.65 mg; 0.18 mmol) were added to the solution and the reaction mixture was stirred at ambient temperature for 45 min. The reaction mixture was cooled to 0° C. and treated by drop wise addition of water. The precipitate formed was removed by filtration and the crude solid was purified by flash chromatography (Heptane/EtOAc=1:1). The fractions containing the product were concentrated and the residue taken in acetonitrile/water freeze and lyophilized to give the title compound (51.2 mg). MS: (M+H).sup.+ found for C.sub.31H.sub.26FN.sub.3O.sub.3: 508.

Example 73

Synthesis of tert-butyl N-[1-amino[4-({[(1R,8S)-12-(2,4-difluorophenyl)-15-oxatetra-cyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaen-4-yl]formamido}methyl)phenyl]methylidene]carbamate

(523) ##STR00697##

(524) (1R,8S)—N-[(4-carbamimidoylphenyl)methyl]-12-(4-fluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide (Example 59; 60.00 mg; 0.13 mmol) was dissolved in 1,4-dioxane (2.40 ml) and N,N-dimethylformamide (1.20 ml) and the mixture was cooled to 0° C. Sodium hydroxide (0.13 ml; 2.50 mol/l; 0.32 mmol) was added drop wise followed by di-tert-butyl dicarbonate (0.03 ml; 0.14 mmol) and when the addition was complete, the reaction flask was removed from the ice bath and left to reach ambient temperature and stirred for 45 min. The reaction flask was cooled to 0° C. and water was added slowly to the reaction mixture. The precipitate was removed by filtration and the crude was purified by flash chromatography (Heptane/EtOAc=2:3). The fractions containing the product were concentrated, suspended in acetonitrile/water, freeze and lyophilized to give the title compound (28.2 mg). MS: (M+H).sup.+ found for C.sub.34H.sub.30FN.sub.3O.sub.4: 562.2.

Example 74

Synthesis of (1R,8S)—N-{[2-fluoro-4-(N′-methoxycarbamimidoyl)phenyl]methyl}-12-(4-fluoro-phenyl)-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(525) ##STR00698##

(526) (1R,8S)-12-(2-fluorophenyl)-1 oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (Example 59, Step 1; 50.00 mg; 0.15 mmol) and 4-(aminomethyl)-3-fluoro-N′-methoxybenzene-1-carboximidamide dihydrochloride (Example 68, Step 1-2; 48.77 mg; 0.18 mmol) were dissolved in N,N-dimethylformamide (0.50 ml) and the mixture was cooled to −78° C. HATU (62.93 mg; 0.17 mmol) was added to the mixture followed by diisopropylethylamine (0.10 ml; 0.60 mmol) and the reaction mixture was stirred 5 min. The flask was removed from the bath and stirred at ambient temperature for 20 min. Water was added slowly to the reaction mixture and the precipitate was removed by filtration. This crude material was purified by flash chromatography (Heptane/EtOAc=2:3) and the fractions containing the product were concentrated to dryness, suspended in acetonitrile/water, freeze and lyophilized to give the title compound. MS: (M+H).sup.+ found for C.sub.30H.sub.23F.sub.2N.sub.3O.sub.3: 512.1.

Example 75

Synthesis of (1R,8S)—N-[(4-carbamimidoylphenyl)methyl]-12-(2,4-difluorophenyl)-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(527) ##STR00699##

(528) Step 1:

(529) To a 10 mL microwave reaction vial was subsequently added sodium (1S,8R)-12-bromo-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (INT-5a1, 330 mg, 0.97 mmol, 1.0 eq.), 2,4-difluorophenylboronic acid (230.5 mg, 1.46 mmol, 1.5 eq.), Pd(dppf).sub.2Cl.sub.2.CH.sub.2Cl.sub.2 (63.6 mg, 0.08 mmol, 0.08 eq.) and KOAc (197 mg, 2.0 mmol, 2.1 eq.), N,N-dimethylformamide (4.0 mL) and water (0.5 mL). The resulting mixture was purged with N.sub.2 for 5 min. The vial was sealed and subjected to microwave reaction condition (120° C. for 30 min). This resulting mixture was allowed to cool to rt, diluted with water and treated with 1.0 N aqueous HCl (1.0 mL), and extracted with EtOAc. The combined organic layers were washed with water and brine, and dried over MgSO.sub.4. After removal of organic solvents under reduced pressure, the residue was subjected to flash chromatography on 10 g silica gel column using 0-100% EtOAc/Hexanes as eluent to provide the desired (1R,8S)-12-(2,4-difluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid as pale brown solid (311 mg).

(530) Step 2:

(531) To a rt solution of (1R,8S)-12-(2,4-difluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (150.0 mg, 0.43 mmol, 1.00 eq.) in DMF (1.65 ml) was added N,N-diisopropylethylamine (0.45 ml, 57 mmol, 6.00 eq.), 1H-1,2,3-benzotriazol-1-ol hydrate (72.13 mg, 0.47 mmol, 1.10 eq.) and N-[3-(dimethylamino)-propyl]-N′-ethylcarbodiimide hydrochloride (164.17 mg, 0.86 mmol, 2.00 eq.) subsequently. This mixture was allowed to stir at rt for 20 min followed by treatment with 4-(aminomethyl)-benzenecarboximidamide dihydrochloride (142.66 mg, 64 mmol, 1.50 eq.). Sonication of the resultant mixture for 10 min led to disappearance of the major white precipitate. The resultant solution was allowed to stir at rt for 5.0 h and the reaction was monitored with LCMS till completion. The crude reaction mixture was filtered and subjected to reverse preparative HPLC (Prep-C18, 5 μM OBD column, 19×250 mm, waters; gradient elution of 20% MeCN in water to 75% MeCN in water over a 20 min period, where both solvents contain 0.1% TFA, flow rate: 20 mL/min) to provide the title compound in the TFA salt as a white solid (110 mg, 54%). MS: (M+H).sup.+ found for C.sub.29H.sub.22F.sub.2N.sub.3O.sub.2: 482.1.

Example 76

Synthesis of (1S,8R)—N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-12-[ethyl(3-fluorophenyl)-amino]-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(532) ##STR00700##

(533) Step 1:

(534) A mixture of methyl (1S,8R)-12-bromo-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (216 mg, 0.65 mmol, 1.0 eq.,), 3-fluoroaniline (253 mg; 2.28 mmol, 3.5 eq.) and Cs.sub.2CO.sub.3 (745 mg, 2.28 mmol, 3.5 eq.) in toluene (5 mL) was purged with N.sub.2 for 10 min. To the mixture was added Xantphos (26.2 mg; 0.05 mmol; 0.08 eq.) followed by Pd.sub.2(dba).sub.3.CHCl.sub.3 (54 mg, 0.05 mmol, 0.08 eq.). The mixture was purged with N.sub.2 for additional 10 min and the reaction vessel was sealed. The mixture was allowed to stir at 100° C. for 3.5 h, cooled to rt, diluted with water, acidified with 1.0 N aqueous HCl to pH˜7.0, and extracted with EtOAc twice. The combined organic layers were washed with water, brine, and dried over MgSO.sub.4. After removal of organic solvents under reduced pressure, the residue was subjected to flash chromatography on 10 g silica gel column using 0-100% EtOAc/Hexanes as eluent to provide methyl (1S,8R)-12-[(3-fluorophenyl)amino]-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate as colorless syrup (158 mg).

(535) Step 2:

(536) To a vial charged with methyl (1S,8R)-12-[(3-fluorophenyl)amino]-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (150.0 mg; 0.42 mmol; 1.00 eq.) and NaH (84 mg, 60% wt, 2.1 mmol; 5.0 eq.) under N.sub.2 atmosphere in 0° C. bath was added DMF (3.5 mL) followed by iodoethane (194 mg, 1.25 mmol, 3.0 eq.). After stirring in the ice bath for 3.5 h, the reaction mixture was slowly poured into saturated aq. NH.sub.4Cl solution under N.sub.2 atmosphere, acidified with HOAc to pH-6 and then extracted with EtOAc twice. The combined organic layers were washed with water and brine, and dried over MgSO.sub.4. Removal of the organic solvents provide the crude of methyl (1S,8R)-12-[ethyl(3-fluorophenyl)amino]-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (140 mg).

(537) Step 3:

(538) To a rt mixture of methyl (1S,8R)-12-[ethyl(3-fluorophenyl)amino]-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (140.00 mg; 0.36 mmol; 1.00 eq.) in dioxane (1.0 mL) and MeOH (1.0 mL) was added aqueous solution of LiOH (0.36 ml; 4.0 M, 1.44 mmol; 4.00 eq.). The resulting mixture was allowed to stir at 80° C. for 1.5 h, cooled to rt, treated with saturated aq. NH.sub.4Cl solution followed by 0.4 mL of HOAc. The resulting mixture was extracted with 20% .sup.iPrOH/CHCl.sub.3. The organic layer was washed with water, brine and dried over MgSO.sub.4. After removal of organic solvents under reduced pressure, the residue was subjected to flash chromatography on 10 g silica gel column using 0-100% EOAc/Hexanes as eluent to (1S,8R)-12-[ethyl(3-fluorophenyl)amino]-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (110 mg).

(539) Step 4:

(540) To a flask charged with (1S,8R)-12-[ethyl(3-fluorophenyl)amino]-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (70.00 mg; 0.19 mmol; 1.00 eq.) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 141.80 mg; 0.37 mmol; 2.00 eq.) was added DMF (2.5 mL) followed by Et.sub.3N (0.93 ml; 0.56 mmol; 3.00 eq.) This mixture was allowed to stir at rt for 3 h, cooled to rt, diluted with water and extracted with EtOAc thrice. The combined organic layers were washed with water and brine and dried over MgSO.sub.4. After removal of organic solvents under reduced pressure, the residue was subjected to reverse preparative HPLC (Prep-C18, 5 M OBD column, 19×250 mm, waters; gradient elution of 10% MeCN in water to 95% MeCN in water over a 20 min period, where both solvents contain 0.1% TFA, flow rate: 20 mL/min) to provide the title compound as a white solid (38 mg, 39%). MS: (M+H).sup.+ found for C.sub.31H.sub.30FN.sub.4O.sub.2: 509.2.

Example 77

Synthesis of (1S,8R)—N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-12-[(3-chlorophenyl)(methyl)amino]-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(541) ##STR00701##

(542) Step 1:

(543) A mixture of methyl (1S,8R)-12-bromo-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (150.00 mg; 0.45 mmol; 1.00 eq., INT-3a1), 3-chloroaniline (0.25 ml; 2.26 mmol; 5.00 eq.) and cesium carbonate (516.5 mg; 1.6 mmol; 3.50 eq.) in toluene (3 mL) was purged with N.sub.2 for 10 min. To the mixture was added 2-dicyclohexyl-phosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]-palladium(II) methanesulfonate (Xantphos; 18.3 mg; 0.04 mmol; 0.08 eq.) followed by Pd.sub.2(dba).sub.3.CHCl.sub.3 (38 mg, 0.04 mmol, 0.08 eq.). The mixture was purged with N.sub.2 for additional 10 min and then allowed to reflux under N.sub.2 atmosphere for 3.5 h. The resulting reaction solution was cooled to rt, diluted with water, acidified with 1.0 N aqueous HCl to pH˜7.0, and extracted with EtOAc. The combined organic layers were washed with water, brine, and dried over MgSO.sub.4. After removal of organic solvents under reduced pressure, the residue was subjected to flash chromatography on 10 g silica gel column using 0-100% EtOAc/Hexanes as eluent to provide methyl (1S,8R)-12-[(3-chlorophenyl)(methyl)amino]-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate as brown syrup (128 mg).

(544) Step 2:

(545) To a vial charged with (1S,8R)-12-[(3-chlorophenyl)(methyl)amino]-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (100.00 mg; 0.26 mmol; 1.00 eq.) and NaH (53 mg, 60% wt, 1.31 mmol; 5.00 eq.) under N.sub.2 atmosphere in ice bath was added DMF (2.5 mL) followed by iodomethane (112.70 mg; 0.79 mmol; 3.00 eq.). After stirring at 0° C. for 3.0 h, the reaction mixture was slowly poured into saturated aq. NH.sub.4Cl solution under N.sub.2 atmosphere, acidified with HOAc to pH-6 and then extracted with EtOAc twice. The combined organic layers were washed with water and brine, and dried over MgSO.sub.4. Removal of the organic solvents provide the crude of methyl (1S,8R)-12-[methyl(3-fluorophenyl)amino]-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (50 mg).

(546) Step 3:

(547) To a rt mixture of (1S,8R)-12-[methyl(3-fluorophenyl)amino]-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (50 mg, 0.13 mmol, 1.0 eq.) in dioxane (0.3 mL) and MeOH (0.3 mL) was added aqueous solution of LiOH (0.15 ml; 4.0 M, 0.60 mmol; 4.6 eq.). This mixture was left stirring at 80° C. for 1.5 h, cooled to rt, treated with saturated aqueous NH.sub.4Cl solution followed by 0.2 mL of HOAc. The resulting mixture was extracted with 20% .sup.iPrOH/CHCl.sub.3 twice. The combined organic layers were washed with water, brine and dried over MgSO.sub.4. Removal of organic solvents under reduced pressure provide the crude product of (1S,8R)-12-[(3-chlorophenyl)(methyl)amino]-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (41 mg).

(548) Step 4:

(549) To a flask charged with (1S,8R)-12-[(3-chlorophenyl)(methyl)amino]-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (16 mg) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 32.20 mg; 0.08 mmol; 2.00 eq.) was added DMF (0.8 mL) followed by Et.sub.3N (0.21 ml). This mixture was allowed to stir at rt for 5 h, cooled to rt, diluted with water and extracted with EtOAc. The combined organic layers were washed with water and brine. After removal of organic solvents under reduced pressure, the residue was subjected to reverse preparative HPLC (Prep-C18, 5 M OBD column, 19×250 mm, waters; gradient elution of 10% MeCN in water to 95% MeCN in water over a 20 min period, where both solvents contain 0.1% TFA, flow rate: 20 mL/min) to provide the title compound as a white solid (8 mg). MS: (M+H).sup.+ found for C.sub.30H.sub.28ClN.sub.4O.sub.2: 511.2.

Example 78

Synthesis of (1S,8R)—N-[(4-carbamimidoylphenyl)methyl]-12-[(3-chlorophenyl)-(methyl)amino]-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide triflate

(550) ##STR00702##

(551) The title compound was made from (1S,8R)-12-[(3-chlorophenyl)(methyl)amino]-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (prepared in Step 3, Example 77) and 4-(aminomethyl)benzenecarboximidamide dihydrochloride, following the same procedure as described in Step 2, Example 59, except that the crude product was purified by reverse preparative HPLC (Prep-C18, 5 M OBD column, 19×250 mm, waters; gradient elution of 10% MeCN in water to 90% MeCN in water over a 20 min period, where both solvents contain 0.1% TFA, flow rate: 20 mL/min) to provide the title compound as TFA salt as white solid (5.1 mg, 41%). MS: (M+H).sup.+ found for C.sub.30H.sub.26ClN.sub.4O.sub.2: 509.1.

Example 79

Synthesis of (1S,8R)—N-[(4-carbamimidoylphenyl)methyl]-12-(1,1-difluoroethyl)-15-oxatetra-cyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,13-hexaene-4-carboxamide triflate salt

(552) ##STR00703##

(553) Step 1:

(554) To a mixture of (1R,8S)-12-bromo-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (INT-4a2, 1.58 g; 4.97 mmol; 1.00 eq.), methoxy-(methyl)amine hydrochloride (0.72 g; 7.46 mmol; 1.50 eq.) and HATU (2.84 g; 7.46 mmol; 1.50 eq.) in N,N-dimethylformamide (15 mL) was added Et.sub.3N (3.0 mL). The resulting mixture was allowed to stir at rt for overnight. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water and brine. After removal of organic solvents under reduced pressure, the residue was subjected to flash chromatography on 40 g silica gel column using 0-100% EtOAc/Hexanes as eluent to provide (1R,8S)-12-bromo-N-methoxy-N-methyl-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide as white solid (1.56 g, 87%).

(555) Step 2:

(556) To a solution of (1R,8S)-12-bromo-N-methoxy-N-methyl-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide (1.56 g; 4.33 mmol; 1.00 eq.) in THF (10 mL) at 0° C. under N.sub.2 atmosphere was added bromo(methyl)magnesium (3.8 ml; 3.4 M; 13.0 mmol; 3.00 eq.). The resulting mixture was allowed to stir in the ice bath for 35 min before being removed from the bath and allowed to stir at ambient temperature overnight. The reaction mixture was quenched with saturated aq. NH.sub.4Cl solution, diluted with water and extracted with EtOAc twice. The combined organic layers were washed with water and brine. After removal of organic solvents under reduced pressure, the residue was subjected to flash chromatography on 40 g silica gel column using 0-100% EtOAc/Hexanes as eluent to provide 1-[(1R,8S)-12-bromo-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9(14),10,12-hexaen-4-yl]ethan-1-one as colorless syrup (1.28 g, 94%).

(557) Step 3:

(558) To art solution of 1-[(1R,8S)-12-bromo-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9(14),10,12-hexaen-4-yl]ethan-1-one (224.0 mg, 0.72 mmol, 1.00 eq.) in CH.sub.2Cl.sub.2 (1.5 mL) was added bis(2-methoxyethyl)(trifluoro-λ.sup.4-sulfanyl)amine (629 mg; 2.84 mmol; 4.00 eq.) dropwise followed by MeOH (0.1 mL) and CH.sub.2Cl.sub.2 (0.8 mL). This mixture was left stirring at rt for 20 min then allowed to stir at 65° C. for 4 h. This mixture was then cooled to rt and additional bis(2-methoxyethyl)(trifluoro-λ.sup.4-sulfanyl)amine (944 mg; 4.26 mmol; 6.00 eq.) was added. The reaction vessel was sealed and allowed to stir at 90° C. overnight. The reaction mixture was allowed to cool to rt, slowly treated with water dropwise, diluted with saturated aq. NaHCO.sub.3 solution, and extracted with CH.sub.2Cl.sub.2 thrice. The organic layers were combined and washed with water and brine. After removal of organic solvents under reduced pressure, the residue was subjected to flash chromatography on 10 g silica gel column using 0-100% EtOAc/Hexanes as eluent to provide (1R,8S)-12-bromo-4-(1,1-difluoroethyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9(14),10,12-hexaene as colorless syrup (100 mg, 42%).

(559) Step 4:

(560) A mixture of (1R,8S)-12-bromo-4-(1,1-difluoroethyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9(14),10,12-hexaene (75 mg; 0.22 mmol; 1.00 eq.), Xantphos (19.5 mg; 0.04 mmol; 0.15 eq.), palladium acetate (8 mg; 0.035 mmol; 0.16 eq.) and triethylamine (90 mg.) in a mixture solvent of DMF/dioxane/water (0.3 mL/0.3 mL/0.3 m L) was purged with CO for 10 min. The reaction vial was sealed and allowed to stir at 90° C. for 2 h. The reaction mixture was cooled to rt, diluted with EtOAc, washed with 1.0 N aqueous HCl, water and then brine. After removal of organic solvents under reduced pressure, the residue was subjected to flash chromatography on 4 g silica gel column using 0-100% EtOAc/Hexanes as eluent to provide (1S,8R)-12-(1,1-difluoroethyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid as colorless syrup (21 mg, 32%).

(561) Step 5:

(562) Reaction of (1S,8R)-12-(1,1-difluoroethyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (12 mg, 0.04 mmol) and 4-(aminomethyl)-benzenecarboximidamide dihydrochloride (11.4 mg, 0.05 mmol) following the conditions and workup procedure as described in Step 2 for the synthesis of Example 59 provided title compound in the TFA salt form as white solid (7.5 mg, 36%). MS: (M+H).sup.+ found for C.sub.25H.sub.22F.sub.2N.sub.3O.sub.2: 434.1.

Example 80

Synthesis of (1S,8R)—N-[(4-carbamimidoylphenyl)methyl]-12-(2-fluoropropan-2-yl)-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide triflate

(563) ##STR00704##

(564) Step 1:

(565) To a 0° C. solution of 1-[(1R,8S)-12-bromo-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9(14),10,12-hexaen-4-yl]ethan-1-one (590.0 mg; 1.87 mmol; 1.00 eq., prepared in Step 2, Example 79 in THF (5 ml) under N.sub.2 atmosphere was added bromo(methyl)-magnesium (1.10 ml; 3.4 m; 3.74 mmol; 2.00 eq.). The mixture was allowed to warm with the ice bath to rt and stir at rt for 1.5 hr. The reaction mixture was poured into saturated aq. NH.sub.4Cl solution, diluted with water and extracted with EtOAc. The organic layers were combined. After removal of organic solvents under reduced pressure, the residue was subjected to flash chromatography on 10 g silica gel column using 0-100% EtOAc/Hexanes as eluent to provide 2-[(1R,8S)-12-bromo-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9(14),10,12-hexaen-4-yl]propan-2-ol as colorless syrup (428 mg, 73%).

(566) Step 2:

(567) A mixture of 2-[(1R,8S)-12-bromo-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9(14),10,12-hexaen-4-yl]propan-2-ol (56.00 mg; 0.17 mmol; 1.00 eq.) and bis(2-methoxyethyl)(trifluoro-λ.sup.4-sulfanyl)amine (561 mg; 2.54 mmol; 15.00 eq.) was allowed to stir at 90° C. for 3.0 h. This resulting mixture was cool to rt, diluted with EtOAc, and slowly poured into saturated aq. NaHCO.sub.3 solution, diluted with water and extracted with EtOAc. The organic layers were combined. After removal of organic solvents under reduced pressure, the residue was subjected to flash chromatography on 10 g silica gel column using 0-100% EtOAc/Hexanes as eluent to provide (1R,8S)-12-bromo-4-(2-fluoropropan-2-yl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9(14),10,12-hexaene as colorless syrup (41 mg, 73%).

(568) Step 3:

(569) A mixture (1R,8S)-12-bromo-4-(2-fluoropropan-2-yl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9(14),10,12-hexaene (41.0 mg; 0.12 mmol; 1.00 eq.), Xantphos (21.36 mg; 0.04 mmol; 0.30 eq.), palladium acetate (8.29 mg; 0.04 mmol; 0.30 eq.) and triethylamine (120 mg) in DMF/dioxane/water (0.3 ml/0.3 ml/0.3 ml) was purged with CO for 10 min. The reaction vial was sealed and allowed to stir at 90° C. for 4 h. The reaction mixture was cooled to rt, diluted with EtOAc, washed with 1.0 N aqueous HCl, water and then brine. After removal of organic solvents under reduced pressure, the residue was subjected to flash chromatography on 4 g silica gel column using 0-100% etoac/hexanes as eluent to provide (1S,8R)-12-(2-fluoropropan-2-yl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylic acid (30 mg, 82%).

(570) Step 4:

(571) Reaction of (1S,8R)-12-(2-fluoropropan-2-yl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylic acid (30 mg, 0.10 mmol) and 4-(aminomethyl)benzenecarboximidamide dihydrochloride (29 mg, 0.13 mmol) following the conditions and workup procedure as described in Step 2, Example 59 provided title compound in the TFA salt form as white solid (5.8 mg, 13%). MS: (M+H).sup.+ found for C.sub.26H.sub.25FN.sub.3O.sub.2: 430.2.

Example 81

Synthesis of (1S,8R)-12-[(3-chlorophenyl)(methyl)amino]-N-({4-[N′-methoxycarbamimidoyl]phenyl}methyl)-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide triflate

(572) ##STR00705##

(573) The title compound was made from (1S,8R)-12-[(3-chlorophenyl)(methyl)amino]-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (prepared in Step 3 Example 77) and 4-(aminomethyl)-N′-methoxybenzimidamide (INT-7), following the same procedure as described in Step 2, Example 63, except that the crude product was purified by reverse preparative HPLC (Prep-C18, 5 μM OBD column, 19×250 mm, waters; gradient elution of 20% MeCN in water to 75% MeCN in water over a 20 min period, where both solvents contain 0.1% TFA, flow rate: 20 mL/min) to provide the title compound in the TFA salt as a white solid (23 mg, 27%). MS: (M+H).sup.+ found for C.sub.31H.sub.28ClN.sub.4O.sub.3: 539.1.

Example 82

Synthesis of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-10-(1-benzofuran-3-yl)tricycle-[6.2.1.02,7]undeca-2,4,6,9-tetraene-4-carboxamide and (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-9-(1-benzofuran-3-yl)tricyclo[6.2.1.02,7]undeca-2,4,6,9-tetraene-4-carboxamide

(574) ##STR00706##

(575) Step 1:

(576) Into a 250-mL sealed tube, was placed a mixture of cyclopenta-1,3-diene (26.4 g, 400 mmol, 1.00 equiv) and (Z)-1,4-dichlorobut-2-ene (100.0 g, 800 mmol, 2.00 equiv). The resulting mixture was stirred for 5 hours at 180° C. in an oil bath. After cooling to room temperature, the crude product was purified by fractional distillation (100° C./10 Torr) to afford 11.8 g (15%, crude product) of (±)-5,6-bis(chloromethyl)bicyclo[2.2.1]hept-2-ene as a brown oil, which was used directly for next step without further purification.

(577) Step 2:

(578) Into a 1000-mL round-bottom flask, was placed a solution of (±)-5,6-bis(chloromethyl)bicyclo[2.2.1]hept-2-ene (19.3 g, 101 mmol, 1.00 equiv) in tetrahydrofuran (300 mL), followed by the addition of NaBH.sub.4 (5.01 g, 135.34 mmol, 1.34 equiv). BF.sub.3.Et.sub.2O (23.0 g, 161.6 mmol, 1.60 equiv) was then added dropwise with stirring at 0° C. and the resulting mixture was stirred for 3 hours at room temperature. Water (19.5 mL), 3 N aqueous potassium hydroxide (29.3 mL), and H.sub.2O.sub.2 (23.4 mL, 30%, 2.30 equiv) were then added dropwise in succession at 0° C., and the mixture was stirred at room temperature for an additional 16 hours. The reaction was then quenched by the addition of saturated aqueous Na.sub.2S.sub.2O.sub.3, diluted with water, extracted with ethyl acetate. The organic layers were combined and concentrated under reduced pressure to afford 19.0 g of a crude mixture of (1R,2S,4R)-5,6-bis(chloromethyl)bicyclo[2.2.1]heptan-2-ol, (1S,2R,4S)-5,6-bis(chloromethyl)bicyclo[2.2.1]-heptan-2-ol and (1S,2S,4S)-5,6-bis(chloromethyl)bicyclo[2.2.1]heptan-2-ol, (1R,2R,4R)-5,6-bis(chloromethyl)bicyclo[2.2.1]heptan-2-ol as a white solid, which was used directly for next step without further purification.

(579) Step 3:

(580) Into a 250-mL round-bottom flask, was placed a solution of a mixture of (1R,2S,4R)-5,6-bis(chloromethyl)bicyclo[2.2.1]heptan-2-ol, (1S,2R,4S)-5,6-bis(chloromethyl)bicyclo[2.2.1]heptan-2-ol and (1S,2S,4S)-5,6-bis(chloromethyl)bicyclo[2.2.1]heptan-2-ol, (1R,2R,4R)-5,6-bis(chloromethyl)bicyclo[2.2.1]heptan-2-ol (19.0 g crude, 101 mmol, 1.00 equiv) in ethanol (150 mL), followed by the addition of potassium hydroxide (15.82 g, 282 mmol, 2.80 equiv) in portions. The resulting mixture was stirred for 16 hours at 80° C. The mixture was then cooled to RT and diluted with water and extracted with dichloromethane. The organic layers were combined and concentrated under vacuum. The crude product was purified by flash chromatography eluting with ethyl acetate/petroleum ether (1/5) to afford 5.60 g (2-step: 41%) of (1R,2S,4R)-5,6-dimethylidenebicyclo[2.2.1]-heptan-2-ol, (1S,2R,4S)-5,6-dimethylidenebicyclo[2.2.1]heptan-2-ol, (1R,2R,4R)-5,6-dimethylidenebicyclo[2.2.1]heptan-2-ol and (1S,2S,4S)-5,6-dimethylidenebicyclo[2.2.1]heptan-2-ol as a yellow oil.

(581) Step 4:

(582) Into a 40-mL sealed tube, was placed a mixture of (1R,2S,4R)-5,6-dimethylidenebicyclo[2.2.1]heptan-2-ol, (1S,2R,4S)-5,6-dimethylidenebicyclo[2.2.1]heptan-2-ol, (1R,2R,4R)-5,6-dimethylidenebicyclo[2.2.1]heptan-2-ol and (1S,2S,4S)-5,6-dimethylidenebicyclo[2.2.1]heptan-2-ol (1.90 g, 14.0 mmol, 1.00 equiv), methyl prop-2-ynoate (8.21 g, 97.7 mmol, 7.00 equiv) and benzene (35 mL). The resulting mixture was stirred for 2 hours at 100° C. in an oil bath. The mixture was then concentrated under vacuum to afford 3.12 g (crude) of methyl (1R,8R,10S)-10-hydroxytricyclo[6.2.1.0.sup.2,7]undeca-2(7),4-diene-4-carboxylate, methyl (1R,8R,10R)-10-hydroxytricyclo[6.2.1.0.sup.2,7]undeca-2(7),4-diene-4-carboxylate, methyl (1S,8S,10S)-10-hydroxytricyclo[6.2.1.0.sup.2,7]undeca-2(7),4-diene-4-carboxylate, methyl (1S,8S,10R)-10-hydroxytricyclo[6.2.1.0.sup.2,7]undeca-2(7),4-diene-4-carboxylate, methyl (1S,8S,9R)-9-hydroxytricyclo[6.2.1.0.sup.2,7]undeca-2(7),4-diene-4-carboxylate, methyl (1S,8S,9S)-9-hydroxytricyclo[6.2.1.0.sup.2,7]undeca-2(7),4-diene-4-carboxylate, methyl (1R,8R,9R)-9-hydroxytricyclo[6.2.1.0.sup.2,7]undeca-2(7),4-diene-4-carboxylate and methyl (1R,8R,9S)-9-hydroxytricyclo[6.2.1.0.sup.2,7]undeca-2(7),4-diene-4-carboxylate as brown oil, which was used directly for the next step without any purification.

(583) Step 5:

(584) Into a 100-mL round-bottom flask, was placed a solution of methyl (1R,8R,10S)-10-hydroxytricyclo[6.2.1.0.sup.2,7]undeca-2(7),4-diene-4-carboxylate, methyl (1R,8R,10R)-10-hydroxytricyclo[6.2.1.0.sup.2,7]undeca-2(7),4-diene-4-carboxylate, methyl (1S,8S,10S)-10-hydroxy-tricyclo[6.2.1.0.sup.2,7]undeca-2(7),4-diene-4-carboxylate, methyl (1S,8S,10R)-10-hydroxytricyclo-[6.2.1.0.sup.2,7]undeca-2(7),4-diene-4-carboxylate, methyl (1S,8S,9R)-9-hydroxytricyclo[6.2.1.0.sup.2,7]-undeca-2(7),4-diene-4-carboxylate, methyl (1S,8S,9S)-9-hydroxytricyclo[6.2.1.0.sup.2,7]undeca-2(7),4-diene-4-carboxylate, methyl (1R,8R,9R)-9-hydroxytricyclo[6.2.1.0.sup.2,7]undeca-2(7),4-diene-4-carboxylate and methyl (1R,8R,9S)-9-hydroxytricyclo[6.2.1.0.sup.2,7]undeca-2(7),4-diene-4-carboxylate (3.12 g crude, 14.0 mmol, 1.00 equiv) in benzene (50 mL) followed by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ; 6.36 g, 28.02 mmol, 2.00 equiv) in portions at 0° C. The resulting mixture was stirred for 16 hours at room temperature. The reaction mixture was then quenched by the addition of 200 mL of 5% aqueous Na.sub.2S.sub.2O.sub.5 solution and stirred for 30 minutes. The solids were separated by filtration and washed with petroleum ether (PE; 20 mL) and the filtrate was extracted with ethyl acetate. The organic layers were combined, washed with 5% Na.sub.2S.sub.2O.sub.5 solution and saturated sodium bicarbonate solution and concentrated under vacuum. The residue was purified by flash chromatography eluting with ethyl acetate/petroleum ether (1/5) to afford 2.58 g (2-steps yield: 83%) of methyl (1R,8R,10S)-10-hydroxytricyclo[6.2.1.0.sup.2,7]undeca-2,4,6-triene-4-carboxylate, methyl (1R,8R,10R)-10-hydroxytricyclo[6.2.1.0.sup.2,7]undeca-2,4,6-triene-4-carboxylate, methyl (1S,8S,10S)-10-hydroxytricyclo[6.2.1.0.sup.2,7]undeca-2,4,6-triene-4-carboxylate, methyl (1S,8S,10R)-10-hydroxytricyclo[6.2.1.0.sup.2,7]undeca-2,4,6-triene-4-carboxylate, methyl (1S,8S,9R)-9-hydroxytricyclo[6.2.1.0.sup.2,7]undeca-2,4,6-triene-4-carboxylate, methyl (1S,8S,9S)-9-hydroxytricyclo[6.2.1.0.sup.2,7]undeca-2,4,6-triene-4-carboxylate, methyl (1R,8R,9R)-9-hydroxy-tricyclo[6.2.1.0.sup.2,7]undeca-2,4,6-triene-4-carboxylate and methyl (1R,8R,9S)-9-hydroxy-tricyclo[6.2.1.0.sup.2,7]undeca-2,4,6-triene-4-carboxylate as brown oil.

(585) Step 6:

(586) Into a 100-mL round-bottom flask, was placed a solution of methyl (1R,8R,10S)-10-hydroxytricyclo[6.2.1.0.sup.2,7]undeca-2,4,6-triene-4-carboxylate, methyl (1R,8R,10R)-10-hydroxytricyclo[6.2.1.0.sup.2,7]undeca-2,4,6-triene-4-carboxylate, methyl (1S,8S,10S)-10-hydroxy-tricyclo[6.2.1.0.sup.2,7]undeca-2,4,6-triene-4-carboxylate, methyl (1S,8S,10R)-10-hydroxytricyclo-[6.2.1.0.sup.2,7]undeca-2,4,6-triene-4-carboxylate, methyl (1S,8S,9R)-9-hydroxytricyclo[6.2.1.0.sup.2,7]-undeca-2,4,6-triene-4-carboxylate, methyl (1S,8S,9S)-9-hydroxytricyclo[6.2.1.0.sup.2,7]undeca-2,4,6-triene-4-carboxylate, methyl (1R,8R,9R)-9-hydroxytricyclo[6.2.1.0.sup.2,7]undeca-2,4,6-triene-4-carboxylate and methyl (1R,8R,9S)-9-hydroxytricyclo[6.2.1.0.sup.2,7]undeca-2,4,6-triene-4-carboxylate (1.50 g, 6.87 mmol, 1.00 equiv) in dichloromethane (30 mL) followed by Dess-Martin reagent (5.83 g, 13.8 mmol, 2.00 equiv) in portions at 0° C. and 0.5 mL of H.sub.2O. The resulting mixture was stirred for 16 hours at 20° C. The solids were then separated by filtration and the filtrate was concentrated under vacuum. The residue was diluted with 50 mL of saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography eluting with ethyl acetate/petroleum ether (1/5) to afford 760 mg (51%) of (±)-methyl 10-oxotricyclo-[6.2.1.0.sup.2,7]-undeca-2,4,6-triene-4-carboxylate and (±)-methyl 9-oxotricyclo[6.2.1.0.sup.2,7]undeca-2,4,6-triene-4-carboxylate as yellow oil.

(587) Step 7:

(588) Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tetrahydrofuran (50 mL) with stirring at −78° C., followed by the drop-wise addition of n-BuLi (5.12 mL, 2.5 M in hexane, 12.74 mmol, 1.10 equiv). A solution of 3-bromo-1-benzofuran (2.51 g, 12.74 mmol, 1.10 equiv) in tetrahydrofuran (10 mL) was then added drop-wise with stirring at −78° C. and the resulting mixture was stirred at −78° C. for an additional 1 h. A mixture of (±)-methyl 10-oxotricyclo[6.2.1.0.sup.2,7]undeca-2,4,6-triene-4-carboxylate and (±)-methyl 9-oxotricyclo[6.2.1.0.sup.2,7]undeca-2,4,6-triene-4-carboxylate (2.50 g, 11.56 mmol, 1.00 equiv) in tetrahydrofuran (10 mL) was then added dropwise and the reaction mixture was stirred for an additional 60 minutes at −78° C. The reaction was then carefully quenched by the addition of 100 mL of saturated aqueous NH.sub.4Cl solution and extracted with 3×100 mL of ethyl acetate. The organic layers were combined, washed with 1×100 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to afford 3.71 g (96%) of methyl (1R,8R,10S)-10-(1-benzofuran-3-yl)-10-hydroxytricyclo[6.2.1.0.sup.2,7]undeca-2,4,6-triene-4-carboxylate, methyl (1R,8R,10R)-10-(1-benzofuran-3-yl)-10-hydroxytricyclo[6.2.1.0.sup.2,7]undeca-2,4,6-triene-4-carboxylate, methyl (1S,8S,10S)-10-(1-benzofuran-3-yl)-10-hydroxytricyclo[6.2.1.0.sup.2,7]undeca-2,4,6-triene-4-carboxylate, methyl (1S,8S,10R)-10-(1-benzofuran-3-yl)-10-hydroxytricyclo[6.2.1.0.sup.2,7]undeca-2,4,6-triene-4-carboxylate, methyl (1R,8R,9S)-9-(1-benzofuran-3-yl)-10-hydroxytricyclo[6.2.1.0.sup.2,7]undeca-2,4,6-triene-4-carboxylate, methyl (1R,8R,9R)-9-(1-benzofuran-3-yl)-10-hydroxytricyclo[6.2.1.0.sup.2,7]undeca-2,4,6-triene-4-carboxylate, methyl (1S,8S,9S)-9-(1-benzofuran-3-yl)-10-hydroxytricyclo[6.2.1.0.sup.2,7]undeca-2,4,6-triene-4-carboxylate and methyl (1S,8S,9R)-9-(1-benzofuran-3-yl)-10-hydroxytricyclo[6.2.1.0.sup.2,7]undeca-2,4,6-triene-4-carboxylate as a yellow solid, which was used for next step without further purification. LCMS (ES) [M+CH.sub.3CN+1].sup.+ m/z 376.0.

(589) Step 8:

(590) Into a 50-mL round-bottom flask, was placed a mixture of methyl (1R,8R,10S)-10-(1-benzofuran-3-yl)-10-hydroxytricyclo[6.2.1.0.sup.2,7]undeca-2,4,6-triene-4-carboxylate, methyl (1R,8R,10R)-10-(1-benzofuran-3-yl)-10-hydroxytricyclo[6.2.1.0.sup.2,7]undeca-2,4,6-triene-4-carboxylate, methyl (1S,8S,10S)-10-(1-benzofuran-3-yl)-10-hydroxytricyclo[6.2.1.0.sup.2,7]undeca-2,4,6-triene-4-carboxylate, methyl (1S,8S,10R)-10-(1-benzofuran-3-yl)-10-hydroxytricyclo[6.2.1.0.sup.2,7]undeca-2,4,6-triene-4-carboxylate, methyl (1R,8R,9S)-9-(1-benzofuran-3-yl)-10-hydroxytricyclo[6.2.1.0.sup.2,7]undeca-2,4,6-triene-4-carboxylate, methyl (1R,8R,9R)-9-(1-benzofuran-3-yl)-10-hydroxytricyclo[6.2.1.0.sup.2,7]undeca-2,4,6-triene-4-carboxylate, methyl (1S,8S,9S)-9-(1-benzofuran-3-yl)-10-hydroxytricyclo-[6.2.1.0.sup.2,7]undeca-2,4,6-triene-4-carboxylate and methyl (1S,8S,9R)-9-(1-benzofuran-3-yl)-10-hydroxytricyclo[6.2.1.0.sup.2,7]undeca-2,4,6-triene-4-carboxylate (1.00 g, 2.99 mmol, 1.00 equiv), dichloromethane (20.0 mL) and TEA (906 mg, 8.95 mmol, 2.50 equiv) followed by the drop-wise addition of MsCl (682 mg, 2.00 equiv) with stirring at 0° C. The resulting mixture was stirred for 2 h at 20° C. then it was diluted with 50 mL of DCM, washed with 1×30 mL of H.sub.2O, 1×30 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography eluting with ethyl acetate/petroleum ether (1/3) to afford 621 mg of a 1:1 mixture of (±)-methyl 10-(1-benzofuran-3-yl)tricyclo[6.2.1.0.sup.2,7]undeca-2,4,6,9-tetraene-4-carboxylate and (±)-methyl 9-(1-benzofuran-3-yl)tricyclo[6.2.1.0.sup.2,7]undeca-2,4,6,9-tetraene-4-carboxylate (66%) as a yellow solid.

(591) Step 9:

(592) Into a 100-mL round-bottom flask, was placed a 1:1 mixture of (±)-methyl 10-(1-benzofuran-3-yl)tricyclo[6.2.1.0.sup.2,7]undeca-2,4,6,9-tetraene-4-carboxylate and (±)-methyl 9-(1-benzofuran-3-yl)tricyclo[6.2.1.0.sup.2,7]undeca-2,4,6,9-tetraene-4-carboxylate (300 mg, 0.95 mmol, 1.00 equiv), LiOH.H.sub.2O (199 mg, 4.74 mmol, 5.00 equiv), methanol (15.0 mL) and water (5.0 mL). The resulting mixture was stirred for 2 hours at 60° C. then it was cooled to RT, diluted with 50 mL of water and the pH value of the aqueous phase was adjusted to 3 with 1 N HCl aqueous solution. The mixture was then extracted with 2×50 mL of a mixed solvents of DCM/MeOH (10/1) and the organic layer was dried and concentrated to afford 193 mg (67%) of (±)-10-(1-benzofuran-3-yl)tricyclo[6.2.1.0.sup.2,7]undeca-2,4,6,9-tetraene-4-carboxylic acid and (±)-9-(1-benzofuran-3-yl)tricyclo[6.2.1.0.sup.2,7]undeca-2,4,6,9-tetraene-4-carboxylic acid as yellow oil, which was used for the next step without further purification.

(593) Step 10:

(594) Into a 25-mL round-bottom flask, was placed 5-(aminomethyl)-4,6-dimethylpyridin-2-amine (84 mg, 0.56 mmol, 1.20 equiv), N,N-dimethylformamide (5.00 mL), (±)-10-(1-benzofuran-3-yl)tricyclo[6.2.1.0.sup.2,7]undeca-2,4,6,9-tetraene-4-carboxylic acid and (±)-9-(1-benzofuran-3-yl)tricyclo[6.2.1.0.sup.2,7]undeca-2,4,6,9-tetraene-4-carboxylic acid (1:1 mixture; 140 mg, 0.46 mmol, 1.00 equiv), TEA (234 mg, 2.31 mmol, 5.00 equiv) and HATU (194 mg, 0.51 mmol, 1.10 equiv). The resulting mixture was stirred for 3 hours at room temperature. The solution was then diluted with 50 mL of water and extracted with 2×50 mL of ethyl acetate. The organic layers were dried and concentrated under reduced pressure and the residue was purified by flash chromatography eluting with methanol/EtOAc (1/8). The collected fractions were concentrated and lyophilized to afford 120 mg (60%) of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-10-(1-benzofuran-3-yl)tricycle-[6.2.1.0.sup.2,7]undeca-2,4,6,9-tetraene-4-carboxamide and (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-9-(1-benzofuran-3-yl)tricyclo[6.2.1.0.sup.2,7]-undeca-2,4,6,9-tetraene-4-carboxamide (1:1 mixture) as light yellow solids. MS: (M+H).sup.+ found for C.sub.28H.sub.25N.sub.3O.sub.2: 436.1.

Example 83

Synthesis of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-10-phenyltricyclo-[6.2.1.02,7]undeca-2,4,6,9-tetraene-4-carboxamide and (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-9-phenyltricyclo[6.2.1.02,7]undeca-2,4,6,9-tetraene-4-carboxamide

(595) ##STR00707##

(596) Step 1:

(597) Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tetrahydrofuran (10.0 mL) and n-BuLi (1.17 mL, 2.5 M in hexane, 2.90 mmol, 1.05 equiv) with stirring at −78° C. Bromobenzene (456 mg, 2.90 mmol, 1.05 equiv) in tetrahydrofuran (5 mL) was then added drop-wise at −78° C. abd the resulting mixture was stirred for 60 minutes at −78° C. A solution of methyl (±)-methyl 10-oxotricyclo[6.2.1.0.sup.2,7]-undeca-2,4,6-triene-4-carboxylate and (±)-methyl 9-oxotricyclo-[6.2.1.0.sup.2,7]undeca-2,4,6-triene-4-carboxylate (1; 1 mixture; 600 mg, 2.77 mmol, 1.00 equiv) in tetrahydrofuran (5 mL) was then added drop-wise and the resulting mixture was stirred for an additional 60 minutes at −78° C. The reaction was then quenched by the addition of 30 mL of saturated NH.sub.4Cl solution and 20 mL of H.sub.2O. The aqueous phase was extracted with ethyl acetate, the organic layers were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude material was purified by flash chromatography eluting with ethyl acetate/petroleum ether (1/5) to afford 250 mg (31%) of a mixture of methyl (1R,8R,10S)-10-hydroxy-10-phenyltricyclo[6.2.1.0.sup.2,7]undeca-2,4,6-triene-4-carboxylate, methyl (1R,8R,10R)-10-hydroxy-10-phenyltricyclo[6.2.1.0.sup.2,7]undeca-2,4,6-triene-4-carboxylate, methyl (1S,8S,10R)-10-hydroxy-10-phenyltricyclo[6.2.1.0.sup.2,7]undeca-2,4,6-triene-4-carboxylate, methyl (1S,8S,10S)-10-hydroxy-10-phenyltricyclo[6.2.1.0.sup.2,7]-undeca-2,4,6-triene-4-carboxylate, methyl (1R,8R,9S)-9-hydroxy-9-phenyltricyclo-[6.2.1.0.sup.2,7]undeca-2,4,6-triene-4-carboxylate, methyl (1R,8R,9R)-9-hydroxy-9-phenyltricyclo[6.2.1.0.sup.2,7]undeca-2,4,6-triene-4-carboxylate, methyl (1S,8S,9R)-9-hydroxy-9-phenyltricyclo[6.2.1.0.sup.2,7]undeca-2,4,6-triene-4-carboxylate and methyl (1S,8S,9S)-9-hydroxy-9-phenyltricyclo[6.2.1.0.sup.2,7]undeca-2,4,6-triene-4-carboxylate as colorless oil.

(598) Step 2:

(599) Into a 25-mL round-bottom flask, was placed a solution of a mixture of methyl (1R,8R,10S)-10-hydroxy-10-phenyltricyclo[6.2.1.0.sup.2,7]undeca-2,4,6-triene-4-carboxylate, methyl (1R,8R,10R)-10-hydroxy-10-phenyltricyclo[6.2.1.0.sup.2,7]undeca-2,4,6-triene-4-carboxylate, methyl (1S,8S,10R)-10-hydroxy-10-phenyltricyclo[6.2.1.0.sup.2,7]undeca-2,4,6-triene-4-carboxylate, methyl (1S,8S,10S)-10-hydroxy-10-phenyltricyclo[6.2.1.0.sup.2,7]undeca-2,4,6-triene-4-carboxylate, methyl (1R,8R,9S)-9-hydroxy-9-phenyltricyclo[6.2.1.0.sup.2,7]-undeca-2,4,6-triene-4-carboxylate, methyl (1R,8R,9R)-9-hydroxy-9-phenyltricyclo[6.2.1.0.sup.2,7]undeca-2,4,6-triene-4-carboxylate, methyl (1S,8S,9R)-9-hydroxy-9-phenyltricyclo[6.2.1.0.sup.2,7]undeca-2,4,6-triene-4-carboxylate and methyl (1S,8S,9S)-9-hydroxy-9-phenyltricyclo[6.2.1.0.sup.2,7]undeca-2,4,6-triene-4-carboxylate (200 mg, 0.68 mmol, 1.00 equiv) and TEA (172 mg, 1.70 mmol, 2.50 equiv) in dichloromethane (5.00 mL) with stirring at 0° C. MsCl (155 mg, 2.00 equiv) was then added drop-wise and the resulting mixture was stirred for 4 hours at 20° C. The mixture was then diluted with H.sub.2O and extracted with dichloromethane. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by prep-TLC (PE/EtOAc=1/1) to afford 53 mg (28%) of a 1:1 mixture of (±)-methyl 10-phenyltricyclo[6.2.1.0.sup.2,7]undeca-2,4,6,9-tetraene-4-carboxylate and (±)-methyl 9-phenyltricyclo[6.2.1.0.sup.2,7]undeca-2,4,6,9-tetraene-4-carboxylate as brown oil.

(600) Step 3:

(601) Into a 25-mL round-bottom flask, was placed a 1:1 mixture of (±)-methyl 10-phenyltricyclo[6.2.1.0.sup.2,7]undeca-2,4,6,9-tetraene-4-carboxylate and (±)-methyl 9-phenyltricyclo[6.2.1.0.sup.2,7]undeca-2,4,6,9-tetraene-4-carboxylate (53 mg, 0.19 mmol, 1.00 equiv), methanol (3 mL), LiOH.H.sub.2O (40 mg, 0.95 mmol, 5.00 equiv) and water (0.5 mL). The resulting mixture was stirred for 60 minutes at 80° C., then it was cooled to RT and concentrated under vacuum. The residue was diluted with 10 mL of H.sub.2O and the pH value of the solution was adjusted to 3 with 2 N aqueous hydrogen chloride solution. The aqueous phase was extracted with 5×10 mL of a mixed solution of DCM/MeOH (10/1). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to afford 36 mg (72%) of a 1:1 mixture of (±)-10-phenyltricyclo[6.2.1.0.sup.2,7]undeca-2,4,6,9-tetraene-4-carboxylic acid and (±)-9-phenyltricyclo[6.2.1.0.sup.2,7]undeca-2,4,6,9-tetraene-4-carboxylic acid as yellow oil, which was used directly for next step without any further purification.

(602) Step 4:

(603) Into a 25-mL round-bottom flask, was placed a mixture of a 1:1 mixture of (±)-10-phenyltricyclo[6.2.1.0.sup.2,7]undeca-2,4,6,9-tetraene-4-carboxylic acid and (±)-9-phenyltricyclo[6.2.1.0.sup.2,7]undeca-2,4,6,9-tetraene-4-carboxylic acid (36 mg, 0.14 mmol, 1.00 equiv), N,N-dimethylformamide (3.00 mL), 5-(aminomethyl)-4,6-dimethylpyridin-2-amine (21 mg, 0.14 mmol, 1.00 equiv), DIEA (43 mg, 0.33 mmol, 2.35 equiv) and HATU (78 mg, 0.21 mmol, 1.50 equiv). The resulting mixture was stirred for 1 h at room temperature, then it was diluted with 5 mL of H.sub.2O and the precipitate thus formed was collected by filtration. The crude product was subjected to reverse preparative HPLC (Prep-C18, 5 μM XBridge column, 19×150 mm, waters; gradient elution of 25% MeCN in water to 55% MeCN in water over a 8 min period, where the aqueous phase contains 10 mM NH.sub.4HCO.sub.3+0.5% ammonia) to provide 13.4 mg (25%) of a 1:1 mixture of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-10-phenyltricyclo[6.2.1.0.sup.2,7]undeca-2,4,6,9-tetraene-4-carboxamide and (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-9-phenyltricyclo[6.2.1.0.sup.2,7]undeca-2,4,6,9-tetraene-4-carboxamide as a white solid. MS: (M+H).sup.+ found for C.sub.26H.sub.25N.sub.3O: 396.1

Example 84

Synthesis of (±)-N-[(6-amino-4-methoxy-2-methylpyridin-3-yl)methyl]-12-[(1H-pyrazol-1-yl)-methyl]-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(604) ##STR00708##

(605) Step 1:

(606) Into a 500-mL 3-necked round-bottom flask, was placed a mixture of 1,4-dioxane (300 mL), acetyl acetate (44.77 g, 438.54 mmol, 1.20 equiv), 2-cyanoacetic acid (37.1 g, 436.16 mmol, 1.20 equiv) and (2Z)-3-aminobut-2-enenitrile (30 g, 365.39 mmol, 1.00 equiv). The resulted solution was heated to reflux for 2 h. The reaction mixture was then cooled to room temperature with a water/ice bath and the solids were collected by filtration to afford 23.2 g (crude) of (2Z)-2-(1-aminoethylidene)-3-oxopentanedinitrile as a yellow solid. This material was used for the next step without further purification.

(607) Step 2:

(608) Into a 500-mL round-bottom flask, was placed a mixture of ethanol (300 mL), (2Z)-2-(1-aminoethylidene)-3-oxopentanedinitrile (23.0 g, 154.21 mmol, 1.00 equiv) and sodium ethoxide (11.0 g, 161.65 mmol, 1.05 equiv). The resulted mixture was heated to reflux for 1 h. The reaction mixture was then cooled to room temperature with a water/ice bath and concentrated under vacuum to afford 20.5 g (crude) of 6-amino-2-methyl-4-oxo-1,4-dihydropyridine-3-carbonitrile as a yellow solid. This material was used for the next step without further purification.

(609) Step 3:

(610) Into a 500-mL 3-necked round-bottom flask, was placed a mixture of K.sub.2CO.sub.3 (27.74 g, 199.26 mmol, 1.50 equiv) and 6-amino-2-methyl-4-oxo-1,4-dihydropyridine-3-carbonitrile (20 g, 134.09 mmol, 1.00 equiv) in N,N-dimethylformamide (200 mL) with stirring at 0° C., followed by the drop-wise addition of iodomethane (22.86 g, 161.06 mmol, 1.20 equiv). The resulting solution was stirred overnight at room temperature, then it was quenched by the addition of water/ice and the solids were collected by filtration to afford 13.5 g (62%) of 6-amino-4-methoxy-2-methylpyridine-3-carbonitrile as a yellow solid.

(611) Step 4:

(612) Into a 50-mL round-bottom flask, was placed a mixture of 6-amino-4-methoxy-2-methylpyridine-3-carbonitrile (330 mg, 2.02 mmol, 1.00 equiv), methanol (23 mL) and Raney Ni (100 mg) under N.sub.2. The mixture was degassed and purged with hydrogen four times. The resulting mixture was stirred for 16 h at room temperature under a hydrogen atmosphere (balloon). The mixture was then filtered through a pad of Celite and the filtrate was concentrated under vacuum. The crude product was purified by Prep.TLC eluting with DMC/MeOH (ratio: 5/1) to afford 80 mg (24%) of 5-(aminomethyl)-4-methoxy-6-methylpyridin-2-amine as a white solid.

(613) Step 5:

(614) Into a 500-mL round-bottom flask, was placed a mixture of (±) sodium 12-bromo-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (INT-5a) (500 mg, 1.47 mmol, 1.00 equiv), dioxane (80 mL), MeOH (20 mL), trimethyl-1,3,5,2,4,6-trioxatriborinane (876 mg, 2.96 mmol, 2.00 equiv, 50% in THF), Cs.sub.2CO.sub.3 (1.21 g, 3.71 mmol, 2.50 equiv) and Pd(dppf)Cl.sub.2 (108 mg, 0.15 mmol, 0.10 equiv). The resulting mixture was stirred for 1 hour at 80° C. then it was cooled to RT and the solids were separated by filtration and washed with MeOH. The filtrate was concentrated under vacuum to afford 1.06 g of crude (±) sodium 12-methyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate as a brown solid, which was used directly for next step without further purification.

(615) Step 6:

(616) Into a 100-mL round-bottom flask, was placed a mixture of (±) sodium 12-methyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (1.06 g crude, 1.47 mmol, 1.00 equiv) in N,N-dimethylformamide (30 mL) with stirring at rt, followed by the drop-wise addition of iodomethane (851 mg, 6.00 mmol, 4.00 equiv). The resulting mixture was stirred for 2 hours at room temperature then it was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel chromatography eluting with ethyl acetate/petroleum ether (1/5) to afford 389 mg (99% over 2 steps) of (±)-methyl 12-methyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate as a yellow solid.

(617) Step 7:

(618) Into a 50-mL round-bottom flask, was placed a mixture of (±)-methyl 12-methyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (350 mg, 1.31 mmol, 1.00 equiv), CCl.sub.4 (20 mL) and NBS (258 mg, 1.45 mmol, 1.10 equiv) with stirring at rt, followed by the addition of AIBN (22 mg, 0.13 mmol, 0.10 equiv). The resulting mixture was stirred for 3 hours at 80° C. then it was cooled to RT and the solids were separated by filtration and washed with 3×5 mL of CCl.sub.4. The filtrate was concentrated under vacuum to afford 580 mg of crude (±)-methyl 12-(bromomethyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate as a yellow solid, which was used directly for next step without any further purification.

(619) Step 8:

(620) Into a 100-mL round-bottom flask, was placed a mixture of (±)-methyl 12-(bromomethyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (580 mg crude, 1.31 mmol, 1.00 equiv), CH.sub.3CN (20 mL), 1H-pyrazole (85 mg, 1.31 mmol, 1.00 equiv) and Cs.sub.2CO.sub.3 (682 mg, 2.09 mmol, 1.60 equiv). The resulting mixture was stirred for 3 hours at room temperature then the solids were separated by filtration and washed with 3×10 mL of CH.sub.3CN. The filtrate was concentrated under vacuum and the residue was purified by Prep-TLC (ethyl acetate/petroleum ether=1/1) to afford 124 mg (27% yield over 2 steps) of (±)-methyl 12-(1H-pyrazol-1-ylmethyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate as a yellow solid.

(621) Step 9:

(622) Into a 50-mL round-bottom flask, was placed a solution of (±)-methyl 12-(1H-pyrazol-1-ylmethyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (78 mg, 0.23 mmol, 1.00 equiv) in methanol (6.00 mL) with stirring, followed by the addition of a solution of sodium hydroxide (47 mg, 1.18 mmol, 5.00 equiv) in water (1.00 mL). The resulting mixture was stirred for 3 hours at 60° C. then it was cooled to RT and the pH value of the solution was adjusted to 3 with aqueous 2N hydrogen chloride solution. The mixture was then concentrated under vacuum and the residue was treated with ethyl acetate. The solids were separated by filtration and washed with ethyl acetate. The filtrate was concentrated under vacuum to afford 75 mg (100%) of (±)-12-(1H-pyrazol-1-ylmethyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid as a yellow solid.

(623) Step 10:

(624) Into a 8-mL vial, was placed a mixture of (±)-12-(1H-pyrazol-1-ylmethyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (83 mg, 0.26 mmol, 1.00 equiv), N,N-dimethylformamide (2.00 mL), 5-(aminomethyl)-4-methoxy-6-methylpyridin-2-amine (42 mg, 0.26 mmol, 1.00 equiv), DIEA (68 mg, 0.52 mmol, 2.00 equiv) and HATU (198 mg, 0.52 mmol, 2.00 equiv). The resulting mixture was stirred for 1 hour at room temperature then it was filtered and subjected to reverse preparative HPLC (Prep-C18, 5 μM XBridge column, 19×150 mm, waters; gradient elution of 28% MeCN in water to 40% MeCN in water over a 4 min period, 40% MeCN in water to 70% MeCN in water over an 8 min period, where the aqueous phase contained 10 mM NH.sub.4HCO.sub.3 and 0.5% ammonia) to provide (±)-N-[(6-amino-4-methoxy-2-methylpyridin-3-yl)methyl]-12-[(1H-pyrazol-1-yl)methyl]-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide as a white solid (23.3 mg, 19%). MS: (M+H).sup.+ found for C.sub.27H.sub.25N.sub.5O.sub.3: 468.2.

Example 85

Synthesis of (±)-N-[(6-amino-4-methoxy-2-methylpyridin-3-yl)methyl]-12-[(4-methyl-1H-pyrazol-1-yl)methyl]-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(625) ##STR00709##

(626) The title compound was prepared following the procedures described for Example 84 but using 4-methyl-1H-pyrazole instead of 1H-pyrazole in Step 8. MS: (M+H).sup.+ found for C.sub.28H.sub.27N.sub.5O.sub.3: 482.2.

Example 86

Synthesis of (±)-N-[(6-amino-4-ethoxy-2-methylpyridin-3-yl)methyl]-12-(2,4-difluorophenyl)-16-oxo-15-azatetracyclo[6.6.2.02,7.09,14]hexadeca-2,4,6,9,11,13-hexaene-4-carboxamide, (±)-N-[(6-amino-4-ethoxy-2-methylpyridin-3-yl)methyl]-11-(2,4-difluorophenyl)-16-oxo-15-azatetracyclo[6.6.2.02,7.09,14]hexadeca-2,4,6,9,11,13-hexaene-4-carboxamide, (±)-N-[(6-amino-4-ethoxy-2-methylpyridin-3-yl)methyl]-12-(2,4-difluorophenyl)-16-oxo-15-azatetracyclo[6.6.2.02,7.09,14]hexadeca-2,4,6,9,11,13-hexaene-5-carboxamide and (±)-N-[(6-amino-4-ethoxy-2-methylpyridin-3-yl)methyl]-11-(2,4-difluorophenyl)-16-oxo-15-azatetracyclo[6.6.2.02,7.09,14]hexadeca-2,4,6,9,11,13-hexaene-5-carboxamide

(627) ##STR00710##

(628) Step 1:

(629) Into a 250-mL round-bottom flask, was placed a mixture of 7-bromoisoquinolin-3-ol (6.69 g, 29.86 mmol, 1.00 equiv), N,N-dimethylformamide (60 mL), 1-(chloromethyl)-4-methoxybenzene (7.02 g, 44.83 mmol, 1.50 equiv) and Cs.sub.2CO.sub.3 (34.23 g, 105.06 mmol, 3.50 equiv). The resulting solution was stirred for 2 h at room temperature, then the solids were separated by filtration and the filtrate was concentrated under vacuum. The residue was purified by silica gel column eluting with ethyl acetate/petroleum ether (1/1) to afford 6.0 g (crude) of 7-bromo-2-[(4-methoxyphenyl)methyl]-2,3-dihydroisoquinolin-3-one as a yellow solid.

(630) Step 2:

(631) Into a 100-mL round-bottom flask, was placed a solution of 7-bromo-2-[(4-methoxyphenyl) methyl]-2,3-dihydroisoquinolin-3-one (631 mg, 1.84 mmol, 1.00 equiv), dichloromethane (30 mL) and [5-(methoxycarbonyl)-2-(trimethylsilyl)phenyl](phenyl) iodanium trifluoromethanesulfonate (2.06 g, 3.68 mmol, 2.00 equiv). To the above solution was added TBAF (3.67 mL, 1.0 M in THF, 3.68 mmol, 2.00 equiv) dropwise at 0° C. and the resulting mixture was stirred for 1 h at room temperature. The suspension was then concentrated under vacuum and the residue was purified by silica gel column eluting with ethyl acetate/petroleum ether (1/2) to afford 365 mg (42%) of a mixture of (±)-methyl 12-bromo-15-[(4-methoxyphenyl)-methyl]-16-oxo-15-azatetracyclo[6.6.2.0.sup.2,7.0.sup.9,14]hexadeca-2,4,6,9,11,13-hexaene-4-carboxylate, (±)-methyl 11-bromo-15-[(4-methoxyphenyl)methyl]-16-oxo-15-azatetracyclo[6.6.2.0.sup.2,7.0.sup.9,14]-hexadeca-2,4,6,9,11,13-hexaene-5-carboxylate, (±)-methyl 11-bromo-15-[(4-methoxyphenyl)-methyl]-16-oxo-15-azatetracyclo[6.6.2.0.sup.2,7.0.sup.9,14]-hexadeca-2,4,6,9,11,13-hexaene-4-carboxylate and (±)-methyl 12-bromo-15-[(4-methoxyphenyl)methyl]-16-oxo-15-azatetracyclo-[6.6.2.0.sup.2,7.0.sup.9,14]hexadeca-2,4,6, 9,11,13-hexaene-5-carboxylate as a light yellow solid.

(632) Step 3:

(633) Into a 10-mL round-bottom flask, was placed a mixture of (±)-methyl 12-bromo-15-[(4-methoxyphenyl)methyl]-16-oxo-15-azatetracyclo[6.6.2.0.sup.2,7.0.sup.9,14]hexadeca-2,4,6,9,11,13-hexaene-4-carboxylate, (±)-methyl 11-bromo-15-[(4-methoxyphenyl)methyl]-16-oxo-15-azatetracyclo[6.6.2.0.sup.2,7.0.sup.9,14]hexadeca-2,4,6,9,11,13-hexaene-5-carboxylate, (±)-methyl 11-bromo-15-[(4-methoxyphenyl)methyl]-16-oxo-15-azatetracyclo[6.6.2.0.sup.2,7.0.sup.9,14]-hexadeca-2,4,6,9,11,13-hexaene-4-carboxylate and (±)-methyl 12-bromo-15-[(4-methoxyphenyl)methyl]-16-oxo-15-azatetracyclo[6.6.2.0.sup.2,7.0.sup.9,14]hexadeca-2,4,6,9,11,13-hexaene-5-carboxylate (287 mg, 0.60 mmol, 1.00 equiv), dioxane (5.00 mL), potassium carbonate (166 mg, 1.20 mmol, 2.00 equiv), (2,4-difluorophenyl)boronic acid (142 mg, 0.90 mmol, 1.50 equiv) and Pd(dppf)Cl.sub.2 (44 mg, 0.06 mmol, 0.10 equiv). The resulting mixture was stirred for 4 h at 110° C. under N.sub.2 then it was concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1/6) to afford 210 mg (68%) of a mixture of (±)-methyl 12-(2,4-difluorophenyl)-15-[(4-methoxyphenyl)methyl]-16-oxo-15-azatetracyclo-[6.6.2.0.sup.2,7.0.sup.9,14]hexadeca-2,4,6,9,11,13-hexaene-4-carboxylate, (±)-methyl 11-(2,4-difluoro-phenyl)-15-[(4-methoxyphenyl)methyl]-16-oxo-15-azatetracyclo[6.6.2.0.sup.2,7.0.sup.9,14]hexadeca-2,4,6,9,11,13-hexaene-5-carboxylate, (±)-methyl 11-(2,4-difluorophenyl)-15-[(4-methoxy-phenyl)methyl]-16-oxo-15-azatetracyclo[6.6.2.0.sup.2,7.0.sup.9,14]hexadeca-2,4,6,9,11,13-hexaene-4-carboxylate and (±)-methyl 12-(2,4-difluorophenyl)-15-[(4-methoxyphenyl)methyl]-16-oxo-15-azatetracyclo-[6.6.2.0.sup.2,7.0.sup.9,14]hexadeca-2,4,6,9,11,13-hexaene-5-carboxylate as a yellow solid.

(634) Step 4:

(635) Into a 10-mL round-bottom flask, was placed a mixture of (±)-methyl 12-(2,4-difluorophenyl)-15-[(4-methoxyphenyl)methyl]-16-oxo-15-azatetracyclo[6.6.2.0.sup.2,7.0.sup.9,14]-hexadeca-2,4,6,9,11,13-hexaene-4-carboxylate, (±)-methyl 11-(2,4-difluorophenyl)-15-[(4-methoxyphenyl)methyl]-16-oxo-15-azatetracyclo[6.6.2.0.sup.2,7.0.sup.9,14]hexadeca-2,4,6,9,11,13-hexaene-5-carboxylate, (±)-methyl 11-(2,4-difluorophenyl)-15-[(4-methoxyphenyl)methyl]-16-oxo-15-azatetracyclo[6.6.2.0.sup.2,7.0.sup.9,14]hexadeca-2,4,6,9,11,13-hexaene-4-carboxylate and (±)-methyl 12-(2,4-difluorophenyl)-15-[(4-methoxyphenyl)methyl]-16-oxo-15-azatetracyclo-[6.6.2.0.sup.2,7.0.sup.9,14]hexadeca-2,4,6,9,11,13-hexaene-5-carboxylate (190 mg, 0.37 mmol, 1.00 equiv) and trifluoroacetic acid (5.00 mL). The resulting mixture was stirred for 6 h at 70° C. then it was concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with dichloromethane/methanol (4/1) to afford 100 mg (69%) of a mixture of (±)-methyl 12-(2,4-difluorophenyl)-16-oxo-15-azatetracyclo[6.6.2.0.sup.2,7.0.sup.9,14]-hexadeca-2,4,6,9,11,13-hexaene-4-carboxylate, (±)-methyl 11-(2,4-difluorophenyl)-16-oxo-15-azatetracyclo-[6.6.2.0.sup.2,7.0.sup.9,14]hexadeca-2,4,6,9,11,13-hexaene-5-carboxylate, (±)-methyl 11-(2,4-difluoro-phenyl)-16-oxo-15-azatetracyclo[6.6.2.0.sup.2,7.0.sup.9,14]hexadeca-2,4,6,9,11,13-hexaene-4-carboxylate and (±)-methyl 12-(2,4-difluorophenyl)-16-oxo-15-azatetracyclo-[6.6.2.0.sup.2,7.0.sup.9,14]hexadeca-2,4,6,9,11,13-hexaene-5-carboxylate as a yellow solid.

(636) Step 5:

(637) Into a 10-mL round-bottom flask, was placed a mixture of (±)-methyl 12-(2,4-difluorophenyl)-16-oxo-15-azatetracyclo[6.6.2.0.sup.2,7.0.sup.9,14]hexadeca-2,4,6,9,11,13-hexaene-4-carboxylate, (±)-methyl 11-(2,4-difluorophenyl)-16-oxo-15-azatetracyclo[6.6.2.0.sup.2,7.0.sup.9,14]hexadeca-2,4,6,9,11,13-hexaene-5-carboxylate, (±)-methyl 11-(2,4-difluorophenyl)-16-oxo-15-azatetracyclo[6.6.2.0.sup.2,7.0.sup.9,14]hexadeca-2,4,6,9,11,13-hexaene-4-carboxylate and (±)-methyl 12-(2,4-difluorophenyl)-16-oxo-15-azatetracyclo[6.6.2.0.sup.2,7.0.sup.9,14]hexadeca-2,4,6,9,11,13-hexaene-5-carboxylate (98 mg, 0.25 mmol, 1.00 equiv), methanol (2 mL), water (0.50 mL) and sodium hydroxide (40 mg, 1.00 mmol, 4.00 equiv). The resulting mixture was stirred for 2 h at 40° C. then it was concentrated under vacuum. The residue was diluted with 5 mL of water; the pH value of the solution was adjusted to 3 with aqueous 2N hydrogen chloride solution and it was extracted with 2×20 mL of ethyl acetate. The organic layers was dried over anhydrous sodium sulfate and concentrated under vacuum to afford 90 mg (95%) of a mixture of (±)-12-(2,4-difluorophenyl)-16-oxo-15-azatetracyclo-[6.6.2.0.sup.2,7.0.sup.9,14]hexadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid, (±)-11-(2,4-difluorophenyl)-16-oxo-15-azatetracyclo[6.6.2.0.sup.2,7.0.sup.9,14]hexadeca-2,4,6,9,11,13-hexaene-5-carboxylic acid, (±)-11-(2,4-difluorophenyl)-16-oxo-15-azatetracyclo-[6.6.2.0.sup.2,7.0.sup.9,14]hexadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid and (±)-12-(2,4-difluoro-phenyl)-16-oxo-15-azatetracyclo[6.6.2.0.sup.2,7.0.sup.9,14]hexadeca-2,4,6,9,11,13-hexaene-5-carboxylic acid as a yellow solid.

(638) Step 6:

(639) Into a 10-mL round-bottom flask, was placed a solution of (±)-12-(2,4-difluorophenyl)-16-oxo-15-azatetracyclo[6.6.2.0.sup.2,7.0.sup.9,14]hexadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid, (±)-11-(2,4-difluorophenyl)-16-oxo-15-azatetracyclo[6.6.2.0.sup.2,7.0.sup.9,14]hexadeca-2,4,6,9,11,13-hexaene-5-carboxylic acid, (±)-11-(2,4-difluorophenyl)-16-oxo-15-azatetracyclo[6.6.2.0.sup.2,7.0.sup.9,14]hexadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid and (±)-12-(2,4-difluorophenyl)-16-oxo-15-azatetracyclo[6.6.2.0.sup.2,7.0.sup.9,14]hexadeca-2,4,6,9,11,13-hexaene-5-carboxylic acid (80 mg, 0.21 mmol, 1.00 equiv), N,N-dimethylformamide (3.00 mL), DIEA (68 mg, 0.53 mmol, 2.50 equiv), 5-(aminomethyl)-4-ethoxy-6-methylpyridin-2-amine (58 mg, 0.32 mmol, 1.50 equiv; prepared following the procedures described in Example 84, Step 1-4 but using ethyl iodide in Step 3 instead of iodomethane) and HATU (95 mg, 0.25 mmol, 1.20 equiv). The resulting solution was stirred for 2 h at room temperature then it was directly subjected to reverse preparative HPLC (Prep-C18, 5 M XBridge column, 19×150 mm, waters; gradient elution of 20% MeCN in water to 60% MeCN in water over a 4 min period and 60% MeCN in water to 85% MeCN in water over a 6 min period, where the aqueous phase contains 10 mMNH.sub.4HCO.sub.3+0.5% ammonia) to provide the title compounds as a yellow solid (26.5 mg, 23%). MS: (M+H).sup.+ found for C.sub.31H.sub.26F.sub.2N.sub.4O.sub.3: 541.2.

Example 87

Synthesis of (±)-N-{[6-amino-2-methyl-4-(propan-2-yl)pyridin-3-yl]methyl}-12-(2,4-difluoro-phenyl)-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(640) ##STR00711##

(641) Step 1:

(642) Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a mixture of 6-amino-2-methyl-4-oxo-1,4-dihydropyridine-3-carbonitrile (Example 84 step 2; 3.00 g, 20.1 mmol, 1.00 equiv) in phosphoryl chloride (POCl.sub.3; 50 mL). The resulting mixture was stirred for 16 hours at 80° C. in an oil bath and then concentrated under vacuum. The residue was diluted with ethyl acetate and poured into saturated aqueous NaHCO.sub.3 solution. The organic layer was separated, washed with 30 mL of brine, dried over anhydrous sodium sulfate and concentrated to dryness to give 6-amino-4-chloro-2-methylpyridine-3-carbonitrile (2.50 g, 74.2%) as a yellow solid.

(643) Step 2:

(644) Into a 25-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a mixture of 6-amino-4-chloro-2-methylpyridine-3-carbonitrile (600 mg, 3.58 mmol, 1.00 equiv) in dioxane/H.sub.2O (10 mL/1 mL), to which were added 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (798 mg, 4.75 mmol, 1.50 equiv), sodium carbonate (1.14 g, 10.76 mmol, 3.00 equiv) and tetrakis(triphenylphosphine)palladium(0) (Pd(PPh.sub.3).sub.4; 83 mg, 0.07 mmol, 0.02 equiv). The resulting mixture was stirred for 3 hours at 90° C. in an oil bath under N.sub.2 then it was concentrated under vacuum. The residue was purified by flash chromatography eluting with ethyl acetate/petroleum ether (1/4) to afford 323 mg (52%) of 6-amino-2-methyl-4-(prop-1-en-2-yl)pyridine-3-carbonitrile as a yellow solid.

(645) Step 3:

(646) Into a 25-mL round-bottom flask (20 atm), was placed a mixture of 6-amino-2-methyl-4-(prop-1-en-2-yl)pyridine-3-carbonitrile (50 mg, 0.29 mmol, 1.00 equiv) in methanol/ammonia (4.00 mL/0.40 mL), followed by Raney Ni (20 mg). The mixture was degassed and purged with hydrogen four times and stirred for 2 days at room temperature.

(647) The mixture was then filtered through a pad of Celite and the filtrate was concentrated under vacuum to afford 58 mg of 5-(aminomethyl)-6-methyl-4-(propan-2-yl)pyridin-2-amine as a yellow crude solid, which was used directly for next step without any purification. Step 4: Into a 25-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of (±) sodium 12-bromo-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (INT-5a) (80 mg, 0.24 mmol, 1.00 equiv) in dioxane/H.sub.2O (1.0/0.2 mL), followed by the addition of (2,4-difluorophenyl)boronic acid (56 mg, 0.35 mmol, 1.50 equiv), sodium carbonate (75 mg, 0.71 mmol, 3.00 equiv) and Pd(PPh.sub.3).sub.4 (27 mg, 0.02 mmol, 0.10 equiv). The resulting mixture was stirred for 16 hours at 90° C. in an oil bath under nitrogen atmosphere then it was cooled to RT, diluted with 10 mL of DCM/MeOH=10/1 and dried over anhydrous sodium sulfate. The mixture was then filtered through a pad of Celite and the filtrate was concentrated under vacuum to afford 140 mg of crude (±) sodium 12-(2,4-difluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate as yellow solids, which were used directly for next step without further purification.

(648) Step 5:

(649) Into a 8-mL vial, was placed a mixture of 5-(aminomethyl)-6-methyl-4-(propan-2-yl)pyridin-2-amine (50 mg, 0.28 mmol, 1.00 equiv) in N,N-dimethylformamide (2.00 mL), followed by the addition of (±) sodium 12-(2,4-difluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (104 mg, 0.28 mmol, 1.00 equiv), HATU (212 mg, 0.56 mmol, 2.00 equiv) and DIEA (180 mg, 1.39 mmol, 5.00 equiv). The resulting mixture was stirred for 20 minutes at room temperature then it was filtered and directly subjected to reverse phase preparative HPLC (Prep-C18, 5 μM XBridge column, 19×150 mm, Waters; gradient elution of 20% MeCN in water to 60% MeCN in water over a 4 min period, 60% MeCN in water to 85% MeCN in water over a 6 min period, where the aqueous phase contained 10 mM NH.sub.4HCO.sub.3 and 0.5% ammonia) to provide 40.7 mg (29% yield over 2 steps) the title compound as a white solid. MS: (M+H).sup.+ found for C.sub.31H.sub.27F.sub.2N.sub.3O.sub.2: 512.1.

Example 88

Synthesis of (1R,8S)—N-[(6-amino-4-ethyl-2-methylpyridin-3-yl)methyl]-12-(2,4-difluoro-phenyl)-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(650) ##STR00712##

(651) Step 1:

(652) Into a 100-mL round-bottom flask, was placed a mixture of 6-amino-4-chloro-2-methylpyridine-3-carbonitrile (Example 87 step 1; 800 mg, 4.77 mmol, 1.00 equiv), COCl.sub.2 (200 mg, 1.54 mmol, 0.32 eq) and methanol (50 mL) with stirring at 0° C., followed by the addition of NaBH.sub.4 (1.76 g, 47.70 mmol, 10.00 equiv) in portions. The resulting mixture was stirred for 1.5 h at 50° C. and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with dichloromethane/methanol (6/1) to afford 200 mg (24%) of 5-(aminomethyl)-4-chloro-6-methylpyridin-2-amine as a light brown solid.

(653) Step 2:

(654) Into a 100-mL round-bottom flask, was placed a solution of 5-(aminomethyl)-4-chloro-6-methylpyridin-2-amine (1.13 g, 6.58 mmol, 1.00 equiv), dichloromethane (30 mL), Boc.sub.2O (5.74 g, 26.32 mmol, 4.00 equiv) and 4-dimethylaminopyridine (401 mg, 3.29 mmol, 0.50 equiv). The resulting mixture was stirred for 10 min at room temperature and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1/5) to afford 1.70 g (55%) of tert-butyl N-[5-([bis[(tert-butoxy)carbonyl]amino]methyl)-4-chloro-6-methylpyridin-2-yl]carbamate as a yellow solid.

(655) Step 3:

(656) Into a 50-mL round-bottom flask, was placed a mixture of tert-butyl N-[5-([bis[(tert-butoxy)carbonyl]amino]methyl)-4-chloro-6-methylpyridin-2-yl]carbamate (400 mg, 0.85 mmol, 1.00 equiv), dioxane (30 mL), water (3 mL), potassium carbonate (938 mg, 6.80 mmol, 8.00 equiv), 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (393 mg, 2.55 mmol, 3.00 equiv) and Pd(PPh.sub.3).sub.4 (983 mg, 0.85 mmol, 1.00 equiv). The resulting mixture was stirred for 16 h at 110° C. under an atmosphere of nitrogen and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1/3) to afford 180 mg (46%) of tert-butyl N-[5-([bis[(tert-butoxy)carbonyl]amino]methyl)-4-ethenyl-6-methylpyridin-2-yl]carbamate as a yellow solid.

(657) Step 4:

(658) Into a 100-mL round-bottom flask, was placed a mixture of tert-butyl N-[5-([bis[(tert-butoxy)carbonyl]amino]methyl)-4-ethenyl-6-methylpyridin-2-yl]carbamate (2.00 g, 4.32 mmol, 1.00 equiv), methanol (20.0 mL), concentrated ammonia (2.00 mL) and Raney Ni (200 mg) under N.sub.2. The mixture was degassed three times and purged with hydrogen then it was stirred for 24 h at room temperature under a H.sub.2 (25 atm) atmosphere. After filtration through a pad of Celite, the filtrate was concentrated under vacuum to deliver 1.80 g (80%) of tert-butyl N-[5-({bis[(tert-butoxy)carbonyl]amino}methyl)-4-ethyl-6-methylpyridin-2-yl]carbamate as a light yellow solid.

(659) Step 5:

(660) Into a 50-mL round-bottom flask, was placed a solution of tert-butyl N-[5-({bis[(tert-butoxy)carbonyl]amino}methy-4-ethy-6-methylpyridin-2-yl]carbamate (1.79 g, 3.87 mmol, 1.00 equiv) in dioxane (10 mL) with stirring at rt, followed by the addition of a solution of dioxane (15.0 mL) freshly saturated with HCl (gas). The resulting mixture was stirred for 0.5 h at room temperature then it was filtered to provide 807 mg (88%) of 5-(aminomethyl)-4-ethyl-6-methylpyridin-2-amine dihydrochloride as a light yellow crude solid.

(661) Step 6:

(662) Into a 25-mL round-bottom flask, was placed a solution of (1R,8S)-12-(2,4-difluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylic acid (Example 7 Step 2; 95.0 mg, 0.27 mmol, 1.00 equiv) in N,N-dimethylformamide (3.00 mL), followed bu the addition of 5-(aminomethyl)-4-ethyl-6-methylpyridin-2-amine dihydrochloride (73.1 mg, 0.27 mmol, 1.00 equiv), DIEA (106 mg, 0.82 mmol, 3.00 equiv) and HATU (156 mg, 0.41 mmol, 1.50 equiv). The resulting mixture was stirred for 20 minutes at room temperature then it was filtered and subjected to reverse phase preparative HPLC (Prep-C18, 5 μM XBridge column, 19×150 mm, Waters; gradient elution of 20% MeCN in water to 30% MeCN in water over a 4 min period, 30% MeCN in water to 65% MeCN in water over a 6 min period, where the aqueous phase contained 10 mMNH.sub.4HCO.sub.3 and 0.5% ammonia) to provide the title compound as a white solid (35.2 mg, 26%). MS: (M+H).sup.+ found for C.sub.30H.sub.25F.sub.2N.sub.3O.sub.2: 498.2.

Example 89

Synthesis of (1R,8S)—N-{[6-amino-2-methyl-4-(propan-2-yl)pyridin-3-yl]methyl}-12-(2,4-difluorophenyl)-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(663) ##STR00713##

(664) The title compound was synthesized following the procedure described for Example 88, Step 6 but using 5-(aminomethyl)-6-methyl-4-(propan-2-yl)pyridin-2-amine (Example 87, Steps 1-3) instead of 5-(aminomethyl)-4-ethyl-6-methylpyridin-2-amine dihydrochloride. MS: (M+H).sup.+ found for C.sub.31H.sub.27F.sub.2N.sub.3O.sub.2: 512.1.

Example 90

Synthesis of (1R,8S)—N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-12-benzoyl-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(665) ##STR00714##

(666) Step 1:

(667) Into a 50-mL round-bottom flask, was placed a mixture of (1R,8S)-12-bromo-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (650 mg, 2.05 mmol, 1.00 equiv) and BH.sub.3.THF (1M, 10 mL). The resulting solution was stirred for 1 hour at room temperature, then the solvent was removed under reduced pressure. The residue was purified by flash chromatography eluting with ethyl acetate/petroleum ether (1/1) to afford 440 mg (71%) of [(1R,8S)-12-bromo-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaen-4-yl]methanol as a white solid.

(668) Step 2:

(669) Into a 500-mL round-bottom flask, was placed a mixture of [(1R,8S)-12-bromo-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaen-4-yl]methanol (440 mg, 1.45 mmol, 1.00 equiv), MnO.sub.2 (636 mg, 7.32 mmol, 5.00 equiv) and dichloromethane (200 mL). The resulted mixture was stirred for 20 minutes at room temperature, then the solids were separated by filtration. The filtrate was concentrated under vacuum to afford 400 mg (92%) of (1R,8S)-12-bromo-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carbaldehyde as a yellow solid.

(670) Step 3:

(671) Into a 50-mL 3-necked round-bottom flask, was placed a solution of (1R,8S)-12-bromo-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carbaldehyde (200 mg, 0.66 mmol, 1.00 equiv) in tetrahydrofuran (25 mL) at −20° C., followed by the dropwise addition of bromo(phenyl)magnesium (1.35 mL, 2.00 equiv, 1 mol/L). The resulting mixture was stirred for 1 hour at −20° C. then it was quenched by the addition of 5 mL of saturated aqueous NH.sub.4Cl, diluted with H.sub.2O and extracted with ethyl acetate. The organic layers were concentrated and purified by flash chromatography eluting with ethyl acetate/petroleum ether (1/5) to afford 120 mg (48%) of a 1:1 mixture of (R)-[(1R,8S)-12-bromo-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-22,4,6,9,11,13-hexaen-4-yl](phenyl)methanol and (S)-[(1R,8S)-12-bromo-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaen-4-yl](phenyl)methanol as alight yellow solid.

(672) Step 4:

(673) Into an 100-mL round-bottom flask, was placed a mixture of (R)-[(1R,8S)-12-bromo-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaen-4-yl](phenyl)methanol and (S)-[(1R,8S)-12-bromo-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaen-4-yl](phenyl)methanol (120 mg, 0.32 mmol, 1.00 equiv), MnO.sub.2 (138 mg, 1.59 mmol, 5.00 equiv) and dichloromethane (30 mL). The resulting mixture was stirred for 30 minutes at room temperature then the solids were separated by filtration. The filtrate was concentrated under vacuum to afford 118 mg (100%) of (1R,8S)-4-benzoyl-12-bromo-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene as an off-white solid.

(674) Step 5:

(675) Into a 50-mL pressure tank reactor, was placed a mixture of (1R,8S)-4-benzoyl-12-bromo-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene (120 mg, 0.32 mmol, 1.00 equiv), Pd(dppf)Cl.sub.2 (24 mg, 0.03 mmol, 0.10 equiv), TEA (161 mg, 1.59 mmol, 5.00 equiv) and methanol (25 mL). The resulting mixture was stirred for 16 hours at 120° C. under a CO atmosphere (20 atm). The mixture was then cooled to RT, concentrated and purified by flash chromatography eluting with ethyl acetate/petroleum ether (1/5) to afford 84 mg (74%) of methyl (1R,8S)-12-benzoyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate as a white solid.

(676) Step 6:

(677) Into a 50-mL round-bottom flask, was placed a mixture of methyl (1R,8S)-12-benzoyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (84 mg, 0.24 mmol, 1.00 equiv), sodium hydroxide (45 mg, 1.12 mmol, 5.00 equiv) and methanol (10 mL). The resulting mixture was stirred for 2 hours at room temperature then it was diluted with 15 mL of water. The pH value of the solution was adjusted to 4 with 2N aqueous HCl solution and the resulting mixture was extracted with 30 mL of ethyl acetate. The organic layer was concentrated and dried to afford 73 mg (90%) of (1R,8S)-12-benzoyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid as a yellow solid.

(678) Step 7:

(679) Into a 20-mL vial, was placed a mixture of 5-(aminomethyl)-4,6-dimethyl-pyridin-2-amine (32 mg, 0.21 mmol, 1.00 equiv), (1R,8S)-12-benzoyl-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (72 mg, 0.21 mmol, 1.00 equiv), DIEA (136 mg, 1.05 mmol, 5.00 equiv), HATU (88 mg, 0.23 mmol, 1.10 equiv) and N,N-dimethylformamide (10 mL). The resulting mixture was stirred for 1 hour at room temperature then it was purified by Prep-HPLC (Column: SunFire Prep C18 19*150 mm, 5 μm; mobile phase: CH.sub.3CN/water (a buffer of 10 mM NH.sub.4HCO.sub.3 and 0.05% ammonia) with a gradient of acetonitrile from 15% to 40% in 4 min, 40% to 48% in 6 min; flow rate: 20 mL/min; detector UV wavelength: 254 nm). The HPLC fractions were concentrated under vacuum and lyophilized to afford 55.8 mg (55%) of the title compound as a light yellow solid. MS: (M+H).sup.+ found for C.sub.30H.sub.25N.sub.3O.sub.3: 476 [M+H].sup.+.

Example 91

Synthesis of (1R,8S)—N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-12-(3-fluorobenzoyl)-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(680) ##STR00715##

(681) The title compound was synthesized following the procedures described for Example 90 (steps 3-7) using bromo (3-fluorophenyl)magnesium instead of bromo(phenyl)magnesium. This resulted in 62.6 mg (47%) of the title compound as a white solid. MS: (M+H).sup.+ found for C.sub.30H.sub.26FN.sub.3O.sub.3: 494.

Example 92

Synthesis of (1R,8S)—N-{[6-amino-2-methyl-4-(oxan-4-yl)pyridin-3-yl]methyl}-12-(2,4-difluorophenyl)-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(682) ##STR00716##

(683) Step 1:

(684) Into a 50-mL 3-necked round-bottom flask was placed a mixture of tert-butyl N-[5-([bis[(tert-butoxy)carbonyl]amino]methyl)-4-chloro-6-methylpyridin-2-yl]carbamate (Example 88, Step 2; 471 mg, 1.00 mmol, 1.00 equiv), dioxane (10.0 mL) and water (1.00 mL), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (840 mg, 4.00 mmol, 4.00 equiv), potassium carbonate (276 mg, 2.00 mmol, 2.00 equiv) and Pd(PPh.sub.3).sub.4 (116 mg, 0.10 mmol, 0.10 equiv). The resulting mixture was stirred overnight at 110° C. under N.sub.2 then it was concentrated under vacuum. The residue was purified by a silica gel column chromatography eluting with ethyl acetate/petroleum ether (1/4) to afford 455 mg (88%) of tert-butyl N-[5-([bis[(tert-butoxy)carbonyl]amino]methyl)-4-(3,6-dihydro-2H-pyran-4-yl)-6-methylpyridin-2-yl]carbamate as yellow oil.

(685) Step 2:

(686) Into a 50-mL 3-necked round-bottom flask, was placed a mixture of tert-butyl N-[5-([bis[(tert-butoxy)carbonyl]amino]methyl)-4-(3,6-dihydro-2H-pyran-4-yl)-6-methylpyridin-2-yl]carbamate (260 mg, 0.5 mmol, 1.00 equiv), MeOH (10.0 mL) and 10% dry palladium on C (100 mg). The resulting suspension was degassed and purged with H.sub.2 several times. The mixture was then stirred for 5 h at room temperature under an atmosphere of hydrogen then it was filtered through a pad of Celite and the filter cake was washed with MeOH (20 mL). The filtrate was combined and concentrated under vacuum to afford 255 mg of tert-butyl N-[5-([bis[(tert-butoxy)carbonyl]amino]methyl)-6-methyl-4-(oxan-4-yl)pyridin-2-yl]carbamate as a white solid.

(687) Step 3:

(688) Into a 50-mL round-bottom flask, was placed a solution of tert-butyl N-[5-([bis[(tert-butoxy)carbonyl]amino]methyl)-6-methyl-4-(oxan-4-yl)pyridin-2-yl]carbamate (255 mg, 0.49 mmol, 1.00 equiv) in dioxane (5.00 mL) followed by the drop-wise addition of a solution of dioxane (5.00 mL) freshly saturated with HCl (gas). The resulting mixture was stirred for 2 h at room temperature and then concentrated under vacuum to afford 108 mg (100%) of 5-(aminomethyl)-6-methyl-4-(oxan-4-yl)pyridin-2-amine as yellow oil. LCMS (ES) [M+1].sup.+ m/z: 222.1.

(689) Step 4:

(690) Into a 10-mL round-bottom flask, was placed a solution of 5-(aminomethyl)-6-methyl-4-(oxan-4-yl)pyridin-2-amine (100 mg, 0.45 mmol, 1.00 equiv), N,N-dimethylformamide (5.00 mL), (1R,8S)-12-(2,4-difluorophenyl)-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (Example 7 Step 2; 158 mg, 0.45 mmol, 1.00 equiv), DIEA (116 mg, 0.90 mmol, 2.00 equiv) and HATU (205 mg, 0.54 mmol, 1.20 equiv). The resulting mixture was stirred for 2 h at room temperature then it was filtered and directly subjected to reverse preparative HPLC (Prep-C18, 5 μM XBridge column, 19×150 mm, waters; gradient elution of 15% MeCN in water to 45% MeCN in water over a 4 min period, 45% MeCN in water to 75% MeCN in water over a 6 min period, where the aqueous phase contains 10 mMNH.sub.4HCO.sub.3+0.5% ammonia) to provide 61.8 mg (25%) of the title compound as a white solid. MS: (M+H).sup.+ found for C.sub.33H.sub.29F.sub.2N.sub.3O.sub.3: 554.1

Example 93

Synthesis of 4-[(1R,8S)-12-{[(6-amino-4-cyclopropyl-2-methylpyridin-3-yl)methyl]-carbamoyl}-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaen-4-yl]-3-fluoropyridin-1-ium-1-olate

(691) ##STR00717##

(692) Step 1:

(693) Into a 100-mL round-bottom flask, was placed a mixture of 6-amino-4-chloro-2-methylpyridine-3-carbonitrile (Example 87 step 1, 500 mg, 2.98 mmol, 1.00 equiv), tetrahydrofuran (30.0 mL), 4-dimethylaminopyridine (36.5 mg, 0.30 mmol, 0.10 equiv) and di-tert-butyl dicarbonate (714 mg, 3.28 mmol, 1.10 equiv). The resulting mixture was stirred for 5 h at 25° C. then it was concentrated and purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1/5) to afford 567 mg (71%) of tert-butyl N-(4-chloro-5-cyano-6-methylpyridin-2-yl)carbamate as yellow oil.

(694) Step 2:

(695) Into a 100-mL round-bottom flask, was placed a mixture of tert-butyl N-(4-chloro-5-cyano-6-methylpyridin-2-yl)carbamate (567 mg, 2.12 mmol, 1.00 equiv), dioxane (40.0 mL), water (4.00 mL), cyclopropyltrifluoro-[4]-borane potassium (1.25 g, 8.48 mmol, 4.00 equiv), Pd(PPh.sub.3).sub.4 (535.3 mg, 0.46 mmol, 0.22 equiv) and Cs.sub.2CO.sub.3 (4.13 g, 12.72 mmol, 6.00 equiv). The resulting mixture was stirred for 12 h at 80° C. under nitrogen then it was concentrated under vacuum, diluted with 30 mL of ethyl acetate and washed with water. The mixture was then extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1/5) to afford 250 mg (43%) of tert-butyl N-(5-cyano-4-cyclopropyl-6-methylpyridin-2-yl)carbamate as a light yellow solid.

(696) Step 3:

(697) Into a 100-mL round-bottom flask, was placed a mixture of tert-butyl N-(5-cyano-4-cyclopropyl-6-methylpyridin-2-yl)carbamate (150 mg, 0.55 mmol, 1.00 equiv), methanol (10.0 mL), ammonia (1.00 mL) and Raney Ni (30 mg). The mixture was degassed three times, purged with hydrogen and stirred for 4 h at 25° C. under a hydrogen atmosphere. The solids were separated by filtration and the filtrate was concentrated under vacuum to deliver 150 mg (99%) of tert-butyl N-[5-(aminomethyl)-4-cyclopropyl-6-methylpyridin-2-yl]carbamate as light yellow oil.

(698) Step 4:

(699) Into a 100-mL round-bottom flask, was placed a solution of tert-butyl N-[5-(aminomethyl)-4-cyclopropyl-6-methylpyridin-2-yl]carbamate (150 mg, 0.55 mmol, 1.00 equiv) in dichloromethane (6.00 mL) and trifluoroacetic acid (1.00 mL). The resulting mixture was stirred for 2 h at 25° C., then the pH was adjusted to 9 with 2N sodium hydroxide aqueous solution. The mixture was then concentrated under vacuum to deliver 160 mg (crude) of 5-(aminomethyl)-4-cyclopropyl-6-methylpyridin-2-amine as yellow oil. LC-MS (ES) [M+1].sup.+ m/z: 178.1.

(700) Step 5:

(701) Into a 50-mL round-bottom flask, was placed a mixture of (1S,8R)-12-bromo-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (INT4a1; 158.0 mg, 0.50 mmol, 1.00 equiv), dioxane (8.0 mL), H.sub.2O (0.8 mL), (3-fluoropyridin-4-yl)boronic acid (212 mg, 1.50 mmol, 3.00 equiv), Pd(PPh.sub.3).sub.4 (18.3 mg, 0.02 mmol, 0.05 equiv) and sodium carbonate (159.0 mg, 1.50 mmol, 3.00 equiv). The resulting mixture was stirred for 3 h at 80° C. then it was cooled to RT and concentrated. The crude product was purified by silica gel column chromatography eluting with DCM/MeOH (5/1) to afford 140.0 mg (84%) of (1R,8S)-12-(3-fluoropyridin-4-yl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid as an off-white solid.

(702) Step 6:

(703) Into a 10-mL round-bottom flask, was placed a mixture of (1R,8S)-12-(3-fluoropyridin-4-yl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (140 mg, 0.42 mmol, 1.00 equiv), N,N-dimethylformamide (5 mL) and meta-chloro-peroxybenzoic acid (m-CPBA; 85.1 mg, 85%/W, 0.42 mmol, 2.00 equiv). The resulting mixture was stirred for 5 h at room temperature then it was diluted with of H.sub.2O and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with DCM/MeOH (5/1) to afford 130 mg (89%) of 4-[(1R,8S)-12-carboxy-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaen-4-yl]-3-fluoropyridin-1-ium-1-olate as a yellow solid.

(704) Step 7:

(705) Into a 25-mL round-bottom flask, was placed 4-[(1R,8S)-12-carboxy-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaen-4-yl]-3-fluoropyridin-1-ium-1-olat (62.0 mg, 0.18 mmol, 1.00 equiv), N,N-dimethylformamide (4 mL), DIEA (69 mg, 0.53 mmol, 3.00 equiv), HATU (81 mg, 0.21 mmol, 1.20 equiv) and 5-(aminomethyl)-4-cyclopropyl-6-methylpyridin-2-amine TFA salt (81.0 mg, 0.20 mmol, 1.10 equiv). The resulting mixture was stirred for 1 h at room temperature then it was filtered and directly subjected to reverse phase preparative HPLC (Prep-C18, 5 M×Bridge column, 19×150 mm, Waters; gradient elution of 10% MeCN in water to 26% MeCN in water over a 1 min period, 26% MeCN in water to 32% MeCN in water over a 6 min period, where the aqueous phase contained 10 mM NH.sub.4HCO.sub.3 and 0.05% NH.sub.3—H.sub.2O) to provide the title compound as an off-white solid (24.6 mg, 27%). MS: (M+H).sup.+ found for C.sub.30H.sub.25FN.sub.4O.sub.3: 509.1.

Example 94

Synthesis of (1R,8S)—N-[(1-amino-6-chloroisoquinolin-5-yl)methyl]-12-(2-fluorophenyl)-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(706) ##STR00718##

(707) Step 1:

(708) Into a 2-L 3-necked round-bottom flask, were placed a solution of 4-chloro-3-methylbenzoic acid (34.0 g, 199.30 mmol, 1.00 equiv), 2,2-dimethoxyethan-1-amine (21.0 g, 199.74 mmol, 1.00 equiv), DIEA (51.6 g, 399.26 mmol, 2.00 equiv) in dichloromethane (600 mL), followed by the addition of HATU (91.2 g, 239.85 mmol, 1.20 equiv) in portions. The resulting mixture was stirred for 5 h at room temperature then it was washed with 3×300 mL of H.sub.2O, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column eluting with ethyl acetate/petroleum ether (1/4) to afford 42.1 g (82%) of 4-chloro-N-(2,2-dimethoxyethyl)-3-methylbenzamide as a yellow solid.

(709) Step 2:

(710) Into a 500-mL 3-necked round-bottom flask, was placed sulfuric acid (150 mL) with stirring at 0° C., followed by the addition of 4-chloro-N-(2,2-dimethoxyethyl)-3-methylbenzamide (20.0 g, 77.61 mmol, 1.00 equiv) in portions. The resulting mixture was stirred at 120° C. for 16 h then it was cooled to room temperature, poured into 1000 mL of iced-water slowly, and extracted with ethyl acetate. The organic layers were combined, washed with 500 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column eluting with dichloromethane/ethyl acetate (1/1) to afford 13.6 g (91%) of a mixture of 6-chloro-5-methylisoquinolin-1-ol and 6-chloro-7-methylisoquinolin-1-ol as a yellow solid.

(711) Step 3:

(712) Into a 500-mL 3-necked round-bottom flask, were placed a mixture of 6-chloro-5-methylisoquinolin-1-ol and 6-chloro-7-methylisoquinolin-1-ol (9.65 g, 49.84 mmol, 1.00 equiv) in POCl.sub.3 (120 mL). The resulting mixture was stirred for 5 h at 100° C. and then concentrated under vacuum. The residue was diluted with DCM, washed with sat. aq. NaHCO.sub.3, brine and concentrated. The crude product was purified by silica gel column eluting with ethyl acetate/petroleum ether (1/8) o afford 9.45 g (89%) mixture of 1,6-dichloro-5-methylisoquinoline and 1,6-dichloro-7-methylisoquinoline as a yellow solid.

(713) Step 4:

(714) Into a 500-mL 3-necked round-bottom flask, were placed a mixture of 1,6-dichloro-5-methylisoquinoline and 1,6-dichloro-7-methylisoquinoline (6.33 g, 29.85 mmol, 1.00 equiv), (2,4-dimethoxyphenyl)methanamine (15.03 g, 89.89 mmol, 3.00 equiv) and DMSO (200 mL). The resulting solution was stirred overnight at 120° C. then it was diluted with 500 mL of water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column eluting with ethyl acetate/petroleum ether (1/4) to afford 8.7 g (85%) of a mixture of 6-chloro-N-[(4-methoxyphenyl)methyl]-5-methylisoquinolin-1-amine and 6-chloro-N-[(4-methoxyphenyl)methyl]-7-methylisoquinolin-1-amine as a yellow solid.

(715) Step 5:

(716) Into a 500-mL 3-necked round-bottom flask, were placed a solution of 6-chloro-N-[(4-methoxyphenyl)methyl]-5-methylisoquinolin-1-amine and 6-chloro-N-[(4-methoxy-phenyl)-methyl]-7-methylisoquinolin-1-amine (10.0 g, 29.17 mmol, 1.00 equiv), dichloromethane (100 mL) and TFA (10 mL). The resulting solution was stirred for 3 h at room temperature and then it was concentrated under vacuum to afford 9.61 g (crude) of a mixture of 6-chloro-5-methylisoquinolin-1-amine and 6-chloro-7-methylisoquinolin-1-amine as a yellow solid.

(717) Step 6:

(718) Into a 1-L round-bottom flask, were placed a solution of 6-chloro-5-methylisoquinolin-1-amine and 6-chloro-7-methylisoquinolin-1-amine (11.52 g, 59.80 mmol, 1.00 equiv), dichloromethane (250 mL), Boc.sub.2O (52.32 g, 239.73 mmol, 4.00 equiv) and 4-dimethylaminopyridine (730 mg, 5.98 mmol, 0.10 equiv). The resulting mixture was stirred for 3 h at room temperature then it was concentrated. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1/4) to afford 8.90 g (38%) of a mixture of tert-butyl N-[(tert-butoxy)carbonyl]-N-(6-chloro-5-methylisoquinolin-1-yl)carbamate and tert-butyl N-[(tert-butoxy)carbonyl]-N-(6-chloro-7-methylisoquinolin-1-yl)carbamate as a yellow solid.

(719) Step 7:

(720) Into a 250-mL 3-necked round-bottom flask, were placed a mixture of tert-butyl N-[(tert-butoxy)carbonyl]-N-(6-chloro-5-methylisoquinolin-1-yl)carbamate and tert-butyl N-[(tert-butoxy)carbonyl]-N-(6-chloro-7-methylisoquinolin-1-yl)carbamate (2.00 g, 5.09 mmol, 1.00 equiv), CCl.sub.4 (40 mL), NBS (1.09 g, 6.12 mmol, 1.20 equiv) and benzoyl peroxide (BPO; 370 mg, 1.44 mmol, 0.30 equiv). The resulting mixture was stirred overnight at 90° C. then it was cooled to RT and concentrated. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1/4) to afford 1.60 g (67%) of a mixture of tert-butyl N-[5-(bromomethyl)-6-chloroisoquinolin-1-yl]-N-[(tert-butoxy)carbonyl]carbamate and tert-butyl N-[7-(bromomethyl)-6-chloroisoquinolin-1-yl]-N-[(tert-butoxy)carbonyl]carbamate as a yellow oil.

(721) Step 8:

(722) Into a 500-mL 3-necked round-bottom flask, were placed a solution of concentrated ammonia (100 mL) and dioxane (50 mL). This was followed by the addition of a solution of tert-butyl N-[5-(bromomethyl)-6-chloroisoquinolin-1-yl]-N-[(tert-butoxy)carbonyl]-carbamate and tert-butyl N-[7-(bromomethyl)-6-chloroisoquinolin-1-yl]-N-[(tert-butoxy)-carbonyl]carbamate (1.60 g, 3.39 mmol, 1.00 equiv) in dioxane (50 mL) dropwise with stirring at room temperature. The resulting mixture was stirred for 4 h at RT and then concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with dichloromethane/methanol (30/1) to afford 480 mg (35%) of a mixture of tert-butyl N-[5-(aminomethyl)-6-chloroisoquinolin-1-yl]-N-[(tert-butoxy)carbonyl]carbamate and tert-butyl N-[7-(aminomethyl)-6-chloroisoquinolin-1-yl]-N-[(tert-butoxy)carbonyl]carbamate as a yellow solid.

(723) Step 9:

(724) Into a 25-mL round-bottom flask, was placed a solution of tert-butyl N-[5-(aminomethyl)-6-chloroisoquinolin-1-yl]-N-[(tert-butoxy)carbonyl]carbamate and tert-butyl N-[7-(aminomethyl)-6-chloroisoquinolin-1-yl]-N-[(tert-butoxy)carbonyl]carbamate (190 mg, 0.47 mmol, 1.00 equiv) in dioxane (5 mL) saturated with HCl gas. The resulting mixture was stirred for 3 h at room temperature then the solids were collected by filtration to afford 90 mg (69%) of a mixture of 5-(aminomethyl)-6-chloroisoquinolin-1-amine dihydrochloride and 7-(aminomethyl)-6-chloroisoquinolin-1-amine dihydrochloride as a yellow solid.

(725) Step 10:

(726) Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, were placed a mixture of (1S,8R)-12-bromo-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (INT-4a1; 158 mg, 0.50 mmol, 1.00 equiv), dioxane (5 mL), water (0.5 mL), (2-fluorophenyl)boronic acid (84 mg, 0.60 mmol, 1.20 equiv), potassium carbonate (138 mg, 1.00 mmol, 2.00 equiv) and Pd(PPh.sub.3).sub.4 (12 mg, 0.01 mmol, 0.02 equiv). The resulting mixture was stirred for 16 h at 100° C. then it was cooled to RT, diluted with 50 mL of DCM and 10 mL of MeOH, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to afford 175 mg (crude) of (1R,8S)-12-(2-fluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid as an off-white solid.

(727) Step 11:

(728) Into a 25-mL round-bottom flask, were placed a solution of (1R,8S)-12-(2-fluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (66 mg, 0.20 mmol, 1.00 equiv), N,N-dimethylformamide (5 mL), a mixture of 5-(aminomethyl)-6-chloroisoquinolin-1-amine dihydrochloride and 7-(aminomethyl)-6-chloroisoquinolin-1-amine dihydrochloride (67 mg, 0.24 mmol, 1.20 equiv), DIEA (129 mg, 1.00 mmol, 5.00 equiv) and HATU (91 mg, 0.24 mmol, 1.20 equiv). The resulting mixture was stirred for 3 h at room temperature then the solids were separated by filtration. The filtrate was purified by Prep-HPLC (Column: Waters×Bridge RP18 19*150 mm, 5 um; mobile phase: CH.sub.3CN and H.sub.2O (it is a buffer of 10 mM NH.sub.4HCO.sub.3+0.05% ammonia) with 51% acetonitrile in 8 min, flow rate: 20 mL/min; detector UV wavelength: 220 nm) to afford 19.6 mg (19%) of (1R,8S)—N-[(1-amino-6-chloroisoquinolin-5-yl)methyl]-12-(2-fluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide as a white solid. MS: (M+H).sup.+ found for C.sub.31H.sub.21ClFN.sub.3O.sub.2: 522.

Example 95

Synthesis of (1R,8S)—N-[(1-amino-6-methylisoquinolin-5-yl)methyl]-12-(2-fluoro-phenyl)-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(729) ##STR00719##

(730) Step 1:

(731) Into a 50-mL 3-necked round-bottom flask, were placed tert-butyl N-[5-(bromomethyl)-6-chloroisoquinolin-1-yl]-N-[(tert-butoxy)carbonyl]carbamate and tert-butyl N-[7-(bromomethyl)-6-chloroisoquinolin-1-yl]-N-[(tert-butoxy)carbonyl]carbamate (Example 94, Step 7; 470 mg, 1.00 mmol, 1.00 equiv), N,N-dimethylformamide (15 mL), tert-butyl N-[(tert-butoxy)carbonyl]carbamate (434 mg, 2.00 mmol, 2.00 equiv), Cs.sub.2CO.sub.3 (1.3 g, 3.99 mmol, 4.00 equiv) and LiI (67 mg, 0.50 equiv). The resulting mixture was stirred for 3 h at room temperature then it was diluted with 50 mL of water, extracted with ethyl acetate. The organic layers were combined, washed with 3×50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1/4) to afford 330 mg (54%) mixture of tert-butyl N-[(1-{bis[(tert-butoxy)carbonyl]amino}-6-chloroisoquinolin-5-yl)methyl]-N-[(tert-butoxy)-carbonyl]-carbamate and tert-butyl N-[(1-{bis[(tert-butoxy)carbonyl]amino}-6-chloro-isoquinolin-7-yl)methyl]-N-[(tert-butoxy)carbonyl]carbamate as a yellow solid.

(732) Step 2:

(733) Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, were placed a mixture of tert-butyl N-[(1-{bis[(tert-butoxy)carbonyl]-amino}-6-chloroisoquinolin-5-yl)methyl]-N-[(tert-butoxy)carbonyl]-carbamate and tert-butyl N-[(1-{bis[(tert-butoxy)carbonyl]amino}-6-chloroisoquinolin-7-yl)methyl]-N-[(tert-butoxy)-carbonyl]carbamate (243 mg, 0.40 mmol, 1.00 equiv), dioxane (5 mL) and water (0.5 mL), trimethyl-1,3,5,2,4,6-trioxatriborinane (528 mg, 4.21 mmol, 5.00 equiv), Pd.sub.2(dba).sub.3.CH.sub.2Cl.sub.2 (41 mg, 0.04 mmol, 0.10 equiv), Cs.sub.2CO.sub.3 (261 mg, 0.80 mmol, 2.00 equiv), and tricyclohexyl phosphine (PCy.sub.3; 22 mg, 0.20 equiv). The resulting mixture was stirred overnight at 100° C. then it was cooled to RT and concentrated. The residue was directly purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1/4) to afford 190 mg (81%) of tert-butyl N-[(1-{bis[(tert-butoxy)carbonyl]amino}-6-methylisoquinolin-5-yl)methyl]-N-[(tert-butoxy)carbonyl]carbamate and tert-butyl N-[(1-{bis[(tert-butoxy)carbonyl]amino}-6-methylisoquinolin-7-yl)methyl]-N-[(tert-butoxy)carbonyl]carbamate as a brown oil.

(734) Step 3:

(735) Into a 25-mL round-bottom flask, was placed a solution of tert-butyl N-[(1-{bis[(tert-butoxy)carbonyl]amino}-6-methylisoquinolin-5-yl)methyl]-N-[(tert-butoxy)carbonyl]-carbamate and tert-butyl N-[(1-{bis[(tert-butoxy)carbonyl]amino}-6-methylisoquinolin-7-yl)methyl]-N-[(tert-butoxy)carbonyl]carbamate (352 mg, 0.60 mmol, 1.00 equiv) in dioxane (5 mL) saturated with HCl gas. The resulting solution was stirred for 5 h at room temperature then the solids were collected by filtration to afford 150 mg (96%) mixture of 5-(aminomethyl)-6-methylisoquinolin-1-amine dihydrochloride and 7-(aminomethyl)-6-methylisoquinolin-1-amine dihydrochloride as a gray solid.

(736) Step 4:

(737) Into a 25-mL round-bottom flask, were placed 5-(aminomethyl)-6-methylisoquinolin-1-amine dihydrochloride and 7-(aminomethyl)-6-methylisoquinolin-1-amine dihydrochloride (62 mg, 0.24 mmol, 1.20 equiv), N,N-dimethylformamide (5 mL), (1R,8S)-12-(2-fluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (Example 94, Step 10; 66 mg, 0.20 mmol, 1.00 equiv), DIEA (129 mg, 1.00 mmol, 5.00 equiv) and HATU (91 mg, 0.24 mmol, 1.20 equiv). The resulting mixture was stirred for 3 h at room temperature then the solids were separated by filtration. The filtrate was purified by Prep-HPLC (Column: Waters×Bridge RP18 19*150 mm, 5 um; mobile phase: CH.sub.3CN/water (a buffer of 10 mM NH.sub.4HCO.sub.3+0.05% ammonia) with a gradient of acetonitrile from 46% to 50% in 8 min, flow rate: 20 mL/min; detector UV wavelength: 254 nm) to afford 25.8 mg (26%) of the title compound as a white solid. MS: (M+H).sup.+ found for C.sub.32H.sub.24FN.sub.3O.sub.2: 502.

Example 96

Synthesis of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-11,12-dimethyl-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9(14),10,12-hexaene-4-carboxamide

(738) ##STR00720##

(739) Step 1:

(740) Into a 1-L 3-necked round-bottom flask, was placed a mixture of 1,2,4,5-tetrabromobenzene (100.0 g, 254.00 mmol, 1.00 equiv), toluene (500 mL) and furan (35.4 g, 2.00 equiv) with stirring at −30° C., followed by the drop-wise addition of n-BuLi (112 mL, 2.5 M in hexane, 279.40 mmol, 1.10 equiv). The resulting mixture was allowed to warm up to room temperature and stirred for 30 min. then it was quenched by the addition of water (20 mL). The mixture was then washed with 500 mL of H.sub.2O. The water layer was extracted with 3×300 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, concentrated under vacuum and purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1/10) to afford 38.5 g (50%) of 4,5-dibromo-11-oxatricyclo[6.2.1.0.sup.2,7]-undeca-2,4,6,9-tetraene as a yellow solid.

(741) Step 2:

(742) Into a 1000-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4,5-dibromo-11-oxatricyclo[6.2.1.0.sup.2,7]-undeca-2,4,6,9-tetraene (10.0 g, 33.12 mmol, 1.00 equiv) in chloroform (150 mL) with stirring at 0° C., followed by the drop-wise addition of bis(pyridin-2-yl)-1,2,4,5-tetrazine (9.40 g, 39.79 mmol, 1.20 equiv) in chloroform (100 mL). The resulting mixture was then stirred for 1 h at 50° C. to deliver 5, 6-dibromo-2-benzofuran in chloroform (150 mL) as a brown liquid (crude).

(743) This solution was cooled to 0° C. with stirring and a solution of [5-(methoxycarbonyl)-2-(trimethylsilyl)phenyl](phenyl)iodanium trifluoromethanesulfonate (18.6 g, 45.22 mmol, 1.00 equiv) in dichloromethane (200 mL) was added drop-wise, followed by TBAF (66.6 mL, 1 mol/L in THF, 66.55 mmol, 1.50 equiv) drop-wise. The resulting mixture was stirred for an additional 30 min at 0° C. then it was concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1/10) to afford 4.80 g (35%) of (±)-methyl 11,12-dibromo-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylate as a yellow solid.

(744) Step 3:

(745) Into a 10-mL round-bottom flask, was placed a mixture of (±)-methyl 11,12-dibromo-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylate (100 mg, 0.24 mmol, 1.00 equiv), dioxane (2 mL), water (0.2 mL), trimethyl-1,3,5,2,4,6-trioxatri-borinane (304 mg, 2.42 mmol, 10.00 equiv), K.sub.3PO.sub.4 (206 mg, 0.97 mmol, 4.00 equiv) and Pd(dppf)Cl.sub.2 (14 mg, 0.02 mmol, 0.05 equiv). The resulting mixture was stirred for 5 h at 80° C. under N.sub.2, then it was cooled to RT and concentrated. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1/5) to afford 45 mg (66%) of (±)-methyl 11,12-dimethyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylate as yellow solids.

(746) Step 4:

(747) Into a 10-mL round-bottom flask, was placed a mixture of (±)-methyl 11,12-dimethyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylate (40 mg, 0.14 mmol, 1.00 equiv), methanol (1.0 mL), water (0.5 mL), dichloromethane (1.0 mL) and 60% sodium hydroxide (in oil suspension, 11.4 mg, 0.29 mmol, 2.00 equiv). The resulting mixture was stirred for 2 h at 50° C. then it was cooled to RT, diluted with 5 mL of water and the pH value of the solution was adjusted to 6 with 2 mol/L HCl aqueous solution. The mixture was then extracted with 3×10 mL of ethyl acetate. The organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to afford 30 mg (79%) of (±)-11,12-dimethyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylic acid as a yellow solid.

(748) Step 5:

(749) Into a 10-mL round-bottom flask, was placed (±)-11,12-dimethyl-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylic acid (30 mg, 0.11 mmol, 1.00 equiv), N,N-dimethylformamide (2 mL), 5-(aminomethyl)-4,6-dimethylpyridin-2-amine (17 mg, 0.11 mmol, 1.00 equiv), DIEA (58 mg, 0.45 mmol, 4.00 equiv) and HATU (42 mg, 0.11 mmol, 1.00 equiv). The resulting mixture was stirred for 5 h at 25° C. then the solids were separated by filtration. The filtrate was directly subjected to reverse preparative HPLC (Prep-C18, 5 M×Bridge column, 19×150 mm, waters; gradient elution of 55% MeCN in water to 65% MeCN in water over a 8 min period, where the aqueous phase contains 10 mM NH.sub.4HCO.sub.3+0.05% ammonia) to provide the title compound as a white solid (25.6 mg, 57%). MS: (M+H).sup.+ found for C.sub.25H.sub.25N.sub.3O.sub.2: 400.2.

Example 97

Synthesis of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-11,12-dicyclopropyl-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide trifluoroacetate salt

(750) ##STR00721##

(751) Step 1:

(752) Into a 100-mL round-bottom flask, was placed (±)-methyl 11,12-dibromo-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylate (Example 96, Steps 1-2; 700 mg, 1.71 mmol, 1.00 equiv), toluene (20 mL), water (2 mL), cyclopropylboronic acid (370 mg, 4.31 mmol, 2.50 equiv), K.sub.3PO.sub.4 (2.53 g, 11.92 mmol, 7.00 equiv), tricyclohexylphosphane (960 mg, 3.42 mmol, 2.00 equiv) and Pd(OAc).sub.2 (380 mg, 1.69 mmol, 1.00 equiv). The resulting mixture was stirred for 4 h at 100° C. under nitrogen then it was cooled to RT and concentrated. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1/5) to deliver 320 mg (56%) of (±)-methyl 11,12-dicyclopropyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate as a light yellow solid.

(753) Step 2:

(754) Into a 50-mL round-bottom flask, was placed (±)-methyl 11,12-dicyclopropyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate (300 mg, 0.90 mmol, 1.00 equiv), THF (4 mL), MeOH (4 mL), H.sub.2O (4 mL) and NaOH (140 mg, 3.50 mmol, 4.00 equiv). The resulting mixture was stirred for 2 h at room temperature then it was diluted with 5 mL of water and acidified with 1 N hydrogen chloride aqueous solution to pH=4. The mixture was then extracted with ethyl acetate (3×10 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum to afford 280 mg (crude) of (±)-11,12-dicyclopropyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid as a yellow solid.

(755) Step 3:

(756) Into a 10-mL round-bottom flask, was placed (±)-11,12-dicyclopropyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylic acid (80 mg, 0.25 mmol, 1.00 equiv), DMF (2 mL), 5-(aminomethyl)-4,6-dimethylpyridin-2-amine dihydrochloride (56 mg, 0.25 mmol, 1.00 equiv), DIEA (162 mg, 1.25 mmol, 5.00 equiv) and HATU (143 mg, 0.38 mmol, 1.50 equiv). The resulting mixture was stirred for 4 h at 25° C. then it was filtered and directly subjected to reverse phase preparative HPLC (Prep-C18, 5 M SunFire column, 19×150 mm, Waters; gradient elution of 66% MeCN in water to 78% MeCN in water over a 8 min period, where both solvents contain 0.1% TFA) to provide the title compound as a white solid (26 mg, 18%). MS: [M-TFA+1].sup.+ found for C.sub.29H.sub.29N.sub.3O.sub.2: 452.1

Example 98

Synthesis of (±)-N-[(4-carbamimidoylphenyl)methyl]-11,12-diethyl-15-oxatetra-cyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9(14),10,12-hexaene-4-carboxamide trifluoroacetate Salt

(757) ##STR00722##

(758) Step 1:

(759) Into a 50-mL round-bottom flask, was placed (±)-methyl 11,12-dibromo-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylate (Example 96, Steps 1-2; 500 mg, 1.22 mmol), ethylboronic acid (910 mg, 12.32 mmol, 10.00 equiv), dioxane (10 mL), H.sub.2O (1 mL), K.sub.3PO.sub.4 (782 mg, 3.68 mmol, 3.00 equiv) and Pd(dppf)Cl.sub.2 (44.9 mg, 0.06 mmol, 0.05 equiv). The resulting mixture was stirred for 12 h at 80° C. then it was cooled to RT and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1/5) to deliver 320 mg (85%) of (±)-methyl 11,12-diethyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylate as yellow oil.

(760) Step 2:

(761) Into a 10-mL round-bottom flask, was placed (±)-methyl 11,12-diethyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylate (308 mg, 1.00 mmol, 1.00 equiv), methanol (2 mL), dichloromethane (2 mL), water (1 mL) and NaOH (160 mg, 4.00 mmol, 4.00 equiv). The resulting mixture was stirred for 2 h at 50° C. then it was cooled to RT and the pH value of the solution was adjusted to 7 with 1 mol/L HCl aqueous solution. The mixture was then concentrated under vacuum to deliver 320 mg (crude) of (±)-11,12-diethyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylic acid as a yellow solid. The crude product was used in the next step without further purification.

(762) Step 3:

(763) Into a 10-mL round-bottom flask, was placed (±)-11,12-diethyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylic acid (100.0 mg, 0.34 mmol, 1.00 equiv), N,N-dimethylformamide (5 mL), DIEA (132 mg, 1.02 mmol, 3.00 equiv), HOBt (55.0 mg, 0.41 mmol, 1.20 equiv), EDC (79.0 mg, 0.51 mmol, 1.50 equiv) and 4-(aminomethyl)benzene-1-carboximidamide dihydrochloride (113.0 mg, 0.51 mmol, 1.50 equiv). The resulting mixture was stirred for 1 h at room temperature then it was filtered and directly subjected to reverse preparative HPLC (Prep-C18, 5 M×Bridge column, 19×150 mm, waters; gradient elution of 29% MeCN in water to 44% MeCN in water over a 7 min period, where both solvents contain 0.1% TFA) to provide the title compound as a white solid (71.8 mg, 39%). MS [M-TFA+1].sup.+ found for C.sub.27H.sub.27N.sub.3O.sub.2:426.2.

Example 99

Synthesis of (±)-N-[(4-carbamimidoylphenyl)methyl]-11,12-dicyclopropyl-15-oxatetracyclo-[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(764) ##STR00723##

(765) The title compound was prepared following the procedure described in Example 97, Step 3, but using 4-(aminomethyl)benzene-1-carboximidamide dihydrochloride instead of 5-(aminomethyl)-4,6-dimethylpyridin-2-amine dihydrochloride. This provided (±)-N-[(4-carbamimidoylphenyl)methyl]-11,12-dicyclopropyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide as an off-white solid (46.0 mg, 33%). MS: (M+H).sup.+ found for C.sub.29H.sub.27N.sub.3O.sub.2: 450.3.

Example 100

Synthesis of (±)-N-[(4-carbamimidoylphenyl)methyl]-11,12-dimethyl-15-oxatetracyclo-[6.6.1.02,7.09,14]pentadeca-2,4,6,9(14),10,12-hexaene-4-carboxamide trifluoroacetate Salt

(766) ##STR00724##

(767) The title compound was prepared following the procedure described in Example 96, Step 5, but using 4-(aminomethyl)benzene-1-carboximidamide dihydrochloride instead of 5-(aminomethyl)-4,6-dimethylpyridin-2-amine dihydrochloride. This provided (±)-N-[(4-carbamimidoylphenyl)methyl]-11,12-dimethyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9(14),10,12-hexaene-4-carboxamide trifluoroacetate salt as a white solid (26.9 mg, 23%). MS [M-TFA+1].sup.+ found for C.sub.25H.sub.23N.sub.3O.sub.2: 398.2.

Example 101

Synthesis of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-12-(2,4-difluorophenyl)-11-ethyl-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9(14),10,12-hexaene-4-carboxamide and (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-11-(2,4-difluorophenyl)-12-ethyl-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9(14),10,12-hexaene-4-carboxamide

(768) ##STR00725##

(769) Step 1:

(770) Into a 25-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed (±)-methyl 11,12-dibromo-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylate (Example 96, Steps 1-2; 300 mg, 0.73 mmol, 1.00 equiv), 1,4-dioxane (4 mL), water (0.5 mL), (2,4-difluorophenyl)boronic acid (115.6 mg, 0.73 mmol, 1.00 equiv), Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 (60 mg, 0.08 mmol, 0.10 equiv) and K.sub.3PO.sub.4 (310 mg, 1.46 mmol, 2.00 equiv). The resulting mixture was degassed and purged with nitrogen 3 times, then it was stirred for 3 h at 80° C. The mixture was then concentrated under vacuum and the residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1/5) to deliver 150 mg (46.3%) of a mixture of (±)-methyl 11-bromo-12-(2,4-difluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylate and (±)-methyl 11-(2,4-difluorophenyl)-12-bromo-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylate as a white solid.

(771) Step 2:

(772) Into a 25-mL round-bottom flask, was placed a mixture of (±)-methyl 11-bromo-12-(2,4-difluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylate and (±)-methyl 11-(2,4-difluorophenyl)-12-bromo-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylate (150 mg, 0.34 mmol, 1.00 equiv), 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (104 mg, 0.68 mmol, 2.00 equiv), dioxane (4.00 mL), water (0.50 mL), K.sub.3PO.sub.4 (216 mg, 1.02 mmol, 3.00 equiv) and Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 (55 mg, 0.08 mmol, 0.20 equiv). This mixture was degassed, purged with nitrogen 3 times and stirred for 3 h at 80° C. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1/5) to deliver 110 mg (83%) a mixture of (±)-methyl 11-ethenyl-12-(2,4-difluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylate and (±)-methyl 11-(2,4-difluorophenyl)-12-ethenyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylate as a light yellow solid.

(773) Step 3:

(774) Into a 50-mL round-bottom flask, was placed a mixture of (±)-methyl 11-ethenyl-12-(2,4-difluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylate and (±)-methyl 11-(2,4-difluorophenyl)-12-ethenyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylate (140 mg, 0.36 mmol, 1.00 equiv), methanol (10 mL), water (5 mL) and sodium hydroxide (144 mg, 3.60 mmol, 10.00 equiv). The resulting mixture was stirred for 2 h at 60° C. then it was cooled to RT and the pH value was adjusted to 5 with 2N HCl aqueous solution. The crude reaction mixture was filtered and directly subjected to reverse preparative HPLC (SunFire Prep C18 5 m 19*150 mm; gradient elution of 19% MeCN in water to 33% MeCN in water over a 6 min period, where both solvents contain 0.1% TFA) to provide a mixture of (±)-1-ethenyl-12-(2,4-difluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylic acid and (±)-11-(2,4-difluorophenyl)-12-ethenyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylic acid as a white solid (110 mg, 54%).

(775) Step 4:

(776) Into a 25-mL round-bottom flask, was placed a mixture of (±)-1-ethenyl-12-(2,4-difluorophenyl)-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylic acid and (±)-11-(2,4-difluorophenyl)-12-ethenyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylic acid (110 mg, 0.29 mmol, 1.00 equiv), N,N-dimethylformamide (4.0 mL), 5-(aminomethyl)-4,6-dimethylpyridin-2-amine dihydrochloride (78 mg, 0.35 mmol, 1.20 equiv), DIEA (151 mg, 1.17 mmol, 4.00 equiv) and HATU (133.4 mg, 0.35 mmol, 1.20 equiv). The resulting mixture was stirred for 2 h at room temperature then it was concentrated. The residue was purified by silica gel column chromatography eluting with dichloromethane/methanol (5/1) to deliver 120 mg (81%) of (±)-N-[(6-amino-2,4-dimethyl-pyridin-3-yl)methyl]-12-(2,4-difluorophenyl)-11-ethenyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9(14),10,12-hexaene-4-carboxamide and (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-1-(2,4-difluorophenyl)-12-ethenyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9(14),10,12-hexaene-4-carboxamide as a light yellow solid.

(777) Step 5:

(778) Into a 100-mL round-bottom flask, was placed (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-12-(2,4-difluorophenyl)-11-ethenyl-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2,4,6,9(14),10,12-hexaene-4-carboxamide and (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-11-(2,4-difluorophenyl)-12-ethenyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9(14),10,12-hexaene-4-carboxamide (80 mg, 0.16 mmol, 1.00 equiv), methanol (50 mL) and 5% palladium on carbon (8 mg). The mixture was degassed, purged with hydrogen 3 times and stirred for 2 h at 25° C. under a hydrogen atmosphere. The solids were then separated by filtration and the filtrate was concentrated under vacuum. The residue was directly subjected to reverse preparative HPLC (Prep-C18, 5 M XBridge column, 19×150 mm, Waters; gradient elution of 52% MeCN in water to 57% MeCN in water over a 6 min period, where both solvents contain 10 mM NH.sub.4HCO.sub.3 and 0.05% ammonia) to provide (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-12-(2,4-difluoro-phenyl)-11-ethyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9(14),10,12-hexaene-4-carboxamide and (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-11-(2,4-difluorophenyl)-12-ethyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2,4,6,9(14),10,12-hexaene-4-carboxamide as a white solid (17.3 mg, 21.5%). MS: (M+H).sup.+ found for C.sub.31H.sub.27F.sub.2N.sub.3O.sub.2: 512.0.

Example 102

Synthesis of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-12-(4-fluorophenyl)-8-methyl-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide, (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-11-(4-fluorophenyl)-8-methyl-15-oxatetra-cyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide, (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-12-(4-fluorophenyl)-1-methyl-15-oxatetracyclo-[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide and (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-11-(4-fluorophenyl)-1-methyl-15-oxatetracyclo-[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide triflate salt

(779) ##STR00726##

(780) Step 1:

(781) Into a 100-mL 3-necked round-bottom flask, was placed a mixture of 1,2,4-tribromobenzene (5.20 g, 16.52 mmol, 1.00 equiv) and 2-methylfuran (4.18 g, 50.91 mmol, 3.00 equiv) in toluene (30 mL) with stirring at −30° C., followed by the drop-wise addition of n-BuLi (7.48 mL, 1.10 equiv). The resulting mixture was stirred for 30 min at −30° C. then it was quenched by the addition of 50 mL of H.sub.2O, cooled to RT and extracted with 3×50 mL of ethyl acetate. The organic layer was washed with 200 mL of H.sub.2O, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by a silica gel column chromatography eluting with ethyl acetate/petroleum ether (1:3) to deliver 2.10 g (54%) of a mixture of (±)-4-bromo-1-methyl-11-oxatricyclo[6.2.1.0.sup.2,7]undeca-2,4,6,9-tetraene and (±)-5-bromo-1-methyl-11-oxatricyclo[6.2.1.0.sup.2,7]undeca-2,4,6,9-tetraene as a light yellow solid.

(782) Step 2:

(783) Into a 100-mL 3-necked round-bottom flask, was placed a solution of (±)-4-bromo-1-methyl-11-oxatricyclo[6.2.1.0.sup.2,7]undeca-2,4,6,9-tetraene and (±)-5-bromo-1-methyl-11-oxatricyclo[6.2.1.0.sup.2,7]undeca-2,4,6,9-tetraene (2.10 g, 8.86 mmol, 1.00 equiv) in chloroform (30 mL) with stirring at rt, followed by the slow addition of a solution of bis(pyridin-2-yl)-1,2,4,5-tetrazine (2.40 g, 10.16 mmol, 1.10 equiv) in chloroform (20 mL). The resulting mixture was stirred for 1 h at 50° C. to deliver the mixture of corresponding isobenzofurans intermediate (50 mL) as a red solution. To this solution into a 100-mL 3-necked round-bottom flask at 0° C. was added a solution of [5-(methoxycarbonyl)-2-(trimethylsilyl)phenyl](phenyl)iodanium trifluoromethanesulfonate (5.60 g, 9.99 mmol, 1.00 equiv) in dichloromethane (40 mL), followed by TBAF (5.23 g, 20.00 mmol, 2.00 equiv). The resulting mixture was stirred for 30 min at 0° C. then it was concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1:3) to deliver 900 mg (26%) of (±)-methyl 12-bromo-8-methyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylate, (±)-methyl 11-bromo-8-methyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylate, (±)-methyl 12-bromo-1-methyl-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylate and (±)-methyl 11-bromo-1-methyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylate as a light yellow solid.

(784) Step 3:

(785) Into a 50-mL round-bottom flask, was placed a mixture of (±)-methyl 12-bromo-8-methyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylate, (±)-methyl 11-bromo-8-methyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylate, (±)-methyl 12-bromo-1-methyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylate and (±)-methyl 11-bromo-1-methyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylate (500.0 mg, 1.45 mmol, 1.00 equiv), dioxane/H.sub.2O (5/0.5 mL), (4-fluorophenyl)boronic acid (665.0 mg, 4.75 mmol, 1.50 equiv), sodium carbonate (461.0 mg, 4.35 mmol, 3.00 equiv) and Pd(dppf)Cl.sub.2 (53.0 mg, 0.07 mmol, 0.05 equiv) with stirring under N.sub.2. The resulting mixture was stirred for 3 h at 90° C. then it was cooled to RT and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1:5) to afford 410.0 mg (79%) of a mixture of (±)-methyl 12-(4-fluorophenyl)-8-methyl-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylate, (±)-methyl 11-(4-fluorophenyl)-8-methyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylate, (±)-methyl 12-(4-fluorophenyl)-1-methyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylate and (±)-methyl 11-(4-fluorophenyl)-1-methyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylate as a light yellow solid.

(786) Step 4:

(787) Into a 25-mL round-bottom flask, was placed a mixture of (±)-methyl 12-(4-fluorophenyl)-8-methyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylate, (±)-methyl 11-(4-fluorophenyl)-8-methyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylate, (±)-methyl 12-(4-fluorophenyl)-1-methyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylate and (±)-methyl 11-(4-fluorophenyl)-1-methyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylate (410.0 mg, 1.14 mmol, 1.00 equiv), methanol/H.sub.2O (5/1 mL) and sodium hydroxide (142.8 mg, 3.57 mmol, 3.00 equiv). The resulting mixture was stirred for 2 h at room temperature then the pH value of the solution was adjusted to 7 with 1N hydrogen chloride aqueous solution. The mixture was then concentrated under vacuum to deliver 430.0 mg (crude) of a mixture of (±)-12-(4-fluorophenyl)-8-methyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylic acid, (±)-11-(4-fluorophenyl)-8-methyl-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylic acid, (±)-12-(4-fluorophenyl)-1-methyl-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylic acid and (±)-11-(4-fluorophenyl)-1-methyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylic acid as a yellow solid.

(788) Step 5:

(789) Into a 8-mL vial, was placed a mixture of (±)-12-(4-fluorophenyl)-8-methyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylic acid, (±)-11-(4-fluorophenyl)-8-methyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylic acid, (±)-12-(4-fluorophenyl)-1-methyl-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylic acid and (±)-11-(4-fluorophenyl)-1-methyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylic acid (100.0 mg, 0.29 mmol, 1.00 equiv), N,N-dimethylformamide (4.0 mL), 5-(aminomethyl)-4,6-dimethyl-pyridin-2-amine dihydrochloride (65.6 mg, 0.29 mmol, 1.00 equiv), HATU (133.3 mg, 0.35 mmol, 1.20 equiv) and DIEA (261.8 mg, 2.03 mmol, 7.00 equiv). The resulting mixture was stirred for 2 h at room temperature then it was filtered and directly subjected to reverse preparative HPLC (SunFire Prep C18 Column, 19*150 mm, Waters; gradient elution of 36% MeCN in water to 51% MeCN in water over a 7 min period, where both solvents contain 0.1% TFA) to provide the title compounds as a light yellow solid (33.0 mg, 19%). MS: (M+H).sup.+ found for C.sub.30H.sub.26FN.sub.3O.sub.2: 480.2.

Example 103

Synthesis of (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-12-(4-fluorophenyl)-10-methyl-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9(14),10,12-hexaene-4-carboxamide and (±)-N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-11-(4-fluorophenyl)-13-methyl-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9(14),10,12-hexaene-4-carboxamide

(790) ##STR00727##

(791) Step 1:

(792) Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a mixture of 1,5-dichloro-2-iodo-3-methylbenzene (5.00 g, 17.43 mmol, 1.00 equiv), toluene (50 mL) and furan (2.40 g, 34.67 mmol, 2.00 equiv) followed by the drop-wise addition of n-BuLi (19.2 mL, 1.10 equiv) with stirring at −30° C. The mixture was then quenched by the addition of 10.0 mL of water, cooled to RT and concentrated under vacuum. The residue was purified by a silica gel column chromatography eluting with ethyl acetate/petroleum ether (1/5) to afford 3.10 g (92%) of (±)-5-chloro-3-methyl-11-oxatricyclo-[6.2.1.0.sup.2,7]undeca-2,4,6,9-tetraene as yellow oil.

(793) Step 2:

(794) Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of (±)-5-chloro-3-methyl-11-oxatricyclo-[6.2.1.0.sup.2,7]undeca-2,4,6,9-tetraene (500 mg, 2.60 mmol, 1.00 equiv) in chloroform (10 mL) with stirring at 0° C., followed by the drop-wise addition of bis(pyridin-2-yl)-1,2,4,5-tetrazine (674 mg, 2.85 mmol, 1.10 equiv) in chloroform (10.0 mL). The resulting mixture was stirred for 1 h at 50° C. then it was cooled to RT to deliver 6-chloro-4-methyl-2-benzofuran in chloroform (20 mL) as a yellow liquid, which was used in the next step directly.

(795) To this solution was added dichloromethane (10 mL) with stirring at 0° C., and a solution of [5-(methoxycarbonyl)-2-(trimethylsilyl)phenyl](phenyl)iodanium trifluoromethanesulfonate (840.0 mg, 1.50 mmol, 0.50 equiv) in dichloromethane (10 mL) drop-wise, followed by the drop-wise addition of TBAF (3.6 mL, 1.20 equiv) with stirring at 0° C. The mixture was stirred for 30 min at 0° C. then it was diluted with 10 mL of DCM, washed with H.sub.2O and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1/5) to afford 220.0 mg (24%) of a mixture of (±)-methyl 12-chloro-10-methyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylate and (±)-methyl 11-chloro-13-methyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylate as an off-white solid.

(796) Step 3:

(797) Into a 10-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a mixture of (±)-methyl 12-chloro-10-methyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylate and (±)-methyl 11-chloro-13-methyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylate (300.0 mg, 1.00 mmol, 1.00 equiv), (4-fluorophenyl)boronic acid (210.0 mg, 1.50 mmol, 1.50 equiv), K.sub.3PO.sub.4 (636.0 mg, 3.00 mmol, 3.00 equiv), dioxane/H.sub.2O (3 mL) and 3.sup.rd generation XPhos (4.0 mg, 0.05 equiv). The resulting mixture was stirred for 2.5 h at 100° C. under nitrogen atmosphere then it was cooled to RT and concentrated. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1/5) to afford 280.0 mg (78%) of a mixture of (±)-methyl 12-(4-fluorophenyl)-10-methyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylate and (±)-methyl 11-(4-fluorophenyl)-13-methyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylate as an off-white solid.

(798) Step 4:

(799) Into a 10-mL round-bottom flask, was placed a mixture of (±)-methyl 12-(4-fluorophenyl)-10-methyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylate and (±)-methyl 11-(4-fluorophenyl)-13-methyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylate (360 mg, 1.00 mmol, 1.00 equiv), methanol (8.00 mL), water (2.00 mL) and sodium hydroxide (80 mg, 2.00 mmol, 2.00 equiv). The resulting mixture was stirred for 3 h at 50° C., then it was cooled to RT and the pH value of the solution was adjusted to 6 with 6N hydrogen chloride aqueous solution. The mixture was then diluted with 10 mL of H.sub.2O and extracted with 3×10 mL of ethyl acetate, the organic layers were combined, dried and concentrated under vacuum to afford 320.0 mg (92%) of a mixture of (±)-12-(4-fluorophenyl)-10-methyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylic acid and (±)-11-(4-fluorophenyl)-13-methyl-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylic acid as a white solid.

(800) Step 5:

(801) Into a 10-mL round-bottom flask, was placed a mixture of (±)-12-(4-fluoro-phenyl)-10-methyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylic acid and (±)-11-(4-fluorophenyl)-13-methyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylic acid (34.6 mg, 0.10 mmol, 1.00 equiv), 5-(aminomethyl)-4,6-dimethylpyridin-2-amine (22.4 mg, 0.10 mmol, 1.00 equiv), N,N-dimethylformamide (2 mL), HATU (38.0 mg, 0.10 mmol, 1.00 equiv) and DIEA (64.5 mg, 0.50 mmol, 5.00 equiv). The resulting mixture was stirred for 2 h at 20° C., the solids were then separated by filtration and the filtrate was directly subjected to reverse preparative HPLC (Prep-C18, 5 mM XBridge column, 19×150 mm, Waters; gradient elution of 35% MeCN in water to 43% MeCN in water over a 7 min period, where the aqueous phase contains 10 mM NH.sub.4HCO.sub.3+0.5% ammonia) to provide a mixture of the title compounds as a white solid (29.9 mg, 62%). MS: (M+H).sup.+ found for C.sub.30H.sub.26FN.sub.3O.sub.2: 480.2

Example 104

Synthesis of (±)-11,12-dicyclopropyl-N-({4-[N′-methoxycarbamimidoyl]phenyl}methyl)-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(802) ##STR00728##

(803) The title compound was prepared following the procedure described in Example 97, Step 3, but using 4-(aminomethyl)-N′-methoxybenzimidamide dihydrochloride (INT-7) instead of 5-(aminomethyl)-4,6-dimethylpyridin-2-amine dihydrochloride. MS: (M+H).sup.+ found for C.sub.30H.sub.29N.sub.3O.sub.3: 480.1.

Example 105

Synthesis of (±)-11,12-diethyl-N-({4-[N′-methoxycarbamimidoyl]phenyl}methyl)-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(804) ##STR00729##

(805) The title compound was prepared following the procedure described in Example 98, Step 3, but using 4-(aminomethyl)-N′-methoxybenzimidamide dihydrochloride (INT-7) instead of 4-(aminomethyl)benzene-1-carboximidamide dihydrochloride. MS: (M+H).sup.+ found for C.sub.28H.sub.29N.sub.3O.sub.3: 456.0.

Example 106

Synthesis of (±)-11,12-dimethyl-N-({4-[N′-methoxycarbamimidoyl]phenyl}methyl)-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(806) ##STR00730##

(807) The title compound was prepared following the procedure described in Example 96, Step 5, but using 4-(aminomethyl)-N′-methoxybenzimidamide dihydrochloride (INT-7) instead of 5-(aminomethyl)-4,6-dimethylpyridin-2-amine. MS: (M+H).sup.+ found for C.sub.26H.sub.25N.sub.3O.sub.3: 482.2.

Example 107

Synthesis of (1R,8S)—N-[(4-carbamimidoylphenyl)methyl]-11,12-diethyl-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9(14),10,12-hexaene-4-carboxamide formate salt

(808) ##STR00731##

(809) Step 1:

(810) (±)-11,12-Diethyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylic acid (Example 98, steps 1-2; 2.40 g, 8.15 mmol, 1.00 equiv) was subjected to chiral purification by Chiral-Prep-HPLC using the following conditions (SHIMADZU LC-20AT): Column: DAICEL CHIRALPAK IA-H 20*250 mm 5 um; mobile phase: Phase A: n-hexane (with 0.1% TFA), Phase B: ethanol; Detector, 230 nm to provide 900 mg (37.5%) of (1R,8S)-11,12-diethyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylic acid as a yellow solid. LC-MS (ES) [M+1]+m/z: 295.2 and 940 mg (39%) of (1S,8R)-11,12-diethyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylic acid as a yellow solid. LC-MS (ES) [M+1].sup.+ m/z: 295.2.

(811) Step 2:

(812) Into a 8-mL vial, was placed a mixture of (1R,8S)-11,12-diethyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylic acid (100 mg, 0.34 mmol, 1.00 equiv), N,N-dimethylformamide (5 mL), 4-(aminomethyl)benzene-1-carboximidamide dihydrochloride (90.2 mg, 0.41 mmol, 1.20 equiv), HATU (155.8 mg, 0.41 mmol, 1.20 equiv) and DIEA (131.6 mg, 1.02 mmol, 3.00 equiv). The resulting mixture was stirred for 1 h at room temperature then the solids were separated by filtration and the filtrate was directly subjected to reverse preparative HPLC (SunFire Prep-C18, 5 mM XBridge column, 19×150 mm, waters; gradient elution of 33% MeCN in water to 48% MeCN in water over a 6 min period, where both solvents contain 0.05% TFA) to provide the title compound as a white solid (35.4 mg, 22%). MS: [M-FA+1].sup.+ found for C.sub.27H.sub.27N.sub.3O.sub.2: 474.3.

Example 108

Synthesis of (1R,8S)-11,12-diethyl-N-({4-[N′-hydroxycarbamimidoyl]-phenyl}methyl)-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9(14),10,12-hexaene-4-carboxamide trifluoroacetate salt

(813) ##STR00732##

(814) Into a 8-mL vial, was placed (1R,8S)-11,12-diethyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylic acid (Example 107, Step 1; 100 mg, 0.34 mmol, 1.00 equiv), N,N-dimethylformamide (5 mL), 4-(aminomethyl)-N-hydroxybenzene-1-carboximidamide dihydrochloride (68 mg, 0.29 mmol, 1.20 equiv), HOBT (55 mg, 0.41 mmol, 1.20 equiv), EDCI (79 mg, 0.41 mmol, 1.20 equiv) and DIEA (132 mg, 1.02 mmol, 3.00 equiv). The resulting mixture was stirred for 4 h at 50° C. then it was cooled to RT, filtered and directly subjected to reverse preparative HPLC (Atlantis Prep T3 OBD Column, 19×150 mm, waters; gradient elution of 38% MeCN in water to 56% MeCN in water over a 8 min period, where both solvents contain 0.05% TFA) to provide the title compound as an off-white solid (23.4 mg, 12%). MS: [M-TFA+1].sup.+ found for C.sub.27H.sub.27N.sub.3O.sub.3: 442.2.

Example 109

Synthesis of (1S,8R)—N-[(4-carbamimidoylphenyl)methyl]-11,12-diethyl-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9(14),10,12-hexaene-4-carboxamide trifluoroacetate salt

(815) ##STR00733##

(816) Into a 8-mL vial, was placed a mixture of (1S,8R)-11,12-diethyl-15-oxatetracyclo-[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylic acid (Example 107, step 1) (100.0 mg, 0.34 mmol, 1.00 equiv), N,N-dimethylformamide (5 mL), 4-(aminomethyl)benzene-1-carboximidamide dihydrochloride (90.2 mg, 0.41 mmol, 1.20 equiv), HATU (155.8 mg, 0.41 mmol, 1.20 equiv) and DIEA (131.6 mg, 1.02 mmol, 3.00 equiv). The resulting mixture was stirred for 1 h at room temperature then it was filtered and directly subjected to reverse preparative HPLC (SunFire Prep-C18, 5 mM XBridge column, 19×150 mm, Waters; gradient elution of 33% MeCN in water to 48% MeCN in water over a 6 min period, where both solvents contain 0.05% TFA) to provide the title compound as an off-white solid (56.6 mg, 31%). MS: [M-TFA+1].sup.+ found for C.sub.27H.sub.27N.sub.3O.sub.2: 442.2.

Example 110

Synthesis of (1S,8R)-11,12-diethyl-N-({4-[N′-hydroxycarbamimidoyl]-phenyl}methyl)-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9(14),10,12-hexaene-4-carboxamide trifluoroacetate salt

(817) ##STR00734##

(818) Into a 8-mL vial, was placed (1S,8R)-11,12-diethyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylic acid (Example 107, Step 1; 100 mg, 0.34 mmol, 1.00 equiv), N,N-dimethylformamide (5 mL), 4-(aminomethyl)-N-hydroxybenzene-1-carboximidamide dihydrochloride 68 mg, 0.29 mmol, 1.20 equiv), HOBT (55 mg, 0.41 mmol, 1.20 equiv), EDCI (79 mg, 0.41 mmol, 1.20 equiv) and DIEA (132 mg, 1.02 mmol, 3.00 equiv). The resulting mixture was stirred for 4 h at 50° C. then it was cooled to RT, filtered and directly subjected to reverse preparative HPLC (Atlantis Prep T3 OBD Column, 19×150 mm, Waters; gradient elution of 38% MeCN in water to 56% MeCN in water over a 8 min period, where both solvents contain 0.05% TFA) to provide the title compound as an off-white solid (13.2 mg, 7%). MS: [M-TFA+1].sup.+ found for C.sub.27H.sub.27N.sub.3O.sub.3: 442.2.

Example 111

Synthesis of (1S,8R)-11,12-diethyl-N-({4N′-methoxycarbamimidoyl]phenyl}methyl)-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4, 6,9(14),10,12-hexaene-4-carboxamide trifluoroacetate salt

(819) ##STR00735##

(820) Into a 50-mL round-bottom flask, was placed a mixture of (1S,8R)-11,12-diethyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylic acid (Example 107, Step 1; 785 mg, 2.67 mmol, 1.00 equiv), N,N-dimethylformamide (20 mL), 4-(aminomethyl)-N′-methoxybenzimidamide dihydrochloride (INT-7; 573 mg, 2.27 mmol, 1.20 equiv), HATU (1.22 g, 3.21 mmol, 1.20 equiv) and DIEA (1.03 g, 7.97 mmol, 3.00 equiv). The resulting mixture was stirred for 1 h at room temperature then it was filtered and directly subjected to reverse preparative HPLC (Atlantis Prep T3 OBD Column, 19×150 mm, Waters; gradient elution of 38% MeCN in water to 56% MeCN in water over a 8 min period, where both solvents contain 0.05% TFA) to provide the title compound as a light yellow solid (1.060 g, 70%). MS: [M-TFA+1].sup.+ found for C.sub.28H.sub.29N.sub.3O.sub.3: 456.3.

Example 112

Synthesis of (1S,8R)—N-[(4-carbamimidoylphenyl)methyl]-11,12-dicyclopropyl-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide trifluoroacetate Salt

(821) ##STR00736##

(822) Step 1:

(823) (±)-11,12-dicyclopropyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylic acid (Example 97, Steps 1-2; 300 mg) was separated by Chiral Prep-HPLC using the following conditions. Column: chiralPAK-AD-3; mobile phase: A: n-Hexane (0.1% TFA), B: isopropanol; gradient elution of 20% B to 100% B in 10 min to deliver 128 mg (43%) of (1S,8R)-11,12-dicyclopropyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]-pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylic acid as a yellow solid and 135 mg (45%) of (1R,8S)-11,12-dicyclopropyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylic acid as a yellow solid. LCMS (ES) [M+1].sup.+ m/z 319.1.

(824) Step 2:

(825) Into a 50-mL round-bottom flask, was placed a mixture of (1S,8R)-11,12-dicyclopropyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylic acid (100 mg, 0.31 mmol, 1.00 equiv), DMF (8 mL), 4-(aminomethyl)benzene-1-carboximidamide dihydrochloride (84 mg, 0.38 mmol, 1.20 equiv), DIEA (202 mg, 1.56 mmol, 5.00 equiv) and HATU (180 mg, 0.47 mmol, 1.50 equiv). The resulting mixture was stirred for 4 h at 25° C. then it was filtered and directly subjected to reverse phase preparative HPLC (Prep-C18, 5 M XBridge column, 19×150 mm, Waters; gradient elution of 30% MeCN in water to 40% MeCN in water over a 10 min period, where both solvents contain 0.1% TFA) to provide the title compound as a light yellow solid (44.8 mg, 25%). MS: [M-TFA+1].sup.+ found for C.sub.29H.sub.27N.sub.3O.sub.2: 450.2.

Example 113

Synthesis of (1S,8R)-11,12-dicyclopropyl-N-({4-[N′-hydroxycarbamimidoyl]-phenyl}methyl)-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide trifluoroacetate Salt

(826) ##STR00737##

(827) Into a 8-mL vial, was placed a mixture of (1S,8R)-11,12-dicyclopropyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylic acid (Example 112, Step 1; 105 mg, 0.33 mmol, 1.00 equiv), N,N-dimethylformamide (5 mL), 4-(aminomethyl)-N-hydroxybenzene-1-carboximidamide dihydrochloride (95 mg, 0.40 mmol, 1.20 equiv), DIEA (170 mg, 1.32 mmol, 4.00 equiv), EDCI (76.4 mg, 0.40 mmol, 1.20 equiv) and HOBT (54 mg, 0.40 mmol, 1.20 equiv). The resulting mixture was stirred for 5 h at 50° C. then it was cooled to RT, filtered and directly subjected to reverse phase preparative HPLC (Prep-C18, 5 mM XBridge column, 19×150 mm, Waters; SunFire gradient elution of 8% MeCN in water to 15% MeCN in water over a 1 min period, then 15% MeCN in water to 18% MeCN in water over a 7 min period, where both solvents contain 0.1% TFA) to provide the title compound as an off-white solid (11.0 mg, 6%). MS: [M-TFA+1].sup.+ found for C.sub.29H.sub.27N.sub.3O.sub.3: 466.5.

Example 114

Synthesis of (1S,8R)-11,12-dicyclopropyl-N-({4-[N′-methoxycarbamimidoyl]-phenyl}methyl)-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxamide

(828) ##STR00738##

(829) Into a 50-mL round-bottom flask, was placed a mixture of (1S,8R)-11,12-dicyclopropyl-15-oxatetracyclo[6.6.1.0.sup.2,7.0.sup.9,14]pentadeca-2(7),3,5,9,11,13-hexaene-4-carboxylic acid (Example 112, Step 1; 900 mg, 2.83 mmol, 1.00 equiv), N,N-dimethylformamide (30 mL), 4-(aminomethyl)-N′-methoxybenzimidamide dihydrochloride (INT-7; 853 mg, 3.38 mmol, 1.20 equiv), HATU (1.29 g, 3.39 mmol, 1.20 equiv) and DIEA (1.46 g, 11.30 mmol, 4.00 equiv). The resulting mixture was stirred for 1 h at room temperature then it was diluted with 20 mL of H.sub.2O and extracted with 3×20 mL of ethyl acetate. The organic layers were washed with 50 mL of H.sub.2O and 50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with dichloromethane/methanol (10:1) to afford 647.1 mg (48%) of the title compound as an off-white solid. MS: [M-TFA+1].sup.+ found for C.sub.30H.sub.29N.sub.3O.sub.3: 480.4.

Biological Assays

Example 1

In Vitro Plasma Kallikrein Inhibition Assay

(830) Materials

(831) The chromogenic substrate D-Pro-Phe-Arg-pNa, 2HCl (BIOPHEN CS-31(02) from Hyphen BioMed, Neuville-Sur-oise, France) was dissolved in 5 mL deionized water and stored at 4° C. Concentration was determined in the spectrophotometer at 342 nm using an extinction coefficient of 8270. All other chemicals were of analytical grade.

(832) Human plasma kallikrein was purchased from Enzyme Research Labs (South Bend, Ind., USA, batch HPKa 2830). A stock solution of 7 μM in 50% glycerol was stored at −20° C.

(833) Enzyme reactions were conducted in “assay buffer” comprised of 20 mM HEPES at pH 7.4, 150 mM NaCl, 0.1% PEG-8000 and 0.01% Triton X-100.

(834) Both enzyme and substrate were diluted in assay buffer.

(835) The compound solutions as well as the enzyme and the substrate solutions were transferred to 96-well plates (Clear, UV-Star, Flat-bottom, Half-Area plates; cat. No. 675801 Greiner Bio-one, purchased from VWR International, Arlington Heights, Ill., USA) using a Rainin LTS 96-channel pipettor (Rainin, Columbus, Ohio, USA). Plate measurements were conducted using a SPECTROStar Nano reader (BMG Labtech, San Francisco, Calif., USA). The SPECTROStar Nano is a spectrophotometer and absorbance was measured at 405 nm. We used discrete wavelength, precise, kinetic reads of 15 cycles with a 60 sec cycle time.

(836) Determination of IC.sub.50 Values

(837) For the determination of IC.sub.50 values, the assays were performed at room temperature in 96-well plates with a total assay volume of 85 μL per well. The test compound was dissolved in 100% DMSO. The compounds were serially diluted in DMSO in a 7 point dose response. For the assays, 66.5 μL of protease solution (protease in assay buffer) was added per well followed by the addition of 8.5 μL of compound in 100% DMSO. The final assay concentration of the human plasma kallikrein was 250 pM. After 30 min. incubation at room temperature on an orbital shaker, the reactions were started by the addition of 10 μL substrate solution (in assay buffer, final assay concentration was 600 uM). After the addition of the substrate solution the final DMSO concentration was 10%. The plate was placed again on the shaker for 5 sec, spun at 2000 rpm for 5 sec and read on the spectrophotometer. The effect of the compound on the enzymatic activity was obtained from the linear part of the progress curves and determined after 15 minutes. The IC.sub.50 value was calculated from the plot of rate vs. inhibitor concentration by a 4 parameter logistic equation:
y=A+((B−A)/(1=((C/x)^D)))

(838) where y is the rate at the inhibitor concentration, x. A is the minimum y value at the highest inhibitor concentration and B is the y value in the absence of inhibitor, C is the IC.sub.50 value and D is the slope factor. The curve fitting was conducted with the non-linear regression routine of the analysis software XLfit (IDBS, version 5.3.1).

Example 2

Kallikrein Chromogenic Assay

(839) A 5.1 mM solution of the chromogenic substrate D-Pro-Phe-Arg-pNA, 2HCl (BIOPHEN CS-31-02) from Hyphen BioMed (Neuville-Sur-oise, France) was prepared by dissolving 25 mg of the chromogenic substrate D-Pro-Phe-Arg-pNA, 2HCl in about 5 ml deionized water a. The concentration was determined by an absorbance measurement at 342 nm (ϵ=8270 l/M cm). The solution was stored in the freezer.

(840) Human plasma kallikrein was obtained from Molecular Innovations (Novi, USA). The purchased stock was diluted to 7 M in 50% glycerol and stored at −20° C. The test compounds were provided as 10 mM solutions in DMSO and were serially diluted in the appropriate concentration range in a polypropylene plate with one well as DMSO control.

(841) The reaction buffer contained 26 mM HEPES, 195 mM NaCl, 0.13% PEG8000, 0.013% Triton X-100 pH 7.4. The assays were performed in UV-Star, flat-bottom, half-area plates 96 well plates (Greiner 675801). For the assay, 65 μL of 325 pM kallikrein solution in reaction buffer was added add to each well of the assay plate and 10 μL of a test compound was added. After 30 min incubation on a shaker, 10 μL of D-Pro-Phe-Arg-pNA, 2HCl solution was added. After mixing with the pipette, air bubbles were removed by centrifugation and the reaction was read on the Envision plate reader (Perkin Elmer, MA, USA) for 10 minutes at 405 nm.

(842) For IC.sub.50 determination the rates of hydrolysis were plotted against inhibitor concentration and analyzed by regression to a logistic curve.

Formulation Examples

(843) The following are representative pharmaceutical formulations containing a compound of the present disclosure.

Tablet Formulation

(844) The following ingredients are mixed intimately and pressed into single scored tablets.

(845) TABLE-US-00003 Quantity per tablet Ingredient mg compound of this disclosure 400 cornstarch 50 croscarmellose sodium 25 lactose 120 magnesium stearate 5

Capsule Formulation

(846) The following ingredients are mixed intimately and loaded into a hard-shell gelatin capsule.

(847) TABLE-US-00004 Quantity per capsule Ingredient mg compound of this disclosure 200 lactose spray dried 148 magnesium stearate 2

Injectable Formulation

(848) Compound of the disclosure (e.g., compound 1) in 2% HPMC, 1% Tween 80 in DI water, pH 2.2 with MSA, q.s. to at least 20 mg/mL.

Inhalation Composition

(849) To prepare a pharmaceutical composition for inhalation delivery, 20 mg of a compound disclosed herein is mixed with 50 mg of anhydrous citric acid and 100 mL of 0.9% sodium chloride solution. The mixture is incorporated into an inhalation delivery unit, such as a nebulizer, which is suitable for inhalation administration.

Topical Gel Composition

(850) To prepare a pharmaceutical topical gel composition, 100 mg of a compound disclosed herein is mixed with 1.75 g of hydroxypropyl cellulose, 10 mL of propylene glycol, 10 mL of isopropyl myristate and 100 mL of purified alcohol USP. The resulting gel mixture is then incorporated into containers, such as tubes, which are suitable for topical administration.

Ophthalmic Solution Composition

(851) To prepare a pharmaceutical ophthalmic solution composition, 100 mg of a compound disclosed herein is mixed with 0.9 g of NaCl in 100 mL of purified water and filtered using a 0.2 micron filter. The resulting isotonic solution is then incorporated into ophthalmic delivery units, such as eye drop containers, which are suitable for ophthalmic administration.

Nasal Spray Solution

(852) To prepare a pharmaceutical nasal spray solution, 10 g of a compound disclosed herein is mixed with 30 mL of a 0.05M phosphate buffer solution (pH 4.4). The solution is placed in a nasal administrator designed to deliver 100 μL of spray for each application.