LV10450B - O-heteroaryl, o-alkylheteroaryl, o-alkenylheteroaryl and o-alkynylheteroarylmacrolides - Google Patents

Abstract

This invention pertains to obtaining the following macrolides, the common structural formula of which is presented below.<IMAGE>These O-heteroaryl-, O-alkylheteroaryl-, O-alkenylheteroaryl- and O-alkynylheteroaryl- macrolides are obtained from the appropriate raw materials, by means of alkylation and/or arylation of C-3'' and/or C-4'' carbon atoms at the cyclohexane ring. These macrolide immune suppressors are suitable for mammal autoimmune disease and infectious disease treatment, as well as for the elimination of transplanted foreign organ rejection.

Description

LV 10450

TITLE OF THE INVENTION

0-HETER0ARYL, 0-ALKYLHETER0ARYL, 0-ALKENYLHETEROARYL AND 0-ALKYNYLHETER0ARYLMACR0LIDES 15 ~

SUMMARY OF THE INVENTION

The present invention is related to 0-heteroaryl, 0-alkylheteroaryl, 0-alkenylheteroaryl and 0-alkynylheteroarylmacrolides which are useful in a mammaiian host for the treatment of autoimmune diseases (such as juvenile-onset diabetes mellitus, multiple sclerosis and rheumatoid arthritis), immunodepression, infectious diseases and/or the prevention of rejection of foreign organ transplants (e.g. bone marrow and heart transplants and xeno transplants) and are also useful in the topical treatment of inflammatory and hyperproliferative skin diseases and cutaneous raanifestations of imraunologically-mediated illnesses (such as: psoriasis, atopical dermatitis, contact 2 dermatitis and further eczematous dermatitises, seborrhoeic dermatitis, Lichen plānus, Pemphigus, bullous Pemphigoid, Epidermolysis bullosa, urticaria, angioedemas, vasculitides, erythemas, cutaneous eosinophilias , Lupus erythematosus , Alopecia areata) , male pattern alopecia, alopecia senilis, reversible obstructive airways disease, particularly asthma, alopecia, inflammation of mucosa and blood vessels, cytomegalovirus infection, multidrug resistance, idiopathic throrabocytopenic purpura, Behcet’s syndrome, conjunctivitis, Crohn's disease, Mooren’s ulcer, uveitis, severe intraocular inflammation, and/or hepatic injury associated with ischēmia. In addition, some of the compounds of this invention may have antagonistic properties and so have utility in the reversai of immunosuppressive activity and/or diminishing the toxicity of other immunosuppressive aģents.

More particularly, this invention relates to compounds of the general structural formula I:

I - 3 - - 3 - LV 10450 wherein R^·, R^, r3 t R^f r5^ rIO^ y an&lt;j n arg hereinafter defined. *

This invention also relates to pharmaceutical compositions containing the compounds and to a method of use of the present compounds and other aģents for the treatment of and prevention of certain afflictions, diseases and illnesses.

BRIEF DESCRIPTION OF DISCLOSURES IN THE ART

Fujisawa United States, European and Japanese patents and applications (U.S. Patent No. 4.894.366. issued January 16, 1990, EPO Publication No. 0.184.162 and PBJ Disclosure 63-17884)‘and publications (J. Am. Chem. Soc.. 1987, ļjž£, 5031 and J. Antibiotics 1987, 4£, 1249) disclose 17-allyl-l,14-dihydroxy-12-[2'-(4''-hydroay-3',-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetra-methyl-ll,28-dioxa-4-azatricyclo-[22.3.1.0^»^]octacos-18-ene-2,3,10,16-tetraone (FR-900506), (FK-506), (L-679,934), 17-ethyl-l,14-dihydroxy-12-[2»-(4· ·-hydroxy-3'1-methoxycyclohexyl)-l•-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^»^]octacos-18-ene-2,3,10,16-tetraone (FR-900520) and related compounds which are the starting materiāls for the preparation of the compounds described. The synthetic preparation of the aforementioned starting material (FR-900506) has recently been reported (J. Am. Chem. Soc.. 1989, 111. 1157). A Sandoz European patent application (EPO Publication No. 0.356.399) discloses stereoisomers of FR-900506 and derivatives at the 17-position. Fisons European and WIP0 patent applications (EPO Publication No. 0.323.042 and PCT Publication No. W0 89/05304) discloses various derivatives of FR-900506, FR-900520 and related compounds. A Sandoz European Patent application (EPO Publication No. 0.437.680) discloses chloro, bromo, iodo and azido derivatives of FR-900506, FR-900520 and related compounds. A Merck European Patent application (EPO Publication No. 0.428.365) discloses various amino derivatives of FR-900506. FR-900520 and related compounds. A . Fujisawa patent application (UK Publication No. GB 2.245.891-A) discloses various derivatives of FR-900506 bearing a heterocyclic group.

Fujisawa United States patents (U.S. Patent No. 4,929.611. issued May 29, 1990, U.S. Patent No. 4.956.352. issued Sept. 11, 1990 and U.S. Patent No. 5.110.811. issued May 5, 1992) discloses the use of FK-506-type compounds in treating resistance to transplantation. A Sandoz European patent application (EPO Publication No. 0.315.978) discloses the use of FR-900506 and related compounds in the topical treatment of inflaramatory and hyperproli-ferative skin diseases and of cutaneous manifestations of immunologically-mediated illness. A Fisons WIP0 patent application (PCT Publication No. W0 91/04025) discloses the use of various derivatives of FR-900506 in the treatment of immunodepression. A Fisons WIP0 patent application (PCT Publication V/0 90/14826) discloses the use of FR-900506 and related compounds in the treatment of reversible obstructive airways disease, particularly asthma. A Fujisava European patent application (EPO Publication No. 0.423.714) discloses the use of FK-506 and derivatives as hair revitalizing aģents. Various studies have suggested the efficacy of FK-506 in the treatment of a number of ailments, including - 5 - LV 10450 rheumatoid arthitis (C. Arita, et al., Clincial exp. Immunol.. 1990, 82».456-461; N. Inamura, et al.,

Clin. Immunol. Immunopathol, 1988, M. 82-90), recent-onset diabetes (N. Murase, et al., Diabetes. 1990, 22, 1584-86; N. Murase, et al., Lancet. 1990, 336. 373-74), posterior uveitis (H. Kawashima, ίο 15 20

Invest. Ophthalmol. Vis. Sci.. 1988, 2i, 1265-71), hepatic injury associated with ischemia (M. Sakr, et al., Life Sci. . 1990, 47., 687-91) allergic encephalomyelitis (K, Deguchi, et al., Brain Nerve. 1990, 4£, 391-97), glomerulonephritis (J. McCauley, et al., Lancet. 1990, 335. 674) and systemic lupus erythematosus (K. Takabayashi, et al., Clin'. Inununol. Immunopathol.. 1989, 21, 110-117) multidrug resistance (M. Naito, et al., Cancer Chemother. Pharmacol.. 1992, 22, 195-200), inflammation of mucosa and blood vessels (PCT Publication W0 91/17754). cytomegalovirus infection (UK Publication GB 2.247.620A). and idiopathic thrombocytophenic purpura and Basedow’s disease (PCT Publication W0 91/19495).

BACKGROUND OF THE INVENTION 25

Immunoregulatory abnormalities have been shown to exist in a wide variety of &quot;autoimmune” and chronic inflammatory diseases, including systemic lupus erythematosis, chronic rheumatoid arthritis, type I and II diabetes mellitus, inflammatory bowel disease, biliary cirrhosis, uveitis, multiple sclerosis and other disorders such as Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, ichthyosis, and Gravēs ophthalmopathy. Although the underlying pathogenesis of each of these 30 5 6 conditions may be quite different, they have in common the appearance of a variety of autoantibodies and self-reactive lymphocytes. Such self-reactivity inay be due, in part, to a loss of the homeostatic Controls under which the normai immune system operates. 10

Similarly, following a bone-marrow or an organ transplantation, the host lymphocytes recognize the foreign tissue antigens and begin to producē antibodies which lead to graft rejection.

One end result of an autoimraune or a rejection process is tissue destruction caused by inflammatory celis and the mediators they release. 15 20

Antiinflammatory aģents such as NSAID’s and corticosteroids act principally by blocking the effect or secretion of these mediators but do nothing to modify the immunologic basis of the disease. On the other hand, cytotoxic aģents such as cyclo-phosphamide, act in such a nonspecific fashion that both the normai and autoimmune responses are shut off. Indeed, patients treated with such nonspecific immunosuppressive aģents are as likely to succumb from infection as they are from their autoimmune disease. 25

Cyclosporin A which was approved by the US FDA in 1983 is currently the leading drug used to prevent rejection of transplanted orgāns. The drug acts by inhibiting the body's immune system from mobilizing its vast arsenal of natūrai protecting aģents to reject the transplant's foreign protein. Though cyclosporin A is effective in fighting transplant rejection, it is nephrotoxic and is known 30 7 7 LV 10450 to cause several undesirable side effects including kidney failure, abnormal liver function and gastrointestinal discomfort.

Newer, safer drugs exhibiting less side effects are constantly being searched for in the field.

The 23-membered tricyclo-macrolide iminunosuppressant, tacroliinus, FR-900506, FK-506,

cir3o OCH3 (17-allyl-l,14-dihydroxy-12-[2'-(4''-hydroxy-3* mel:lioxycyclohexyl)-l' -metliylvinyl]-23,25-diraethoxy-13,19,21,27-tetrametlvyl-ll, 28-dioxa-4-azatricyclo-[22.3.1.0^’^]-octacos-18-ene-2,3,10,16-tetraone) and related corapounds which were isolated and characterized by Tanaka, Kuroda, and co-workers at

Fujisawa Pharmaceutical Co. in Japan, see J. Am.

Chp.m. Soc., 1987, 109. 5031, and U.S. Patent No., 4.894.366. issued January 16, 1990) have been shown to possess exceptional immunosuppressive activity. Fujisawa United States patents (U.S. Patent No. 4.929.611. issued May 29, 1990, U.S. Patent No. 4.956.352. issued September 11, 1990 and U.S. Patent No. 5.110.811. issued May 5, 1992) disclose the use of FK-506-type compounds in treating resistance to transplantation. In particular, the compound FR-900506 has been reported to be 100 tinies tnore effective than cyclosporin in the supression of in vitro immune systems (J. Antibiotics 1987, 4£, 1256). In addition, these compounds are reputed to possess topical activity in the treatment of inflammatory and hyperproliferative skin diseases and cutaneous manifestations of immunologically-mediated illnesses (EPO Pub. No. 0.315.978).

The compound FK-506 and related compounds further have been suggested to be useful in the treatment of obstructive airways disease, particularly asthma (PCT Publication W0 90/14826). male pattern alopecia or alopecia senilis (EPO Publication No. 0.423.714). rheumatoid arthitis (C. Arita, et al., Clincial exp. Immunol.. 1990, 82. 456-461; N. Inamura, et al., Clin. Immunol. Immunopathol. 1988, 4£, 82-90), recent-onset diabetes (N. llurase, et al. , Diabetes. 1990, 31, 1584-86; N. Murase, et al. , Lancet. 1990, 336. 373-74), posterior uveitis (H. Kavashima, Invest. Ophthalmol. Vis. Sci.t 1988, 21, 1265-71), hepatic injury associated with ischemia (M. Sakr, et al., Life Sci.. 1990, 47, 687-91) allergic encephalomyelitis (K, Deguchi, et al., Brain Nerve. 1990, 42, 391-97), glomerulo- - 9 - - 9 - LV 10450 nephritis (J. McCauley, et al., Lancet. 1990, 335. 674), systemic lupus erythematosus (K. Tal&lt;;abayashi, et al., Clin. Immunol. Immunopathol.. 1989, 51. 110-117) multidrug resistance (M. Naito, et al., Cancer Chemother. Pharmacol.. 1992, Zl, 195-200), inflanunation of mucosa and blood vessels (PCT Publication W0 92/17754), cytomegalovirus infection (UK_Xubļ.icaJtXon_GB_2.u2^7_,A2i)A), and idiopathic thrombocytophenic purpura and Basedow's disease CPCT Publication WO 91/19495^. DETAILED DESCRIPTION OF THE INVENTION A. Scope of the Invention

The novel compound of this invention has structural Formula I:

I 5 10 or a pharmaceufcically acceptable salt thereof, uherein: r! is selected from: (1) heteroaryl; (2) substituted heteroaryl in which the substituents are X, Y and Z; (3) heteroaryl-C1_10alkyl; 10 (4) substituted heteroaryl-Cļ_ļQalkyl in which the heteroaryl group is substituted by X, Y and Z and the alkyl portion may be substituted with one or more of the substituent(s) selected from: (a) liydroxy, 15 (b) oxo, (c) C1_6-alkoxy, (d) aryl-Cļ_3alkoxy, (e) substituted aryl-Cļ_3alkoxy, in which the substituents on aryl are X, Y and Z, 20 (f) unsubstituted or substituted aryloxy, in which the substituents on aryl are X, Y and Z, (g) -OCO-C1_^alkyl, 25 (h) -NR^R^, wherein R^ and R^ are independently selected from (i) hydrogen, (ii) Cļ_ļQalkyl unsubstituted or substituted with one or more of the substituent(s) selected from: (a') aryl, which is unsubstituted or substituted with X, Y and &amp; i 30 - 11 - - 11 - LV 10450 (b'&gt; heteroaryl, which is unsubstituted or substituted with X, Y and Z, (c') -0H, (d') C1_6alkoxy, (e’&gt; -C02H, (f') -COz-C^all^l, (g‘) -C3_7cycloalkyl, and Ch') -OR11, (iii) C3_ļQalkenyl unsubstituted or substituted with one or more of the substituent(s) selected from: (a*&gt; aryl, which is unsubstituted or substituted with X, Y and Z, (b') heteroaryl, which is unsubstituted or substituted with X, Y and Z, (c') -0H, (d') Cj^alkosT-, (e·) -C02H, (f’&gt; -C02-C1_6alkyl, (g1) -C3_7cycloalkyl, and (h') -OR11, (iv) or where R^ and R^ and the N to which they are attached may form an unsubstituted or substituted 3-7-raembered heterocyclic ring which may include one or two additional heteroatoms independently selected from the group consisting of 0, S(0)p, NR1^, vherein R1^ is hydrogen or 12 Cļ_6 alkyl unsubstituted or substituted by phenyl, and p is 0, 1 or 2, such as morpholine, thiomorpholine, piperidine, or piperizine, (i) -NR^C0-Cļ_5alkyl-R1, wherein R are as defined above, (j) -NR2C02-C1_6alkyl-R3, (k) -NR4 5CONR5R6, (1) -OCONR5R6, (m) -C00R5, (n) -CHO, (o) aryl, (p) substituted aryl in which the substituents are X, Y and Z, (q&gt; -OR7, and (r) -S(0)p-C1_6alkyl; 1 (a) hydroxy, 2 (b) oxo, 3 (c) C1_6alkoxy, 4 heteroaryl-Cļ_ļoal^yl wherein one or more of the alkyl carbons is replaced by a group selected from: -NR^-, -0-, -S(0)p-, -C02-, -02C-, -C0NR5-, -NR5C0-, -NR^CONR -; 5 substituted heteroaryl-Cļ_iQalkyl wherein one or inore of the alkyl carbons is replaced by a group selected from: -NR^-, -0-, -S(0)p-, -C02-, -02C-, -C0NR5-, -NR5C0-, and -NR^CONR6-, the heteroaryl group is substituted with X, Y, and Z, and the alkyl 6 group may be substituted with one or more of the substituent(s) selected from: 7 (d) aryl-C]__3alkoxy, - 13 - LV 10450 (e) substituted aryl-Cļ_3alkoxy, in which tlie substituents on aryl are X, Y and Z, (f) unsubstituted or substituted aryloxy, in which the substituents on aryl are 5 X, Y and Z, (g) -OCO-Cj^a^l, (h) -NR*&gt;R7, wherein R*&gt; and R7 are as defined above, (i) -NR6C0-C1_6alkyl-R7, 10 (j) -NR6C02-C1_6alkyl-R7, (k) -NR6C0NR6R7, (l) -0C0NR6R7, (m) -C00R6, (n) -CHO, 15 (o) aryl, (p) substituted aryl in which the substituents are X, Y and Z, (q) -OR^, and (r) -S(0)p-C1_6alkyl; 20 (7) heteroaryl-C3_ļQalkenyl wherein alkenyl contains one to four double bonds; /&quot;s, 00 heteroaryl-C3_ļQalkenyl wherein alkenyl contains one to four double bonds and vherein one or more of the alkyl carbons is 25 replaced by a group selected from: -NR^-, -0-, -S(0)p-, -C02-, -02C-, -C0NR6-, -NR6C0-, and -NR6C0NR7-; (9 ) substituted heteroaryl-C3_ļ0alkenyl vherein alkenyl contains one to four double bonds 30 and wherein one or more of the alkyl carbons may be replaced by a group selected from: -NR6-, -0-, -S(0)p-, -C02-, -02C-, -C0NR6-, -NR^CO-, and -NR^CONR7, the heteroaryl group 14 is substituted with X, Y, and Z, and the alkyl group may be substituted with one or more of the substituent(s) selected from: (a) hydroxy, (b) oxo, (c) C1_6alkoxy, (d) aryl-Cļ_3alkoxy, (e) substituted aryl-Cļ_3alkoxy, in which the substituents on aryl are X, Y and Z, (f) unsubstituted or substituted aryloxy, in which the substituents on aryl are X, Y and Z, (g) -OCO-C^a^l, (h) -NR^R7, wherein R^ and R7 as defined above, (i) ^NR^C0-Cļ_5alkyl, wherein R6 is as defined above, (j) -NR6C02-C1_6alkyl, (k) -NR6C0NR6R7, (l) -OCONR6R7, (m) -C00R6, (n) -CHO, (o) aryl, (p) substituted aryl in which the substituents are X, Y and Z, and (q) -OR11, and (r) -S(0)p-C1.6alkyl; R^ is selected from: (1) the definitions of R1; (2) hydrogen; (3) phenyl; - 15 - LV 10450 (4) substituted phenyl in which the substituents are X, Y and Z; (5) 1- or 2~naphthyl; (6) substituted 1- or 2-naphthyl in which the substituents are X, Y and Z; 5 (7) biphenyl; (8) substituted biphenyl in which the substituents are X, Y and Z; (9) ci-ioalky;Li 10 &lt;10) substituted-Cļ_ļQalkyl one or more substituent(s) is(are) selected from: (a) hydroxy, (b) oxo, &lt;c&gt; C1_6alkoxy, 15 (d) aryl-Cļ_3alkoxy, (e) substituted aryl-Cļ_3alkoxy, in which the substituents on aryl are X, Y and Z (f) unsubstituted or substituted aryloxy, in which the substituents on aryl are 20 X, Y and Z, (g) -0C0-C1_6alkyl, (h) -NR^R^, wherein R^ and R^ are as defined above (i) -NR6CO-Cļ_^alkyl-R7, vherein R^ and R7 25 are as defined above, (j) -COOR^, wherein R^ is as defined above, (k) -CHO, (l) phenyl, (m) substituted phenyl in which the 30 substituents are X, Y and Z, (η) 1- or 2-naphthyl, (o) substituted 1- or 2-naphthyl in which the substituents are X, Y and Z, 16 (p) biphenyl, (q) substituted biphenyl in which the substituents are X, Y and Z, (r) -0R11, and (s) -S(0)p-C1_6alkyl; (11) C3_10alkenyl; (12) substituted C3_ļQalkenyl in which one or inore substituent(s) is(are) selected frora: (a) hydroxy, (b) oxo, (c) C1_6alkoxy, (d) phenyl-Cļ_3alkoxy, (e) substituted phenyl-Cļ_3alkoxy, in which the substituents on phenyl are X, Y and Z, (f) -0C0-C1-6alkyl, (g) -NR^R?, wherein R^ and R^ are as defined above (h) -NR^CO-Cļ_^alkyl, wherein R6 is as defined above, (i) -COOR^, wherein R^ is as defined above, (j) -CHO, (k) phenyl, (l) substituted phenyl in which the substituents are X, Y and Z, (m) 1- or 2-naphthyl, (n) substituted 1- or 2-naphthyl in which the substituents are X, Y and Z, (o) biphenyl, (p) substituted biphenyl in which the substituents are X, Y and Z, (q) -OR-^ , and (r) -S(0)p-C1_6alkyl; - 17 - LV 10450 (13) C3_10alkynyl; (14) substituted C3_10alkynyl in which one or more substituent(s) is(are) selected frora: (a) hydroxy, (b) oxo, (c) C1_6alkoxy, (d) phenyl-Cļ_3alkoxy, (e) substituted phenyl-Cļ_3alkoxy, in which the substituents on phenyl are X, Y and Z, (f) -0C0-C]_6alkyl, (g) -NR^R^t vherein R^ and R^ are as defined above, (h) -NR^CO-Cļ_^alkyl, wherein R^ is as defined above, (i) -COOR^, wherein R*&gt; is as (defined above, (j) -CHO, (k) phenyl, (l) substituted phenyl in which the substituents are X, Y and Z, (m) 1- or 2-naphthyl, (n) substituted 1- or 2-naphthyl in which the substituents are X, Y and Z, (o) biphenyl, (p) substituted biphenyl in which the substituents are X, Y and Z, (q) -OR11; and (15) -R11; R3 is hydrogen, hydroxy, -OR11, or Cļ_6alkoxy; is hydrogen, or R3 and R^ taken together form a double bond; R3 is methyl, ethyl, propyl or allyl; R10 is hydrogen, hydroxy, -OR11 or fluoro; 5 18 R7-'- is selected froin: (a) -P0(0H)0~M+, wherein M+ is a positively charged inorganic or organic counterion, (b) -so3-m+, (c) -C0(CH2&gt;qC02-M+, wherein q is 1-3, and (d) -CO-Cļ^ali^l-NR6!!7, wherein R6 and R7 are as defined above and the alkyl is unsubstituted or substituted with one or more substituents selected frora: 10 (i) hydroxy, &lt;ii) C1_6alkoxy, (iii) -NR^R·^·7, wherein R·^ and R^-7 are independently selected from: 15 (a') hydrogen, and (b') Cļ.galkļrl, (iv) -COOR^, wherein R^ is as defined above, (v) phenyl, 20 (iv) substituted phenyl in which the substituents are X, Y and Z, (vii) heteroaryl, (viii) -SH, and (ix) -S-C1_6alkyl; W is 0 or (H, 0H); 25 X, Y and Z independently are selected from: (a) hydrogen, (b) C-ļ_ļoalkyl, unsubstituted or substituted with one or raore substituents selected from: 3 0 (i) aryl, (ii) substituted aryl in which the substituents are X1, Y' and Z', (iii) heteroaryl, I. - 19 - I. - 19 - LV 10450 (iv) substituted heteroaryl in which the substituents are X', Y', and Z' , (v) unsubstituted or substituted 5 aryloxy, in which the substituents on aryl are X', Y' and Z', (vi) -OR6, (vii) -OR11, (viii) -OCOR6, 10 (ix) -0C02R6, (x) -NR6R7, (xi) -CHO, (xii) -NR6COC1_6alkyl-R7, (xiii) -NR6C02C1_6alkyl-R7, 15 (xiv) -NR6C0NR6R7, (xv) -OCONR6R7, (xvi) -C0NR6R7, (c) Cļ_ļQalkyl wherein one or more of the alkyl carbons is replaced by a group 20 selected from -NR6-, -0-, -S(0)p-, -C02-, -02C-, -CONR6-, -NR6C0-, -NR6CONR7-, -C0-, -CH(OH)-, alkenyl or alkynyl and the alkyl may be unsubstituted or substituted with one or 25 more substituents selected from: (i) aryl, (ii) substituted aryl in which the substituents are Xf, Y' and Z', (iii) heteroaryl, 30 (iv) substituted heteroaryl in which the substituents are X', Y', and Z' , 20 (v) unsubstituted or substituted aryloxy, in which the substituents on aryl are X', Y', and Z', (vi) -OR6, (vii) -OR11, (viii) -0C0R6, (ix) -0C02R6, (x) -NR6R7,

(xi ) -CIIO &lt;xii) -NR6COC1_6alkyl-R7, (xiii) -NR6C02C1_6alkyl-R7, (xiv) -NR6C0NR6R7, (xv) -OCONR6R7, (xvi) -CONR6R7, (d) 2ialogen, (e) -NR6R7, (f) -CN, (g) -CHO, 20 00 -cf3, (i) -SR8, wherein R8 is hydrogen, Ci_ga1kyi, trifluororaethyl, or phenyl, (j) -S0R8, (k) -so2r8, 25 (1) -conr6r7, (m) R90(CH2)m- vherein R9 is hydrogen, Cļ_0alkyl, hydroxy-C2_3alkyl, -CF3, phenyl, R11 or naphthyl and m is 0, 1, 2, or 3, 30 (n) -CH(0Rlz)(0R13), vherein R12 and R13 are Cj__3alkyl or taken together form a etliyl or propyl bridge, - 21 - LV 10450 X' Υ' ο (ο) R^CO(CH2&gt;in- wherein R9 and m are as defined above, 0 (p) R9OC(CH2)ra- wherein R9 and m are as defined above, and (q) -R11; or any two of X, Y and Z inay be joined to form a saturated ring having 5, 6 or 7 ring aboms, said ring atoms comprising 1 or 2 oxygen atoms, the remaining ring atoms being carbon, sucli as dioxolanyl or dioxanyl; and Z' independently are selected from: (a) hydrogen, (b) C1_7alkyl, (c) C2_$alkenyl, (d) halogen, (e) -(CH2)m-NR8R7, wherein R8, R7, and m are as defined above, (f) -CN, (g) -CHO, (h) -CF3, (i) -SR8, wherein R8 is hydrogen, Cļ_^alkyl, trifluoromethyl, or phenyl, (j) -S0R8, wlierein R8 is as defined above, (k) -S02R8, wherein R8 is as defined above, (l) -CONR6R7, wherein R8 and R7 are as defined above, (m) R90(CH2&gt;m- wherein R9 and m are as defined above, (n) -CH(OR12)(OR13), wherein R12 and R13 are as defined above, 0

Qn . Q (o) RvC0(CH2)m- wherein R* and m are as defined above, 0 22 (p) R90C(CH2&gt;m- wherein R^ and m are as deūined above, and &lt;q) -R11; n is 1 or 2.

The compounds of the present invention have asyimnetric centers and this invention includes ali of the optical isomers and mixtures thereof.

In addition compounds with carbon-carbon double bonds may occur in Z- and E- forms with ali isomeric forms of the compounds being included in the present invention.

When any variable (e.g., alkyl, aryl, R8, R7, R8, R^, R·^, R^, X, Y, Z, etc.) occurs more than one time in any variable or in Formula I, its definition on each ocurrence is independent of its definition at every other occurrence.

As used herein, the term &quot;alkyl&quot; includes those alkyl groups of a designated number of carbon atoms of either a straight, branched, or cyclic configuration. Examples of MalkylM include methyl, ethyl, propyl, isopropyl, butyl, sec-and tert-butyl, pentyl, hexyl, heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and the like. &quot;Alkoxy&quot; represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge, such as methoxy, ethoxy, propoxy, butoxy and pentoxy. &quot;Alkenyl&quot; is intended to include hydrocarbon chains of a specified number of carbon atoms of either a straight- or branched-corifiguration and at least one unsaturation, - 23 - - 23 - LV 10450 which may occur at any point along the chain, such as ethenyl, propenyl, butenyl, pentenyl, dimethylpentyl, and the like, and i'ncludes E and Z forms, where applicable; and &quot;heteroarylalkyl&quot; represents heteroaryl groups as herein defined which are attached through a straight or branched chain alkyl group of from one to ten carbon atoms. &quot;Halogen&quot;, as used herein, means fluoro, chloro, bromo and iodo.

As will be understood by those skilled in the art, pharraaceutically acceptable salts include, but are not limited to salts with inorganic acids such as liydroclxloride, sulfate, phosphate, diphosphate, hydrobromide, and nitrate or salts with an organic acid such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, — methanesulfonate, p-toluenesulfonate or palmoate, salicylate and stearate. Similarly pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium and anunonium (especially ammonium salts with amines of the formula HNR^R?).

The heteroaryl group as used herein includes acridine, carbazole, cinnoline, dibenzofuran, dibenzothiophene, quinoxaline, pyrrazole, indole, benzotriazole, furan, benzofuran, quinoline, isoquinoline, pyrazine, pyridazine, pyridine, pj'-rimidine, pyrrole which are optionally substituted.

In the compounds of Formula I the heteroaryl group inay be optionally substituted with X, Y and Z at any available carbon atom or nitrogen atom (if present), but compounds bearing certain of X, Y and Z directly substituted to a nitrogen atom of the heteroaryl ring inay be relatively unstable and are not preferred. 24

The term &quot;heteroaryl&quot; as utilized herein is intended to include tlie following heteraromatic groups which inay include X, Y and Z substitution as indicated and vherein Q is -N(X&gt;-, -0-, -S-, -S0-, or 5 -S02-:

Ϊ z

(Pyr irridine)

- 25 -

Y Z

X N (Quinoxaline) LV 10450 26 15 20 25

The aryl or aromatic group may include phenyl or naphthyl which are optionally substituted by from one- to three-members independently selected froin the group consisting of: alkyl, alkenyl, halogen, carboxyl, CHO, amino, mono-alkylamino, di-alkylamino, aminoalkyl, mono-alkylaminoalkyl, di~alkylaminoalkyl, alkylthio, alkylsulfinyl, alkysulfonyl, trifluoromethyl, amido, mono-alkylamido, dialkylamido, hydroxy, hydroxyalkyl, R-^0-alkyl, alkoxy, alkoxyalkyl, formamido, alkyl-C02-, formamidoalkyl, alkyl-C02-alkyl-, carboxyl, alkyl-C02H, alkyl-02C-, alkyl-02C-alkyl-, and OR^-l. 30 - 27 - - 27 -LV 10450

In the compound of formula I it is preferred that heteroaryl is selected from the group consisting of:

28

wherein X is as defined above. - 29 - - 29 -LV 10450 jn the compound of formula I it is also preferred tliat: s se lected from: (1) hydrogen, (2) methyl, (3) ethyl, (4) propyl, (5) a.llyl, (6) R11, (7) -C2_3alkyl-0H; and (8) -C2_3alkyl-0Rn; r3 is selected from: (1) hydrogen, (2) hydroxy, (3) -OR11, or r3 and R4 taken together form a double bond; R10 is hydrogen, hydroxy, fluoro, or -0R11; W is 0; and n is 2. 30

In one erabodiment of the present invention, heteroaryl is indole, which may be represented by: 30

wherein X, Y and Z are as defined above,

Preferred compounds of the present invention are the compounds identified as follows: 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(2-furanyl)methoxy-3&quot;-metlioxycyclohexyl )-l' -raethylvinylJ-23,25-dimethoxy- 13.19.21.27- tetramethyl-ll,28-dioxa-4-azatricyclo-[22.3.1.Ο4» 9]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(2-furanyl)methoxy-3&quot;-hydroxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy- 13.19.21.27- tetramethyl-ll,28-dioxa-4-azatricyclo-[22.3.1.0^»^]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[21-(4&quot;-hydroxy-3&quot;-(2-furanyl)methoxycyclohexyl)-l'-raethylvinyl]-23,25-d inie thoxy-13,19,21,27-tetramethyl-ll, 28-dioxa-4-aza-tricyclo[22.3.1.0^’^]octacos-18-ene-2,3,10,16-Lelraone; - 31 - - 31 - LV 10450 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(2-thiophene)-methoxy-3,,-methoxycyclohexyl)-l1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetraraethyl-ll,28-dioxa-4-aza-tricyclo[22.3.1.04·9]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(2-thiophene)-methoxy-3M-hydroxycyclohexyl)-l’-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-aza-tricyclo[22.3.1.0^» ^]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[2,-(4&quot;-(3-thiophene)-methoxy-3&quot;-hydroxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-aza-tricyclo[22.3.1.0^»^]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[2 ,-(4',-hydroxy-3&quot;-(2-thio-phene)methoxycyclohexyl)-l1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-aza-tricyclo[22.3.1.0^» ^]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-hydroxy-3&quot;-(3-thiophene)methoxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-aza-tricyclo[22.3.1.0^* ^]octacos-18-ene-2,3,10,16-tetraone; 32 17-Etliyl-1,14-dihydroxy-12-[Z '-(4&quot;-(2-thiophene)oxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy- 13.19.21.27- tetramethyl-ll,28-dioxa-4-azatricyclo-[22.3.1.0^'^]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(2-benzothienyl)-oxy-3&quot;-niethoxycyclohexyl)-l'-methylvinyl]-23,25-dime-thoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatri-cyclo-[22.3.1.0^»^]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-l, 14-dihydroxy-12-[2 '-(4&quot;-(5-indolyl)oxy-3&quot;-niethoxycyclohexyl )-l1 -methylvinyl]-23,25-dimethoxy- 13.19.21.27- tetramethyl-ll,28-dioxa-4-azatricyclo-[22.3.1.0^»^]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[21-(4&quot;-(5-indolyl)oxy-3M-hydroxycyclohexyl&gt;-l1-methylvinyl]-23,25-dimethoxy- 13.19.21.27- tetramethyl-ll,28-dioxa-4-azatricyclo-[22.3.1.0^1^]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14,20-trihydroxy-12-[2'-(4&quot;-(5-indolyl)-oxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]-23,25-di-methoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatri-cyclo-[22.3.1.0^ * ^]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,20-dihyd roxy-12-[2'-(4&quot;-(5-indolyl)oxy-3&quot;-methoxycycloliexyl)-l' -methylvinyl]-23,25-dimethoxy- 13,19,21,27-tetrainethyl-ll,28-dioxa-4-azatricyclo- [22.3.1.0^ * 9]octacos-18-ene-2,3,10,16-tetraone; - 33 - - 33 - LV 10450 17-Ethyl-l-hydroxy-12-[2,-(4&quot;-(5-indolyl)oxy-3&quot;-methoxycyclohexyl)-l ’ -inethylvinyl]-23,25-dimethoxy- 13.19.21.27- tetramethyl-ll,28-dioxa-4-azatricyclo-[22.3.1.04* 9]octacos-18-ene-2,3,10,16-tetraone; 5 17-Allyl-1,14-dihydroxy-12-[2'-(4M-(5-indolyl)oxy-3&quot;-inethoxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy- 13.19.21.27- tetramethyl-ll,28-dioxa-4-azatricyclo-[22.3.1.04&gt; 9]octacos-18-ene-2,3,10,16-tetraone; 10 J.7-Allyl-1,14-dihydroxy-12-[2,-(4&quot;-(5-indolyl)oxy-3&quot;-hydroxycyclohexyl)-l '-methylvinyl]-23,25-dimethoxy- 13.19.21.27- tetramethyl-ll,28-dioxa-4-azatricyclo-[22.3.1.04» 9]očtacos-18-ene-2,3,10,16-tetraone; 15 ”” 17-Allyl-1,14,20-trihydroxy-12-[2'-(4&quot;-(5-indolyl)-oxy-3&quot;-raethoxycyclohexyl)-l'-methylvinyl]-23,25-di-methoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatri-cyclo-[22.3.1.04* 9]octacos-18-ene-2,3,10,16-tetraone; 20 17-Allyl-1,20-dihydroxy-12-[2'-(4&quot;-(5-indolyl)oxy-3&quot;-methoxycyclohexyl)-l1 -metliylvinyl]-23,25-dimethoxy- 13.19.21.27- tetraraethyl-ll,28-dioxa-4-azatricyclo-[22.3.1.O4·9]octacos-18-ene-2,3,10,16-tetraone; 25 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(5-indolyl)oxy-3M-ethoxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy- 13.19.21.27- tetramethyl-ll,28-dioxa-4-azatricyclo-[22.3.1.04 * 9]octacos-18-ene-2,3,10,16-tetraone; 30 34 - 17-Allyl-1,14-dihydroxy-12-[2'-(4&quot;-(5-indolyl)oxy-3M-ethoxycyclohexyl&gt;-l1-methylvinyl]-23,25-dimethoxy- 13.19.21.27- tetramēthyl-ll,28-dioxa-4-azatricyclo-[22.3.1.0^»^ļoctacos_i8_ene_2,3,10,16-tetraone; 17-Allyl-l-hydroxy-12-[21-(4M-(5-indolyl)oxy-3M-methoxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy- 13.19.21.27- tetramethyl-ll,28-dioxa-4-azatricyclo-[22.3.1.0^*9]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(l-N-methyl-5-indolyl)oxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]- 23.25- dimethoxy-13,19,21,27-tetramethyl-ll-, 28-dioxa-4-azatricyclo[22.3.1.0^·^]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(l-N-methyl-5-i ndoly1)oxy-3 M-hyd roxycyclohexyl)-11-methylvinyl]- 23.25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^* ^]octacos-18-ene-2,3,10,16-tetraone ; 17-Ethyl-1,14,20-trihydroxy-12-[2 T-(4M-(l-N-methyl-5-indolyl)oxy-3&quot;-methoxycyclohexyl)-l,-methylvinyl]- 23.25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^»^]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14,20-trihydroxy-12-[2'-(4&quot;-(l-N-methyl-5-indolyl)oxy-3&quot;-hydroxycyclohexyl)-l'-methylvinyl]- 23.25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatr icyclo[22.3.1.0^·^]octacos-18-ene-2,3,10,16-tetraone ; - 35 - - 35 -LV 10450 17-Ethyl-1,20-dihydroxy-12-[2'-(4M-(l-N-methyl-5-indolyl)oxy-3&quot;-methoxycyclohexyl)-l * -methylvinyl]- 23.25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.04&gt; 9]octacos-18-ene-2,3,10,16-tetraone; 17-Etliyl-1,20-dihydroxy-12-[2'-(4&quot;-(l-N-methyl-5- I. indolyl)oxy-3&quot;-hydroxycyclohexyl)-l1-methylvinyl]- 23.25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^* ^]octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14-dihydroxy-12-[2'-(4&quot;-(l-N-methyl-5-indolyl)oxy-3&quot;-niethoxycyclohexyl)-l '-methylvinyl]- 23.25- diinethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^» ^]octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14,20-trihydroxy-12-[2'-(4&quot;-(l-N-methyl-5-indolyl)oxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]- 23.25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^» ^]octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,20-dihydroxy-12-[2'-(4&quot;-(l-N-methyl-5-indolyl)oxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]- 23.25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^ *^]octacos-18-ene-2,3,10,16-tetraone; 36 17-Ethyl-l-hydroxy-12-[2'-(4&quot;-(l-N-methyl-5-indolyl)-oxy-3&quot;-methoxycyclohexyl)-l 1-methylvinyl]-23,25-d imethoxy-13,19,21 ,'27-tetramethyl-ll, 28-dioxa-4-aza-tr icyclo[22.3.1.0^·9]octacos-18-ene-2,3,10,16-5 tetraone; 17-Ethyl-1,14-dihydroxy-12-[2'-(4M-(l-N-methyl-5-indolyl)oxy-3&quot;-ethoxycyclohexyl)-l1-methylvinyl]- 23.25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa- 10 4-azatricyclo[22.3.1.0^* 9]octacos-18-ene-2,3,10,16- tetraone; 17-Allyl-1,14-dihydroxy-12-[2,-(4&quot;-(l-N-methyl-5-indolyl)oxy-3&quot;-ethoxycyclohexyl)-l1-methylvinyl]-15 23,25-diraethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4- azatricyclo[22.3.1.0^»9]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(l-N-ethyl-5-20 indolyl)oxy-3&quot;-ethoxycyclohexyl)-l'-methylvinyl]- 23.25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^»9]octacos-18-ene-2,3,10,16-tetraone; 25 17-Allyl-l-hydroxy-12-[2'-(4M-(l-N-methyl-5-indolyl)-oxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-aza-tricyclo[22.3.1.0^ &gt;9]octacos-18-ene-2,3,10,16-tetraone; 30 - 37 - - 37 - LV 10450 17-Ethyl-1,14-dihydroxy-12-[2·-(4&quot;-&lt;l-N-methyl-5-indolyl)oxy-3&quot;~allyloxycyclohexyl)-l'-methylvinyl]-23,25-d imethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22. 3.1.04&gt;9]octacos-18-ene-2,3,10,16-5 tetraone; 17-Ethyl-l-hydroxy-12-[2'-&lt;4&quot;-(l-N-methyl-5-indolyl)-oxy-3&quot;-allyloxycyclohexyl)-l' -inethylvinyl]-23,25-dj methoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-aza-10 tricyclo[22.3.1.04 &gt; 9]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[2 · -(4&quot;-(l-N-methyl-5- ·· indolyl)oxy-3&quot;-n-propyloxycyclohexyl)-l'-methylvinyl]-15 23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4- azatri cyclo[22.3.1.04»9]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-l-hydroxy-12-[21-(4&quot;-(l-N-raethyl-5-indolyl)-20 oxy-3&quot;-n-propyloxycycloliexyl&gt;-l '-methylvinyl]-23,25-d imethoxy-13,19,21,27-tetraraethyl-ll,28-dioxa-4-aza-tricyclo[22.3.1.04&gt; 9]octacos-18-ene-2,3,10,16-tetraone; 25 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(l-N-methyl-5- indolyl)oxy-3&quot;-i-propyloxycyclohexyl)-l'-methylvinyl]-23,25-diinethoxy-13,19,21,27-tetramethyl-ll, 28-dioxa-4-azatricyclo[22.3.1.04 * 9]octacos-18-ene-2,3,10,16-tetraone; 30 38 i'7-F.thyl-l, 14-dihydroxy-12-[2 ' -(4&quot;-(l-N-ethyl-5-indol)rl )oxy-3&quot;-methoxycyclohexyl)-l' -methylvinyl]- 23.25- diinethoxy-13,19,21,27-tetramethyl-ll, 28-dioxa-4~ azatricyclo[22.3.1.0/ll·&gt; ^]octacos-18-ene-2,3,10,16- 5 tetraone; J. 7 —/Dtliyl—1,14,20-tr ihydroxy-12-[2 1 -(4&quot;-(l-N-ethyl-5-indolyl)oxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]- 23.25- dimethoxy-13,19,21,27-tetrainethyl-ll, 28-dioxa-4-10 azatricyclo[22.3.1.0^ * ^]octacos-18-ene-2,3,10,16- tetraone; 17-Ethyl-1,20-dihydroxy-12-[2'-(4''-(l-N-ethyl-5-indolyl)oxy-3”-methoxycyclohexyl)-l'-methylvinyl]-15 23,25-dimethoxy-13,19,21,27-tetramethyl~ll,28-dioxa-4- azatricyclo[22.3.1.0^’^]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(l-N-ethyl-5-20 indolyl)oxy-3M-hydroxycyclohexyl)-l'-methylvinyl]- 23.25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^»^]octacos-18-ene-2,3,10,16- tetraone; 25 17-Allyl-1,14-dihydroxy-12-[2'-(4&quot;-(l-N-ethyl-5- indolyl)oxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]- 23.25- diinethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^» ^]octacos-18-ene-2,3,10,16-tet raone; 30 - 39 - - 39 - LV 10450 17-Allyl-1,14,20-trihydroxy-12-[2'-(4&quot;-(l-N-ethyl-5-indolyl)oxy-3,,-methoxycyclohexyl)-l'-methylvinylj- 23.25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatr icyclo[22.3.1.0^♦^]octacos-18-ene-2,3,10,16-tetraone; 17-A.Llyl-l, 20-d ihydroxy-12-[21-(4&quot;-(l-N-ethyl-5-indolyl)oxy-3&quot;-methoxycyclohexyl)-l’-methylvinyl]-23,23-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-asatr icyclo[22.3.1.0^» ^]octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14-dihydroxy-12-[2'-(4&quot;-(l-N-ethyl-5-indolyl)oxy-3”-hydroxycyclohexyl)-l'-methylvinyl]- 23.25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatr icyclo[22.3.1. O^'^octacos-ie-ene^.S, 10,16- tetraone; 17-Ethyl-l-hydroxy-12-[21-(4&quot;-(l-N-ethyl-5-indolyl)-oxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]-23,25-diinethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-aza-tr icyclo[22.3.1.0^·· ^]octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-l-hydroxy-12-[2'-(4&quot;-(l-N-ethyl-5-indolyl)-oxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-aza-tricyclo[22.3.1.0^ * ^]octacos-18-ene-2,3,10,16-tetraone; 40 17-Allyl-1,14-dihydroxy-12-[2'-(4&quot;-(l-N-ethyl-5-indolyl)oxy-3&quot;-ethoxycyclohexyl)-l'-raethylvinyl]- 23.25- dimethoxy-13 i19,21,27-tetramethyl-ll, 28-dioxa-4-azatr icyclo[22.3.1.0^&gt; ^]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(l-N-propyl-5-indolyl)oxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]- 23.25- dijneLlioxy-13,19,21,27-tetraniethyl-ll, 28-dioxa-4-azatricyclo[22.3.1.0^* ^]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14,20-trihydroxy-12-[2'-(4&quot;-(l-N-propyl-5-indolyl )oxy-3&quot;-metlioxycyclohexyl )-l * -methylvinyl]- 23.25- diinethoxy-13,19,21,27-tetramethyl-ll, 28-dioxa-4-azatricyclo[22.3.1.0^»g]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,20-dihydroxy-l2-[2'-&lt;4&quot;-(l-N-propyl-5-indolyl)oxy-3&quot;-methoxycyclohexyl)-l·-methylvinyl]- 23.25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatr icyclo[22.3.1.. 0^»^]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(l-N-propyl-5-indolyl)oxy-3&quot;-hydroxycyclohexyl)-l'-methylvinyl]~ 23.25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatr icyclo[22.3.1.0^·^]octacos-18-ene-2,3,10,16-tetraone; - 41 - - 41 - LV 10450 7-Ethyl-l,14,20-trihydroxy-12-[2'-(4&quot;-(l-N-propyl-5-indolyl )oxy-3&quot;-hydi:oxycyclohexyl)-l '-methylvinyl]- 23.25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^* ^]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,20-dihydroxy-12-[2'-(4&quot;-(l-N-propyl-5-indolyl)oxy-3&quot;-hydroxycyclohexyl)-l'-methylvinyl]- 23.25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^ &gt; ^]octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14-dihydroxy-12-[2,-(4&quot;-(l-N-propyl-5-indoly1)oxy-3&quot;-methoxycyclohexy1)-1'-methylviny1]- 23.25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^»^]octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14,20-trihydroxy-12-[21-(4&quot;-(l-N-propyl-5-indolyl)oxy-3&quot;-methoxycyclohexyl)-l*-methylvinyl]- 23.25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatr i cyclo[22.3.1.0^·octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,20-dihydroxy-12-[21-(4&quot;-(l-N-propyl-5-indolyl )oxy-3&quot;-inethoxycyclohexyl)-l'-methylvinyl]- 23.25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^* 9]octacos-18-ene-2,3,10,16- tetraone; 30 42 17-Allyl~l,14-dihydroxy-12-[2'-(4&quot;-(l-N-propyl-5-j.ndolyl )oxy-3&quot;-liydroxycyclohexyl)-l1 -methylvinyl]- 23.25- diinethoxy-13,19,21,27-tetramethyl-ll, 28-dioxa- 5 4-azatricyclo[22.3.1.0^»^]octacos-18-ene-2,3,10,16- tetraone; I7-Ethyl-l-liydroxy-12-[2' -(4&quot;-(l-N-propyl-5-indolyl)-oxy-3&quot;-!nethoxycyclohexyl)-l1 -methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-aza-tricyclo[22.3.1.0^»^]octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-l-hydroxy-12-[21-(4&quot;-(l-N-propyl-5-indolyl)-15 oxy-3”-methoxycyclohexyl)-l'-methylvinyl]-23,25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-aza-tricyclo[22.3.1.0^*^]octacos-18-ene-2,3,10,16-tetraone; 20 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(l-N-propyl-5-indolyl)oxy-3&quot;-ethoxycyclohexyl)-l'-methylvinyl]- 23.25- diinethoxy-13,19,21,27-tetramethyl-ll, 28-dioxa-4-azatricyclo[22.3.1.0^’^]octacos-18-ene-2,3,10,16-tetraone; 25 17-Allyl-1,14-diliydroxy-12-[2 ' -(4&quot;-(l-N-propyl-5-indo.lyl)oxy-3&quot;-ethoxycyclohexyl)-l'-methylvinyl]- 23.25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatr icyclo[22.3.1.0^» ^]octacos-18-ene-2,3,10,16-tetraone; 30 - 43 - - 43 - LV 10450 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(l-N-allyl-5-indolyl)oxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]- 23.25- dimethoxy-13 ', 19,21,27-tetramethyl-ll, 28-dioxa-4--azatr icyclo[22.3.1.0^» ^]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14,20~trihydroxy-12-[2 1-(4&quot;-(l-N-allyl-5-indolyl)oxy-3&quot;-metlioxycyclohexyl)-l1-methylvinyl]~ 23.25- dimethoxy-13,19,21,27-tetramethyl-ll, 28-dioxa-4-azatricyclo[22.3.1.0^·^]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-l,20-dihydroxy-12-[2'-(4&quot;-(l-N-allyl-5-indolyl)oxy-3&quot;-raethoxycyclohexyl)-l1-methylvinyl]- 23.25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^»^]octacos-18-ene-2,3,10,16- tetraone; 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(l-N-allyl-5-indoly 1)oxy-3&quot;-hydroxycyclohexy 1 )-l' -īnethylvinyl]- 23.25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^* ^]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14,20-trihydroxy-12-[2'-(4”-(l-N-allyl-5-indolyl)oxy-3&quot;-hydroxycyclohexyl)-l1-methylvinyl]- 23.25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^»^]octacos-18-ene-2,3,10,16-tetraone; 44 17-Etliyl-1,20-dihydroxy-12-[2 ' -(4&quot;-(l-N-allyl-5-incloJ.yl )oxy-3&quot;-hydroxytyclohexyl )-l ’ -methylvinyl]- 23,25-c1iniethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.04&gt; 9]octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14-dihydroxy-12-[2'-(4&quot;-(l-N-allyl-5-iTidolyl)oxy-3&quot;-methoxycyclohexyl)-l' -methylvinyl]- 23.25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.04» 9]octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14,20-trihydroxy-12-[2'-(4&quot;-(l-N-allyl-5-indolyl)oxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]- 23.25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.04·9]octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,20-dihydroxy-12-[2'-(4&quot;-(l-N-allyl-5-indolyl)oxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]- 23.25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.04»9]octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14-dihydroxy-12-[2'-&lt;4&quot;-(l-N-allyl-5-indolyl)oxy-3&quot;-hydroxycyclohexyl)-l'-methylvinyl]- 23.25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone; - 45 - - 45 - LV 10450 17-Ethyl-l-hydroxy-12-[2'-(4M-(l-N-allyl-5-indolyl)-oxy-3&quot;-metlioxycyclohexyl)-l' -methylvinyl]-23,25-dimethoxy-13,19, 21,27-tetramethyl-ll,28-dioxa-4-aza-tricyclo[22.3.1.0^»^]octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-l-hydroxy-12-[2'-(4&quot;-(l-N-allyl-5-indolyl)-oxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetrametliyl-ll, 28-dioxa-4-aza-tricyclo[22.3.1.0^»^]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[2'-(4M-(l-N-allyl-5-indolyl)oxy-3&quot;-ethoxycyclohexyl)-l'-methylvinyl]- 23.25- d imethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^·^]octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14-dihydroxy-12-[2'-(4&quot;-(l-N-allyl-5-indolyl)oxy-3&quot;-ethoxycyclohexyl)-l'-methylvinyl]- 23.25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^ * ^]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[2,-(4”-(l-N-2-hydroxy-ethyl-5-indolyl)oxy-3&quot;-methoxycyclohexyl)-l'-methyl-vinyl]-23,25-dimetlioxy-13,19,21,27-tetramethyl-ll, 28-d ioxa-4-azatricyclo[22.3.1.0^’^]octacos-18-ene-2,3,10,16-tetraone; 46 17-Ethyl-1,14,20-trihydroxy-12-[2'-(4&quot;-(l-N-2-hydroxy-etliyl-5-indolyl)oxy-3M-methoxycyclohexyl)-l1 -methyl-vinyl]-23,25-dimettioxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^»9]octacos-18-ene- 2.3.10.16- tetraone; 17-Ethyl-1,20-dihydroxy-12-[2'-(4&quot;-(l-N-2-hydroxy-ethyl-5-indolyl)oxy-3&quot;-methoxycyclohexyl)-l'-methyl-vinyl]-23,25-dimetlioxy-13,19,21,27-tetramethyl-ll, 28-dioxa-4-azatricyclo[22.3.1.0^*^]octacos-18-ene- 2.3.10.16- tetraone; 17-Ethyl-1,14-dihydroxy-12-[2 *-(4&quot;-(l-N-2-hydroxy-ethyl-5-indolyl)oxy-3&quot;-hydroxycyclohexyl)-l'-methyl-vinyl]-23,25-dimetlioxy-13,19,21,27-tetramethyl-ll~; 28-dioxa-4-azatricycloC22.3.1.0^»^]octacos-18-ene- 2.3.10.16- tetraone; 17-Ethyl-1,14,20-trihydroxy-12-[2'-(4&quot;-(l-N-2-hydroxy-ethyl-5-indolyl)oxy-3&quot;-hydroxycyclohexyl)-l’-methyl-vinyl]-23,25-diinethoxy-13,19,21,27-tetramethyl-ll, 28-dioxa-4-azatricyclo[22.3.1.0^&gt;^]octacos-18-ene- 2.3.10.16- tetraone; 17-Ethyl-1,20-diliydroxy-12-[2 '-(4&quot;-(l-N-2-hydroxy-ethyl-5-indolyl)oxy-3&quot;-hydroxycyclohexyl)-l'-methyl-vinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-asatricyclo[22.3.1.0^·^]octacos-18-ene- 2.3.10.16- tetraone; - 47 - LV 10450 17-Allyl-1,14-dihydroxy-12-[2,-(4&quot;-(l-N-2-hydroxy-ethyl-5-indolyl)oxy-3&quot;-Inethoxycyclohexyl)-l '-methyl-vinyl J-23,25-dimeth'oxy-13,19,21,27-tetramethyl-ll, 28-dioxa-4-azatricyclo[22-3.1.0^»9]octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14-dihydroxy-12-[2·-(4&quot;-(l-N-hydroxyethyl-5-indoly1)oxy-3”-hyd roxycyclohexyl)-l'-methylvinyl]- 23.25- dimethoxy-13,19,21,27-tetrainethyl-ll, 28-dioxa-4-azatricyclo[22.3.1.0^»^]octacos-18-ene-2,3,10,16-tetraone ; 17-Ethyl-1,14-dihydroxy-12-[2'-(4M-(l-N-benzyl-5-indoly1)oxy-3&quot;-methoxycyclohexyl)-1'-methylvinyl]- 23.25- diinethoxy-13,19,21,27-tetramethyl-ll, 28-dioxa-4-azatricyclo[22.3.1.0^»^]octacos-18-ene-2,3,10,16-tetraone ; 17-Ethyl-1,14,20-trihydroxy-12-[21-(4&quot;-(l-N-benzyl-5-indolyl)oxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]- 23.25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^ * ^ joctacos-18-ene-2,3,10,16-tetraone ; 17-Ethyl-1,20-dihydroxy-12-[2*-(4M-(l-N-benzyl-5-indolyl)oxy-3&quot;-methoxycyclohexyl)-l*-methylvinyl]- 23.25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^ *^]octacos-18-ene-2,3,10,16- tetraone ;

S 48 17-Etliyl-1,14-dihydroxy-12-[2' -(4M-(l-Ņ-benzyl-5-indolyl)oxy-3&quot;-hydroxycyclohexyl&gt;-l'-methylvinyl]- 23.25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatr icyclo[22.3.1.04·9]octacos-18-ene-2,3,10,16- tetraone; 17-Ethyl-1,14,20-trihydroxy-12-[2'-(4&quot;-(l-N-benzyl-5-indc&gt;J.yl )oxy-3&quot;-hydroxycyclohexyl)-l' -methylvinyl]- 23.25- d.i.methoxy-13,19,21,27-tetramethyl-ll, 28-dioxa-4-azatricyclo[22.3.1.04»9]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,20-dihydroxy-12-[21-(4&quot;-(l-N-benzyl-5-indolyl)oxy-3&quot;-hydi:oxycyclohexyl)-l'-methylvinyl]- 23.25- diraethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.04’^]octacos-18-ene-2,3,10,16- tetraone; 17-Allyl-1,14-dihydroxy-12-[2'-(4&quot;-(l-N-benzyl-5-indolyl)oxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]- 23.25- diinethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.04»9]octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14,20-trihydroxy-12-[2'-(4&quot;-(l-N-benzyl-5-i ndoly1&gt; oxy-3”-methoxycyclohexyl)-1'-raethylvinyl]- 23.25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.04 &gt;^]octacos-18-ene-2,3,10,16-tetraone; 30 - 49 - - 49 -LV 10450 17-Allyl-1,20-dihydroxy-12-[2'-(4&quot;-(l-N-benzyl-5-indolyl)oxy-3M-methoxycyclohexyl )-l '-methylvinyl]- 23.25- diinethoxy-13,19,21,27-tetramethyl-ll, 28-dioxa-4-azatricyclo[22.3.1.0^»^]octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14-dihydroxy-12-[2'-&lt;4&quot;-(l-N-benzyl-5-indolyl)oxy-3&quot;-hydroxycyclohexyl)-l'-methylvinyl]- - 23.25- diinethoxy-13,19,21,27-tetramethyl-ll, 28-dioxa-4-azatricyclo[22.3.1.0^»^]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-l-hydroxy-12-[2'-(4&quot;-(l-N-benzyl-5-indolyl)-oxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-aza- — tricyclo[22.3.1.0^»^]octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-l-hydroxy-12-[2 ,-(4,,-(l-N-benzyl-5-indolyl)-oxy-3&quot;-methoxycyclohexyl)-l'-raethylvinyl]-23,25-d iinethoxy-13,19,21,27-tetramethyl-ll, 28-dioxa-4-aza-tricyclo[22.3.1.0^»^]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(l-N-benzyl-5-indolyl)oxy-3&quot;-etlioxycyclohexyl)-l' -methylvinyl]- 23,25-diinethoxy-13,19,21,27-tetramethyl-ll, 28-dioxa-4-azatricyclo[22.3.1.0^·^]octacos-18-ene-2,3,10,16-tetraone; -50- 17-Allyl-1,14-dihydroxy-12-[2'-(4&quot;-(l-N-benzyl-5-indolyl)oxy-3&quot;-ethoxycyclohexyl)-l'-methylvinyl]- 23.25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa- 4- azatricyclo[22.3.1.0^’9]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(l-N-cyclopropyl- 5- indolyl)oxy-3&quot;-methoxycyclohexyl)-l1 -methylvinyl]- 23.25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3^1.0^* ^]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[2’-(4&quot;-(l-N-cyclopropyl-5 indolyl)oxy-3&quot;-hydroxycyclohexyl)-l'-methylvinyl]- 23.25- diraethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^»^]octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14-dihydroxy-12-[2'-(4&quot;-(l-N-cyclopropyl-5 indolyl)oxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]- 23.25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4 azatricyclo[22.3.1.0^* ^]octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14-dihydroxy-12-[2·-(4&quot;-(l-N-cyclopropyl-5 indolyl)oxy-3&quot;-hydroxycyclohexyl)-l'-methylvinyl]- 23.25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4 azatricyclo[22.3.1.0^* ^]octacos-18-ene-2,3,10,16-tetraone; -51- -51-LV 10450 17-Ethyl-1,l4-dihydroxy-12-[2'-(4&quot;-(l-N-cyclopropyl-5-indolyl)oxy-3&quot;-ethoxycyclohexyl)-l'-methylvinyl]- 23.25- diinethoxy-13,19,21,27-tetramethyl-ll, 28-dioxa-4-azatricyclo[22.3.1.0^*^]octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14-dihydroxy-12-[2,-(4&quot;-(l-N-cyclopropyl-5-indolyl)oxy-3M-ethoxycyclohexyl)-l'-methylvinyl]- 23.25- dimetlioxy-13,19,21,27-tetramethyl-ll, 28-dioxa-4-azatricyclo[22.3.1.0^ * ^]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-l-hydroxy-12-[2,-(4&quot;-(l-N-cyclopropyl-5-indolyl )oxy-3 &quot;-methoxycyclohexyl )-l'-methylvinyl]- 23.25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^'^]octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-l-hydroxy-12-[2'-(4&quot;-(l-N-cyclopΓopyl-5-indolyl)oxy-3&quot;-methoxycyclohexyl)-l '-methylvinyl]- 23.25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^ * ^]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-l-hydroxy-12-[2'-(4&quot;-methoxy-N-tryptophanyl-carbonylinethoxy-3&quot;-methoxycyclohexyl)-l '-methylvinyl]- 23.25- diinethoxy-13,19,21,27-tetramethyl-ll, 28-dioxa-4-azatricyclo[22.3.1.0^’^]octacos-18-ene-2,3,10,16-tetraone; -52- 17-Ethyl-l-hydroxy-12-[2'-(4&quot;-(3-indolyl)ethylamino-carbonylmethoxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^ &gt; ^]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(l-(3-hydroxy-propyl) i uclol-5-yl )oxy-3&quot;-methoxycyclohexyl )-l' -methyl-viny J. j -23,25-dimethoxy-13,19,21,27-tetramethyl-ll ,28-dioxa-4-azatr icyclo[22.3.1.0^»^]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[2,-(3&quot;-hydroxy-4&quot;-(l-hydroxyethylindol-5-yl)oxycyclohexyl)-l'-methylvinyl]-15 23,25-diraethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4- azatricyclo[22.3.1.0^* ^]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[2,-(4&quot;-(l-hydroxyethyl-20 indol-6--yl)oxy-3&quot;-metlioxycyclohexyl)-l · -methylvinyl]-23,25-diniethoxy-13,19,21,27-tetramethyl-ll, 28-dioxa-4-azatricyclo[22.3.1.0^» ^]octacos-18-ene-2,3,10,16-tet raone ; 25 17-Ethyl-1,14-d ihydroxy-12-[21-(4&quot;-(l-methylindol-6- yl)oxy-3&quot;-methoxycyclohexyl)-l1-methylvinyl]-23,25-diinethoxy-13,19,21,27-tetramethyl-ll, 28-dioxa-4-aza-tricyclo[22.3.1.0^»^]octacos-18-ene-2,3,10,16-tet raone ; 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(l~dibenzyl-phosphonoxy-ethylindol-5-yl)oxy-3&quot;-methoxycyclohexyl)-I ’ -inethy.lvinyl J-23,25-diinethoxy-13,19,21,27-tetra- 30 -53- -53- LV 10450 methyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^»^]octacos-18-ene-2 f 3,10,16-tetraone;

Monopotassium salt of 17-Ethyl-1,14-dihydroxy-12-[21-(4&quot;-(l-phosphonoxy-ethylindol-5-yl)oxy-3&quot;-methoxy-cyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21, 27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^*^]-octacos-18-ene-2,3,10,16-tetraone; 17- Ethyl-1,14-dihydroxy-12-[2l-(4&quot;-(l-(N,N-dimethyl-glycyloxy)ethylindol-5-yl)oxy-3&quot;-methoxycyclohexyl)-11-raethylvinyl]-23,25-dimethoxy-13,19,21,27-tetra-methyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^·^]octacos- 18- ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(l-succinyloxy-ethy1indol-5-y1)oxy-3&quot;-methoxycyclohexyl)-11-methy1-vinyl]23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1. O^-» ^]octacos-18-ene-2,3 ,- 10.16- tetraone; 17-Ethyl-1,14-dihydroxy-12-[2' -(4&quot;-(l-methyl-3-phenyl-indol-5-yl)oxy-3&quot;-methoxycyc1ohexy1)-1'-methy1vi ny1]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.04»^]octacos-18-ene-2,3,10,16-tetraone ; 17-Ethyl-1,14-dihydroxy-12-[21-(4&quot;-(l-methy1-3-(2-hydroxyethyl)indol-5-yl)oxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0^ &gt;^]octacos-18-ene- 2.3.10.16- tetraone; -54- 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(l,3-dimethylindol-5-yl)oxy-3&quot;-inethoxycyclohexyl)-l1 -methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-aza-tricyclo[22.3.1.0^* ^]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(9'-methylcarbazol-3'-yl)oxy-3&quot;-raethoxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-aza-t r icyclo[22.3.1.0^»^]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-((2''''-&lt;3' &quot; ' diethylaminopropionyloxy)ethyl)indol-5'''-yl)oxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy- 13.19.21.27- tetramethyl-ll,28-dioxa-4-azatricyclo-[22.3.1.0^»^]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-((2'«·«-(3* »· &quot;-dimethylaminopropionyloxy)ethyl)indol-51''-yl)oxy-3M-methoxycyclohexyl)-l'-raethylvinyl]-23,25-dimethoxy- 13.19.21.27- tetramethyl-ll,28-dioxa-4-azatricyclo-[22.3.1.0^*^]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-((21'''-(3' &quot; ' aminopropionyloxy)ethyl)indol-5'''-yl)oxy-3M-methoxycyclohexyl)-l1-methylvinyl]-23,25-dimethoxy- 13.19.21.27- tetramethyl-ll,28-dioxa-4-azatricyclo-[22.3.1.0^’^]octacos-18-ene-2,3,10,16-tetraone; -55- -55- LV 10450 17-Ethyl-1,14-dihydroxy-12-[2(2''''-(3'''·'-benzyloxycarbonyl-21'''1-benzyloxycarbonylami.no-propionyloxy)ethyl)indol-5''*-yl)oxy-3&quot;-methoxycyclo-hexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^»^]-octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-l2-[2'-(4&quot;-((2''''-(aspartyl-oxy)ethyl)indol-5'''-yl)oxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]-23,25-dimetlioxy-13,19,21,27-tetramethyl-11,28-di.oxa-4-azatr icyclo[22.3.1.0^» ^]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[21-(4&quot;-((2''''-(1''&quot;'-imidazolylcarbonyloxy)ethyl)indol-5'1'-yl)oxy-3M-rnethoxycyclohexyl)-l1 -niethylvinyl]-23,25-dimethoxy- 13.19.21.27- tetramethyl-ll,28-dioxa-4-azatricyclo- [22.3.1. »^]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-((2 1 · '*-(l&quot; · · ·-piperazinocarbonyloxy)ethyl)indol-5’',-yl)oxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy- 13.19.21.27- tetramethyl-ll,28-dioxa-4-azatricyclo-[22.3.1.0/f»9]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[2’-(4&quot;-(l1''-(2&quot; ''-(2'''''-hydroxy)ethylaminocarbonyloxy)ethyl)indol-5'''-yl)oxy-3&quot;-raethoxycyclohexyl)-l,-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-aza-tricyclo[22.3.1.0^»9]octacos-18-ene-2,3,10,16-tetraone ; -56- 17-Ethyl-l,14-dihydroxy-12-[2'-(4&quot;-(l'''-(2''''-(isopropyaininocarbonyloxy)ethyl)indol-5 ' 1 1-yl)oxy-3&quot;-methoxycyclohexyl)-l' -inethylvinyl]-23,25-dimethoxy- 13.19.21.27- tetramethyl-ll,28-dioxa-4-azatricyclo-[22.3.1.04v']octacos-18-ene-2,3,10,16-tetraone; J.7-Ethyl-1, 14-dihydroxy-12-[2 '-(4&quot;-(l' r '-(2 (1··'''-piperidinocarbonyloxy)ethyl)indol-511'-yl)oxy-3&quot;-niethoxycyclohexyl)-l' -methylvinyl]-23,25-dimethoxy- 13.19.21.27- tetramethyl-ll,28-dioxa-4-azatricyclo-[22.3.1.04·9]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[2'-&lt;4&quot;-(l'·'-(2·'' ’- (1' ' ' ' ' -inorpholinocarbonyloxy)ethyl) indol-5' ' '-yl)oxy- 3&quot;-methoxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy- 13.19.21.27- tetramethyl-ll,28-dioxa-4-azatricyclo-[22.3.1.04' ^]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(l' &quot;-(2&quot; &quot;-(diphenylaininocarbonyloxy)ethyl) indol-5 ' ' '-yl)oxy-3M-methoxycyclohexyl)-l1-methylvinyl]-23,25-dimethoxy- 13.19.21.27- tetramethyl-ll,28-dioxa-4-azatricyclo- [22.3.1.04 * 9]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(l'''-(2' 1 ' '-(diethylaminocarbonyloxy)ethyl)indol-5'''-yl)oxy-3M-methoxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy- 13.19.21.27- tetramethyl-ll,28-dioxa-4-azatricyclo-[22.3.1.04»9]octacos-18-ene-2,3,10,16-tetraone; -57- -57-LV 10450 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(l1''-(2''''-methanesulfonyloxyethyl)indol-5·'1-yl)oxy-3&quot;-methoxy-cyclohexyl)-l-methylvinyl]-23,25-dimethoxy-13,19,21, 27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^»^]-5 octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(l1''-(21' ' '-azido-ethyl)indol-5'’’-yl)oxy-3&quot;-methoxycyclohexyl)-l'-metliylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-10 11,28-dioxa-4-azatricyclo[22.3.1.0^»^]octacos-18-ene- 2.3.10.16- tetraone; 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(l'1'-(2''’'-amino-ethyl)indol-5'''-yl)oxy-3&quot;-methoxycyclohexyl)-l·-15 methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl- 11.28- dioxa-4-azatricyclo[22.3.1.0^*^]octacos-18-ene- 2.3.10.16- tetraone; 17-Ethyl-l,14-dihydroxy-12-[2'-(4&quot;-(l'''-t-butyldi- 20 methylsilyloxyethoxyethylindol-5'''-yl)oxy-3&quot;-methoxy-cyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21, 27-tetrametliyl-ll, 28-dioxa-4-azatricyclo[22.3.1.0^» ^]-octac.os-18-ene-2,3,10,16-tetraone; 25 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(l1'1-hydroxy- ethoxyethylindol-5'''-yl)oxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl- 11.28- dioxa-4-azatricyclo[22.3.1.0^*^]octacos-18-ene- 2.3.10.16- tetraone; 30 -58- 17- Etliyl-1,14-dihydroxy-12-[2'-(3&quot;-methoxy-4&quot;-(l' ' (1''''-oxoprop-311''-yl)indol-5'''-yl)oxycyclohexyl)-11-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetra-methyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^»^]octacos- 18- ene-2,3,10,16-tetraone; and 17-Ethyl-1,14-dihydroxy-12-[2'-(3&quot;-methoxy-4M-(l'''-(1’'''-carboxyeth-2''''-yl)indol-5'''-yl)oxycyclo-hexyl )-l' -methylvinyl]-23,25-diinethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^»^]-octacos-18-ene-2,3,10,16-tetraone.

Representative compounds of the present invention include the compounds of Formula X, XI, XII and XIII: -59- -59- LV 10450 Λ

I R7 \

CH30 och3

•X -60-

30

XI LV 10450 -βί ο p6a Αι

N I Cch2) -i _4

s7 I

XII 5 -62- CCHOt-4

1ϋ 15

20 XIII whei:ein Rrja is II or CH3 and the definitions of , R3, and R7 are selected from the fclloving groups of substituents: 25 R6 R7 R2 R3 R5 phenyl phenyl ch3 0H ethyl plienyl H ch3 0H ethyl benzyl H ch3 0H ethyl 4-H02C-benzyl H ch3 0H ethyl -63-LV 10450 4-H2NC0-benzyl H ch3 OH ethyl 4-CH30-benzyl H ch3 OH ethyl 4-H0-benzyl H ch3 OH ethyl 4-Cl-benzyl H ch3 OH ethyl 5 4-(CH3)2N-benzyl H ch3 OH ethyl 3-H02C-benzyl H ch3 OH ethyl 3-H2NC0-benzyl H ch3 OH ethyl 3-CH30-benzyl H ch3 OH ethyl 3-H0-benzyl H ch3 OH ethyl 10 3-Cl-benzyl H ch3 OH ethyl 3-(CH3)2N-benzyl H ch3 OH ethyl 4-pyridyl H ch3 OH ethyl 3-pyridyl H ch3 OH ethyl 2-pyridyl H ch3 OH ethyl 15' 4-pyr idylmethyl H ch3 OH ethyl 3-pyridylmethyl H ch3 OH ethyl 2-pyridylmethyl H ch3 OH ethyl phenyl • phenyl ch3 H ethyl phenyl H ch3 H ethyl 20 benzyl H ch3 H ethyl 4-H02C-benzyl H ch3 H ethyl 4-H2NCO-benzyl H ch3 H ethyl 4-CH30-benzyl H ch3 H ethyl 4-H0-benzyl H ch3 H ethyl 25 4-Cl-benzyl H ch3 H ethyl 4-(CH3)2N-benzyl H ch3 H ethyl 3-H02C-benzyl H ch3 H ethyl 3-H2NCO-benzyl H ch3 H ethyl 3-CH30-benzyl H ch3 H ethyl 30 3-H0-benzyl H ch3 H ethyl 3-Cl-benzyl H ch3 H ethyl 3-(CH3)2N-benzyl H ch3 H ethyl -64- 4-pyridyl H ch3 H ethyl 3-pyridyl H ch3 H ethyl 2-pyridyl H ch3 H ethyl 4-pyridylmethyl H ch3 H ethyl 5 3-pyridylmethyl H ch3 H ethyl 2-pyridylmethyl H ch3 H ethyl phenyl phenyl ch3 OH allyl phenyl H ch3 OH allyl benzyl H ch3 OH allyl 10 4-H02C-benzyl H ch3 OH allyl 4-H2NC0-benzyl H ch3 OH allyl 4-CH30-benzyl H ch3 OH allyl 4-HO-benzyl H ch3 OH allyl 4-Cl-benzyl H ch3 OH allyl 15 4-(CH3)2N-benzyl H ch3 OH alīyl 3-H02C-benzyl H ch3 OH allyl 3-H2NCO-benzyl H ch3 OH allyl 3-CH30-benzyl H CH 3 OH allyl 3-HO-benzyl H ch3 OH allyl 20 3-Cl-benzyl H ch3 OH allyl 3-(CH3)2N-benzyl H ch3 OH allyl 4-pyridyl H ch3 OH allyl 3-pyridyl H ch3 OH allyl 2-pyridyl H ch3 OH allyl 25 4-pyridylmethyl H ch3 OH allyl 3-pyridylmethyl H ch3 OH allyl 2-pyr idylmethyl H ch3 OH allyl ch3 H ch3 OH ethyl ch3ch2 H ch3 OH ethyl 30 CH3CH2CH2 H ch3 OH ethyl (CII3 ) 2CII H ch3 OH ethyl HO2CCH2CH2 H ch3 OH ethyl -65-LV 10450 fI?NCOCH2CH2 H ch3 0H ethyl hoch2ch2 H ch3 OH ethyl hoch2ch2cii2 II ch3 OH ethyl ch3 ch3 ch3 OH ethyl 5 ch3cii2 ch3ch2 ch3 OH ethyl ch3ch2ch2 ch3ch2ch2 ch3 OH ethyl hoch2cii2 hoch2ch2 ch3 OH ethyl hoch2ch2cii2 iioch2cii2ch2 ch3 OH ethyl CI13 II ch3 H ethyl 10 ch3cii2 Π ch3 H ethyl CH3ClI2Cn2 H ch3 H ethyl (CH3)2CH H ch3 H ethyl ho2cch2ch2 H ch3 H ethyl h2ncoch2ch2 H ch3 H ethyl 15 hoch2ch2 H ch3 H ethyl hoch2ch2ch2 H ch3 H ethyl ch3 ch3 ch3 H ethyl ch3ch2 ch3ch2 ch3 H ethyl ch3ch2ch2 ch3ch2ch2 ch3 H ethyl 20 H0CH2C112 iiocii2ch2 cii3 H ethyl hoch2ch2ch2 hoch2ch2ch2 ch3 H ethyl ch3 H H OH ethyl cii3ch2 H H OH ethyl CH3CH2CI!2 H H OH ethyl 25 (ch3)2ch H H OH ethyl iio2cch2ch2 II H OH ethyl h2hcocii2ch2 II H OH ethyl IK)CH2CH2 11 H OH ethyl hoch2ch2cii2 H H OH ethyl 3 0 ch3 CII3 H OH ethyl ch3cii2 ch3ch2 H OH ethyl cii3cir20H2 ch3cii2cii2 H OH ethyl -66- hoch2ch2 hoch2ch2 H 0H ethyl hoch2cii2ch2 hoch2ch2ch2 H OH ethyl -ch2ch2och2ch2_ ch3 H ethyl 5 -ch2ch2ch2ch2ch2- ch3 H ethyl -ch2ch2och2ch2_ ch3 OH ethyl -ch2ch2ch2ch2ch2- H OH ethyl -ch2ch2ocii2ch2_ II OH ethyl 1 0 -cii2ch2cii2ch2ch2- H OH ethyl -ch2ch?och2cii2_ CII3 H allyl -Cn2CH2CH2CH2CH2- ch3 H allyl -ch2ch2ocii2cii2_ ch3 OH allyl -cii2ch2ch2cii2ch2- H OH allyl -ch2ch2och2cii2_ H OH allyl 15 -cii2cii2ch2ch2cii2- II 011 al’lyl,

Representative compounds of the present invention include the compounds of formula XIV, XV, XVI and XVII: 25 30 -67- LV 10450

ch3o och3

XIV -οβ- ο

XV -69- LV 10450

O

XVI -70- r6 25

χνιι 30

-71- wiierein R 6a and Rb are LV 10450 is D or CII3 and R^, R3, selected from the following groups of substituents: R6 R2 R3 R5 H ch3 OH ethyl ch3 ch3 OH ethyl (•ii3cn? CU3 OH ethyl CII2=CHCH2 CIi3 OH ethyl CII3CH 2^Η2 ch3 OH ethyl (CH3)2CH ch3 OH ethyl ho2cch2ch2 ch3 0H ethyl h2ncoch2ch2 ch3 OH· ethyl hoch2ch2 ch3 OH ethyl hoch2ch2ch2 ch3 OH ethyl (CH3)2CH2 ch3 OH ethyl phenyl ch3 OH ethyl 4-pyridyl ch3 OH ethyl 3-pyridyl ch3 OH ethyl 2-pyridyl ch3 OH ethyl 4-pyridylmethyl ch3 OH ethyl 3-pyridylmethyl ch3 OH ethyl 2-pyridylmethyl ch3 OH ethyl benzyl ch3 OH ethyl 4-H02C-benzyl ch3 OH ethyl 4-H2NC0-benzyl ch3 OH ethyl 4-CH30-benzyl ch3 OH ethyl 4-H0-benzyl ch3 OH ethyl 4-Cl-benzyl ch3 OH ethyl 4-(CH3)2N-benzyl ch3 OH ethyl -72- 3-H02C-benzyl ch3 0H ethyl 3-H2NCO-benzyl ch3 0H • ethyl 3-CH3-benzyl ch3 OH ethyl 3-HO-benzyl ch3 OH ethyl 3-Cl-benzyl ch3 OH ethyl 3-(CH3 )2N-benzyl ch3 OH ethyl 2-IIO-benzyl ch3 OH ethyl 2-Cl-benzyl ch3 OH ethyl 2-(CH3)2N-benzyl ch3 OH ethyl ch3 ch3 H ethyl ch3ch2 ch3 H ethyl ch2=chcii2 ch3 H ethyl ch3ch 2cii2 ch3 H ethyl (ch3)2_ch ch3 H ethyl ho2cch2ch2 ch3 H ethyl h2ncoch2ch2 ch3 H ethyl hoch2ch2 ch3 H ethyl hoch2ch2ch2 ch3 H ethyl (ch3)2ch2 ch3 H ethyl phenyl ch3 H ethyl 4-pyr idyl ch3 H ethyl 3-pyr idyl ch3 H ethyl 2-pyridyl ch3 H ethyl 4-pyr idylmethyl ch3 H ethyl 3-pyr idylmethyl ch3 H ethyl 2-pyr idylmethyl ch3 II ethyl benzyl ch3 H ethyl 4-H02C-benzyl ch3 H ethyl 4-H2WC0-benzyl ch3 H ethyl 4-CH30-benzyl ch3 H ethyl -73- LV 10450 4-H0-benzyl ch3 H ethyl 4-Cl-benzyl ch3 H ethyl 4- ( CII3 ) 2N-benzyl ch3 H ethyl 3-H02C-benzyl ch3 H ethyl 5 3-H2NCO-benzyl ch3 H ethyl 3-CII30-benzyl ch3 H ethyl 3-HO-benzyl ch3 H ethyl 3-Cl-benzyl ch3 H ethyl 3-(CH3)2N-benzyl ch3 H ethyl 10 2-H02C-benzyl ch3 H ethyl 2-II2NC0-benzyl ch3 H ethyl 2-CH30-benzyl ch3 H ethyl 2-HO-benzyl ch3 H · ethyl 2-Cl-benzyl ch3 H ethyl 15 2-(CH3)2N-benzyl ch3 H ethyl CHo CH3 0H allyl ch3ch2 ch3 OH allyl ch2=chch2 ch3 0H allyl ch3ch 2ch2 ch3 OH allyl 20 (CH3)2CH ch3 OH allyl ho2ccii2ch2 ch3 OH allyl h2ncoch2cii2 ch3 OH allyl iioch2cii2 ch3 OH allyl hoch2cii2cii2 ch3 OH allyl 25 (CH3 )2ch2 ch3 OH allyl phenyl ch3 OH allyl 4~pyridyl ch3 OH allyl 3-pyridyl ch3 OH allyl 2-pyridyl ch3 OH allyl 30 4-py r idy].inethyl ch3 OH allyl -74-

-74- 3-pyridylmethyl ch3 0H 2-pyridylmethyl ch3 OH benzyl ch3 OH 4~II02C-benzyl ch3 OH 5 4-H2NCO-benzyl ch3 OH 4-CH30-berizyl ch3 OH 4-HO-benzyl ch3 OH 4-Cl-benzyl ch3 OH 4-(CH3)2N-benzyl ch3 OH 10 3-H02C-benzyl cei3 OH 3-H2HCO-benzyJ. ch3 OH 3-CII30-benzyl ch3 OH 3-H0-benzyl ch3 OH 3-Cl-benzyl ch3 OH 15 3-(CH3&gt;2N-benzyl ch3 OH 2-H02C-benzyl ch3 OH 2-H2NC0-benzyl ch3 OH 2-CH30-benzyl ch3 OH 2-H0-benzyl ch3 OH 20 2-Cl-benzyl ch3 OH 2-(CH3)2N-benzyl ch3 OH allyl allyl allyl allyl allyl allyl allyl allyl allyl allyl allyl allyl allyl allyl allyl allyl allyl allyl allyl allyl allyl. 25 30 -75-LV 10450

Representative compounds of the present invention include the compounds of Formula XVIII, XIX, XX and XXI: 5

O

10 15 20

ch3o och3 25

XVIII

-76-OH

XIX -77- LV 10450

Ra

XX 78-

3 0 -79-LV 10450 wherein R6a is H or CH3 and R, R2, R3 selected from the following groups of

Ra ch3 CH3CH2 ch2=chcii2 CH3CII 2C1I2 &lt;ch3)2ch ho2cch2ch2 h2ncoch2ch2 hoch2ch2 hoch2ch2ch2 (CH3)2CH2 phenyl 4-pyridyl 3- pyr idyl 2- pyridyl 4- pyridylmethyl 3- pyridylmethyl 2- pyr idylmetliyl benzyl 4- H02C-benzyl 4-Il2HC0-benzyl 4-CH30-benzyl 4-II0-benzyI 4-C.l-benzy 1 4-(CH3)2H-benzyl 3- H02C-benzyl

1 - bcnzy I 3-CH30-benzyl and R3 are substituents: R5 ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl

R2 R3 ch3 0H ch3 0H ch3 OH ch3 OH ch3 OH ch3 OH ch3 OH ch3 OH CII3 OH ch3 OH ch3 OH ch3 OH ch3 OH ch3 OH ch3 OH ch3 OH ch3 OH ch3 OH ch3 OH ch3 OH ch3 OH CI13 OH ch3 OH ch3 OH ch3 OH (:»3 OfI C1I3 OH -80- 3-HO-benzyl ch3 OH ethyl 3-Cl-benzyl ch3 OH ethyl 3-(CH3)2N-benzyl CII3 OH ethyl 2-H02C-benzyl ch3 OH ethyl 2-H2NCO-benzyl ch3 OH ethyl 2-CH30-benzyl ch3 OH ethyl 2-I10-benzyl cii3 OH ethyl 2-Cl--beuzyl cii3 Oli ethyl 2-(CII3 )2N-benzyl ch3 OH ethyl CII3 cii3 H ethyl CH3CH2 ch3 H ethyl ch2=chch2 CII3 H ethyl ch3ch 2ch2 CII3 H ethyl (CH3)2CH ch3 H ethyl iiū2cch2cii2 cn3 H ethyl h7wcocn2cn2 ch3 H ethyl hoch2ch2 CII3 H ethyl iioch2ch2ch2 CII3 II ethyl (CH3)2CH2 ch3 H ethyl phenyl ch3 H ethyl 4-py r i dy1 CII3 II ethyl 3-pyr i cly 1 CI13 II ethyl 2-pyridyl ch3 H ethyl /i-pyr idylmethyl ch3 II ethyl 3-pyr idyj.iiietliyl ch3 H ethyl 2 - py r i d y line 1: hy 1 ch3 H ethyl beuzyl ch3 H ethyl ^i-H02C-benzyl CII3 H ethyl A-lI?NCO-benzyl cn3 H ethyl A-CII30-benzyJ. ch3 H ethyl ^~IlU-benzy 1 CH3 II ethyl /+-C.l-benzy I CII3 H ethyl ^1 - (Cll3 ) 2 M - b e nzy 1 Cll 3 H ethyl -81- 5 1ϋ 15 20 25 3-H02C-benzyl 3-II2NCO-beazyl 3-CH30-benzyl 3-II0-benzyl 3-Cl-beazyl 3- (CH3)2H-beazyl 2-H02C-beazyl 2 - II21IC 0-· b e n zy 1 2-CH30-beazyl 2-H0-beazy.l 2-Cl-beazy.l 2- (CII3&gt;2N-benzyl Cfl3 ch3ch2 ch2=chch2 ch3ch 2ch2 (CH3)2CH II02CCII2CH2 B2IJC0CH2CIl2 hoch2ch2 HOCH2CH2CII2 (CIl3)2CH2 phenyl 4- pyr idyl 3- pyridyl 2- pyridyl 4- pyr idylinethyl 3- pyridylmethyl 2-pyridylinethyl beazyl 4- II02C-benzyl 4-II2NCO-beazyl

CII3 H Cll3 H ch3 H ch3 H ch3 H ch3 H ch3 H ch3 H CII3 II cn3 H ch3 H cii3 H CH3 0H CII3 OH ch3 OH CH3 OH CII3 OH ch3 OH ch3 OH ch3 OH ch3 OH CII3 OH CH3 OH ch3 OH ch3 OH ch3 OH ch3 OH ch3 OH ch3 OH CII3 OH ch3 OH ch3 OH ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl allyl allyl allyl allyl . allyl allyl allyl allyl allyl allyl allyl allyl allyl allyl allyl allyl allyl allyl allyl allyl LV 10450 30 5 -82- 10 15 4-CH30-benzy.l cn3 OH allyl 4-HO-benzyl cii3 OH allyl 4 --Cl-benzy 1 cn3 011 allyl 4-(CIl3 )2N-benzyl ch3 OH allyl 3-fI02C-benzyl ch3 OH allyl 3-fJ2NCO-benzyl ch3 OH allyl 3-CII30-benzyl ch3 OH allyl 3-IIO-benzyl ch3 OH allyl 3-Cl-benzyl ch3 OH allyl 3-(CH3)2N-benzyl ch3 OH allyl 2-H02C-benzyl ch3 OH allyl 2-H2NCO-benzyl ch3 OH allyl 2-CH30-benzyl cii3 OH allyl 2-II0-benzyl ch3 03 allyl 2-Cl-benzyl ch3 OH allyl 2-(CH3)2N-benzyl ch3 OH allyl,

Representative compounds of the present invention include the compounds of Formula XVIII: 20 25 30 -83- 5 10 15 20 X \

LV 10450 vzlierein X, R^, R^ and R5 are selected from the folloving groups of sul)SlilueiiLs : 25

X -84- 1- iinidazolylinethyl 2- iinidazolylmethyl 5 3-thiazolylmethyl 2-thi azolylmethyl 2-oxazolylmethyl 5 -1etrazolylmet.hyJ. /,_pyr ' dyliue thy 1 10 3-p3rridylniethyl 2- pyr idylniethyl benzyl 4-H02C-benzyl 4-H2NC0-benzyl 15 4-CH30-benzyl 4-H0-benzyl 4-R-^0-benzyl 4-Cl-benzyl 4— (CII3 )2N-benzyl 20 3-H02C-benzyl 3- II2NCO-benzyl 3-CJl3Ū-benzyl 3-H0-benzyl 3-R^-0-benzyl 25 3-Cl-benzyl 3 — (CH'ļ )2N-benzyl 2-lI02C-benzyl 2-II2NCO-benzyl Z-CIIjO-benzyl 20 2--I10-benzyl 2 -R^ ^ 0-benzy J 2-(J l-benzyl 2 — (Cilq )2N-beazyl R2 E3 E5 ch3 OH ethyl ch3 OH ethyl ch3 OH ethyl ch3 OH ethyl ch3 OH ethyl ch3 OH ethyl CI13 OH ethy 1 ch3 OH ethyl ch3 OH ethyl ch3 OH ethyl ch3 OH ethyl ch3 OH ethyl ch3 OH ethyl ch3 OH ethyl ch3 OH ethyl ch3 OH ethyl ch3 OH ethyl ch3 OH ethyl ch3 OH ethyl ch3 OH ethyl ch3 OH ethyl ch3 OH ethyl ch3 OH ethyl ch3 OH ethyl ch3 OH ethyl CII3 OH ethyl ch3 OH ethyl ch3 OH ethyl ch3 OH ethyl ch3 OH ethvl ch3 OH ethyl -85- LV 10450 3-(4-pyridyl )-imidazol-2-ylmethyl ch3 0H ethyl 3-(3-pyiidyl)-imidazol-2-ylniethyl ch3 &quot; OH ethyl 3-(2-pyridyl)-imidazol-2-ylmethyl ch3 OH ethyl 3-phenyliraidazol-2-ylmethyl ch3 OH ethyl 3-(4-H02C-phenyl)-iinidazol-2-ylmethyl ch3 OH ethyl 3-(4-Il2NCO-phenyl )-imidazol-2-ylinethyl ch3 OH ethyl 3-(4-CH30-phenyl )-iinidazol-2-ylmethyl ch3 OH ethyl 3_(4-ll0-p]ienyl)-iinidazol-2-ylinethyl ch3 OH ethyl 3-(4_pllo-phenyl)-imidazol-2-ylmethyl ch3 OH ethyl 3-(4-C.l-phenyl)-imidazol-2-ylmethyl ch3 OH ethyl 3-(4-(CII3) 2N~phenyl )-imidazol-2-ylmethyl ch3 OH ethyl 3-( 3~Jl02C-phenyl)-imidazol-2-ylmethyl ch3 OH ethyl 3-13-Il2HCO-plienyl) -imidazol-2-ylmethyl ch3 OH ethyl 3-(3-CH30-phenyl )-iinidazol-2-ylmethyl ch3 OH ethyl 3-(3-I10-phenyl )-imidazol-2-yTmethyl ch3 OH ethyl 3-(3-R^^O-phenyl )-iinidazol-2-ylmethyl ch3 OH ethyl 3-(3-Cl-phenyl)-imidazol-2-ylmethyl ch3 OH ethyl 3— C 3 — C CII3 &gt;2N-phenyl )-imidazol-2-ylmethyl ch3 OH ethyl 3-(2-II02C-phenyl)-imidazol-2-ylmethyl ch3 OH ethyl 3-(2-H2NCO-phenyl)-imidazol-2-ylinethyl ch3 OH ethyl 3- ( 2-CIl30-phenyl )-imidazol-2-ylmethyl ch3 OH ethyl 3-(2-II0-phenyl)-imidazol-2-ylmethyl ch3 OH ethyl 3-(2-R-*-^0-phenyl )-imidazol-2-ylmethyl ch3 OH ethyl 3-(2-Cl-plienyl)-imidazol-2-ylmethyl ch3 OH ethyl 3-(2-(CH3)2N-phenyl)-imidazol-2-ylmethyl ch3 OH ethyl l-iinida7X)lylmethyl ch3 H ethyl 2-iinidazolylmethyl ch3 H ethyl 3-thiazolylmethyl ch3 H ethyl 2-thiazolylmethyl ch3 H ethyl 2-oxazolylinethyl ch3 H ethyl 5-tetrazolylmethyl ch3 H ethyl 4-pyr idylmethyl ch3 H ethyl 3-pyr idylm,ethyl ch3 H ethyl -86- 2-py r .idylmethyl ch3 H ethyl benzyl ch3 H ethyl 4-H02C-bensyl ch3 H ethyl 4-Il2NC0-benzyl . ch3 H ethyl 4-CH30-benzyl ch3 H ethyl 4-II0-benzyl ch3 E. ethyl 4-R-^0-benzyl ch3 H ethyl 4-Cl-benzyl ch3 H ethyl 4-(CH3)2N-benzyl ch3 H ethyl 3-H02C-benzyl ch3 H ethyl 3-H2NCO-benzyl ch3 H ethyl 3-CH30-benzyl ch3 H ethyl 3-H0-benzyl ch3 H ethyl 3-R-^0-benzyl ch3 H ethyl 3-Cl-benzyl ch3 H ethyl 3-(CH3)2N-benzyl ch3 H ethyl 2-H02C-benzyl ch3 H ethyl 2-ll2NCO-benzyl ch3 H ethyl 2-Cil30-benzyl ch3 H ethyl 2-I10-benzyl ch3 H ethyl 2-R-*-^0-benzyl ch3 H ethyl 2-Cl-benzyl ch3 H ethyl 2-(CH3)2N-benzyl ch3 H ethyl 3-( 4-pyr idyl)-iinidazol-2-ylmethyl ch3 H ethyl 3-(3-pyridyl)-imidazol-2-ylmethyl ch3 H ethyl 3-( 2-pyr i dyl )-imidazol-2-yJLmethyl ch3 H ethyl 3-phenylimidazol-2-ylmethyl ch3 H ethyl 3-( 4-H02C-plienyl )-imidazol-2-ylmethyl ch3 H ethyl 3-(4-Il2NC0-phenyl )-imidazol-2-ylmethyl ch3 H ethyl 3-(4-CH30-pheny1 )-imidazol-2-ylmethyl ch3 H ethyl 3_( 4-H0-plienyl)-imidazol-2-ylmethyl ch3 H ethyl 3-( 4-R-*-1 u-phenyl )-imidazol-2-ylmethyl ch3 H ethyl 3-( 4-C.|.-plieny 1)-imidazol-2-ylmethyl ch3 H ethyl -87- LV 10450 3_(4_(CH3)2N-phenyl)-imidazol-2-ylmethyl ch3 H ethyl 3-(3-II02C-phenyl)-imidazol-2-ylmethyl ch3 H ethyl 3-(3-H2NCO-phenyl)-imidazol-2-ylmethyl ch3 H ethyl 3-(3-CH30-phenyl)-iinidazol-2-ylmethyl ch3 H ethyl 3-(3-H0-phenyl)-iinidazol-2-ylraethyl ch3 H ethyl 3-(3-R-^0-phenyl)-imidazol-2-ylmethyl ch3 H ethyl 3_(3_Cl-phenyl)-imidazol-2-ylmethyl ch3 H ethyl 3_(3_(Cii3)2N-phenyl)-imidazol-2-ylmethyl ch3 H ethyl 3_(2_H02C-phenyl)-imidazol-2-ylmethyl ch3 H ethyl 3-(2-II?NC0-phenyl&gt;-imidazol-2-ylinethyl ch3 H ethyl 3-(2-CIl30-phenyl)-imidazol-2-ylmethyl ch3 H ethyl 3-(2-fI0-phenyl)-imidazol-2-ylmethyl ch3 . H ethyl 3_(2-R1:i0-phenyl)-imidazol-2-ylmethyl ch3 H ethyl 3-(2-Cl-phenyl)-imidazol-2-ylmethyl ch3 H ethyl 3-(2-(CH3)2N-phenyl)-imidazol-2-ylmethyl ch3 H ethyl l-iinidazolylmethyl H 0H ethyl 2-imidazolylmethyl H OH ethyl 3-thiazolylmethyl H OH ethyl 2-thiazolylmethyi H OH ethyl 2-oxazolylmethyl H OH ethyl 5-tetrazolylmet:hyl H OH ethyl 4-pyr.idyltnelhyl H OH ethyl 3-pyr idylinethyl H OH ethyl 2-pyr idy.lme thy 1 H OH ethyl benzyl H OH ethyl 4-H02C-benzyl H OH ethyl 4-H2NCO-benzyl H OH ethyl 4~CH30-benzy.l H OH ethyl 4-HO-benzyl H OH ethyl 4-R^0-benzyl H OH ethyl 4-Cl-benzyl H OH ethyl 4-(CH3)2W-benzyl H OH ethyl 3-H02C-benzyl H OH ethyl -88- 3-II2NCO-benayl H OH ethyl 3-CII30-benzyl H OH ethyl 3-H0-benzyl H OH ethyl 3-R^0-benzyl H OH ethyl 3-Cl-benzyl H OH ethyl 3-(CH3)2H-benzyl H OH ethyl 2-H02C-beuzyl H OH ethyl 2 -IIpNCO--benzvJ H OH ethyl 2-CIl3U-benzyl H OH ethyl 2-HO-benzyl H OH ethyl 2-R^^()-benzyl H OH ethyl 2-Cl~benzyJ. H &quot;OH ethyl Z— (CII3 )2N-benzyl H OH ethyl 3-(4-pyridyl)-imidazol-2-ylmethyl H OH ethyl 3-(3-pyridyl)-imidazol-2-ylraethyl ~ H OH ethyl 3-(2-pyr idyl)-imidazol-2-ylraethyl H OH ethyl 3-pheny.liinidazol-2-ylinethyl H OH ethyl 3-(4-IIO?C-phenyJ. )-iniidazol-2-ylmethyl H OH ethyl 3-( 4-H2HCO-phenyl )-imidazol-2-ylmethyl H OH ethyl 3-(4-CH30-phenyl)-imidazol-2-ylmethyl H OH ethyl 3-(4-IIO-phenyl )-imidazol-2-ylraethyl H OH ethyl 3_(4-R^0-phenyl )-imidazol-2-ylmethyl H OH ethyl 3-(4-Cl-phenyl)-imidazol-2-ylmethyl H OH ethyl 3-(4-(CIl3 )2N-phenyl )-imidazol-2-ylniethyl H OH ethyl 3-(3-H02C-phenyl)-iinidazol-2-ylmethyl H OH ethyl 3-(3-H2NCO-phenyl)-imidazol-2-ylmethyl H OH ethyl 3-( 3-CII30-phenyl )-imidazol-2-ylmethyl H OH ethyl 3-( 3-HO-phenyl )-iinidazol-2-ylmethyl H OH ethyl 3-(3-R^O-phenyl )-imidazol-2-ylmethyl H OH ethyl 3-(3-Cl-phenyl)-imidazol-2-y Irtie thyl H OH ethyl 3 — (3 — (CĪI3 )2N-pbenyl)-iinidazol-2-ylmethyl H OH ethyl 3-(2-If02C-phenyl )-irnidazol-2-ylmethyl H OH ethyl 3-(2-H2NCO-pheuyl) -iinidazol-2~ylmethyl H OH ethyl -89- LV 10450 3- &lt;?.-CH30-phenyl)-imidazol-2-ylmethyl H 0E ethyl 3-( 2~HO-phenyl)-iniidazol-2-ylmethyl H OE ethyl 3~( 2-R·* ^0-plienyl )-iinidazol-2-ylmethyl H OE ethyl 3-( 2-Cl-phenyl )-iinidazol-2-ylmethyl H OE ethyl 5 3- -(2-(0113 )2N-phenyl )-imidazol-2-ylmethyl H OE ethyl l-imidazolylmethyl H H ethyl 2-imidazolylmethyl H H ethyl 3-thiazolylmethyl H E ethyl 2- t.hiazolylmeLhyl H H ethyl 10 2-oxazolylmethyl H E ethyl . 5-tetrazolylmelhyl H E ethyl 4-pyridylmethyl H E ethyl 3-pyr idylmethyl H Ξ ethyl 2-pyridylmethyl H E ethyl 15&quot; benzyl H E ethyl 4-H02C-benzyl H E ethyl 4-H2NC0-benzyl H E ethyl 4-CH30-benzyl H E ethyl 4-H0-benzyl H E ethyl 20 4-R^--*-0-benzyl H E ethyl 4-Cl-benzyl H E ethyl 4-(CH3)2N-benzyl H E ethyl 3-H02C-benzyl E E ethyl 3-H2NC0-benzyl H H ethyl 25 3-CIl30-benzyl E E ethyl 3-H0-benzyl E E ethyl 3-R-*-^0-benzyl H E ethyl 3-Cl-benzyl E H ethyl 3-(CII3)2N-benzyl E E ethyl 30 2-H02C-benzyl E E ethyl 2-II2MC0-benzy.l E E ethyl 2-CII30-benzyl E E ethyl 2-UO-benzyl E E ethyl -90- 2-RŪO-benzyl H H ethyl 2-CM-benzyl H H ethyl Z — (CII3 )2N-benzyl H H ethyl 3-(4-pyr idyl)-imidazol-2-ylmethyl H H ethyl 3-(3-pyridyl)-imidazol-2-ylmethyl H H ethyl 3 - ( 2-py r idyl )-iinidazol-2-ylmethyl H H ethyl 3-plienyl imidazol-2-ylmethyl H H ethyl 3-(4-IlO'/&gt;C-phenyl)-iinidazol-2-ylmethyl H H ethyl 3- ( 4-il2NC0-phenyl )-iinidazol-2-ylmethyl H H ethyl 3_(4_CH30-phenyl)-imidazol-2-ylmethyl H H ethyl 3-(4-HO-phenyl)-imidazol-2-ylmethyl H H ethyl 3-( ^-R^-*-0-phenyl)-imidazol-2-ylmethyl H H ethyl 3--( 4-Cl-phenyl )-imidazol-2-ylmethyl H H ethyl 3-(4-(CH3)2N-phenyl)-imidazol-2-ylmethyl H H ethyl 3-(3-H07C-phenyl)-imidazol-2-ylraethyl H H ethyl 3-(3-H2NCO-phenyl)-iinidazol-2-ylmethyl H H ethyl 3-(3-CH30-phenyl)-imi dazol-2-ylmethyl H H ethyl 3-(3-HO-phenyl)-imidazol-2-ylmethyl H H- ethyl 3-(3-R-^0-phenyl)-iniidazol-2-ylmethyl H H ethyl 3-(3-Cl-phenyl)-imidazol-2-ylmethyl H H ethyl 3-(3-(CH3 &gt;2N-phenyl)-imidazol-2-ylmethyl H H ethyl 3-(2-H02C-phenyl)-imidazol-2-ylraethyl H H ethyl 3-(2-H2NC0-phenyl )-iinidazol-2-ylmethyl H H ethyl 3-(2-CH30-phenyl)-imidazol-2-ylmethyl H H ethyl 3-( 2-IIO-phenyl )-imidazol-2-ylmethyl H H ethyl 3-( 2-R^-^0-phenyl )-imidazol-2-ylraethyl H H ethyl 3-(2-Cl-phenyl)-imidazol-2-ylmethyl H H ethyl 3-( 2 — ( CII3 &gt;2N-phenyl )-imidazol-2-ylmethyl H H ethyl l-imidazolylniethyl ch3 0H allyl 2-imidazolylinethyl ch3 OH allyl 3-th i.azolylmetliyl ch3 OH allyl 2 -1 h i a 7.01y 1 rne t hy 1 ch3 OH allyl 2-oxar,o 1 yimet:hyl ch3 OH allyl -91- LV 10450

5-tetrazolylinethyl ch3 0H 4-pyridylmethyl ch3 OH 3-pyr idylniethyl ch3 OH 2-pyridylmethyl ch3 OH benzyl ch3 OH 4-II02C-benzyl ch3 OH 4-H2NCO-benzyl ch3 OH 4~CH30-benzy1 ch3 OH 4-II0-benzyl ch3 OH 4-R?-^0-benzyl ch3 OH 4-Cl-benzyl ch3 OH 4~(CH3)2N~benzyl ch3 OH 3-H02C-benzyl ch3 OH 3-H2NCO-benzyl ch3 OH 3-CH30-benzy.l ch3 OH 3-HO-benzyl ch3 OH 3-R^O-benzyl ch3 OH 3-Cl-benzyl ch3 OH 3-(CH3)2N-benzyl ch3 OH 2-H02C-benzyl ch3 OH 2-H2HCO-benzyl ch3 OH 2-CH30-benzyl ch3 OH 2-HU-benzyl ch3 OH 2-R·'--’ 0-benzyl ch3 OH 2-Cl-benzyl ch3 OH 2--(011} )7N-benzyl ch3 OH 3 - (4-pyr idyl l-iniidazol-2-ylmethyl ch3 OH 3-(3 pyridyl )-iinidazol-2-ylmethyl ch3 OH 3-(2-pyri&lt;ly.l)-imidazol-2-ylmethyl ch3 OH 3 - p li e ny .1 i iii i d a z 01 - 2 -y 1 m e t liy 1 ch3 OH 3-(4-II02C-phenyl)-imidazol-2-ylraethyl ch3 OH 3 - (. 4 - H 711C 0 - p h e ny 1) - i m i d a z 01 - 2 - y 1 m e t hy 1 ch3 OH 3-&lt;; 4—CIl30-plienyl )-imidazol-2-ylmethyl ch3 OH allyl allyl allyl allyl allyl allyl allyl allyl allyl allyl allyl allyl allyl allyl allyl allyl allyl allyl allyl &quot;allyl allyl allyl allyl allyl allyl allyl allyl allyl allyl allyl allyl allyl allyl -92- 3-(4-H0-phenyl)-imidazol-2-ylmethyl ch3 OH allyl 3-( 4-R ·*·* 0-phenyl )-iinidazol-2-ylraethyl ch3 OH allyl 3-(4-Cl-phenyl )-iinidazol-2-ylmethyl ch3 OH allyl 3-(4-(CH3)2N-phenyl)-imi dazol-2-ylmethyl ch3 OH allyl 3-(3-iIO?C-phenyl )-imidazol-2-ylmethyl ch3 OH allyl 3-(3-H2NCO-phenyl)-imidazol-2-ylmethyl ch3 OH allyl 3-(3-CH30-phenyl)-imidazol-2-ylmethyl ch3 OH allyl 3-( 3-H0-phenyl )-imidazol-2-ylrnethyl ch3 OH allyl 3- (3-pJ ^0-phenyl )-imidazol-2-ylmethyl ch3 Oli allyl 3- (3-CJ.-pheny.l )-imidazol-2-ylraethyl ch3 OH allyl 3 — ( 3 — CH3 )2N-phenyl )-imidazol-2-ylmethyl ch3 OH allyl 3-( 2-H02C~phenyl )~iinidazol-2-ylmethyl ch3 OH allyl 3-( 2-II2tICO-phenyl )-iinidazol-2-ylmethyl ch3 OH allyl 3- (2-CH30-phenyl )-imidazol-2-ylmethyl ch3 OH allyl 3-( 2-II0-phenyl )-imidazol-2-ylmethyl ch3 OH allyl 3-( 2~R-^0-phenyl )-imidazol-2-ylmethyl ch3 OH allyl 3-(2-Cl-phenyl)-imidazol-2-ylraethyl ch3 OH allyl 3-(2-(0Η3)2N-phenyl)-imidazol-2-ylmethyl ch3 OH allyl l-imidazolylinethyl ch3 H allyl 2-imidazolylmetliyl ch3 H allyl 3-thiazolylmethyl ch3 H allyl 2-thiazolylmethyl ch3 H allyl 2-oxazolylmetliyl ch3 .H allyl 5-tet:razolylmetliyl ch3 H allyl 4-pyri dylme thyl ch3 H allyl 3-pyridylmethyl ch3 H allyl 2-pyr idylinethyl ch3 H allyl. benzyl ch3 H allyl /*-II02C-benzyl ch3 H allyl 4 -H'} ĪICV - b e n zy 1 ch3 H allyl 4-Cfi30-benzyl ch3 H allyl 4-IiO-benzyl ch3 H allyl 4-R-*-^0-benzyl ch3 H allyl LV 10450

4~C l-benzyl ch3 H allyl ^ (CII3 )pH- benzyl ch3 H allyl 3-IIO^C-benzyl ch3 H allyl 3~H^HCO-benzyl ch3 H allyl 3-CII30-benzyl ch3 H allyl 3-H0-benzyl ch3 H allyl 3~R-*-^-0-benzyl ch3 H allyl 3~C J.~benzyl ch3 H allyl 3 -(011-( &gt;2W--bensyl ch3 H allyl 2-H07C-benzyl ch3 H allyl 2-II?NCO-bensyl ch3 H allyl 2-CH30-benzyl ch3 H allyl 2-HO-benzyl ch3 H allyl 2-R1:L0-benzyl ch3 H allyl 2-Cl-benzyl ch3 H allyl 2-(CH3bsnzyl ch3 H allyl 3-(4-pyridyl )-iniidazol-2-ylmethyl ch3 H allyl 3-(3-pyridyl)-imidazol-2-ylmethyl ch3 H allyl 3-(2-pyi'idyl)-imidazol-2-ylmethyl ch3 Π allyl 3-phenyliinidazol-2-ylmethyl ch3 H allyl 3-(4-H02C-phenyl)-imidazol-2-ylmethyl ch3 H allyl 3-(4-H2NC0-phenyl)-imidazol-2-ylmethyl ch3 H allyl 3-(4-CH30-phenyl)-imidazol-2-ylmethyl ch3 H allyl 3- ( 4-II0-phenyl )-imidazol-2-ylmethyl ch3 H allyl 3-(4-R^-^0-phenyl )-imidazol-2-ylmethyl ch3 H allyl 3-(4~01-phenyl)-imidazol-2-ylmethyl ch3 . H allyl 3-(4-(CII3 &gt;2N-pbenyl )-imidazol-2-ylmethyl ch3 H allyl 3-(3-H02C-phenyl)-imidazol-2-ylmethyl ch3 H allyl 3-(3-H2HC0-phenyl)-imidazol-2-ylmethyl ch3 H allyl 3-(3-CH30-phenyl)-imidazol-2-ylmethyl ch3 H allyl 3-(3-H0-phenyl)-imidazol-2-ylmethyl ch3 H allyl 3-(3-RI--l-Ū-phenyl)-imidazol-2-ylmethyl ch3 H allyl 3-( 3~Cl-phenyl)-iinidazol-2-ylmethyl ch3 H allyl -94-

3-(3-(CH3)2N-phenyl)-iinidazol-2-ylmethyl ch3 H 3-( 2-IIC»2C-phenyl )-imidazol-2-ylmethyl ch3 H 3-( 2-Il2NCO-phenyl)-iinidazol-2-ylmethyl ch3 H 3_(2-CH30-phenyl)-iinidazol-2-ylmethyl ch3 H 3--(2-l.l0~phenyl )-imidazol-2-ylmethyl ch3 H 3_( 2-R^-lo-phenyl )-iinidazol-2-ylmethyl ch3 H 3-(2-Cl-phenyl )-iinidazol-2-ylraethyl ch3 H 3_(2-(CIl3)2N-p^enyl)-imidazol-2-ylmethyl ch3 H l-imidazolylmethyl H 0H 2-imidazolylinethyl H OH 3-thiazolylmethyl H OH 2-thiazolylmethyl H OH 2-oxazolylinethyl H OH 5-tetrazolylmethyl H OH 4-pyr idylniethyl H OH 3-pyr idylniethyl H OH 2-pyr idylinethyl H OH benzyl H OH 4-H02C-benzyl H OH 4-H2l'lCO-benzyl H OH 4-CIl30-benzyl H OH 4-II0-benzyl H OH 4-R^-*-0-benzyl H OH 4-Cl-benzyl H OH 4-(CIl3 &gt;2N-benzyl H OH 3-H02C-benzyl H OH 3-Il2NCO-benzyl H OH 3-CIl30-benzyl H OH 3-HO-benzyl H OH 3-RJ10-benzyl H OH 3-Cl-benzyl H OH 3- (CII3 ) 2W-benzy.l H OH ZIlŪ2C-benzyl H OH LV 10450

2-H2NCO-benzyl H OH allyl 2-Cn30-benzyl H OH allyl 2-H0-benzyl H OH allyl 2-R1*0-benzyl H OH allyl 5 2-Cl-benzyl H OH allyl 2-(CH3)2N-benzyl H OH allyl 3_(4_py]:idyl)-imidazol-2-ylmethyl H OH allyl 3_(3_pyr idyl)-iinidazol-2-ylmethyl H OH allyl 3-(2-pyr idyl )-~imidazol-2-ylmethyl H OH allyl 10 3-phenylimidazol-2-ylmethyl H OH allyl 3_(4_H02C-phenyl)-imidazol-2-ylmethyl H OH allyl 3_(4_H2NC0-phenyl)-imidazol-2-ylmethyl H OH allyl 3_(4_CH30-phenyl)-imidazol-2-ylmethyl H OH allyl 3-(4-H0-phenyl)-imidazol-2-ylmethyl H OH allyl 15 3_(4_pllo-phenyl)-imidazol-2-ylmethyl H OH allyl 3-(4-Cl-phenyl)-imidazol-2-ylmethyl H OH allyl 3_(4_(CH3)2N-phenyl)-iniidazol-2-ylmethyl H OH allyl 3-(3-H02C-phenyl)-iinidazol-2-ylmethyl H OH allyl 3-(3-H2NC0-phenyl)-irnidazol-2-ylmethyl H OH allyl 20 3-(3-CH30-phenyl)-imidazol-2-ylmethyl H OH allyl 3-(3-HO-phenyl)-imidazol-2-ylmethyl H OH allyl 3-(3-R11-0-phenyl)-imidazol-2-ylmethyl H OH allyl 3-(3-Cl-phenyl)-imidazol-2-ylmethyl H OH allyl 3-(3-(CII3 )2N-phenyl )-imidazol-2-ylmethyl H OH allyl 25 3-(2-H02C-phenyl)-imidazol-2-ylmethyl H OH allyl 3-(2-Il2HCO-p1ienyl)-imidazol-2-ylmethyl H OH allyl 3-( 2-CII30-plienyl )-iinidazol-2-ylmethyl H OH allyl 3-(2-HO-phenyl)-imidazol-2-ylmethyl H OH allyl 3-(2-R-J ^0-phenyl)-iinidazol-2-ylmethyl H OH allyl 30 3-(2-Cl-phenyl)-imidazol-2-ylmethyl H OH allyl 3 ~ (2- (Cil i) 2H-pheny 1) -imidazol-2-ylinethyl H OH allyl -96- l-imidazolylinethyl H H allyl 2-imidazolylmethyl H H allyl 3-thiazolylmethyl H H allyl 2-thiazolylinethyl H H allyl 5 2-oxazolylmethyl H H allyl 5-tet razolylmethyl' H H allyl 4-pyridylmethyl H H allyl 3-py r i d y1me thy1 H H allyl 2-py r idy lmet:liyl H H allyl 10 benzyl H H allyl 4-II02C-benzyl H H allyl 4-Il2HC0-benzyl H H allyl 4-CH30-benzyl H H allyl 4-II0-benzyl H H allyl 15 4-R^0-benzyl H H allyl 4-Cl-benzyl H H allyl 4-(CIl3 )2N-benzyl H H allyl 3-II02C-benzyl H H allyl 3-H2HC0-benzyl H H allyl 20 3-CH3Ū-benzyl H H allyl 3-HO-benzyl H H allyl 3-R1:L0-benzyl H H allyl 3-Cl.-benzyl H H allyl 3-(CHļ)?N-benzyl H H allyl 2 5 2-II02C~benzy 1 H H allyl 2-II?HCO-benzyl H H allyl 2-CH30-benzyl H H allyl 2-H0-benzyl H H allvl 2-R^0-benzyl H H allyl 3 0 2-Cl-benzyl H H allyl Z — (CJĪo )2H-benzyl H H allyl 3 — (4 -py i' i dy J.) — imi dazο 1—2 —yimsthy 1 H H allyl 3 - ( 3 - p y r i d y 1) - i m i d a z ο 1 - 2 -y 1m e t hy 1 H H allyl -97- 11) 15 20 3-( 2-py r idyl )-iinidazol-2-ylmethyl 3~phenylj midazol-2-ylmethyl 3-(4-U02C-phenyl)-imidazol-2-ylmethyl 3 - ( Λ -112 N C 0 - p h e ny 1) - i tn i d a z ο 1 - 2 -y 1 in e t hy 1 3-(^ —CH3 0—pheny 1 )-iinidazol-2-ylmethyl 3-(/i~H0~phenyl)~imidazol-2-ylmethyl 3-(/'i-pJ-'o-phenyl)-iraidazol-2-ylraethyl 3_(4_CJ.-phenyl)-imidazol-2-ylmethyl 3- (4-(CH3 &gt;2N-plienyl)-imidazol-2-ylmethyl 3 (3-II0-;C-phenyl)-iinidazol-2-ylmethyl 3-(3~H2NOO-phenyl)~imidazol-2-ylinethyl 3-(3-CH30-plienyI )-imidazol-2-ylmethyl 3 - (3-H0-phenyl)-iinidazol-2-ylmethyl 3-(3-R-1--1-0-phenyl)-iniidazol-2-ylinethyl 3-(3-Cl-phenyl)-imidazol-2-ylmethyl 3- (3- (CII3) 2N-phenyl )-iinidazol-2-ylmethyl 3-(2-HC&gt;2C-phenyl )-iraidazol-2-ylraethyl 3-(2-il2HC0-phenyl)-injidazol-2-ylmethyl 3-(2-CH30-phenyl)-imidazol-2-ylmethyl 3-(2-II0-phenyl)-imidazol-2-ylmethyl 3-(2-R^-*-0-phenyl)-imidazol-2-ylmethyl 3-(2-Cl-phenyl)-imidazol-2-ylmethyl 3-(2-(CH3 &gt;2N-phenyl)-imidazol-2-ylmethyl

II H H H H H H H H H H H H H H H H H H H H H H II H H H H H H H H H H H H H H H H H H H H H H LV 10450 allyl allyl allyl allyl allyl allyl allyl allyl allyl allyl allyl allyl allyl allyl allyl allyl allyl allyl allvl allyl allyl allyl allyl. B. Preparation of Conipounds Within the Scope of FresenL Invention The starting inaterials for the preparat of the compounds of this invention are represented Formula II: the ion by 30 -98- 20 25

II 30 -99- -99- LV 10450 wherein: E is hydrogeu or niethyl; W is 0 or (II, 011); R^ is hydrogen, hydroxy, or Cļ_£ alkoxy; 5 R/f is hydrogen, or R^ and R^ taken together form a double bond; R^ is methyl, ethyl, propyl or allyl; and n is 1 or 2. 10 The production and characterization of compounds of Formula II is well known in the literature (see U.S. Patent No. 4.894.366 issued Januarv 16, 1990; U.S. Patent No. 4.929,611 issued May 29, 1990; U.S. Patent No. 3.244.592 issued April 15 15, 1966; EPO Publication No. 0.323,042,; EPfl ~

Publication No. 0.356. 399; PBJ Disclosure 63-17884; J. Am. Chem. Soc.. 1987, 109. 5031; J. Antibiotics. 1987, 4£, 1249, J. Antibiotics. 1988, 41(11), 1592; and J. Antibiotics. 1992, 4£&lt;1), 118). Both 20 biological fermentation and synthetic processes may be found. A synthetic route to compounds of Formula II can involve modifications of a route described in J. Am. Chem. Soc.. 1989, 111. 1157.

Biological fermentation followed by 25 synthet.ic modification is presently favored in the art as the method to producē compounds of Formula II. Organisms belonging to the gēnus Strentomvces such as Streptomvces tsukubaensis. No. 9993 and Streptomvces hygroscopicus. var. ascomvcetis. No. 30 14891 placed in an aqueous nutrient medium will producē desired compounds in isolable amounts. The nutrienf. medium contains sources of assimilable carbou aud nitro&amp;en, preferably under aerobie 100 conditions. Produced in fermentation are four compounds of Formula II, (A) where E is methyl, W is 0, is hydroxyl, is hydrogen, R^ is allyl and n is 2; (B) where E is methyl, V/ is 0, R·* is hydroxyl,

5 R^ is hydrogen, is ethyl and n is 2; (C) where E is methyl, W is 0, R^ is hydroxyl, R^ is hydrogen, R^ is methyl and n is 2; and (D) where E is methyl W is o, R3 :is hydroxyl, is hydrogen, R-&gt; is allyl and n i s 1. i0 A lyophilized sample of the isolated

StxepLomyc_es tsukubaensis. No. 9993 was deposited with tlie Fermentation Research Institute, Agency of Industrial Science and Technology (No. 1-3, Higashi 1-chome, Yatabemachi Tsukuba-gun, Ibaraki Prefecture, 15 Japan) under the deposit number of FERM P-7886 (deposit datē: October 5th, 1984), and then converted to Budapest Treaty route of the same depository on October 19, 1983 under the new deposit number of FERM BP-927. 20 Using the four compounds produced in fermentation above, the remaining compounds of Formula 11 may be easily produced. The allyl of R^ may be conveniently reduced to propyl by well known methods, for example as described in U.S. Patent No. 25 4,u894.,..3„6_6.· The hydroxy of R^ inay be protected by v;ell known methods, for exarnple as disclosed in EP0 PtfhĻication No. 0.323,042. Likewise, the hydroxyl at C-41' may also be protected. In addition, the hydroxy of R^ may be reduced to a hydrogen or 30 eliminated to forin a double bond with (by methods d.isoiosed in U.S. Patent No. 4.894,366. EP0

PubL i.caL.i.on_No_._U . 323.042 or EPO Publication No. 0 ,^pl3..,.33.2). The carbonyl of W may be reduced to the - 101 - LV 10450 alcohol by methods disclosed in EFO Publication No. 0.323.042 or by methods disclosed in EPQ Publication No. 0.445.975. )0

The methyl of E as produced may be replaced with hydrogen or demethylated and subsequently protected as desired, if necessary. This deinethyIation of conipounds wherein E is methyl may be carried out in a fermentation reaction using the compounds of Formula II as a feedstock. For instance, compound Λ nained under Formula II above may be demethylated at E above by using the microorganism Actijxoinyc_e_taļe_s. ATCC No. 53771 (described in U.S.

Patent No._4.981.792) or by using the microorganism 15

Streptomvces tsukubaensis. No. 9993 (described in EPO Publication No. 0.353.678). SimilarTy, compound B nained under Formula II above may be demethylated at E above using tiie microorganism Actinoplanacete sp. ATCC No. 53771 (described in EPO Publication No. 20 25 0,349.061). In addition the compound of Formula II oherein E is H, W is 0, R^ is hydroxy, R^ is hydrogen, is ethyl and n is 2 may be produced directly by fermentation using the mutant microorganism Streptomvces hvgroscopicus sup. as_c_omvceticus . No. 53855 (being a blocked mutant of .^trepJ^omy£_ej3 hvgroscopicus sup. ascomvceticus. No. 14891) (as described in EPO Publication No. 0ο_38^,_15_2) . Similarly, the compound of Formula II «herein E is hydrogen, W is 0, R^ is hydroxy, R^ is hydrogen, R^ is methyl and n is 2 may be produced directly by fermentation using the mutant microorganism Streptomvces hvgroscopicus sup. as_QfiniyiLe£-i_cus, No. 53855 (being a blocked mutant of 5_tiiepiorņyc_es. liygroscopicus sup. ascomvceticus. No. 30 - 102 14891) (EPO Publication No. 0.388.153). The hydroxy of C-3&quot; may be protected by methods similar to those known for the protection of the hydroxyl groups of and/or C-4&quot;, for exainple as disclosed in U.S. Patenl: Mo. 4.894.366.

Suitable protecting groups for hydroxyl include those groups well known in the art such as: methyl tliiomethyl, ethylthiomethyl; tr isubstituted silyl such as trimethylsilyl, triethylsilyl, tributylsilyl, tri-i-propylsilyl, t-butyldimethyl-silyl, tri-t-butylsilyl, methyl-diphenylsilyl, ethyldiphenylsilyl, t-butyldiphenylsilyl, and the like; acyl such as acetyl, pivaloyl benzoyl, 4-methoxybenzoyl, 4-nitrobenzoyl and aliphatic acyl substituted with aromatic group, which are derived from carboxylic acids; and the like.

Compounds A, B, C and D of Formula II, organisms to producē the-same, conditions of fermentation, separation techniques, and Chemical modification of the products are fully described in U.S. Patent No. 4.894.366. dated January 16, 1990, U.S. Patent No. 4.929.611. issued May 29, 1990 and U.S. Patent No. 5.110.811. issued May 5, 1992.

The novel processes for preparing the novel compounds of the present invention are illustrated as folloos, v/herein R^ , , R^,R^, R^, R^, R^, R^, R^ , E, W and n are as defined above unless otherwise indicated. It will be readily apparent to one of ordinary skill in the art reviewing the synthetic route depicted below that other compounds within Formula I can be synthesized by substitution of appropriate reactants and aģents in the synthesis shoou bdvw. - 103 - 25

REACTION SCHEME A LV 10450

30 104 RJEACTIOŅ _S_CIIEME_Jl 30

4c 4b - 105 -LV 10450 KF.ACTTOH SrHF.ME B (CONT .1 5 10 15

4a

5a 20 25

4b

5b 30

5 106 KF.ACTION SCHEI1E C

25 3 0 - 107 -LV 10450

RF.ACTION SCHEME D 5 10 15

20 25 5 108

REACTION SCHEME E 10 15 20 25

4c 4b 30 - 109 -LV 10450 RTCACTTON SCHEME E (CONT.) ίο 15 20 25

4a’

4 b'

5a'

5 b’ 30

5 110 REACTIOH SCHEME F

25 30 - 111 -LV 10450 REACTION SCHEME G.

30 5 112 BF.ACTION SCHEME G (CONT.)

20 25 30 - 113 -LV 10450

RF.ACTION SCHEME H 5 1.0 15

20 25 12 14

15 30 114 REACTI0IL_SCHEJ1ĪL_I_

ο

- 115 - 5

REACTION LV 10450

30 116 ργδΓΤΤΟΝ SCHEME J (CONT'Dl TBSO, R20' (CHj I h3c

1 9 - 117 -LV 10450 ΠΈΛΓΤ'ΓΟΝ SCHEME J (CON'T) 25

30 118 SCHEME J ( CONT 1 D)_

- 119 - 5 10 15 20 2 5 3 0 LV 10450 REACTION SCHEME A: As shown in Reaction Scheme A, a solution of a 4&quot;-hydroxy-3&quot;-methoxy macrolide 1 in an inert organic solvent such as methylene chloride, benzene, toluene, chloroform, or the like or mixtures thereof is treated with a triheteroarylbismuth diacetate reaģent (wherein is heteroaryl) (prepared iinmediately prior to use by the addition of acetic acid to a suspension of a triheteroarylbismuth carbonate in an inert organic solvent such as methylene chloride, choroform or the like or mixture thereof) in the presence of a catalytic amount of copper(II) acetate at a.temperature of 20-50eC, preferably room temperature, for a period of one hour to seven days, preferably one day, to give the 4&quot;-0-heterOaryl-3&quot;-methoxy macrolide 2. Alter-natively, the triheteroarylbismuth(V) reaģent can be prepared by treatment of a triheteroarylbismuthine with a suitable oxidant such as peracetic acid, benzoyl peroxide, hydrogen peroxide, iodobenzene diacetate, bis(trifluoroacetoxy) iodobenzene and the like in an inert solvent such as methylene chloride, chloroform, benzene, toluene and the like. The triheteroarylbismuth(V) reaģent can be used without purification or can be purified by silica gel chromatography. Triheteroarylbismuthines may be prepared by the reaction of an appropriate heteroaryl Grignard reaģent or lithiated heteroaryl species with bismuth trichloride in an inert organic solvent such as tetrahydrofuran, diethyl ether, toluene, or I , 4 (1 i ajcanp, or mixtures thereof, at or near room temperature for a period of 1 to 48 hours. General procedures for the preparation and use of triaryl 120 bisinutli reaģents may be found in Barton, D.H.E., et al. , J. Chem. Soc. Chein. Commun. . 1986, 65 and references cited therein.

Reaction Scheme B: 5imilarly, as shown in Reaction Scheme B, a solution of the 3&quot;,4&quot;-dihydroxy macrolide 2. treated nith a tr iheteroarylbisinuth diacetate reaģent as described in Reaction Scheme A, to give a mixture of the 3&quot;-hydroxy-4”-0-heteroaryl macrolide 4a, the 3&quot;-0-heteroaryl-4&quot;-hydroxy macrolide 4k, and the 3&quot;, 4&quot;-di-0-heteroaryl macrolide 4ς.. At this stage, a solution of 3&quot;-hydroxy-4&quot;-0-heteroaryl macrolide 4a. or 3&quot;-0-heteroaryl-4&quot;-hydroxy macrolide 4&amp; can be treated with a triarylbismuth diacetate reaģent (prepared inunediately prior to use by procedures analogous to tliose disclosed above), to give 3&quot;-0-aryl-4&quot;-0-heteroaryl macrolide 5^. or 3&quot;-0-heteroaryl-4&quot;-0-aryl macrolide £a, respectively.

Reac.t.i on. _Schenig._C

As shown in Reaction Scheme C the 14-hydroxy group of a macrolide ,5a. or 5b (wherein R·*·, R^, R^, R^°, w and n are as defined above) may be eliminated by treatment with p-toluenesulfonic acid, benzenesulfonic acid or methanesulfonic acid in an inert organic solvent such as benzene, or toluene at from 40°C to 60°C, for about 0.5 to 6 hours, or a sufficient period of time to eliminate the 14-hydroxy group. ileutralization with an aqueous solution of a weak base such as aqueous saturated sodium bicarbonate gives the 14,15-dehydro macrolides 65. or - 121 - - 121 -LV 10450 6b. The 14-hydroxy group may also be eliminated by activation followed by basie elimination, as deseribed in U.S. Patent No. 4.894.366.

By cliangiug tlie sequence of synthetic steps, ali possible variatious of substitution can be aehieved.

Reac t.i on Scheine D:

As sliown in Reaction Scheme D, a solution of the 4&quot;-hydroxy 3”-methoxy maerolide ļ. in an inert organic solvent sucli as raethylene chloride, chloroform, pentane, hexane, cyclohexane, heptane or mixtures thereof is treated with a heteroarylalkyl, heteroarylalkenyl or heteroarylalkynyl trichloroacetimidate reaģent (prepared by the reaction of an appropriate sodium alkoxide with trichloroacetonitrile, such as deseribed by Wessel, H.P., Iversen, T., Bundle, D.R., J. Chem. Soc..

Perkin Trans. I. 1985, 2247) in the presence of a inild acid catalyst such as trifluoro-methanesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, or inixtures thereof at a temperature of 20-50°C for a period of from one hour to seven days to give the 4&quot;-0-heteroarylalkyl-, 4&quot;-0-heteroarylalkenyl- or 4”-0-heteroarylalkynyl-3&quot;-methoxy maerolide &quot;

Reaction Scheme E:

Similarly, as shown in Reaction Scheme E, a solution of the 3&quot;,4M-dihydroxy maerolide 2 in an inert organic solvent such as methylene chloride, chloroform, pentane, hexane, cyclohexane, heptane or the like or mixtures thereof is treated with a heteroarylalkyl, heteroarylalkenyl or hetero-aryl.alkynyl trichloroacetimidate (prepared as described in Reaction Scheine D) at a temperature of 20-50°C, preferably 40°C, for a period of one hour to seven days, preferably 0 hours, to give a mixture of the 4”-0-heteroarylalkyl, 4&quot;-0-heteroarylalkenyl, or V-0-heteroarylalkynyl-3-hydroxy macrolide 4a1 . 3&quot;-0-heteroarylalkyl, 3&quot;-0-heteroarylalkenyl, or 3&quot;-0--heteroarylalkynyl-4&quot;-hydroxymacrolide 4b 1 and the 3&quot;,4&quot;-di-0-heteroarylalkyl,-heteroarylalkenyl or -heteroarylalkynyl macrolide 4c1. Subsequently, a solution of 4&quot;-0-heteroaryl, 4&quot;-0-heteroarylalkyl, 4&quot;-0-heteroarylalkenyl or 4&quot;-0~heteroarylalkynyl-3-hydroxy macrolide 4a (from Reaction Scheine B or 4a1. or 3&quot;-0-heteroaryl-, 3&quot;-0-heteroarylalkyl, 3&quot;-0-heteroarylalkenyl, 3&quot;-0-heteroarylalkynyl-4&quot;-hydroxyinacrolide 4b from Reaction Scheme B or 4J?' can be treated with an arylalkyl, alkenyl or alkynyl trichloroacetimidate by procedures described above.) to give macrolides 5aJL or 5b' .

The procedures described in Reaction Schemes C and D may optionally be conducted following the procedures of Reaction Scheme E or F. Alternatively, the procedures described in Reaction Scheme F may be performed.

In any of the aforementioned Reaction Schemes, the macrolide (wherein R^ and/or contains an alkenyl, substituted alkenyl, alkynyl or substituted alkynyl and wherein R^ is hydroxy or Cļ_£ alkoxy, R^ is hydrogen, or R^ and taken together form a double bond) can be reduced with tri-Q-butyltin hvdride in the presence of tetrakis(triphenylphosp- liine) palladium (0) catalyst and acetic acid in an organic solvent such as toluene or tetrahydrofuran at or near room temperature for about 2 to 10 hours to give the reduced macrolide.

The procedures described in Reaction Scheme F inay be conducted on the mono-substituted products of Reaction Scheme B (and visa vērsa) to obtain the mixed disubstituted compounds. In fact, within Reaction Schemes B and F, treatraent of the mono-substituted product with a different reaģent will afford the mixed disubstituted compounds.

Reaction Scheme F:

Protection of the C-3&quot;, C-4&quot; and/or the C-14 hydroxyl group(s) may be accomplished by methods known in the prior art for compounds of Formula II such as by treatment with: 2,6-lutidine and triisopropylsilyl trifluoromethanesulfonate in a solution of methylene chloride; 2,6-lutidine and t-butyldimethylsilyl tr if luoromethanesulfonate in a solution of methylene chloride; pyridine and acetic anhydride in a solution of methylene chloride; pyridine and benzoyl chloride in a solution of dichloromethane; pyridine and p-nitrobenzoyl chloride in a solution of dichloromethane; imidazole and t-butyldiphenylsilyl chloride in a solution of methylene chloride; and the like. For example, as shown in Reaction Scheme F, the C-4&quot;,14-dihydroxy-C-3&quot;-methoxy macrolide 7 may be protected at C-14 as the t-butyldimethylsilyl ether by treatment with t-butyldiinethylsilyl trif luoromethanesulf onate in methylene cliloride to give the C-4&quot;, 14-di-O-TBDMS 124 inacrolide. Treatment with toluenesulfonic acid in meUianol results in selective reraoval of the C-4&quot; silyl ether to give the C-14-0-TBDMS macrolide

Reaction Scheme G:

As shown in Reaction Scheme G, the 4&quot;-hydroxy-3''-R2o macrolide 3. or alternatively the 3&quot;-hydroxy-4&quot;-R^0 inacrolide (not depicted) (wherein R^ is protected hydroxy or hydrogen) may be reacted with an alkenyl trichloroacetimidate (wherein alkenyl is C3_ļQ alkenyl) under conditions described in Reaction Scheme E to give the 0-alkenyl macrolide 10.. Treatment witli a stoichiometric amount of osmium tetroxide_in an inert organic solvent, such. as diethyl ether or tetrahydrofuran, in the presence of an amine base, such as pyridine, at or near room temperature gives the corresponding glycol H (wherein A is Cļ_3 alkyl). Treatment of glycol 1JL with sodium metaperiodate in a solution of tetrahydrofuran/water gives aldehyde 12..

Alternatively, the alkenyl macrolide 10 may be treated with sodiurn metaper iodate in the presence of a catalvtic amount of osmium tetroxide in an organic solvent to give the aldeliyde directly. Aldehyde 12 can be further oxidized to carboxylic acid U. by any number of methods cominonly used. R ea c.t ,ip.n _.S..c h enie._IIj. Λ variety of compounds inay be prepared from a.Ldehyde 12 as illustrated in Reaction Scheme H. Aldehyde .12 may be reacted with a primary or secondar;/ amine, HHR^R^ (v/herein R^ and/or R^ are as defined and contaiu(s) a heteroaryl group) in an - 125 - - 125 -LV 10450 organic solvent such as tetrahydrofuran to give an irnine which is reduced in situ with a hydride reducing aģent, such as sodium cyanoborohydride, to give macrolide 14 bearing an aminoalkoxy 5 functionality at C-4&quot;. Aldehyde 12 may also be reduced to the corresponding alcohol 15. by treatment with a hydride reducing aģent, such as potassium I: r i phenvl borohyd r ide or sodiuīn cyanoborohydr ide in an organic solvent such as tetrahydrofuran. Alcohol 10 .15. may be further modified by utilizing the methods of Reaction Scheine B (wherein R^· is as defined) or Reaction Scheme E to producē macrolide 16. The procedures described in Reaction Scheme H are readily applicable to the preparation of compounds bearing 15 analagous functionality at C-3&quot;.

REACTION SCIIEME I

Amide derivatives may be prepared from the carboxylic acid 12 as illustrated in Reaction Scheme 20 I. The carboxylic acid 12 may be coupled with a priinary or secondary ainine, HNR^R^ (wherein R^ and/or R^ are as defined and contain(s) a heteroaryl group) by any of the peptide coupling methods commonly used in the art, such as with BOP reaģent or DCC/HOBT. 25

REACTION SCHEME J A hydroxyl or fluoro group may be introduced at C-20 essentially by the procedures of Reaction Scheme J. As shown in Reaction Scheme R the 4&quot;,14-dihydroxy macrolide (or the 14-deoxymacrolide) is protected as the di(t-butyldimethylsilyl ether) by 30 126 treatment with _t-butyldimethylsilyl triflate in an inert organic solvent such as niethylene chloride, chJ.oro.form or the like in the presence of a non-nucleopliillic base such as 2,6-lutidine. The diprotected macrolide is oxidized at C-20 as further shoon in Reaction Scheme J by treatment with selenium dio&gt;d.de in an alcoholic solvent such as ethanol in the presence of pyridine at solvent reflux temperature to give the 20-hydroxy macrolide (18.).

The 20-hydroxy macrolide may be further derivatized at C-20 by a.lkylation, acylation or phosphorylation to give ether, ester or phosphate derivatives by procedures well known to the practitioner of the art. As further illustrated, treatment of the 20-liydroxy 4&quot;, 14-di-OTBS macrolide with diethylaminosulfur trifluoride in an inert organic solvent such as methylene chloride, chloroform or the like at a temperature of about 0°C to -90eC, preferably about -78°C, gives the 20-fluoro 4&quot;, 14-di-OTBS macrolide (H). Removal of the silyl ether protecting groups by treatment with hydrogen fluoride-pyridine coinplex in tetrahydrofuran gives the 20-fluoro 4&quot;,14-dihydroxy macrolide which may be further derivatized by any of the methods previously described. Reaction Scheme J may also be performed on the 3”, 4”, 14-trihydroxy macrolide to give the 20-fluoro 3&quot;, 4”, 14-trihydroxy macrolide. The procedures of Reaction Scheme J may be conducted prior to, concurrent with, or subseguent to the procedures of Reaction Schemes A-I. 30 - 127 - - 127 -LV 10450 ι·

The object compounds of Formula I obtained according to the reactions as explained above can be isolated and purified in a conventional manner, for exainple, extractionf precipitation, fractional crystallization, recrystallization, chromatography, and the like. īn the compounds of Formula I, 0R1 may be substituted at C-4&quot; or C-3&quot;, or both C-4&quot; and C-3&quot; (wherein R^ is independently selected from the definitions of R1), but it is preferred that -OR1 is substituted at C-4&quot;.

It is to be noted that in the aforeraentioned reactions and the post-treatment of the reaction mixture therein, the stereoisomer(s) of starting and object compounds due to asymraet.ric carbon atom(s) or double bond(s) of the object compounds of Formula I may occasionally be transformed into the other stereo isomer(s), and such cases are also included within the scope of the present invention.

In the present invention, compounds with asyinmetric centers may occur as racemates, as diastereomeric mixtures and as individual diastereomers, with ali isomeric forms of the compounds being included in the present invention. These may be prepared by methods such as those disclosed in publications which describe synthetic routes to fragments of the macrolide FR-900506 and the total synthesis of the macrolide FR-900506 itself (J. Am. Chem. Soc. 1989, 111f 1157; J. Am. Chem. Soc. 1990, 112, 2998; J. Org. Chem. 1990, 15, 2786; J. Am. Clie.in ,. Soc.r. 1990, 112, 5583. Tetrahedron Lett. 1988, 29., 27 7; Tetrahedron Lett. 1988, 29. 281; Tetrahedron Lett. 1988, 29., 3895; J. Org. Chem. 1988, 51, 4643; 128

Tetrahedron Lett. 1988, 2_i, 4245; Tetrahedron Lett. 1988, 21, 4481; J. Ore. Chem. 1989, 14, 9; J. Ore.

Chem. 1989, 54, 11; J. Ore. Chem. 1989, 14, 12; Ji Οι-g. Chem. 1989, 54, 15; -L. Org. Chem. 1989, 14, 17; 5 Tetrahedron Lett. 1989, 31, 919; Tetrahedron Lett. 1989, 3.0, 1037; J. Org. Chem. 1989, 14, 2785; J. Org,

Chem. 1989, 54, 4267; Tetrahedron Lett. 1989, 30, 5235; Tetrahedron Lett. 1989, 30, 6611; Tetrahedron Lett.. 1989, 31, 6963; Svnlett 1990, 38; J. Org. Chein. 10 1990, 15, 2284; Org. Chem. 1990, H, 2771; J. Org.

Chein,. 1990, 11, 2776; Tetrahedron Lett, 1990, 31, 1439; Tetrahedron Lett, 1990, 31, 1443; Tetrahedron Leti:.. 1990, 31, 3007; Tetrahedron Lett. 1990, 31, 3283, 3287). 15 The compounds of the present invention are capable of fortning salts with various inorganic and organic acids and bases and such salts are also within the scope of tliis invention. Examples of such acid addition salts (which are negative counterions 20 defined herein as H“) include acetate, adipate, benzoate, benzenesulfonate, bisulfate, butyrate, ci. trate, camphorate, camphorsulfonate, ethanesulfonate, fumarate, hemisulfate, heptanoate, liexanoate, hydrochlor ide , hydrobromide , hydroiodide, 25 inethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, oxalate, pamoate, persulfate, picrate, pivalate, propionate, succinate, tartrate, tosylate, and undecanoate. Base salts (which are positive counterions defined herein as M+) include 00 aminonium salts, alhali mētai salts such as sodium, lithium and potassiuiu salts, alkaline earth mētai salts sūdi as calcium and rnagnesium salts, salts with \ - 129 - - 129 -LV 10450 organic bases such as dicyclohexylamine salts, U-rnethyl-D-glucamine, and salts with amino acids such as arginirie, lysine and so forth. Also, the basie nitrogen-eontaining groups may be quaternized with 5 such aģents as: lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibut-y.l; diamy.l. sulfates; long chain halides such as decyl, J.auryl, iiiyri.styl and stearyl chlorides, 1U bromides and iodides; aralkyl halides like benzyl bromide and others. The non-toxic physiologically acceptable salts are preferred, although other salts are also useful, such as in isolating or purifying the produet.

The salts raay be formed by conventional means, such as by reacting the free base form of the produet with one or inore equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water 20 which is removed in vacuo or by freeze drying or by exchanging the anions of an existing salt for another anion on a suitable ion exchange resin. C· Utilitv of the compounds within the scone of 25 the invention

The compounds of Formula I may be employed as immunosuppressants or antimicrobial compounds by methods and in dosages known in the prior art for compounds of Formula II. These compounds possess pharmacological activity such as immunosuppressive activity, antiinicrobial activity, and the like, and therefore are useful for the treatment and prevention 30 5 130 5 130 10 15 υΓ tlie resistance to transplantation or transplan-tation rejection of orgāns or tissues (such as heart, hidney, liver, lung, bone marrow, cornea, pancreas, intestinum tenue, limb, muscle, nervus, medulla ossium, duodenum, small-boviel, medulla ossium, skin, pancreatic islet-cell, etc. including xeno transplantation), grāft-versus-host diseases by medulla ossium transplantation, autoimmune diseases such as rheutnaloid arthritis, systemic lupus erythematosis, uephrotic syndrome lupus, Hashimoto's thvroiditis, multiple sclerosis, myasthenia grāvis, type I diabetes mellitus, type II adult onset diabetes, uveitis, neplirotic syndrome, steroid-dependent and steroid-resistant nephrosis, Palino-planter pustulosis, allergic encephalomyelitis, glomerulonephritis, etc., and infectious diseases caused by pathogenic microorganisms. 20 25

The compounds of Formula I are also useful for treating inflammatory, proliferative and hyperproliferative skin diseases and cutaneous manifestations of iminunologically-mediated illnesses such as: psoriasis, psoriatic arthritis, atopical dermatitis, contact dermatitis and further eczematous dermatitises, seborrhoeic dermatitis, Lichen plānus, Pemphigus, bullous Pemphigoid, Epidermolysis bullosa, urticaria, angioederaas, vasculitides, erythemas, cutaneous eosinophilias, acne, Alopecia areata, eosinophilic fasciitis, and atherosclerosis. More particularly, the coinpounds of Formula I are useful in hair revitalizing, such as in the treatment of male or female pattern alopecia or alopecia senilis, by providing epilation prevention, hair germination, and/or a promotion of hair generation and hair growth. 30 - 131 - - 131 -LV 10450

The compounds of Formula I are further useful in the treatment of respiratory diseases, for example sarcoidosis, fibroid lung, idiopathic interstitial pneumonia, and reversible obstructive airways disease, including conditions such as asthma, including bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma and dust asthma, particularly chronic or inveterate asthma (for example late asthma and airway hyper-reponsiveness), bronchitis and the like. The compounds of Formula I may also be useful for treating hepatic injury associated with ischemia.

The compounds of the invention are also indicated in certain eye diseases such as keratoconjunctivitis, vernal conjunctivitis, uveitis associated with Behcet's disease, keratitis, herpetic keratitis, conical cornea, dystorphia epithelialis corneae, corneal leukoma, ocular pemphigus, Mooren’s ulcer, Scleritis, Gravēs’ ophthalmopathy, severe intraocular inflammation, and the like.

The compounds of Formula I are also useful for treating multidrug resistance of tumor celis, (i.e. enhancing the activity and/or sensitivity of chemotherapeutic aģents), preventing or treating inflammation of rnucosa or blood vessels (such as leukotriene B^-inediated diseases, gastric ulcers, vascular damage caused by ischemic diseases and thrombosis, ischemic bowel disease, inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis) necrotizing enterocolitis), or intestinal lesions associated with thermal burns, cytomegalovirus infection, particularly HCMV infec t iou. 132

Further, the coinpounds of Formula I are also useful for treating or preventing rēnai diseases including interstitial nephritis, Goodpasture's syndrome, hemolytic-uremic syndrome and diabētic 5 nephropathy; nervous diseases selected from multiple myositis, Guillain-Barre syndrome, Meniere's disease and radiculopathy; endocrine diseases including Uyperthyroidism and Basedow's disease; hematic diseases including pure red celi aplasia, aplastic 1° anemia, hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis and anerythroplasia; bone diseases including osteoporosis; respiratory diseases including sarcoidosis, fibroid lung and idiopathic 15 interstitial pneumonia; skin diseases including dermatomyositis, leukoderma vulgaris, ichthyosis vnlgaris, photoallergic sensitivity and cutaneous T celi lymphoma; circulatory diseases including arteriosclerosis, aortitis syndrome, polyarteritis 20 nodosa and myocardosis; collagen including scleroderina, V/egener's granuloma and Sjogren's syndrome; adiposis; eosinophilic fasciitis; periodontal disease; nephrotic syndrome; hemolytic-uremic syndrome; and rauscular dystrophy. 25 Further, the compounds of the invention are indicated in the treatment of diseases including intestina.l inflainmations/allergies such as Coeliac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease and ulcerative colitis; 30 aud food related allergic diseases which have i' y m ļ»I. orn-a l: j c mani f es ta t ion remote from the gastro-intestinal tract, for example migraine, rhinitis and eczema. - 133 - - 133 - LV 10450

The compounds of the invention also have liver regenerating activity and/or activity in stimulating hypertrophy and hyperplasia of hepatocytes. Therefore, they are useful for the 5 treatment and prevention of hepatic diseases such as iminunogenic diseases (e.g. chronic autoimmune liver diseases including autoimmune hepatitis, primary biliary cirrhosis and sclerosing cholangitis), partial liver resection, acute liver necrosis &lt;e.g. 10 necrosis caused by toxins, virai hepatitis, shock or anoxia), B-virus hepatitis, non-A/non-B hepatitis and cirrhosis·

The compounds of the invention are also indicated for use as antimicrobial aģents, and thus 15 may be used in the treatment of diseases caused by I· pathogenic microorganisms and the like.

The compounds of Formula I may also act as antagonists of macrocyclic immunosuppressive compounds, including derivatives of 20 12-(2'-cyclohexyl-l'-methylvinyl)-13,19,21,27-tetra- inethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^»^ļoctacos-18-ene, and so be useful in the treatment of iininunodepression (such as AIDS, cancer, senile dementia, trauma (including wound healing, surgery 25 and shock), chronic bacterial infection and certain Central nervous system disorders), overdosages or toxicity of such immunosuppressive compounds, and as an adjunct to the administration of an antigen in vaccination.

The pharmaceutical compositions of this invention can be used in the form of a pharmaceutical preparation, for example, in solid, seraisolid or liquid form, which contains one or more of the compounds of the present invention, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral applications. The active ingredient may be compounded, for example, with the usual non-t.oxic, pharinaceutically acceptable carriers for tablets, pellets, capsules, suppositories, Solutions, emulsions, suspensions, and any other forra suitable for use. The carriers which can be used are water, glucose, lactose, gum acacia, gelatin, mannitol, starch paste, inagnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch,. uvea and other carriers suitable for use in manu-facturing preparations, in solid, semisolid', or liquid form, and in addition auxiliary, stabilizing, thickening and coloring aģents and perfumes may be used. For example, the compounds of Formula I may be utilized with hydroxypropyl methylcellulose essentially as described in U.S Patent No. 4.916.138. issued April 10, 1990, or with a s.urfactant essentially as described in EPO Publication 0.428.169. Oral dosage forms may be prepared essentially as described by T. Hondo, et al., Transplantation Proceedings. 1987, XIX. Supp. 6, 17-22. Dosage forms for external applic.ation may be prepared essentially as described in EPO Publication 0.423.714. The active object compound is included in the pharmaceutical composition in an amount sufficient to producē the desired effect upon the process or condition of diseases.

For the treatrnent of these conditions and diseases caused by iimmnunoirregularity a compound of Formula I may be administered orally, topically, - 135 - - 135 - LV 10450 pareuterally, by inhalation spray Or rectally in dosage unit formulations containing conventional non-Loxic pharinaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.

For the treatment of reversible obstructive airways disease, it is preferable that the compound of Formula I be administered by inhalation to the lung, especially in the form of a powder.

For modifying the activity and/or toxicity of FK-506-type immunosuppressants, a compound of Formula I tuay be administered prior to, in conjuction witli or subsequent to the administration of an FK-506-type of a compound.

The compounds of Formula I may optionally be einployed in co-therapy with anti-proliferative aģents. Particularly preferred is co-therapy with an antiproliferative aģent selected from the group consisting of: azathioprine, brequinar sodium, deoxyspergualin, mizaribine, mycophenolic acid morpholino ester, cyclosporin, and rapamycin.

Dosage Ievels of the compounds of the present invention are of the order from about 0.005 mg to about 50 mg per kilogram of body veight per day, preferably from about 0.1 mg to about 10 mg per kilogram of body weight per day, are useful in the treatment of the above-indicated conditions (from about 0.7 mg to about 3.5 mg per patient per day, assuming a 70 kg patient). In addition, the compounds of the present invention may be administered on an intermittent basis; i.e. at daily, semiweekly, weekly, semi-monthly or monthly intervāls.

The amount of active ingredient that may be combined with the carrier materiāls to producē a single dosage form will vary depending upon the host treated and the particular mode of administration.

For example, a formulation intended for the oral administration of humāns may contain from 0.5 mg to 5 gm of active aģent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total compo-sition. Dosage unit forms will generally comprise from about 0.01 mg to about 500 mg, and preferably about 0.5 mg to about 100 mg of active ingredient.

For external administration the compound of Formula I may be formulated within the range of, for example, 0.00017o to 60% by weight, preferably from 0.001 to 107o by weight, and most preferably from about 0.005 to 0.8% by weight.

It will be understood, however, that the specific dose Ievel for any particular patient will depend on a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rāte of excretion, drug combination and the severity of the particular disease undergoing therapy.

The following examples are given for the purpose of illustrating the present invention and shall not be construed as being limitations on the r:f·f&gt;ļ»r* or r:p i r M of l.lio i nstant invention. - 137 - - 137 - LV 10450 P R E ΡΛ RATipH__QF_S_TARTJil(L_IŅTEEH.EDĪAX£S. 17-Ethyl-l-hydroxy-12-[2'-(4&quot;-hydroxy-3&quot;-methoxycyclo-hexyl)-l'-raethylvinylj-23,25-dimethoxy-13,19,21,27-tet ramethyl-ll, 28-dioxa-4-azatricyclo-[22.3.1.0^»^]- octacos-18-ene-2.3.10.16-tet raone_ A solution of 500 mg of 17-ethyl-l,14-di-hyd r oxy-12-[2'-(4' ’-hyd roxy-3' '-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0^*^]octacos-18-ene-2,3,10,16-tetraone in 7 ml of benzene was treated with 10 mg of p-toluenesulfonic acid and the solution was heated at 60°C for two hours. The reaction mixture was quenclied into saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layers were washed with water and saturated sodium chloride solution, dried with anhydrous magnesium sulfate and concentrated. The residue was chromatographed on si.lica gel (667o ethyl acetate: 33% hexane: 1% methanol) to give 350 mg of product. This material was dissolved in 10 ml of ethyl acetate and treated with 15 ing of 57» Rh/C. A balloon containing hydrogen was placed over the reaction mixture and the mixture stirred until the reaction was complete. The mixture was filtered through diatomaceous earth, concentrated and the residue subjected to chromatography (75% CM^Clz'· 5% MeOH: 20% Hexane) to give 294 mg of product. 138 17-ELhyl-l-hydroxy-12-[2'-(4&quot;,3&quot;-dihydroxyoxycyclo-hexy1)-l1-methylviny1]-23,25-d imethoxy-13,19,21,27-tetramethyl-ll, 28-d ioxa-4-azatricyclo- Γ22.3.1.0^ » 9 1octacos-18-ene-2.3.10.16-tetraone_ 5 A solution ‘of 17-ethyl-l,14-dihydroxy-12-[2'- (4&quot;-hydroxy-3&quot;-hydroxycyclohexyl)-l' -inethylvinyl]-23,25-dimethoxy-13,19,21, 27-tetraznethyl-ll,28-dioxa-4~azatricyclo-[22.3.1.0^ &gt; 9]octacos-18-ene-2,3,10,16-tetraone (210 mg) and a catalytic amount of 10 p-Loluenesulfonic acid in 40 ml of benzene was refluxed for 4 hours under a nitrogen atmosphere.

The solvent was removed under reduced pressure and the dark residue was purified by chromatography (silica gel, 77. i-propanol/CE^C^) to give 15 17-ethyl-l~hydroxy-12-[2'-(4&quot;-hydroxy-3&quot;-isopropyloxy-cycloliexyl )-l1 -methylvinyl]-23,25-dimethoxy-13,19,21,-27-tetramethyl-ll,28-dioxa-4-azatricyclo-[22.3.1.0^&gt; 9]octacos-14,18-diene-2,3,10,16-tetraone (180 mg) as a white solid. This material was 20 dissolved in ethanol (20 ml) and treated with 5% Rh/C (40 mg). Hydrogen was introduced via balloon for 30 min. and the mixture was filtered through celite. Removal of solvent followed by chromatography (silica gel) gavē 172 mg of the title compound. Mass, and 25 13ς· &lt;jata were consistant with the title structure. 17-Ethyl-l-hydroxy-12-[2'-(4&quot;-triisopropylsilyloxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]-14-triisopropyl-s ilyloxy-23,25-dimethoxy-13,19,21,27-tetramethyl-ll 3 0 28-d ioxa-4-aza tricyclo-[22.3.1.0^»9]octacos-18-ene- 2., 3.,.10.,.16,- t_e.tr.aone__________

To a cooled solution (0°C) of 17-ethyl-l,14-dihydroxy-12-[2'—(4’'-hydroxy-3''-methoxycyclohexyl)- - 139 - - 139 -LV 10450 1'-methjlvii^l]·^,25-dimethoxy-13,19,21,27-tetra-inel:hyl-J.l, 28-dioxa-4-azatricyclo[22.3.1.0^»^]-octacos-18-ene-2,3,10,16-tetraone (120 mg) in dry methylene chloride (15 ml) was added 2,6-lutidine (64.3 mg) followed by triisopropylsilyl trifluoro-methanesulfonate (184 mg). Reaction temperature was raised to r.t. and stirred overnight under nitrogen atmosphere. The reaction was quenched with 10 ml of water and extracted witli ethyl acetate. Organic layer was washed (v?ater, sat'd NaHC03, sat'd NaCl) and dried (anhydrous HgSO^.). Removal Of solvent followed by chromatography on silica gel (707. hexane/ethyl acetate) gavē 150 mg of product. MASS: (FAB) 1110 (M+ + Li). 17-Ethyl-l-hydroxy-12-[2'-(4&quot;-hydroxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]-14-triisopropyl-silyloxy-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,-28-dioxa-4-azatricyclo[22.3.1.0^» ^j-octacos-18-ene- 2.3.10.16-tetraone_

The title compound from the previous preparation (680 mg) was dissolved in methylene chloride (45 ml) and 10% solution of p-toluene-sulfonic acid in methanol (45 ml) was added with stirring. The inixture was stirred at room temperature and the progress was followed by tic analysis. After 4 hr, reaction was quenched with sat'd sodiurn bicarbonate and extracted with ethyl acetate tliree times. Normai work-up and removal of solvent followed by purification on silica gel coluran (807o etliyl acetate/liexane) gavē 560 mg of the product (2a) as a white solid. MASS: (FAB) 954 (M+ + Li). 140 17-Ethyl-l-hydroxy-12-[2'-(4&quot;-t-butyl-d imethyls ilyloxy-3”-methoxycyclohexyl)-l'-methyl-vinyl]-14-t-butyldimethylsilyloxy-23,25-dimethoxy-13,19,21,27-tetrainethyl-ll, 28-dioxa-4-azatri-cyclo- 5 Γ22.3.1.04191octacos-18-ene-2.3.10.16-tetraone__

To a cooled solution (0*C) of 17-ethyl-1,14-dihydroxy-12-[2'-(4''-hydroxy-3'1-methoxycyclo-hexyl)-l' -metlxylvinyl]-23,25-dimethoxy-13,19,21,27-tetra-inethyl-ll, 28-dioxa-4-azatricyclo[22.3.1.0^»^]-10 octacos-18-ene-2,3,10,16-tetraone (la) (395 mg) in dry methylene chloride (15 ml) was added 2,6-lutidine (160 ing) followed by t-butyldimethylsilyl triflouromethanesulfonate (250 mg). Reaction temperature was raised to r.t. and stirred under 15 nitrogen atmospliere. After 6 hr, the reaction was quenched with 10 ml of water and extracted with ethyl acetate. Organic layer was vrashed (water, saturated NaIIC03, saturated NaCl) and dried (anhydrous MgSC^). Removal of solvent under reduced pressure gavē 500 mg 20 0f crude product. MASS: (FAB) 1023 (M+ + Li). 17-Ethyl-l-hydroxy-12-[2'-(4&quot;-hydroxy-3&quot;-inethoxycyclohexyl )-l' -methylvinyl]-14-t-butyl-dimethylsilyloxy-23,25-dimethoxy-13,19,21,27-tetra-25 methyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^»^]- octacos-18-ene-2.3.10.16-tetraone_

The product froin the previous example (500 mg) v;as dissolved in acetonitrile (20 ml) and 100 ml of liydrogen fluoride (487.) was added. Reaction was 30 sLirred for 20 minūtes at room temperature, quenched with saturated sodium bicarbonate, then extracted with ethyl acetate. Reinoval of solvent in vacuo followed by chromatography on silica gel (807. ethyl - 141 - LV 10450 acetate/ hexane) gavē 300 mg of product (Mass, '•H and -^c NMR data consistent with the title compound. 17-Eth}'l-l-hydroxy-12-[2'-(4&quot;-(tert-butyldimethylsil-oxy)-3&quot;-hydroxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetraraethyl-ll,28-dioxa-4-aza-tricvclor22.3.1.0^»9~loctacos-18-ene-2.3. 10.16-tetraon.e.

To a solution of 17-ethyl-l-hydroxy-12-[2'-(3&quot; , 4&quot;-dihydroxycycloliexyl)-l1 -rnethylvinyl]-23,25-diinethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-aza-tricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetra-one (3.01 g) in dry methylene chloride (70 ml) was added an excess of imidasole (809 mg) followed by tert-butyldimethylsilyl chloride (716 mg). After 3 days of stirring at room temperature, tRē mixture was diluted with ethyl acetate which in turn was washed with IN HC1, saturated sodium bicarbonate and brine, dried over magnesium sulfate and purified by flash chromatography (ethyl acetae:hexane (1:3)) to give the title compound (941 mg). NMR consistent with the desired structure. 17-Ethyl-l-hydroxy-12-[2’-(4&quot;-(tert-butyldimethyl-s ilyloxy)-3&quot;-methoxycyclohexyl)-l1 -methylvinyl]-23,25-d imethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^·9)octacos-18-ene-2,3,10,16- .t e_t r_a ο n e_________

To a solution of 17-ethyl-l-hydroxy-12-[2'-(4”-hydroxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]-23,2 5-d imethoxy-13,19,21,-27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^9]octacos-18-ene-2,3,10,16-tetraone (200 mg) in dry methylene chloride (3 ml) was added an excess of 2,6-lutidine (45 μΐ) and the 142 mixture was stirred at room temperature. After 10 minūtes, tert-butyldimethylsilyl trifluoromethane-sulfonate (64 μΐ) was added by syringe. After 15 minūtes the reaction mixture was diluted with ethyl acetate, extracted from saturated bicarbonate, washed witli brine and the organic phase dried over magnesium sulfate. Removal of solvent in vacuo and flash chromatography on silica gel (ethyl acetate: hexane (1:2) + 17. methanol) gavē the title compound (235 mg ) . (½ IlMR consistent with the desired structure). 17-Ethyl-1,20-diliydroxy-12-[2 '-(4M-tert-butyldimethyl- i. s j.lyloxy )-3&quot;-methoxycyclohexyl)-4&quot;l' -methylvinyl]-23,2 5-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-aza-tricvcloFZZ.3.1.0^» ^1octacos-18-ene-2.3. 10.16-tetraone To a stirred solution of 17-ethyl-l-hydroxy-12-[2'-(4&quot;-(tert-butyldimethylsilyloxy)-3&quot;-methoxy-cyclohexyl )-l' -inethylvinyl]-23,25-dimethoxy-13,19,21, 27-tet ramethyl-ll,28-dioxa-4-azatricyclo[22. 3.1.0^ &gt; ^] octacos~18-ene-2,3,10,16-tetraone (235 mg) in 957. ethanol (2.2 ml) was added 53 μΐ of pyridine followed by seJ.enium dioxide (58 mg). The flask was fitted with a water condenser and heated to 70°C on a mantle. After 20 hours the mixture was cooled to toom temperature filtered through diatomaceous earth and the filtrate poured into a saturated sodium bicarbonate solution. This was extracted with ethyl acetate, v;ashed with brine and dried over magnesium sulfate. The solution was concentrated and purified by flasli c!iromatography on silica gel (ethyl acetate: hexane (1:2) + 17. methanol) to give the title compound (89 mg). (hī NHR consistent with the desired structure). - 143 - - 143 - LV 10450 17-Elhyl-20-fluoro-l-hydroxy-12-[2'-(4&quot;-(tert-butyl-dimethylsiloxy)-3&quot;-methoxycyclohexyl)-l1 -methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azaLricyclo[22.3.1.0^*^]octacos-18-ene-2,3,10.16- 5 t e l.rapji e___________________________;___ Λ solution of 17-ethyl-20-dihydroxy-12-[2 (4&quot;-( tert-butyldiinethylsiloxy)-3&quot;-methoxycyclohexyl )-i.' inotljy.Lvinyl J-23,25-dimēthoxy-13,19,21,27-tetra-iiiol hy.l -J1,28-dioxa-4-asatricyclo[22.3.1.0^* ^joctacos-10 18-ene-2,3,10.16-tetraone (30.5 mg) in methylene chloride (0.5 ml) was cooled to -78eC in a dry ice/isopropanol bath. To this stirred solution, diethylaminosulfur trifluoride (4.5 μΐ) was added.

After 3 minūtes, saturated sodium bicarbonate (500 15 μΐ) was added followed by ethyl acetate (2 ml) and tlie mixture was warmed to room temperature.

Extraction froin ethyl acetate, drying over magnesium sulfate and purification by flash chromatography on silica gel (ethyl acetate: hexane (1:2) + 17« MeoH) 20 gavē the title compound (22 mg). (½ NMR consistent with the desired structure). 30 144 17-Ethyl-1,20-dihydroxy-12-[2'-(4M-(hydroxy-3M-me thoxycyclohexyl)-l' -iuethylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo- Γ 22.3 1 l/1 ’ 9~loctacos-18-ene-2.3.10.16-tetraone___

To a solution of 17-ethyl-l,20-dihydroxy-12-[2'-(4&quot;-(tert-butyldimethylsiloxy)-3&quot;-methoxy-cycloliexyl)-l1 -methylvinyl]23,25-dimethoxy-13,19,21,-27-tetramethyl-ll,28-dioxa-4-asatricyclo[22.3.1.0^’^]-octacos-l8-ene-2,3 , .1.0.16-tetraone (7 mg) in acetonitrile (0.3 ml) was added a solution of 27. hydrogen fluoride in aqueous acetonitrile (100 μΐ), and the mixture stirred at room temperature. After 28 hours the solution was diluted with ethyl acetate, extracted with saturated sodium bicarbonate and the organic phase dried by passage through a magnesium sulfate column. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate: hexane (2:1) + 17» methanol) gavē the title compound. - 145 - LV 10450 17-Ethyl-20-fluoro-l-hydroxy-12-[2'-(4&quot;-(hydroxy-3&quot;-methoxycyclohexyl)-l '-methylvinyl]-23,25-dimethoxy- 13.19.21.27- tetramethyl-ll,28-dioxa-4-azatricyclo- I2..2.J.3.1.0^’ 9ļoctacos-18-ene-2.3.10.16-tetraone_ 5 To a solution of 17-ethyl-20-fluoro-1- hydroxy-12-[2'-(4&quot;-(tert-butyldimethylsiloxy)-3M-methoxycyclohexyl)-l'-methylvinyl]23,25-dimethoxy- 13.19.21.27- tetramethyl-ll,28-dioxa-4-azatricyclo-[22.3.1. (/* * ^]octaeos-18-ene-2,3,10.1.6-tetraone (7 ing) i0 in acetonitrile (0.3 ml) was added a solution of 2% hydrogen fluoride in aqueous acetonitrile (100 μΐ), and the mixture stirred at room temperature. After 2 hours the solution was diluted with ethyl acetate, extracted with saturated sodium bicarbonate and the 15 organic phase dried by passage through a magnesium sulfate column. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate: hexane (1:1) + 1% methanol) gavē the title compound. 11ASS: (FAB) 816 (M+Na) . 20 partial 13C NMR δ: 211.5 (C-16); 196.1 (2) 169.3 (10); 165.0 (3); 138.1 (C-19); 135.8 (C-l'); 121.0 (C-18' major); 84.1 (C-3&quot;); 43’.'l (C-15); 26.0 (C-21). 30 146 17-Ethyl-1,14,20-trihydroxy-12-[2'-(4M-hydroxy-3”-methoxycyclohexyl)-l·-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo- [22.3.1.0^ &gt; 9]octacos-18-ene-2,3,10,16-tetraone ALTERHATE ROUTE__

To a solution of 17-ethyl-l,14-dihydroxy-12-[2 ' -(4&quot;-hydroxy-3&quot;-metlioxycyclohexyl)-l '-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0**’^]octacos-18-ene-2,3,10,16-tetraone (5.15 gm, 0.065mol) in glacial acetic acid (500 ml) at room temperature, was added a solution of selenium dioxide (9.27 gm, 0.083 mol) in E^O (90 ml). The reaction mixture was stirred at room temperature for 41 liours vhereupon, it was poured into a stirred mixture of H2O (3 L) and celite.

After stirring for 15 minūtes, the mixture was filtered through a pad of celite and extracted with diethyl ether (lx2L, 2X1L). The organic fractions were washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate, filtrated and evaporated iņ y,acuo. The product was purified by chromatography (silica, acetone:hexanes 2:5) to give the title compound MASS and NMR were consistent with the structure. 30 LV 10450 - 147 -EXA11PLE 1 .1 7-ELhyJ.-l, 14-diliydroxy-12-[2 '-(4&quot;-(2-furanyl)methoxy-3&quot;-methoxycyclohexyl )-l' -inethylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo- 1..?· 2_._3.JL_j/1,»^loctacos-18-ene-2.3.10.16-tetraone_

To a solution of 17-ethyl-l,14-dihydroxy-12-1.2 ' (4&quot; hydroxy-3&quot;-methoxycyclohexyl)-l '-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetrametliyl-ll, 28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone (63 mg in 1.0 ml methylene chloride) furfuryl trichloroacetimidate (39μ1 neat) was added and the reaģents allowed to mix for 5 minūtes. Camphorsulforiic acid (3.7ing) was added and the mixture stirred at room temperature. After 4.5 hours the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3x5 ml). The corabined organics were washed with brine and dried over raagnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate : hexane (1:2) + 17. methanol) gavē the title compound (20 mg). I1AS: (FAB) 878 (M+Li). Partial *11 NMR δ: 7.38(brs, 1H); 6.30(m, 3H); 5.32M, 5.19m(brd J = 3Hz, 1H); 4.83m, 4.21M(brs, 1H); 4.62(dd J = 15Hz, 211); 4.41(brd J = 14Hz, 1H) . -148- ΕΧ Ali PLEŠ 2 and 3 17-Ethyl-1,14-dihydroxy-12-C2'-(4&quot;-(2-furanyl)methoxy-3&quot;-h3'·dι·oxycyclohexyl )-l1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo-[22.3.1.0^1^]octacos-18-ene-2,3,10,16-tetraone and 17-Etliyl-1,14-dihydroxy-12-[2 ' -(4&quot;-hydroxy-3&quot;-(2-furanyl)methoxycyclohexyl)-l'-methylvinyl]-23,25-d iinethoxy—13,19,21,27-tetramethyl-ll, 28-dioxa-4-aza-tricvclor22.3.1.0/-t* ^1octacos-18-ene-2.3.10.16-tetraone To a solution of 17-ethyl-l,14-dihydroxy-12-[2'-(3”,4&quot;-dihydroxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-aza-tricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone (52 mg in 0.9 ml methylene chloride) furfuryl ~ trichloroacetimidate (20 μΐ neat) was added and the reaģents allowed to mix for 5 minūtes.

Cainphorsulfonic acid (2mg) was added and the mixture stirred at room temperature. After 3.5 hours the reaction v;as tļuenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3 x 5 inl). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate:hexane (1:1) + 17« methanol) gavē the title compounds (16 mg 4&quot; ether; 13 mg 3&quot; ether). 4&quot; ether: I1ASS: (FAB) 864 (H+Li); Partial ^ NMR o: 7 . 41(brs, 1H); 6.30(m, 2H); 5.32M, 5.19m(brd J = 3Ilz, III); 4.87m, 4.19M(brs, 1H); 4.41(brd J = 14Hz, III). -149- LV 10450

3&quot; ether: MASS: (FAB) 864 (M+Li); Partial 1H ΠΜΚ 6: 7.44(brs, 1H); 6.37(m, 2H); 5.32M, 5.19m(brd J = 3Hz, 1H); 4.88m, 4.27M(brs, 1H); 4.41(brd J = 14Hz, 1Η). 5 EXAMPLE 4 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(2-thiophene)-iiiethoxy-3&quot;-methoxycyclohexyl)-l' -methylvinyl]-23,25-10 dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-aza-tricyclo[22.3.1.0^*^]octacos-18-ene-2,3,10,16- tetraone__

The title coinpound was prepared essentially as described in Example 1 using 2-thiophenylmethyl 15 trichloroacetimidate as the alkylating aģent.

Partial NMR δ: 7.27(m, 1H); 6.96(m, 2H); 5.31M, 5.18m(brd J = 3Hz, 1H); 4.81m, 4.22M(brs, 1H); 4.4l(brd J = 14Hz, 1H); 3.07(d J = 4Hz, 1H). 20 EXAMPLES 5 and 6 17-EUiyl-l,14-dihydroxy-12-[2'-(4&quot;-(2-thiophene&gt;-tnethoxy-3&quot;-hydroxycyclohexyl)-l'-methylvinyl]-23,25-dimetlioxy-13,19,21,27-tetramethyl-ll, 28-dioxa-4-aza-25 tr icyclo[22.3.1.0^♦^]octacos-18-ene-2,3,10,16-tetraone and J.7-Ethyl-1,14-dihydroxy-12-[2,-(4&quot;-hydroxy-3M-(2-thiophetie)methoxycyclohexyl )-l' -methylvinyl]-23,25-d iinethoxy-13,19,21,27-tetramethyl-ll, 28-dioxa-4-aza-t r icvclof 22.3.1.0^’ 9loctaeos-18-ene-2.3.10.16-tetraone 39 The title compounds were prepared essentially as described in Exainples 2 and 3 using 2~thiopheny.Lmethyl trichloroacetimidate as the a I hv I ai. i ng aģent. -150- 4&quot; ether: MASS: (FAB) 896 (M+Na); Partial ^ HHR δ: 7.29(111, III); 6.97(m, 2H); 5.31M, 5.19tn(brd J = 3Hz, III); 4.41 (brd J = 14Hz, 1H); 3.04(d J = 411”., 1H); 2.63M, 2,61m(s, 1H); 5 3&quot; ether: MASS: (FAB) 880 (M+Li); Partial 1H NMR δ: 7.28 (m, III); 6.97 (m, 2H); 5.31 M, 5.19 m (brd J = 3Hz, III); 4.41 (brd J = 14 Hz, 1H); 3.08 (d J = 3

Uz, 111); 2.69 (sf III). 10 EXAMPLES 7 and 8 17-Ethyl-1,14—dihydroxy-12-[2'-(4&quot;-(3-thiophene)-inethoxy-3&quot;-hydroxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-aza-tricyclo[22.3.1.0^»^]octacos-18-ene-2,3,10,16-tetraone and 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-hydroxy-3M-(3-thiophene)me thoxycyclohexyl)-l’-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^·^]octacos- ene-2,3.10,16-tetraone_

The title coinpounds were prepared essentially as described in Examples 2 and 3 using 3-thiophenyl-niethyj. trichloroacetimidate as the alkylating aģent. 4&quot; ether: MASS: (FAB) 880 (M+Li); Partial lE NMR δ: 7·30 (in, III); 7.04 (ιη, 211); 5.31 M, 5.19 m (brd J = 3Hz, III); 4.89 m, 4.19 H (s, 1H); 4.41 (brd J = 14 Hz, III); 3.04 (d J = 4Hz, 1H); 3” ether: MASS: (FAB) 880 (M+Li); Partial ^ NMR δ: 7 -28 (ιη, 711) ; 7.05 &lt;dd, J = 5, 2 Hz, 1H) ; 5.31 M, 3- 19 m (brd J = 3 Hz, 1H); 4.83 m, 4.25 M (brs, 1H); 4- 41. (brd J = 14 Hz, III); 3.06 (d J = 3 Hz, 1H); 2.69 (s, lii). 30 LV 10450 -151-EXAMPLE 9 17-EtliyJ.-l, 14-diliydroxy-12-[2 ' -(4&quot;-(benzothien-2-yl)-oxy-3&quot;-methoxycyclohexyl)-l' -methylvinyl]-23,25-di-meUioxy~13,19,21, 27-tetramethyl-ll, 28-dioxa-4-azatri-cvclof22.3.1.0,y i^'loct.acos-lS-ene-Z .3.10.16-tetraone To a stirred solution of tri(benzothien-2-yl)bismutlxine (lOOuig., 0.164mmol.) in CH2C12 (2 mL. ) was added peracetic acid ( 0.050mL., 0.224 mmol., 327, in acetic acid) followed in 10 minūtes by 17-ethyl-l, 1Λ-d ihydroxy-12-[2 ' ~(/i&quot;-hydroxy-3&quot;-methoxycyclo-hexyl) -1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetrameth yl-ll,28-dioxa-4-azatricyclo[22.3.1.0^'^]octacos-18-en e-2,3,10,16-tetraone (lOOrng., 0.126 mmol.) and Cu(0Ac)2 (15ing., 0.083 mmol.). The reaction mixture was stirred for 16 hours at room temperature. The reaction was then guenched with saturated agueous NaHC03 and the mixture extracted 3X with CH2C12. The extracts were combined, dried with Na2SC&gt;4, filtered, and concentrated in vacuo. The product was isolated and purified by preparative TLC 3X on silica gel (3:1, hexane/acetone) to give 23 mg of 17-ethyl-l,14-dihydroxy-12-[2·-(4&quot;-(benzothien-2-yl)oxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-aza-tricyclo[22.3.1.0^*9]octacos-18-ene-2,3,10,16-tetraone . -152- EXAMPLE 10 · 17-Ethyl-1,14-dihydroxy-12-[2'-(4”-(thien-2-yl)oxy-3”-methoxycyclohexyl)-l’-methylvinyl]-23,25-dimethoxy-J 13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo-£.22.3.1. Q/f ’ ^1octacos-18-ene-2.3.10.16-tetraone To a stirred solution of tri(thien-2-yl)bis-imiLliine (80mg.f 0.375 mmol. ) in CH2CI2 (2 mL. ) was added peracetic acid (0.060 raL., 0.253 mmol., 32% in acetic acid) followed in 15 minūtes by 17-ethyl-1,14-dihydroxy-12-[21-(4&quot;-hydroxy-3&quot;-methoxycyclo-hexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^»^]-octacos-18-ene-2,3,10,16-tetraone (100 mg., 0.126 15 minol.) and Cu(0Ac)2 (10 mg. , 0.055 mmol.). The reaction mixture was allowed to stir at r00m temperature for 3 days. The reaction was quenched with saturated aqueous NaHC03, and the mixture extracted with CH2CI2· The extracts were combined, 2° dried with I^SO^, filtered and concentrated in vacuo. The product was isolated and purified by preparative TLC 2X on silica gel (2:1, hexane/acetone) to give 36 mg of 17-ethyl-l,14-diliydroxy-12-[2'-(4&quot;-(thien-2-yl)oxy-3&quot;-methoxycyclo-25 hexyl )-l' -inethylvinyl]-23,25-dimethoxy-13,19,21,27- tetramethyl-ll,28-dioxa-4-asatricyclo[22. 3.1.04 &gt;9]-octacos-18-ene-2,3,10,16-tetraone. 30 -153- LV 10450 EXAMPLE 11 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-5-indolylamino-carbonylmethoxy-3&quot;-methoxycyclohexyl)-1·-methylvinyl]-5 23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4- azatr icyclo[22.3.1.0^» ^]octacos-18-ene-2,3,10,16-tetraone_ STEP 11Λ 10 17-Ethyl-l-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4&quot;-(tert-butyldimethylsiloxy)-3&quot;-methoxycyclo-hexyl)-l' -metliylvinyl]-23,25-dimethoxy-13,19,21,27-tetrainethyl-ll, 28-dioxa-4-azatricyclo[22.3.1.0^»^]- 15 octacos-18-ene-2.3.10.16-tetraone_

To a solution of 17-ethyl-l,14-dihydroxy-12-[2'-(4&quot;-hyd roxy-3 M-methoxycyclohexyl)-l'-methyl-vinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,-?·0 16-tetraone (2.0 g) in dry methylene chloride (25 ml) was added an excess of 2,6-lutidine (1.2 ml) and the mixture was stirred at room temperature. After 10 minūtes, tert-butyldimethylsilyl trifluorometlianesulfonate (1.8 ml) was added via syringe. After 1 hour the reaction mixture was diluted with ethyl acetate, washed with 1N HC1, water, saturated sodium bicarbonate and brine. The organic phase was dried over inagnesium sulfate.

Removal of the solvent in vacuo and flash 30 chromatography on silica gel (ethyl acetate: hexane (J:6) + 17. inethaiiol) gavē the title compound (2.37 g). *11 MMR consistent with the desired structure. -154-

.sTEP__niJ 17-Ethyl-l-hydroxy-14-(tert-butyldiraethylsiloxy)-12-[2'-(4&quot;-hydroxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]~ 23,25-dimethoxy-13,19,21,27-tetramethyl-ll, 28-dioxa-4-azatricyclo[22.3.1.0^* ^]octacos-18-ene-2,3,10,16- tetraone_

To a solution of 17-ethyl-l-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4&quot;-(tert-butyldimethyl-s iloxy)-3&quot;-methoxycyclohexyl)-l'-methylvinyl]-23,25-diinethoxy-13,19,21,27-tetramethyl-ll, 28-dioxa-4-aza-tr icyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone (2.37 g) (STEP 11A) in dry methylene chloride (25 ml) was added a solution of 10% p-toluenesulfonic acid in methanol (25 ml), and the mixture was stirred at room temperature. After 10 minūtes, the mixture was cooled to 0°C and quenched with saturated sodium bicarbonate. The mixture was diluted with ethyl acetate and the layers were separated. The organic layer was washed with saturated sodium bicarbonate and brine and dried over magnesium sulfate. Furification of the concentrate by flash cliromatography on silica gel (ethyl acetate: hexane (1:2) ·»· 17« methanol) gavē the title compound (2.1 g). *-Π MMR consistent with the desired structure.

STEP 11C 17-Ethyl-l-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4&quot;-allyloxy-3&quot;-methoxycyclohexyl)-l1-methyl-v j. nyl'1-23,25-d iinethoxy-13,19,21,27-tetramethyl-ll, 28-dioxa-4-azatr icyclo[22.3.1.0/4'^]octacos-18-ene-2,3,-10 16.-1_et_ra.one_________ -155- LV 10450

To a solution of 17-ethyl-l-hydroxy-14r(tert-bu l..y Īd i methyls iloxy ) -12 -[2 ' -(4&quot;-hydroxy-3&quot;-methoxy-cyclohexyl)-l' -metliylvinyl]-23,25-dimethoxy-13,19,21,-27-tetramethyl-ll, 28-dioxa-4-asatricyclo[22.3.1.04,9]-octacos-18-ene-2,3,10,16-tetraone (2.1 g) (STEP 11B) in 24 ml 337o methylene chloride in cyclohexane, was added allyl trichloroacetimidate (938 mg neat) and the reaction mixture was āllowed to mix for 5 minūtes. Trifluoroinethanesulfonic acid (41 μΐ neat) v;as added slowly via syringe and the mixture stirred at rooin temperature. After 24 hours, the reaction inixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate, water and brine.

The organic layer was dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate: hexane (1:5)) + 1Ί, methanol) gavē the title compound (1.03 g). NHR consistent with the desired structure. 20

STEP IIP 17- Ethyl-l-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4&quot;-(2,3-dioxy-l-propoxy)-3&quot;-methoxycyclohexyl)-1' -methylvinyl]-23 ,'25-dimethoxy-13,19,21,27-tetra- 25 methyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^»^]octacos- 18- ene-2.3.10.16-tetraone_

To a solution of 17-ethyl-l-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4&quot;-allyloxy-3&quot;-methoxy-cyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,-30 27-tetrainethyl-ll, 28-dioxa-4-azatricyclo[22.3.1.04,9]-octacos-18-ene-2,3,10,16-tetraone (STEP 11C) (1.03 g) in 22 ml tetrahydrofuran was added N-methylmorpholine -156- [i-oxide (883 mg) followed by 0.25M osraium tetraoxide solution in TIIF (871 μΐ), and the raixture was stirred at rooin temperature. After 3 hours, the reaction was guenched by the addition of 207» sodium bisulfite (20 ml), and the precipitate was filtered through Celite and rinsed with ethyl acetate. The corabined filtrate was v/ashed witli 207* sodium bisulfite (2x), saturated sodium bicarbonate and brine and dried over magnesium sulfate. The concentrale was purified by flasli chromatography on silica gel (ethyl acetate:hexane (2:1) i- 17, methanol) to give the title compound (705 ing). 1H N1-1R consistent with the desired structure.

STEP 11E 17-Ethyl-l-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4&quot;-ethanaloxy-3”-methoxycyclohexyl)-l'-methyl-vinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-a3atricyclo[22.3.1.0^» ^]octacos-18-ene-2,3,- 10.16-tetraone__~

To a solution of 17-ethyl-l-hydroxy-14-(tert-butyldiinethylsiloxy)-12-[2 '-(4&quot;-(2,3-dioxy-l-propoxy)-3''-methoxycyclohexyl)-l '-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3 .1.04,9]octacos-18-ene-2,3,10,16-tetraone (1.56 g) (STEP 11D) in 20% agueous tetrahydrofuran (20 ml) was added sodium metaperiodate (510 mg) and the mixture stirred vigorously for 30 minūtes. At this time an additional 170 mg of sodium metaperiodate were added. After 30 minūtes the mixture was diluted with ol;hyl acetate, filtered through Celite and the residue rinsed with ethyl acetate. The organic -157- -157-LV 10450 portion was washed witli saturated sodium bicarbonate and brine, dried over magnesium sulfate and purified by flash chromatography on silica gel (ethyl acetate:hexane (1:2) + 1% inethanol) to give the title 5 eompound (1.45 g). MMR consistent with the desired structure.

STEP 11F 1° 17-Ethyl-l-hydroxy-14-(tert-butyldimethylsiloxy)-12-[21-(4n-carboxymethoxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0^·^]octacos-18-ene- 2.3.10.16-tetraone_ 15 To a solution of 17-ethyl-l-hydroxy-14-(tert- butyldiiuethylsiloxy)-12-[2 '-(4&quot;-ethanaloxy-3&quot;-methoxy-cyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,-27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.04,9]-octacos-18-ene-2,3,10,16-tetraone (311 mg) (STEP 11E) 20 in tert-butanol (6.6 ml) and 2-methyl-2-butene (1.65 ml) v;as added sodium chlorite (273 mg) and sodium dihydrogen phosphate (272 mg) in water (2.7 ml) slowly. After 2 hours, the solvent was removed in vacuo, and the resulting residue was dissolved in 25 water and acidified to pil 3 with IN HC1. The agueous portion was extracted v;ith ethyl acetate (3 x 10 ml) and the combined organic portion was washed with brine. TUis v;as dried over magenesium sulfate and purified by flash chromatography on silica gel (2% 30 methanol in methylene chloride followed by 27. metliano.l. in methy.lene chloride + 0.57. acetic acid) to gjve llie title eompound (255 mg). N11R consistent with the desired structure. STEP 11G 17-Ethyl-l-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4&quot;-5-indolylamino-carbonylmethoxy-3&quot;-methoxy-cyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,-27-tetramethyl-ll, 28-dioxa-4-azatricyclo[22.3.1.0^ &gt;9]- octacos-18-ene-2.3.10.16-tetraone_

To a so.lution of 17-ethyl-l-hydroxy-14-(tert-butyidimethylsiloxy)-12-[2'-(4&quot;-carboxymethoxy-3&quot;-methoxycyclohexyl)-l ’ -methylvinyl]-23,25-dimethoxy-13,19,21,27-tetrainethyl-ll, 28-dioxa-4-azatricyclo-[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone (150 ing) (STEP 11F) in methylene chloride (1.6 ml) was added benzotriazol-l-yloxy-tris(dimēthylami.no)-phosphonium hexafluorophosphate (103 mg) followed by triethylamine (43 μΐ). After 10 minūtes, 5-aminoindole (43 mg) was added to the reaction mixtuie and stirred for 1 hour. The mixture was diluted with ethyl acetate and washed with 1N HC1, water, saturated sodium bicarbonate and brine, respectively. The organic portion was dried over magnesium sulfate and purified by flash chroinatography on silica gel (ethyl acetate:hexane (1:2) -i 17o methanol) to give the title compound (138 mg). ΓUiR consistent with the desired structure.

STEP _1.1II 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-5-indolylamino-carbonylmethoxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]-73,25- &lt;1 iinethoxy-13,19,21,27-tetramethyl-ll, 28-dioxa-4-azatr icyclo[22.3.1.0/f« 9]octacos-18-ene-2,3,10,16-t.e.tr.aoiie____________________________ -159- LV 10450

To a solution of 17-ethyl-l-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4M-5-indolylaminocarbonyl methoxy-3&quot;-methoxycyclohexyl)-l’-methylvinyl]-23,25-d i methoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricy clo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone (138 mg in 1 ml tetrahydrofuran contained in a polypropylene vial) was added 200 μΐ of a solution of hydrogen fluoride-pyridine complex (407· in (2:1) Letrahydrofuran:pyridine), and the mixture was stirred at room teinperature. After 2 days, the reaction was quenched by the careful addition of saturated sodium bicarbonate and extracted with ethyl acetate. The coiubined organic portion was washed with brine, dried over magnesium sulfate, concentrated in vacuo and purified by flash chromatography (ethyl acetate :hexane (1:1) + 1% inethanol) to give the title compound. MASS (FAB) 971 (M+Li); partial XH NMR δ: 9.52 (brs, III); 8.15 (brs, 1H); 7.91 (s, 1H); 7.30 (s, 2H); 7.16 (dd, J=3,3Hz, 1H); 6.49 (dd, J=,3Hz, 1H); 4.41 (brd, J=14Hz, 1H). EXAMPLE 12 17-Ethyl-l-hydroxy-12-[2*-(4&quot;-(methyl-N-tryptophanyl-carbonylmethoxy)-3&quot;-methoxycyclohexyl)-l'-methyl-vinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^* ^]octacos-18-ene-2,3,-10.16-tetraone__

STEP 12A 1.7-Ethyl-l-hydroxy-12-[2'-(4&quot;-allyloxy-3&quot;-methoxy-cycloliexyl)-l '-methylvinyl]-23,25-dimethoxy-13,19 ,-21,27-tet rainethyl-ll, 28-dioxa-4-azatricyclo[22.3.1.-O7' ’ 9 loci acos- 18-ene-2.3.10.16-tetraone_ -160-

To a solution of 17-ethyl-l-hydroxy-12-[2,-(4&quot;-hydroxy-3&quot;-methoxycycloliexyl)-l '-methylvinyl]-23,25-d imethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-aza-tricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetra-one (510 mg) in 6.6 ml 33% methylene chloride in cyclohexane, was added allyl trichloroacetimidate (266 mg neat) and the reaction mixture was allowed to mix for 5 minūtes. Trifluoromethanesulfonic acid (12 μΐ neat) was added slowly via syringe and the mixture stirred at room temperature. After 24 hours the reaction mixlure was diluted with ethyl acetate and washed with saturated sodium carbonate, water and brine. The organic layer was dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate: hexane (1:9)) + 1% methanol) gavē the title compound (434 mg). NHR consistent with the desired structure.

STEP 12B 17-Ethyl-l-hydroxy-12-[21-(4&quot;-(2,3-dioxy-l-propoxy)-3&quot;-methoxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo-Γ22.3.1.0^19ļoctacos-18-ene-2.3.10.16-tetraone

To a solution of 17-ethyl-l-hydroxy-12-[2&quot;'-(4&quot;-a.llyloxy-3&quot;-methoxycyclohexyl)-l' -methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-aza-tr icyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone (434 mg)(STEP 12A) in 15 ml tetrahydrofuran, was added W-tnethylinorpholine N-oxide (431 mg) folloved by 0.25M ostnium tetraoxide solution in THF (425 μΐ), and the mixlure was stirred at room temperature. After -161- LV 10450 4.5 hours, the reaction was guenched by the addition of 207« sodium bisulfite, and the precipitat'e was filtered through Celite and rinsed with ethyl acetate. The combined filtrate was washed with 207. sodium bisulfite (2x), saturated sodium bicarbonate and brine and dried over magnesium sulfate. The concentrate was purified by flash chromatography on silica gel (ethyl acetate:hexane (3:1) + 1% methanol) to give the title compound (177 mg). NMR consistent with the desired structure. STEP 12C 17-Ethyl-l~hydroxy-12-[2'-(4&quot;-ethanaloxy-3&quot;-methoxy-cyclohexyl)-l,-methylvinyl]-23,25-dimethoxy-13,19,-21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.-04»91octacos-18-ene-2.3.10.16-tetraone

To a solution of 17-ethyl-l-hydroxy-12-[2'-(4&quot;-(2,3-d i oxy-1 -p r opoxy ) -3' ’-me t hoxycy cl.ohexyl) -11 -me thy 1-vinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,-10,16-tetraone (177 mg)(STEP 12B) in 20% aqueous tetrahydrofuran (2 ml) was added sodium metaperiodate (67 mg) and the inixture stirred vigorously for 30 minūtes. At this time an additional 20 mg of sodium metaperiodate were added. After 30 minūtes the mixture was diluted with ethyl acetate, filtered through Celite and the residue rinsed with ethyl acetate. The organic portion was washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate and purified by flash chromatography on silica gel (ethyl acetate:hexane (.2:3) i 1% methanol) to give the title compound (157 mg). *11 IIHR consistent v/ith the desired structure. -162-

STEP 12D 17-Ethyl-l-hydroxy-12-[2'-(4&quot;-carboxymethoxy-3M-methoxycyclohexyl)-l'-raethylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo-Γ22.3.1.04»91octacos-18-ene-2,3.10.16-tetraone

To a solution of 17-ethyl-l-hydroxy-12-[2'-(4''-et:hanaloxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl)-23 , Z5-dimethoxy-13,19,21,27-tetramethyl-ll, 28-dioxa-4-asatr icyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone (157 mg) (STEP 12C) in tert-butanol (4 ml) and 2-methyl-2-butene (1 ml) was added sodium chlorite (159 tng) and sodium dihydrogen phosphate (159 mg) in water (1.6 ml) slowly. After 1 hour, the solvent was removed in vacuo, and the resulting residue was dissolved in water and acidified to pH 3 with IN HC1. The aqueous portion was with ethyl acetate (3 x 10 ml), and the combined organic portion was washed with brine. It was dried over magenesium sulfate and purified by flash chromatography on silica gel (27. methanol in methylene chloride foilowed by 27. meliianol in methylene chloride + 0.57, acetic acid) to give the title compound (114 mg). ·*·Η tlMR consistent vjitli the desired structure.

.STEP_12E r7-Elhyl~l-hydroxy-12-[2'-(4&quot;-methoxy-N-tryptophanyΙοβι· bonyJ.methoxy-3&quot;-methoxycyclohexyl)-l ' -methylvinylJ-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatr .i cyc I o[22.3.1.0/+ &gt; ^]octacos-18-ene-2,3,10,16-t_e_t r .ap. 11 e__________. __ 30 -163- -163- LV 10450

To a solution of 17-ethyl-l-hydroxy-12-[2'~(4&quot;-cai:boxymethoxy-3&quot;-methoxycyclohexyl)-l ,-methylvinyl]-23,25-diinethoxy-13,19,21,27-tetramethyl-ll, 28-dioxa-4-azatiieycJ.o(.'22.3.1.04,9]octacos-18-ene-2,3,10,16-tetiaone (39 ing)(STEP 12D) in methylene cliloride (0.5 ml) was added benzotriazol-l-yloxy-tris(dimethyl-a;nino)phosphonium hexafluorophosphate (31 mg) followed by triethylamine (14 μΐ). After 10 minūtes, tryptophan methyl ester hydrochloride (24 mg) was added to the reaction mixture and stirred for 1 liour. The mixture was diluted with ethyl acetate and washed with 1N IIC1, water, saturated sodium bicarbonate and brine, respectively. The organic portion was dried over magnesium sulfate and purified by flasii chromatography on silica gel (ethyl acetate:hexane (1:1) + 17. methanol) to give the title compound (28 mg). MASS (FAB) 1041 (M + Li); Partial ]H NMR δ: 8.21 (brs, 1H); 8.04 (brd, J=8Hz, 1H); 7.56 (d, J=8Hz, III); 7.33 (d, J=8Hz, 1H); 7.11(m, 3H); 4.41 (brd, J=14Hz, III); 3.64 (s, 3H). 17-ELhyl-l-hydroxy-12-[2'-(4&quot;-3-indolylethylamino-ca rbonylmethoxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatr icyclo[22.3.1.0/+1 ^]octacos-18-ene-2,3,10,16- tet raone_

To a solution of 17-ethyl-l-hydroxy-12-[2'-(4&quot;-carboxymethyloxy-3&quot;-methoxycyclohexyl)-l'-methyl-vinyl)-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,- -164- 10,16-tetraone (13 mg) (STEP 12D) in methylene chJ.oi: ide (150 ļil) was added benzotriazol-l-yloxy-tris-(dimethylamino)phosphonium hexafluorophosphate (10.3 mg) fol.lowed by triethylainine (4.3 μΐ). After 10 5 minūtes, tryptamlne (5 mg) was added to the reaction mixture and stirred for 1 hour. The mixture was diluted with etliyl acetate and washed with 1N HC1, water, saturated sodium bicarbonate and brine, respectively. The organic portion was dried over 10 magnesium sulfate and purified by flash chromatography on silica gel (ethyl acetate:hexane (1:1) -i- 1% methanol) to give the title compound (7.5 mg). HASS (FAB) 983 (M + Li); partial 1H NMR 8: 8.32 (brs, 1H); 7.89 (m, 1H); 7.58 (d, J=8Hz 1H); 15 7.31 (m, 1H); 7.10 (in, 3H); 4.51 (brd, J=3Hz, 1H); 4.41 (brd, J=14IIz, 1H). EXAMPLE 14 20 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(l-N-methyl-5- indolyl)oxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]-23, 25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^* ^]octacos-18-ene-2,3,10,16- tetraone_________ 25

STEP 14A 1 - MeJ:11 y 1-5-bron toindole A mixture of sodium hydroxide (0.4g.,l0 mmol.) 30 in DMS0 (20 inL.) was heated to 80-85° C for 6 hours to dissolve most of the solids then allowed to cool to room teinperature. To the stirred mixture was -165- LV 10450 added 5-broinoindole ( 2.0 g., 10 mmol.) folloved in 1 hour by methyliodide ( 0.62 mL. , 10 mmol.). After stirring for an additional 3 hours the reaction was shown by TLC analysis to be complete. The reaction 5 mixture was diluted with water then extracted with ether. The extracts were washed 2x with water, dried with Wa2S04, and concentrated in vacuo to give 2.08 g. of l-methyl-5-bromoindole as a yellow oil which crystallized on standing. 10

STEP 14B

Tr i (l-methvl-indol-5-yl)bismuthine

3U

To a solution of l-methyl-5-bromoindole (5.0g.,23.8 mmol.) in ether (100 mL.) at -78°C was added a 1.7M solution of t-butyllithium in pentane (28mL. 47.6 mmol.). The mixture was stirred at -78°C for 1 hour. To this mixture was then added a solution of bisinuth trichloride (2.36g. , 7.5 mmol.) in THF (25 mL.) via syringe. The cooling bath was maintained for 2 hours then allowed to warm to room temperature overnight. In the morning the mixture was quenched with ice water and the product extracted 2X with toluene. The extracts were combined, washed with water, dried with Na2S0^, and concentrated in vacuo to a volume of about 30mL.. After chilling in the refrigerator for several hours the solid product was filtered, washed with cold toluene and vacuum dried to give tri(l-methyl-indol-5-yl)bismuthine (1.7g.) as ^ mustard color solid. -166- STEP 14C 17-Ethyl-1,14-dihydroxy-12-[2,-(4',-(l-N-methyl-5-indolyl)oxy-3&quot;-methoxycyclohexyl)-l'-methylvinyi]-23, 25-diinethoxy-13,19,21,27-tetramethyl-ll, 28-dioxa-4-azatricyclo[22.3.1.0^»^]octacos-l8-ene-2,3,10,16- tetraone__

To a stirred solution of tri(l-methylindol-5-yl)bismuthine (450 mg. , 0.75 mmol.)(STEP 14B) in CH2CI2 (10 mL.) was added peracetic acid (0.158 inL.,0.75 mmol. 327« in acetic acid) followed in 15 minūtes by 17-ethyl-l,14-dihydroxy-12-[2'-(4&quot;-hydroxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo-[22.3.1.0^’^]octacos-18-ene-2,3,10,16-tetraone (350 mg., 0.442 mmol.) and Cu(0Ac)2· The mixture was stirred at room temperature for 2 days. The reaction was quenched with saturated aqueous NaHC03 and the product extracted 3X with CH2C12.' The extracts were combined ,dried' over anhydrous Na2S0^, filtered, and concentrated i.n vacuo. The product was isolated and purified 2X by preparative TLC to give 203 mg. of the title coinpound as a colorless solid. MASS (FAB), m + Li 927. Partial 1H NMR (CDCI3, 200 MHz) 5:7.19 (bs, J FI); 7.17 (d, J=10Hz, 1H); 6.98 (d, J=4Hz, 1H); 6.91 (dd, J=3 Hz and 10Hz, 1H); 6.34 (d, J=4Hz, 1H); 3.72 (s, 3H); 3.51 (s, 3H). -167- LV 10450 17-Ethyl-1,14,20-trihydroxy-12-[2'-(4&quot;-(l-N-methyl-indol-5-yl)oxy-3&quot;-inethoxycyclohexyl)-l' -methylvinyl]-5 23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4- azatricyclo[22.3.1.0^»^]octacos-18-ene-2,3,10,16- tetraone_

To a stirred solution of tri(l-methylindol-5-yl)bismutliine (350 ing. , 0.584 mmol. ) in CH2CI2 (6 10 111L.) was added peracetic acid (0.15 mL. , 0.74 mmol.,327i in acetic acid) followed in 15 minūtes by 17-ethyl-l, 14,20-trihydroxy-12-[2'-(4&quot;-hydroxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]-23,25-diraethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo-15 [22.3.1.0^»^]octacos-18-ene-2,3,10,16-tetraone (250 mg., 0.32 mmol.) and Cu(0Ac)2 (35 mg., 0.138 mmol.). The reaction mixture was stirred for 2 days at room temperature. The reaction was quenched with saturated aqueous NaHC03 and the mixture extracted 2X 20 with CH2CI2· The extracts were combined, dried with Na2S04, filtered and concentrated in vacuo. The produet was isolated by flash column chromatography 011 silica gel (3:1 hexane/acetone) followed by preparative TLC (3% CH3OH in CH2C12) to give 111 mg 25 of the title compound. MASS (FAB), M + Li 943.

Partial 1H NMR (CDCI3, 200 MHz) 6:7.21 (bs, 1H); 7.18 (d, J = 7.5IIz, 1H); 6.98 (d, J=3Hz, 1H); 6.94 (dd, J= 2.5Hz and 7.5Hz, 1H); 6.37 (d, J=3Hz, 1H); 3.75 (s, 3H); 3.59 (s, 3H). 30 -168- E3CAMPLE 16 17-Elliy.l-l-hydroxy-12-[2 '-(4&quot;-(l-N-methylindol-5-yl) oxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]-23,25-dime-tlvoxy-13,19,21,27-tetramethyl-ll, 28-dioxa-4-azatri-cy_c_l,W._L22.3.1.0^ ’ ^1octacos-18-ene-2.3.10.16-tetraone To a stirred solution of tri(l-methylindol-5-y.1.)bismuthine (35 mg . , 0.058 mmol.) in CHļClļ (0.7 mL) v;as added peracetic acid (0.015 mL. , 0.074 mmol., 327. in acetic acid) followed in 15 minūtes by 17-ethyl-l-hydroxy-12-[2'-(4&quot;-hydroxy-3&quot;-methoxycyclo-hexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^*^]-octacos-18-ene-2,3,10,16-tetraone (25mg., 0.032 mmol.) and Cu(0Ac)2 ( 5 mg., 0.03mmol.). The reaction mixture was stirred for 3 days at room temperature.

The reaction was quenched with saturated agueous NaIlC03 and extracted 2X with CH2CI2. The extracts were coīnbined, dried with Na2SŪ4, filtered and concentrated in vacuo. The product was isolated and purified by preparative TLC on silica gel (2:1 hexane/acetone then 57. CH3OH in CH2CI2) to give 10.2 mg of the title compound. Partial NMR (CDCI3, 200 MHz) δ :7.18 (bs, 1H); 7.16 (d, J=7.5Hz, 1H); 6.98 (d, J=3Hz, 1H); 6.92 (dd, J=2.5Hz and 7.5Hz, 1H); 6.33 (d, J=3Hz, 1H); 3.64 (s, 3H); 3.51 (s, 3H). -169- -169-LV 10450 EXAMPLES 17 AND 18 17-Ethyl-1,14-dihydroxy-12-[21-(3&quot;-hydroxy-4&quot;-(l-N-methylindol-5-yl)oxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll, 28-dioxa-4-aza-tricyclo[22.3.1.0^ &gt;9]octacos-18-ene-2,3,10,16-tetra-one and 17-Ethyl-l,14-dihydroxy-12-[2,-(4&quot;-hydroxy-3&quot;-(l-N-metliylindol-5-yl)oxycyclohexyl)-l '-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll, 28-dioxa-4-azatricyclo[22.3.1.0^·9]-octacos-18-ene-2,3,10,16- tetraone____

To a stirred solution of tri(l-methylindol-5-yl)bismuthine (150 mg., 0.25 mmol.) in CKļClļ (2 mL.) was added peracetic acid (0.05 mL., 0.23 mmol.,32% in acetic acid) followed in 10 minūtes by 17-ethyl-l,14-dihydroxy-12-[2'-(3M,4&quot;-dihydroxycyclohe xyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetra methyl-ll,28-dioxa-4-azatricyclo[22.3.1.04» 9]octacos-l 8-ene-2,3,10,16-tetraone (100 mg, 0.129 mmol) and Cu(0Ac)2 (20 mg.,0.11 mmol.). The reaction mixture was stirred for 2 days at room temperature.The reaction was guenched with saturated agueous NaHCOļ and Lhe inixture extracted 2X with CH2CI2· The extracts were combined, dried with Na2S04« filtered and concentrated in vacuo. The products were separated and purified 2X by preparative TLC (2:1 hexane/acetone then 5% CH3OH in CH2CI2) to give 19mg of 17-ethyl-l,l4-dihydroxy-12-[2'-(3&quot;-hydroxy-4”-(l-methylindol-5-yl)oxycyclohexyl)-l'-methylvinyl]-23,25-diinethoxy-13,19,21,27-tetramethyl-ll, 28-dioxa-Λ-a znt r i c.yclo[22.3.1.0^ * 9]octacos-18-ene-2,3,10,16-tetraone, Partial 1H NMR (CDCI3, 200 MHz) 5:7.19 (d, J-lOIlz, līt); 7.17 (d, J=2.5Hz, 1H); 7.00 (d, J=3Hz, 1.11); 6.88 (dd, J=2.5Hz and 10Hz, 1H); 6.35 (d, J=3Hz, III.); 3.73 (s, 31i). -170- and 33mg of 17-ethyl-l,14-dihydroxy-12-[2'-(4&quot;-hydroxy-3&quot;-( l-metliylindol-5-yl )oxycyclohexyl)-l1 -methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0^ * ^]octacos-18-5 ene-2,3,10,16-tetraone. Partial 1H N1LR (CDC13, 200 11Hz) 6:7.18 (d, J=8Hz, 1H); 7.16 (d, J=2.5Hz, 1H); 6.98 &lt;d, J=3Hz, 1H); 6.88 (dd, J=2.5Hz and 8Hz, 1H); 6.33 (d, J=3Hz, 1H); 3.73 (s, 3H). 10 EXAMPLE 19

Iri (indol-5-vl)bismuthine A solution of 5-bromoindole &lt;5.0 g., 25.5 mmol.) in ether (50 mL.) was slowly added, at 0°C, to a slurry 15 of KH (2.8g., 25 mmol., 35% in oil; washed 3x with ~ hexanes) in ether (40 mL.). The reaction mixture was stirred for 20 minūtes then chilled to -78eC. A precooled solution of t-butyllithium (29.7 mL., 50.5 mmol., 1.7M in pentane) was added dropwise via 20 syringe to the inixture followed in 40 minūtes by a solution of BiCl3 (1.89g., 6.0 mmol.) in THE (25 mL.). The cooling bath was maintained for 2 hours then allowed to warm to room temperature overnight.

The reaction was quenched with ice water and 25 extracted 3x with toluene. The extracts were combined, dried with Ma2S04, filtered and concentrated i_n vacuo. The residue was diluted with 7 5 inJ.. of toluene then stored at 4°C overnight. The solīds were filtered and air dried to give 1.53g of tri(indol-5-yl)bismuthine. 30 -171- -171- LV 10450

STEP 19B 17-Ethyl-1,l4-dihydroxy-12-[2'-(4&quot;-(indol-5-yl)oxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl)-23,25-dimethoxy-13,19, 21,27-tetrainethyl-ll,28-dioxa-4-azatricyclo- [.22.. 3.1.0** ’ 91octacos-18-ene-2.3,10.16-tetraone_

To a stirred solution of tri(indol-5-yl)bis-mulhine (1.3g. , 2.33mmol. ), prepared by procedures outlined in STEP 14B in CII2CI2 (30mL.) was added peracetic acid (0.50 111L. , 2.31 mmol. , 32% in acetic acid) followed in 10 minūtes by 17-ethyl-l,14-dihydroxy-12-[2'-(4&quot;-hydroxy-3&quot;-methoxycyclohexyl)-l ' -inethylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0^ »^]octacos-18-ene-2,3,10,16-tetraone (l.Og., 1.26 mmol.) and Cu(0Ac&gt;2 (100 mg.,0.55 mmol.). The reaction mixture was allowed to stir at room temperature for 3 days.

The reaction was quenched with saturated agueous IlalICOj and the mixture extracted 2X with CH2CI2· The extracts were combined, dried with Na2S04, filtered and concentrated in vacuo. The product was isolated and purified by preparative TLC 2X with 2:1 ]iexane/ac.etone and once with 2:1 hexane/EtOAc to give 208ing of the title coinpound. MASS (FAB), M + 906. Partial ^-II NMR (CDCI3, 200 MHz) 5:8.12 (bs, 1H); 7.26 (d, J=10Hz, 1H); 7.22 (d, J=2.5Hz, 1H); 7.18 (m, 1H); 6.9 (dd, J=2.5Hz and 10Hz, 1H); 6.44 (m, 1H); 3.53 (s, 3H). -172- EXAMPLE 20 17-Allyl-1,14-dihydroxy-12-[2'-(4&quot;-(indol-5-yl)oxy-3&quot;-methoxycyclohexyl)-l'-metkylvinyl]-23,25-dimethoxy-5 13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo- J_22....3.1. Q/f ’ ^ loctacQS-18-ene-2,3.10,16-tef rarmp_

To a stirred solution of tri(indol-5-yl)bis-inulhine (150 mg. , 0.27 ininol.) in CEļClļ (3 mL.) was ndded peracelic acid (0.05 mL., 0.23 mmol., 32¾ in acetic acid) followed in 15 minūtes by 17-allyl-l, 14-dihydroxy-12-[2' -(4&quot;-hydroxy-3&quot;-methoxy-cyclohexyl)-l1 -methylvinyl]-23,25-dimethoxy-13,19,21,-27-tetramethyl-ll,28-d ioxa-4-azatricyclo-[22.3.1.0^’^]octacos-18-ene-2,3,10,16-tetraone 15 (lOOmg., 0.124 mmol.) and Cu(OAc&gt;2 (20 rag., 0.llnunol.). The reaction mixture was allowed to stir at room temperature for 2 days. The reaction was quenched with saturated aqueous NaHCC&gt;3 and the rnixture extracted with CH2CI2· The extracts were 20 combined, dried witli Na2SŪ4, filtered and concentrated in vacuo. The product was isolated and purified by preparative TLC 2x (2:1 hexane/acetone then 57o CH3OH in CH2CI2) to give llmg of the title compound. 11ASS (FAB), M + Li 925. Partial NMR 25 (CDCI3, 200 MHz) 5:8.12 (bs, 1H); 7.24 (d, J=10Hz, 1H); 7.22 (d, J=2.5Hz, 1H); 7.17 (t, J=3Hz, 1H); 6.9 (dd, J=3Hz and 10Hz, 1H); 6.44 (bs, 1H); 5.70 (m, III) ; 3.53 (s, 311) . 30 -173- LV 10450 EXAMPLE 21 17-Ethyl-1,l4-dihydroxy-12-[2'-(4&quot;-(l-ethylindol-5-yl )oxy-3&quot;-inethoxycyclohexyl)-l1 -methylvinyl]-23,25-5 dimethoxy-13,19,21,27-tetramethyl-ll, 28-dioxa-4-aza- tricyclo[22.3.1.0^ * ^]octacos-18-ene-2,3,10,16-tetra- one_______

To a stirred solution of tri(l-ethylindol-5-yl)bismuthine (150rag., 0.23iumol.)» prepared by 10 proeedures outlined in STEP 14A &amp; B, in CEļClļ (3 ml) v;as added peracetic acid (.063mL., 0.3 mmol., 327e in acetic acid) followed in 15 minūtes by 17-ethyl-l, 14-dihydroxy-12-[2'-(4&quot;-hydroxy-3&quot;-methoxycyclohexyl)-l methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-15 11,28-dioxa-4-azatricyclo[22.3.1.0^*^]octacos-18- ene-2,3,10,16-tetraone (100 mg., 0.126 mmol.) and Cu(0Ac)2 (20 mg., 0.11 mmol.). The reaction mixture was allowed to stir at room temperature for 3 days. The reaction was then quenched with saturated aqueous 20 NaHCOj and the mixture extracted 2X with CH2CI2. The extracts were combined, dried with Na2SŪ4, filtered, and concentrated in vacuo to a brown oil. The . product was isolated and purified by preparative TLC on silica gel (first with 2:1 hexane/acetone folloved 25 by 37. CH3OH in CH2C12) to give 60 mg of the title compound. MASS (FAB) M + Na 957. Partial ^·Η NMR (CDCI3, 200 MHz) 6:7.19 (d, J=10Hz, 1H); 7.18 (d, J=3Hz, 1H); 7.05 (d, J=4Hz, 1H); 6.90 (dd, J=3Hz, 10Hz, 1H); 6.35 (d, J=4Hz, 1H); 4.09 (q, J=6.7Hz, 30 211); 3.5 (s, 311); 1.4 (t, J=6.7Hz, 3H). EXAHPLE 22 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(l-ethylindol-5-yl)oxy-3&quot;-hydroxycyclohexyl)-l'-methylvinyl]-23,25-d imethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-aza-tr icyclo[22.3.1.0^·^]octacos-18-ene-2,3,10,16-tetra- one__

To a solution of tri(l-ethylindol-5-yl)bis-muthine (0.2 gm) prepared by procedures outlined in Step 14A &amp; B in CHļClļ (2 ml) at room temperature was added peracetic acid (37 μΙ,, 0.2 mmol). After stirring for 15 minūtes at room temperature, was added 17-ethyl-l,14-dihydroxy-12-[2'-(4&quot;,3&quot;-dihydroxy-cyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21, 28-tetramethyl-ll, 28-dioxa-4~azatricyclo[22.3.1.04» octacos-18-ene-2,3,10,16-tetraone (0.2 gm, 0.25 mmol) followed by Cu(0Ac)2 (20 mg) and the reaction mixture was stirred for 2 days. To the reaction mixture was theu added saturated WaHC03 (approximately 20 ml) and the inixture was extracted twice with CH2CI2· The combined organic extracts were dried over Na2S04, filtered and concentrated iri vacuo. The mixture of 17-ethyl-l,14-dihydroxy-12-[2'-(4&quot;-(l-ethylindol-5-yl)oxy-3&quot;-hydroxycyclohexyl)-l'-methylvinyl]-23,25-dimethyoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricvclo-[22.3.1,0^·^]octacos-18-ene-2,3,10,16-tetraone and 17-ethyl-l,l4-dihydroxy-12-[21-(4&quot;-hydroxy-3&quot;-(l-ethyl-indol-5-yl)oxycyclohexyl)-l'-tnel;liylv.inyl]-23,25-dimethoxy-13,19,21,27-tetra-me 11 ty1 — 11,28-dioxa-4-azatricyclo[22.3.1.0^·^]-o&lt;:.haeos-l8--ene-2,3,10,16-tetraone were separated by clnoinatography (silica, 3:1, hexanes: ethyl acetate) to give the title compound (0.035 gm). -175- LV 10450 TLC (silica, 3:1, hexanes:ethyl acetate) Rf=0.55. Partial 1H NMR (CDC13, 200 MHz) 6:7.21 (d, J=10Hz, III); 7.14 (d, J=3Hž, 1H); 7.08 (d, J=4Hz, 1H); 6.85 (dd, J=3IIz and 10Hz, III); 6.36 (d, J=4Hz, 1H), 4.10 5 &lt;q, J=6.7Hz, 2H); 1.42 (t, J=6.7Hz, 3H). EXAMPLE 23 17-Ethyl-1,l4-dihydroxy-12-(2'-(4&quot;-(l-propylindol-5-yl)oxy-3&quot;-inethoxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-aza-tricyclo[22.3.1.0^* ^]octacos-18-ene-2,3,10,16-tetra- one_:_

To a stirred solution of tri(l-propylindol-15 5-yl)bismuthine (200 mg., 0.29 mmol.), prepared by procedures analogous to STEP 14A and B, in CH2C12 (3 mL.) v;as added peracetic acid ( 0.075mL., 0.36 mmol.,32% in acetic acid) followed in 10 minūtes by 17-ethyl-l,14-dihydroxy-12-[2'-(4&quot;-hydroxy-3&quot;-methoxy-20 cyclohexyl)-l'-methylvinyl]-23,25-dimethoxy~13,19,21,-27-tetramethyl-ll,28-dioxa-4-azatricyclo-|22.3.1.0^·^]octacos-18-ene-2,3,10,16-tetraone (150 mg., 0.19 mmol.) and Cu(OAc)2 (30 mg., 0.17mmol.).

The reaction mixture was stirred for 20 hours at room 25 temperature. The reaction was then quenched with saturated aqueous NaHC03 and the mixture extracted with CII2C12. The extracts were combined, dried with ria2S0/v, filtered and concentrated in vacuo. The product was isolated and purified by preparative TLC 30 3X on silica gel (2:1, hexane/acetone; 3% CH3OH ,.in CIi2Cl2; 2:1, hexane/acetone) to give 70mg of the Litle compound. 11ASS (FAB) M + Na 971. Partial ·®-Η -176- NMR (CDCJ.-J, 200 HIIz) 6:7.17 &lt;d, J=10IIz, 1H); 7.02 (d , . J-Mlz, III) ; 6.88 (dd, J=3Hz and 10Hz, 1H) ; 6.32 (d, J = 4IIz, 1H); 3.97 (t, J=7IIz, 2H) , 3.50 (s, 3H); 1.80 (m, 211). £XAMPLE 24 17--Ethyl-1,14-dihydroxy-12-[2 '-(4&quot;-(l-propylindol-5-yl )oxy--3&quot;-liydroxycyclohexyl)-l' -methylvinyl]-23,25-d.imethoxy-13,19,21,27-tetraniethyl-ll, 28-dioxa-4-aza-t. r i cyc.l.o[22.3.1.0^*» ^]octacos-18-ene-2,3,10,16- tetraone_

To a stirred solution of tri(l-propylindol-5-yl)bismuthine (200 mg., 0.29 mmol.), prepared by procedures analogous to Step 14A and B, in CH2CI2 (3 mL.) is added peracetic acid ( 0.075mL., 0.36 mmol.,32% in acetic acid) followed in 10 minūtes by 17-ethyl-l,14-dihydroxy-12-[2'-(3&quot;,4&quot;-dihydroxy-3&quot;-cyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21-,-27-tetramethyl-ll, 28-dioxa-4-azatricyclo- &gt;- [22.3.1.04»^]octacos-18-ene-2,3,10,16-tetraone (150 mg., 0.19 mmol.) and Cu(0Ac)2 (30 mg., 0.17mmol.).

The reaction mixture is stirred for 20 hours at room temperature. The reaction is then quenched with sarurated aqueous NaHCOļ and the raixture extracted with CH2CI2. The extracts are combined, dried with IlapSO^, filtered and concentrated in vacuo. The product is isolated and purified from the C-3&quot; ether by preparative TLC on silica gel to give the title compound. LV 10450 -177-EXAHPLE 25 17-Ethyl-1,14-dihydroxy-l2-[2'-(4&quot;-(l-hydroxyethyl-indol-5-yl)oxy-3&quot;-methoxycyclohexyl)-l '-methylvinylj-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatr icyclo[22.3.1.0^»^]octacos-18-ene-2,3,10,16-tej; ra o ne_______

STEP 25A l-(2-Hydroxyethvl)-5-bromoindole A mixture of NaOH (4.4 gm, 0.011 mol) in DMSO (175 inl) was stirred at 100°C for 5 hours at which time it was cooled to 20eC. To this mixture was added 5-bromoindole (20 gm, 0.102 mol) and the reaction was stirred for 8 hours at room temperature. A solution of ethylene oxide (5.1 gm, 0.125 mol) in DMSO (20 ml) was prepared by bubbling the gas into DMSO. To the bromoindole reaction mixture was slowly added the ethylene oxide solution and stirring was continued for another 2.5 hours.

The reaction mixture was then poured into ice water and extracted twice with diethyl ether. The combined ether extracts were concentrated iņ vacuo whereupon crystalli2ation took place. The crude product was recrystallized from diethyl ether:hexanes (3:2) to afford the title compound (6.25 gm). -178-

STEP_25_B l-( 2-t-Bu_tvldiinethvlsilvloxvethvl)-5-bromoindole A solution of l(2-hydroxyethyl)-5-broraoindole 5 (6 gm, 0.025 mol), t-butyldimethylsilyl chloride (4.5 gm, 0.03 mol) and triethylamine (4.2 ml, 0.03 mol) in CH2Cl2 (60 nil) was stirred for 12 hours at room temperature. The reaction mixture was then washed twice with I^O, dried over Na2S0^, filtered and concentrated in vacuo to provide the title compound as a yellow oil. NMR was consistent with the desired structure.

STEP 25C 15

Tr i[1-(2-t-butyld imethyls ilyloxyethyl)-indol-5-yl]- bismutliine_

To a solution of l(2-t-butyldimethylsilyloxy-ethyl)-5-bromoindole (1.4 gm, 0.004 mol) in diethyl 20 ether (14 ml) at -78eC was added t-butyl lithium (4.7 ml of a 1.7 M solution in pentanes, 0.008 mol).

After stirring for 1.5 hours, a solution of bismuth trichloride (0.4 gm, 0.013 mol) in THF (4 mL) was added. The reaction was stirred at -78eC for 2 hours 25 and then allowed to warm slowly to room temperature and stirring was continued a further 8 hours. The reaction mixture was then poured into H20 and extracted with toluene. The combined organic extracts were dried over Na2SO^, filtered and the 30 filtrate was concentred iņ vacuo. Purification by cln:omatography (silica, 4:1, hexanes:ethyl acetate) [)i:ovideni the title compound (1.03 gin) as a semisolid. J-fl MHR was consistent with desired structure. -179- LV 10450

STEP 25D 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(l-t-butyldi-methylsilyloxyethylindol-5-yl)oxy-3&quot;-methoxycyclo-hexyl)-l’-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetiamethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^»^]- octacos-18-ene-2.3.10.16-tetraone_

To a solution of tri[l-(2-t-butyldimethylsilyl-oxyeLhyl)-indol-5-yl]bismuthine (1.03 gm, 0.001 mol) in CII2CI2 (10 ml) at room temperature was added peracetic acid (150 pL). After stirring for 15 minūtes, 17-ethyl-l,14-dihydroxy-12-[2'-(4&quot;-hydroxy-3&quot;-tnethoxycyclohexyl)-l1 -methylvinyl]-23,25-dimethoxy-13,19,21,27-tetrainethyl-ll, 28-dioxa-4-azatricyclo-[22.3.1.0/+ · 9]octacos-18-ene-2,3,10,16-tetraone (1 gm) was added to the reaction mixture followed by Cu(0Ac)2 (0.04 gm) and the reacton mixture was stirred for 20 hours. To the reaction mixture was then added saturated NaHC03 and it was then extracted with CII2CI2· The organic extracts were dried over Na2S04, filtered and the filtrate was concentrated in vacuo.. The crude product was purified by chromatography (silica, 3:1, hexanes:ethyl acetate) to provide the tītie coinpound (0.38 gm). NMR was consistent with desited structure. -180-

STEP 25E 17-Ethyl-1,14-dihydroxy-12-[21-(4&quot;-(l-hydroxyethyl-indol-5-yl)oxy-3&quot;-methoxycyclohexyl)-l' -raethylvinyl]-5 23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4- azatricyclo[22.3.1.0^»^]octacos-18-ene-2,3,10,16- tetraone_

To a solution of 17-ethyl-l,14-dihydroxy-12-\7 ' -(4&quot;-( l.-t-butyldimethylsilyloxyethylindol-5-yl)oxy-10 3&quot;-inethoxycyclohexyl )-l' -methylvinyl]-23,25-dimethoxy- 13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo-[22.3.1.0^&gt; 9]octacos-18-ene-2,3,10,16-tetraone (0.38 gm) in CH2CI2 (10 ml) at room temperature was added a solution of parā-toluene sulfonic acid (0.05 gm) in 15 CII3OII (10 ml). Tlie reaction mixture was stirred for 3 hours until TLC (silica, 2:1, hexanes:ethyl acetate) verified that reaction was complete. The reaction mixture was poured into saturated NaHC03 and extracted twice vjith CH2C12· The combined organic 20 extracts were dried over Na2S04, filtered and concentrated in vacuo. The crude product was purified by chromatography (silica, 2:1 hexanes:ethyl acetate) to provide the title compound 0.245 gm. HASS (FAB) 25 H + Li 957. Partial 1H MMR (CDCI3, 200 MHz) 5:7.18 (d, J=10IIz, III); 7.16 (bs, 1H); 7.06 (d, J=4Hz, 1H); 6.86 (dd, J=3Hz and 10Hz, 1H); 6.33 (d, J=4Hz, 1H); 4.13 (t, J=6.7Hz, 2H); 3.83 (t, J=6.7Hz, 2H); 3.43 (s, 3H). 30 -181- -181- LV 10450 EXAMPLE 26 J.7-Ethyl~l, 14-dihydroxy-12-[2 '-(4&quot;-(l'-allylindol-5 yJ.)oxy-3&quot;-methoxycyclohexyl)-l '-methylvinyl]-23,25-d j.methoxy-13,19,21,27-tetraniethyl-ll , 28-dioxa-4-aza-tricyclo[22.3.1.0^·^]octacos-18-ene-2,3,10,16-tetraone__ STEP__26A l-Allvl-5-bromoindole

To a stirred mixture of NaOH (204 mg., 5.1 nimol., 1 eq. ) in DMS0 (10 mL.) was added 5-bromoindole (1.0 g., 5.1 mmol., 1 eq.). The solution was stirred for three hours upon complete dissolution of the NaOH (approximately 1 h.). To tliis solution was added allyl iodide (0.466 mL. , 5.1 mtnol., 1 eq.) via syringe. After 2 h. the mixture was diluted with water and extracted 2x with diethyl ether. The organic extracts were combined, dried over anhydrous HgSO^, filtered and concentrated in vacuo. The product was purified by flash column chromatograpliy on silica gel (4:1 hexanes/acetone) affording 730 mg l-allyl-5-bromoindole.

STEP 26B

Tri (Ί-allvlindol-5-vl)bismuthine

To a stirred solution of l-allyl-5-bromoindole (730 mg., 3.09 nunol., 1 eq.) in diethyl ether (15 mL) at -78°C under N2 was added t-butyllithium (1.8mL., 3.09 inmol. , 1 eq., 1.7M solution in pentane). The inixture was stirred at -78°C under N2 for 1 h. To -182- this mixture was added a solution of bismuth trichloride (292 mg. , 0.93 mmol., 0.3 eq.) in dry THF (3 inL.) dropwise via syringe. The ice bath was packed with dry ice and tlie flask covered. The mixture was allowed to warm slowly to room temperature overnight. The·reaction mixture was then diluted with toluene and washed with brine. The layers were separated and the aqueous layer extracted 3x with toluene. The organic extracts were combined, dried over anhydrous Na2S04, filtered and concentrated in vacuo. The residue was dissolved in ether and filtered through a 0.4 micron pTFE membrane. The product started to crystallize.

Cooled solution in freezer. Collected crystals giving 200 mg. of tris-l-allylindol-5-yl)bismuthine. STEP 26C 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(l'-allylindol-5 yl)oxy-3&quot;-raethoxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-aza-tr icyclo[22.3.1.0/+ &gt; ^]octacos-18-ene-2,3,10,16-tetra- one_

To a stirred solution of tri(l-allylindol-5-yl)bismuthine (186 mg. , 0.275 nunol. , 1.2 eq.) in CH2Cl2 (3 mL.) was added peracetic acid (0.064 mL., 0.303 mmol., 1.32 eq., 327, solution in dilute acetic acid). To this solution was added THF (1 mL.), 17-ethyl-l,14-dihydroxy-12-[2'-(4&quot;-hydroxy-3”-methoxy-cyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,-21,27-tetramethy1-11,28-dioxa-4-azatricyclo-[22.3.1.0^’^]octacos-18-ene-2,3,10,16-tetraone (181 mg., 0.229 mmol., 1 eq.) and copper(II)acetate (10 -183- -183- LV 10450 mg., 0.055 rnmol., 0.24 eq.). The mixture was capped and stirred overnight. The reaction was diluted with saturated aqueous NaHC03 and extracted 4x with CII2CI2· The organic extracts were combined, dried over anhydrous Na2S04, filtered and concentrated in vacuo. The product was isolated and purified by flash column chromatography on silica gel (2:1 hexanes/acetone) followed by preparative TLC (3.57* methanol/CH2Cl2&gt; affording 56 mg pure title compound. MASS (FAB) M + Li 953. Partial NMR (CDCI3, 200 MHz) 6:7.17 (bs, 1H); 7.15 (d, J=10Hz, 1H); 7.02 (d, J=3Hz, 1H); 6.88 (dd, J=2Hz and 10Hz, 1H); 6.36 (d, J=3Hz, 1H); 5.95 (ra, 1H); 4.63 (bd, J=14Hz, 1H); 3.50 (s, 3H). EXAMPLE 27 17-Ethyl-1,14-dihydroxy-12-[2'-&lt;4&quot;-(l'-allylindol-5 'yl)oxy-3''-hydroxycyclohexyl)-l ,-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetraraethyl-ll,28-dioxa-4-aza-tr icyclo[22.3.1.0^»^]octacos-18-ene-2,3,10,16- te_traone_____

To a stirred solution of tri(l-allylindol-5-yl)bisinuthine (1.0 g, 1.48 mmol, 1.2 eq) in CII2CI2 (9 mL) and THF (3 mL) was added peracetic acid (0.315 mL, 1.62 mmol, 1.32 eq, 32% solution in diluted acetic acid). To this solution was added l.7-ethyl-l, 14-dihydroxy-12-[2 ·-4(4&quot;, 3·»-dihydroxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetrainethyl-ll, 28-dioxa-4-azatricyclo-[22.3.1.0ή »9]octacos-18-ene-2,3,10,16-tetraone (956 mg, 1.23 mmol, 1 eq) and copper (Il)acetate (22 mg, -184 -184 1.0 0.123 nunol, 0.1 eq). The mixture was capped and stirred for four days. The reaction was diluted with saturated aqueous NalICOg and extracted 4x with CII7CI2. The organic extracts were combined, dried over anhydrous IlaSO^., filtered and concentrated in vacu_Q. The product was isolated and purfied by flash column chroinat;ography on silica gel (3:1 hexanes/acetone) followed by preparative TLC (3.5% inel;hauo.J./CII7CI2) affording 163 mg pure 17-ethyl-l, 14-dihydroxy-12-[2'-(4&quot;-l'-allylindol-5'yl)oxy-3&quot;-hydroxy cyclohexyl ]-l1 -inetliy lvinyl]-23,25-dimethoxy-13,19,21, 27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^»^] octacos-18-ene-2,3,10,16-tetrone. 15 11ASS (FAB), M+Li 953. Partial ΧΗ NMR (CDCL3, 200 MHz) δ: 7.17 (d, J=10 Hz, 1H); 7.15 (brs, 1H); 7.05 (d, J=3 Hz, Īli); 6.86 (dd, J=10 Hz, J=2.5 Hz, 1H); 6.39 (d, J=3 Hz, 1H); 6.05-5.85 (m, 1H0; 4.66 (brd, J=8.5 Hz, 211); 4.57 (brd, J=5 Hz, 1H); 4.38 (brd, J=13 Hz, 1H). 20 EXAMPLE 28 25 17-Ethyl-1,14-d ihydroxy-12-[2'-(4&quot;-(9'-methylcarbazol-31-yl)oxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-aza-tricyclo[22.3.1.0^’^]octacos-18-ene-2,3,10,16-tet raone_ _ 30 -185- LV 10450

STEP_28A

Tri (9-metliylcarbaz01-3-vl)bismuthine

To a stirred niixture of 3-bromo-9-methyl-5 carbazole (646 mg. , 2.48 minol. , 1 eq. ) in diethyl eUier (12 mL) at -78°C (not ali carbazole in solution) under N2 was added t-butyllithium (3.0 mL. , 4.96 minol., 2 eq., 1.7M solution in pentane). The inixture was warmed quickly to room temperature and 10 then quickly cooled to -78°C and stirred under N2 for 40 minūtes. To this mixture was added a solution of bismuth trichloride (235 mg., 0.744 mmol., 0.3 eq.) in dry TIIF (2.5 mL.) dropwise via syringe.- The ice bath was packed with dry ice and the flask covered. 15 The mixture was allowed to warm slowly to room temperature overnight. The reaction mixture was poured into a separatory funnel containing brine and etracted 4x with The organic extracts were combined, dried over anhydrous Na2SC&gt;4, filtered and 20 concentrated in vacuo. The solid residue was triturated with ether and ether/methanol. The solids were collected giving 200 mg. of tri(9-inethylcarbazol-3-yl)bismuthine. The supernatant was saved for further purification. 25

STEP 28B 17-Ethyl-1,14-dihydroxy-12-[2’-(4”-(9'-methylcarbazol-3'-yl)oxy-3M-methoxycyclohexyl)-l'-methylvinyl]-23,25-30 dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-aza-tricyclo[22.3.1.0^'^]octacos-18-ene-2,3,10,16-tetraone_ -186-

To a stirred mixture of tri(9-raethylcarbazol-3-yl)bismuthine (200 mg., 0.267 mmol., 1.2 eq.) in CH2Cl2 (3 mL.) and’THF (1 mL.) was added peracetic acid (0.062 mL. , .295 minol., 1.32 eq. , 32% solution 5 in dilute acetic acid). To this solution was added 17-ethyl-l,14-dihydroxy-12-[2'-(4&quot;-hydroxy-3&quot;-methoxycyclohexyl)-l1 -methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo-[22.3.1.0^’^]octacos-18-ene-2,3,10,16-tetraone (175 10 mg. , 0.222minol., 1 eq.) and copper(II)acetate (10

mg., 0.055 mmol., 0.24 eq.). The mixture was capped and stirred for 48 hours. The reaction was diluted x^ith saturated aqueous NaHC03 and extracted 4x with CH2CI2· The organic extracts were combined, dried 15 over anhydrous Na2S0^, filtered and concentrated in vacuo. The product was isolated and purified by flash column chromatography on silica gel (3:1 hexanes/acetone) followed by preparative TLC (3.5% methanol/CH2Cl2) affording 100 mg of the title 20 coinpound. 1IASS (FAB) M + Li 977. Partial 1H NMR (CDCI3, 200 MHz) 5:7.68 (d, J=2Hz, 1H); 7.48-7.10 (m, 6H); 4.58 (bd, J=4.8Hz, 1H); 4.39 (bd, J=14Hz, 1H); 3.80 (s, 3H); 3.53 (s, 2H). 25 EĀAHPLE 29 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(l'-benzylindol-5-yl )oxy-3&quot;-methoxycyclohexyl )-l' -inethylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-aza-tr icyc.lo[22.3.1.0^’ 9]octacos-18-ene-2,3,10,16-t.e l:.r_a one_________________________________ -187- LV 10450

STEP 29A l-Benzvl-5-bromoindole

To a stirred mixture of NaOH (204 mg., 5.1 5 minol., 1 eq.) in DMSO (10 mL.) was added 5-bromoindole (1.0 g., 5.1 mmol., 1 eq.). The solution was stirred for 20 hours upon complete dissolution of the NaOH (approximately 1 h.). To this solution was added benzyl bromide (0.606mL., 5.1 10 mmol., 1 eq.) via syringe. After 7 h. the mixture was diluted with water and extracted 4x with diethyl ether. The organic extracts were combined, dried over anhydrous MgSO^ filtered and concentrated in vacuo. The'product was purified by crystallization 15 (ether/hexanes) affording 888mg of l-benzyl-5-bromoindole.

STEP 29B 20 Tri d-benzvlindol-5-vl)bismuthine

To a stirred mixture of l-benzyl-5-bromoindole-3 (888 ing., 3.105 mmol., 1 eq.) in diethyl ether (15 mL) at -78°C (not ali indole was in solution) under M2 was added t-butyllithiura (3.65 mL., 6.21 mmol., 2 25 eq., 1.7M solution in pentane). The mixture was stirred at -78°C under N2 for 1 hour. To this inixtuie was added a solution of bismuth trichloride (294 mg., 0.932 mmol., 0.3 eq.) in dry THF (3 mL.) dropwise via syr.inge. The ice bath was packed with 30 dry ice and the flask. covered. The mixture was aJ..lowed to warm slowly to room temperature overnight. The reaction mixture was poured into a -188- separatory funnel containing brine and etracted 4x with CII2CI2 The organic extracts were combined, dried over anhydrous ^2-90^, filtered and concentrated in vacuo. The solid residue was triurated with ether. The solīds were collected giving 200 mg. of tri(l-benzylindol-5-yl)-bismuthine. The supernatant was saved for further purification. 10

STEP_29_C 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(l1-benzylindol-5-yI)oxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-aza-tricyclo[22.3.1.0^*^]octacos-18-ene-2,3,10,16- teJL.ra.one.__________ 20 25

To a stirred mixture of tri(l-benzylindol-5-yl)-bismuthine (200 mg. , 0.242 mmol., 1.2 eq.) in CH2CI2 (3 111L.) and THF (1 mL. ) was added peracetic acid (0.060 mL., .285 mmol., 1.4 eq., 32% solution in dilute acetic acid). To this solution was added 17-ethyl-l,14-dihydroxy-12-[2'-(4&quot;-hydroxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo-[22.3.1.0^*9]octacos-18-ene-2,3,10,16-tetraone (159 mg., 0.202 mmol., 1 eq.) and copper(Il)acetate (10 mg. , 0.055 inmol., 0.24 eq. ). The mixture was capped and stirred overnight. The reaction was diluted with saturated aqueous NaHC03 and extracted 4x with CII2 C12 - The organic extracts were combined, dried over anhydrous Na2S0^, filtered and concentrated in vacuo. The product was isolated and purified by 30 -189- -189- LV 10450 CJ.ash co.l.uinn eliroinaLogiaphy on silica gel (3:1 hexanes/acetone) followed by preparative TLC (3.57. inethanol/CI^C^) affording 100 mg of the title compound. MASS (FAB) M + Li 1003. Partial NHR (C0C13, 200 MHz) 5:7.3-7.0 (m, 8H); 6.84 (dd, J=9Hz, III) ; 6.40 (d, 3Hz, 1H); 5.23 (bs, 2H); 4.6 (bd, J = 6IIz, 1H); 4.38 (bd, J=14Hz, 1H); 3.50 (s, 3H). EXAMPLE 31 17-Ethyl-l-hydroxy-12-[2'-(4&quot;-(l-N-methyl-5-indolyl)-oxy-3”-allyloxycyclohexyl)-l'-methylvinyl]-23,25-climethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-aza-tr_icvclor22· 3.1 ._04 ’ 91octacos-18-ene-2.3.10.16-tetraone

STEP 31A 17-Ethyl-l-hydroxy-12-[2,-(4&quot;-(tert-butyldimethyl-siloxy)-3&quot;-allyloxycyclohexyl)-l'-raethylvinyl]-23,25-d imethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-aza-tricvclor22.3.1.0^» 91octacos-18-ene-2.3.10.16-tetraone To a solution of 17-ethyl-l-hydroxy-12-[2'-(4&quot;-(tert-butyldimethylsiloxy)-3&quot;-hydroxycyclohexyl)-l'-methylvinyl]-23,25-diraethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0^*^] octacos-18-ene-2,3,10,16-tetraone (300 mg) in 9 ml 337. methylene chloride in cyclohexane was added allyl trichloroacetimidate (138 mg neat) and the reaction mixture was allowed to inix for 5 minūtes.

Trifluoromethanesulfonic acid (18 μΐ neat) was added slov;ly via syringe and the mixture stirred at room temperature. After 3 days the reaction was diluted with ethyl acetate and quenched with saturated sodiuīn bicarbonate. The layers were separated, and the organic layer was washed with brine then dried over inagnesium sulfate. Purification of the concentrate by flash chroroatography on silica gel (ethyl acetate: hexane (1:4) + 17„ methanol) gavē the title compound (230 mg; trichloroacatamide present). NMR consistent with the desired structure.

STEP 31B 17-Ethyl-l-hydroxy-12-[21-(4&quot;-hydroxy-3&quot;-allyloxy-cyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13, 19,- 21.27- tetramethyl-ll,28-dioxa-4-azatricyclo- Γ22.3.1.0^’^1octacos-18-ene-2.3.10.16-tetraone_

To a solution of 17-ethyl-l-hydroxy-12-[21-(4&quot;-(tert-butyldimethylsiloxy)-3&quot;-allyloxycyclohexyl)-l methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl- 11.28- dioxa-4-azatricyclo[22.3.1.0^» 9Joctacos-18-ene- 2,3,10,16-tetraone (115 mg) (STEP 31A) in acetonitrile (2.5 ml) was added a solution of 2% HF in aqueous acetonitrile (40 μΐ), and the mixture was stirred at room temperature. After 4 hours, the solution was diluted with ethyl acetate and guenched with saturated sodium bicarbonate. The layers were separated, and the organic layer was washed with brine and dried over inagnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate:hexane (1:2)) gavē the title compound (42 ing). ^·Η NMR consistent with the desired structure. -191- -191-LV 10450

STEP 31C 17-Ethyl-l-hydroxy-12-[21-(4&quot;-(l-N-methyl-5-indolyl)-oxy-3&quot;-allyloxycyclohexyl)-l1-methylvinyl]-23,25-di-methoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatri-cvclor22.3.1.0^’^1octacos-18-ene-2.3.10.16-tetraone To a solution of tri(l-methylindol-5-yl)bis-muthine (53 mg) in methylene chloride (700 μΐ) was added peracetic acid (17 μΐ), and the mixture was stirred at roorn temperature for 15 minūtes. 17-ethyl-l-hydroxy-12-[2'-(4&quot;-hydroxy-3&quot;-allyloxy-cyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,-21,27-tetramethyl-ll,28-dioxa-4-azatricyclo-[22.3.1.0^·’ ^]octacos-18-ene-2,3,10,16-tetraone (42 rng) was dissolved in methylene chloride (270 μΐ) and added to the reaction mixture. After 18 hours the mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate and brine then dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate:hexane (1:3) + 1% methanol) gavē the title conipound (25 mg). MASS (FAB) 938 (M + Li); Partial XH NMR δ: 7.19 (s, 1H); 7.18 (d, J=9Hz, 1H); 6.98 (d. J=3Hz, III); 6.92 (dd, J=9,3Hz, 1H); 6.34 (d, J=3IIz, III); 5.89 (m.lH); 4.56 (brd, J=4Hz, 1H); 3.72 (s, 311). 17-Ethyl-l-hydroxy-12-[2'-(4&quot;-(l-N-methyl-5-indolyl)-oxy-3&quot;-n-propyloxycyclohexyl)-l'-methylvinyl]-23,25- · dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-aza-tricvclor22.3.1.04^loctacos-18-ene-2.3.10.16-tetraone 5 -192 5 -192 Π) Το a solution of 17-ethyl-l-hydroxy-12-[2'-(4&quot;-(l-N-inethyl-5-indolyl )oxy-3&quot;-allyloxycyclohexyl )-l' -methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatr icyclo[22.3.1.0^ »^]octacos-18-ene-2,3,10,16-tetraone (20 mg) (EXA11PLE 31) in ethyl acetate (500 μΐ) was added rhodium on carbon (5 mg). The flask was filled with hydrogen, and the mixture was stirred at room temperature. After 1.5 hours the iuixtui:e was filtered through Celite then the solvent was removed in vacuo to give the title compound (20 mg). MASS (FAB) 940 (M + Li); Partial XH NMR δ: 7.18 (s,1H); 7.16 (d, J=9Hz, 1H); 6.96 (d, J=3Hz, III); 6.92 (dd, J=9,3Hz, 1H); 6.34 (d, J=3Hz, 1H); 4.55 (brd, J=4Hz, 1H); 3.72 (s, 3H). 15 EXAMPLE 33 17-Ethyl-1,14-dihydroxy-12-[2,-(4u-(l-N-methyl-5-indolyl)oxy-3&quot;-i-propyloxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-asatricyclo[22.3.1.0^*^]octacos-18-ene-2,3,10,16-tetraone_

STEP 33A 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-hydroxy-3&quot;-i-propyloxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo-Γ 22.3.1.0^» 9ļoctacos-18-ene-2.3.10.16-tetraone

To a solution of 17-ethyl-l,14-dihydroxy-12-[2'-(3&quot;,4&quot;-dihydroxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-aza- -193- LV 10450 1;r icyclo[22.3.1.0^» ^]octacos-18-ene-2,3,10,16-tetraone (300 mg in 4.5 ml 337, methylene chloride in cyclohexane) isopropyl trichloroacetimidate (142 mg neat) was added and the reaģents allowed to mix for 5 minūtes. Trifluoromethanesulfonic acid (13.4 μΐ neat) was added slowly via syringe and the mixture stirred at room temperature. After 5 days the reaction was diluted with ethyl acetate and quenched with saturated sodiuīn bicarbonate. The layers were separated, and the organic layer was washed with brine tlien dried over magnesium sulfate.

Purification of the concentrate by preparative TLC on silica gel (ethyl acetate : hexane (1:1) +1% methanol) gavē the title compound (42 mg). NMR consistent with the desired structure. STEP 33B 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(l-N-methyl-5-indolyl)oxy-3&quot;-i-propyloxycyclohexyl)-l’-methylvinyl]-23,25-d imethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^»^]octacos-18-ene-2,3,10,16- tetraone_

To a solution of tri(l-methylindol-5-yl)bis-muthine (52 mg) in methylene chloride (700 μΐ) was added peracetic acid (17 μΐ), and the mixture was stirred at room temperature for 15 minūtes. 17-ethyl-l,14-dihydroxy-12-[2'-(4M-hydroxy-3&quot;-i-p ropyloxycyclohexyl)-1'-methylvinyl]-23,25-d imethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo-[22.3.1.0^·9]octacos-18-ene-2,3,10,16-tetraone (42 ing) was dissolved in methylene chloride (450 μΐ) and added to the reaction inixture. After 18 hours the 5 -194- mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate and brine then dried over magnesium sulfate. Purification of' the concentrate by preparātive TLC on silica gel (ethyl acetate :hexane (1:1 + 17* raethanol) gavē the title coinpound (9 ing). MASS (FAB) 956 (M + Li) Partial NllR δ: 7.19 (s, 1H) ; 7.16 (d, J=9Hz, 1H); 6.97 (d, J=3Hz, III); 6.92 (dd, J=9, 3Hz, 1H); 6.34 (d, J=3Hz, 1H); 4.41 (brd, J=14Hz, 1H); 2.72 (s,’3H). 10 EXAMPLE 34 17-Ethyl-1,14-dihydroxy-12-[2'-(4”-(l-N-methyl-5-indolyl)oxy-3&quot;-allyloxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.04,^]octacos-18-ene-2,3,10,16-tetraone_

STEP 34A 20 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(tert-butyldi-inetlr/ls iloxy )-3&quot;-hydroxycyclohexyl)-l' -methylvinyl]-23,25-dimetlioxy-13,19,21,27-tetramethyl-ll, 28-dioxa-4-azatricyclo[22.3.1.04»^]octacos-18-ene-2,3,10,16- 2 5 te_t_rapn e_

To a solution of 17-ethyl-l,14-dihydroxy-12-[2'-(3&quot;,4&quot;-dihydroxycyclohexyl)-l'-methylvinyl]-23,25-d imethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-aza-tr icyo.lo[22.3.1.0419]octacos-18-ene-2,3,10,16-tetraone 3() (1.0 g) in dry methylene chloride (14 ml) was added 2,6-lutidine (240 μΐ) and the mixture was stirred at room temperature. After 10 minūtes, tert-butyl- -195- LV 10450 dimethylsilyl trifluoromethanesulfonate (295 μΐ) was added via syringe. After 15 minūtes the reaction inixture was diluted with ethyl acetate, washed with 1N HC1, water, saturated sodium bicarbonate and brine. The organic phase was dried over magnesium sulfate. Removal of the solvent in vacuo and flash chromatography on silica gel (ethyl acetate: hexane (1:3) i- 17» methanol) gavē the title compound (293 mg). -*-11 NMR consistent with the desired structure.

STEP 34B 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(tert-butyldi-methylsiloxy)-3&quot;-allyloxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-H,28-dioxa-4-azatr icyclo[22.3.1.0^»^]octacos-18-ene-2,3,10,16- tetraone_____

To a solution of 17-ethyl-l,14-dihydroxy-12-[2'-(4&quot;-(tert-butyldimethylsiloxy)-3”-hydroxycyclo-hexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetrainethyl-ll, 28-dioxa-4-azatr icyclo[22.3.1.04,9] octacos-18-ene-2,3,10,16-tetraone (290 mg in 3.9 ml 33% methylene cliloride in cyclohexane) allyl trichloroacetimidate (131 mg neat) was added and the reaģents allowed to mix for 5 minūtes. Trifluoromethanesulf onic acid (6 μΐ neat) was added slowly via syringe and the mixture stirred at room temperature. After 5 days the reaction was diluted with ethyl acetate and quenched with saturated sodium bicarbonate. The layers were separated, and the organic layer was washed with brine then dried over magnesiuīn sulfate. Purification of the concentrate -196- bv preparative TLC on silica gel (ethyl acetate : hexane (1:5) h- 1% methanol) gavē the title compound (150 ing). -'-II NHR consistent with the desired structure.

STEP 34C 17-Ethyl-1,14-dihydroxy-12-[2' -(4&quot;-hydroxy-3&quot;7;allyl-oxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,-19,21, 27-tetramethyl-ll,28-dioxa-4-azatricyclo-Γ22.3.1.0^ ’ ^'loctacos-18-ene-2.3,10.16-tetraone

To a solution of 17-ethyl-l,14-dihydroxy-12-[2'-(4&quot;-(tert-butyldimethylsiloxy)-3&quot;-allyloxycyclo-hexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetrainethyl-ll, 28-dioxa-4-azatr icyclo[22. 3.1.0^»9]-octacos-18-ene-2,3,10,16-tetraone (150 mg) in acetonitrile (3 ml) was added a solution of 2% HF in aqueous acetonitrile (80 μΐ), and the mixture was stirred at room temperature. After 2 hours, the solution was diluted with ethyl acetate and quenched with saturated sodium bicarbonate. The layers were separated, and the organic layer was washed with brine and dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate:hexane (1:1) + 17. methanol) gavē the title compound (63 mg). NMR consistent with the desired structure. -197- -197-LV 10450

S'JL'EP 34D 17-Ethyl-1,14-diliydroxy-12-[2 '-(4&quot;-(l-N-methyl-5-indolyl)oxy-3&quot;-allyloxycyclohexyl)-l · -methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^»9]octacos-18-ene-2,3,10,16- tetraone__

To a solution of tri(l-methylindol-5-yl)bis-inuthine (60 mg) in methylene chloride (1.0 ml) was added peracetic acid (23 μΐ), and the mixture was„ stirred at room temperature for 15 minūtes. 17-ethyl-l,14-dihydroxy-12-[2'-(4&quot;-hydroxy-3&quot;-allyl-oxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo-[22.3.1.0^*^]octacos-18-ene-2,3,10,IF-tetraone (60 mg) was dissolved in methylene chloride (500 μΐ) and added to the reaction mixture. After 20 hours the mixture was diluted with ethyl acetate and vashed with saturated sodium bicarbonate and brine then dried over magnesium sulfate. Purification of the concentrate by preparative TLC on silica gel (ethyl acetate:hexane (1:2) + 17» methanol) gavē the title compound (26 mg). partial NMR δ: 7.18 (s, 1H); 7.16 (d, J=9Hz, 1H); 6.97 (d, J=3Hz, 1H); 6.91 (dd, J=9,3Hz, III); 6.34 (d, J=3Hz, 1H); 5.89 (m, 1H); 4.57 (brd, J=4 Hz, 1H); 4.41 (brd, J=14Hz, 1H); 3.70 (s, 3II) . 198 EXAI1PLE 35 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(l-N-methyl-5-indolyl)oxy-3&quot;-n-propyloxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^ &gt; ^]octacos-18-ene-2,3,10,16-tetraone_

To a solution of 17-ethyl-l,14-dihydroxy-12-[2'-(4&quot;-(l-N-methyl-5-indolyl)oxy-3&quot;-allyloxycyclo-liexyl)-l·-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^*^]-octacos-18-ene-2,3,10,16-tetraone (14 mg) in ethyl acetate (400 μΐ) was added rhodium on carbon (4 mg). The flask was filled with hydrogen, and the mixture was stirred at room temperature. After 1.5 hours the mixture was filtered through Celite then the solvent was reraoved in vacuo . Purification by flash chroinatography (ethyl acetate:hexane (1:1) + 17. methanol) gavē the title compound (10 mg). partial 1H NMR d: 7.17 (s, 1H); 7.15 (d, J=9Hz, 1H); 6.97 (d, J=3Hz, 1H); 6.92 (dd, J=9,3Hz, 1H); 6.34 (d, J=3Hz, 1H); 4.56 (brd, J=4 Hz, 1H); 4.40 (brd, J=14Hz, ĪH); 3.71 (s, 3fl). - 199 - - 199 - LV 10450 EXAMPLE 36 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(l-(3-t-butyldi-inethylsilyloxypropyl)indol-5-yl)oxy-3&quot;-methoxycyclo-liexyl)-l' -inethylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22. 3.1. O^-»9]- octacos-18-ene-2.3.10.16-tetraone_

To a solution of tri[l-(3-t-butyldimethyl-silyloxypropyl)-indol-5-yl] bismuthine (0.43 gra, 0.4mmol.) in CIĪ2CI2 (4mL.) at room temperature was added peracetic acid (0.075 raL., 32% in acetc acid) followed in 15 minūtes by 17-ethyl-l,14-dihydroxy-12-[2,-(4&quot;-hydroxy-3”-methoxycyclohexyl)-l,-methyl-vinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^»9]octacos-18^ene-2,3,10, 16-tetraone (350 mg., 0.44mmol.) and Cu(0Ac&gt;2 (3Θ mg.). The reaction mixture was stirred for 2 days.

The reaction was then quenched with saturated NaHCŪ3 and the mixture extracted with CH2Cl2· The organic extracts were čoīnbined, dried over Na2S04, filtered, and concentrated in vacuo . The product was isolated and purified by preparative TLC on silica gel (3:1, hexane/acetone) to give 144 mg. of the title compound. 200 EXAMPĻE_ 17-Ethyl-1,14-diliydroxy-12-[2 '-(4,,-(l-(3-hydroxy-propyl )indol-5-yl)oxy-3&quot;-methoxycyclohexyl)-l'-methyl-viuy.l]-23,25-diinethoxy-13,19,21,27-tetramethyl-ll, 28-dioxa-4-azatricyclo[22.3.1.0^» ^]octacos-18-ene- 2_,_3_,10 . lG-tetraone_____

To a solution of 17-ethyl-l,14-dihydroxy-12 -[2 ' -(.4&quot;-(!-(3-l-butyldimethylsilyloxy-propyl)indol-5-yl)oxy-3&quot;-raethoxycyclohexyl)-l'-methylvinyl]-23,25-d imethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-aza-tricyclo[22.3.1.0^·^]octacos-18-ene-2,3,10,16-tetraone (144mg) in CII2CI2 (4 mL.) at rt was added a solution of p-toluene sulfonic acid (20 mg.) in CH3OH (4 mL.). The reaction raixture was stirred for 3 hr., quenched with saturated NaHC03» then extracted with CH2CI2·

The extracts were combined, dried over Na2SŪ4, filtered and concentrated in vacuo. The product was purified by preparative TLC on silica gel (2:1, hexane/acetone) to give 81 mg of the title compound. Partial 1H NMR (CDCI3, 200 MHz) d: 7.22 (d, J=9 Hz, III); 7.18 (d, J=3 Hz, 1H); 7.07 (d, J=3 Hz, 1H); 6.89 (dd, J=3 Hz and J=9 Hz, 1H); 6.34 (d, J=3 Hz, 1H); 4.20 (t, J=6.5 Hz, 2H); 2.00 (m, 2H). 30 LV 10450 - 201 -EXAMPLE 38 17- Ethyl-1,14-dihydroxy-12-[2'-(3&quot;-hydroxy-4&quot;-(l-t-butyldimethylsilyloxyethylindol-5-yl)oxycyclohexyl)- 5 1'-methylvinyl]-Z3,25-dimethoxy-13,19,21,27-tetra- methyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^»^Joctacos- 18- ene-_2,3.10.16-tetraone_!_

To a solution of tri [l-(2-t-butyldimethyl-silyloxyethyl)-indol-5-yl] bismuthine &lt;250 mg. , 0.24 10 nunol.) in CH2CI2 (2mL.) at ft was added peracetic acid ( 0.05 inL. , 32% in acetic acid) followed in 15 minūtes by 17-ethyl-l,14-dihydroxy-12-[2'-(3&quot;,4&quot;-dihydroxycyclohexyl)-l' -methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo- I5 [22.3.1.0^ * 9]octacos-18-ene-2&gt; 3 f10,16-tetraonē (200mg, 0.25 mmol) and Cu(0Ac&gt;2 (20 mg.). The reaction mixture was stirred for 2 days. The reaction was then quenched with saturated NaHC03 and extracted with CH2CI2· The organic extracts were combined, 20 dried with Na2SŪ4, filtered and concentrated in vacuo. The product was isolated and purified by preparative TLC (3:1, hexane/acetone) to afford 74 mg. of the title compound. 30 202 EXAMPLE 39 17-Etliyl-1,14-dihydroxy-12-[2 '-(3M-hydroxy-4&quot;-(l-hydroxyethylindol-5-yl)oxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^»^]octacos-18-ene-2,3,10,16- tetraone_

To a solution of 17-ethyl-l,14-dihydroxy-12-[2'-(3&quot;-hyd roxy-4&quot;-(l-t-butyl-d imethyls ilyloxy-ethylindol-5-yl)oxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll ,.28-dioxa-4-aza-tricyclo[22.3.1.0^»9]octacos-18-ene-2,3,10,16-tetraone &lt;74ing) in CEļClļ (2 mL.) at rt was added a solution of p-toluene sulfonic acid (10 mg.) in CH3OH (2 mL.). The reaction mixture was stirred for 3 hr., guenched w.ith saturated NaHC03, then extracted with CH2CI2·

The extracts were combined, dried over Na2SŪ4, filtered and concentrated in vacuo.. The product was purified by preparative TLC on silica gel (2:1, liexane/acetone) to give 44.8 mg of the title compound. Partial 1H NMR (CDC1, 200 MHz) d: 7.24 (d, J=9Hz, 1H); 7.15 (d, J=3Hz, 1H); 7.12 (d, J=3.5Hz, 1H); 6.86 (dd, J=3 and J=9 Uz, 1H); 6.39 (d, J=3.5, 1H); 4.20 (t, J=5, 2H). - 203 -LV 10450 EXAMPLE 40

Tri[l-2(t-butyldimethylsilyloxyethyl)-indol-6-vll-bismuthine_ 10 15 20 25

To a solution of 4-bromo-2-nitrotoluene &lt;4.3 g., 20 mmol.) in DMF (40 mL.) was added DMF diinethylacetal (7.15g., 60 mmol.) and pyrrolidine (1.4 g., 20 mmol.). The solution was heated to 110° C for 4 hr.then cooled to rt. and diluted with ethyl ether. The mixture was vashed 3X with water, dried with Ma2S0^, filtered and the solvent evaporated. The residue was dissolved in 80% aqueous acetic acid (125 mL.) and heated to 75° C. Zinc dust (9.75 g., 150 mmol.) was added gradually over 20 min. The reaction inixture was heated to 85° C for 2 hr. then cooled to -35° C and filtered to remove unreacted zinc. The filtrate was diluted with ethyl ether, vashed 3X with vater then with saturated aqueous NaHCOg. The solution was dried with Na2S04, filtered and concentrated in vacuo to ~30 mL. then diluted with hexanes and filtered. The filtrate was concentrated to an off-white solid which was dissolved in hexane, filtered, and concentrated to give 1.65 g. of the title compound as a light green solid.

Steu B: 1-(2-t-Butyldimethylsilyloxyethyl)-6- bromoindole_l_ 30 To a slurry of NaH (192 mg., 4.8 mmol., 607» oil dispersion) in DMF (4 mL.) was added, dropwise, a solution of 6-bromoindole (0.85 g., 4.34 204 imnol.) in DMF (4 mL.)· After stirring for 10 min. at it;., 2-t-butyldiinethylsiloxyethyl bromide ((1.15 g., 4.8 īnmol. , neat) was added and the mixture stirred for 1.5 hr. The reaction mixture was partitioned between ice water and hexane. The organics were washed 2X with water, dried with Na2SC&gt;4, filtered and concentrated in vacuo to a dark oil. The product was isoiated by flash coluiim chroinatography (silica, 4:1 hexanes/acetone) to give 1.04 g. of the title compound as an oil.

Step C: Tri[l-(2-t-butyldimethylsilyloxyethyl)- indol-6-yn-bismuthine_;_

To a solution of l-(2-t-butyldimethyl-silyloxyethyl)-6-bromoindole (1.0 g., 2.81 mmol.) in ethyl ether (10 mL.) at -78° C was added t-butyllithium (3.4 mL., 5.8 mmol., 1.7M in pentane). After stirring for 10 min. a solution of B1CI3 (285 mg., 0.9 mmol.) in THF (3 mL.) was added. The reaction mixture was stirred for an additional 10 min. at -78° C then allowed to warm to rt overnight. The reaction raixture was partitioned between ice v/ater and CH2CI2· The organic layer was washed with water, dried with Na2SŪ4 and concentrated to a dark oil. Flash column chroraatography (silica, 4:1 hexane/acetone) afforded 630 mg. of the title compound as an dark oil (-607. pure) which was used without further purification in Example 41/the next step. 30 LV 10450 - 205 -EXAMPLE 41 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(l-t-butyldiraethyl-silyloxyethylindol-6-y1&gt;oxy-3' ’-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0^»^]octacos-18-ene- 2.3.10.16-tetraone_

To a solution of tri[l-(2“t-butyldimethyl-silyloxyethyl)-indol-6-yl] bismuthine (0.60 g., 0.58mmol.) in CH2CI2 (5mL.) at room temperature was added peracetic acid (0.080 mL. , 327. in acetic acid) followed in 15 minūtes by 17-ethyl-l,14-dihydroxy-12-[2'-(4&quot;-hydroxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-a2atricyclo[22.3.1.0^» ^]octacos-18-ene-2,3,10,16-tetraone (350 mg., 0.44mmol.) and Cu(0Ac&gt;2 (30 mg.).

The reaction mixture was stirred for 20 hr. The reaction was then quenched with saturated NaHCOg and the mixture extracted with CH2CI2. The organic extracts were combined, dried over Na2S04, filtered, and concent.rated in vacuo. The product was isolated and purified by preparative TLC on silica gel (3:1, hexane/acetone) to give 150 mg. of the title compound. 206 EXAMPLE 42 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(l-hydroxyethyl-indol-6-yl)oxy-3&quot;-methoxycyclohexyl)-l1 -methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^»^]octacos-18-ene-2,3,10,16- te_txaone_

To a solution of 17-ethyl-l,14-dihydroxy-12-[2’-(4&quot;-(l-t-butyld imethyls ilyloxyethylindol-6-yl)-oxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]-23,25-d imethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^*^]octacos-18-ene-2,3,10,16-tetraone (150 ing) in CH2CI2 (4 mL.) at rt was added a solution of p-toluene sulfonic acid (20 mg.) in CH3OH (4 mL.)· The reaction mixture was stirred for 2 hr., quenched with saturated NaHCC&gt;3, then extracted with CH2CI2· The extracts were combined, dried over Na2S0^, filtered and concentrated in vacuo. The product was purified by preparative TLC on silica gel (2:1, hexane/acetone) to give 55 mg of the title compound.

Partial 1H NMR (CDC1, 200 MHz) d: 7.47 (d, J=6 Hz, III); 7.03 (d, J=3 Hz, 1H); 6.94 (bs, 1H); 6.82 (dd, J = 1.5 IIz and J=6 Hz, 1H); 6.41 (d,J=3 Hz, 1H); 6.41 (d, J=3 Hz, 1H); 4.20 (t, J=5 Hz, 2H); 3.93 (t, J=5 Hz, 211); 3.50 (s, 3H). 30 20 25 - 207 -EXAMPLE 43 Tri(l-niethvlindol-6-vl)bismuthine To a solution of l-methyl-6-bromoindole (760 mg., 3.6 mmol.) in ethyl ether (15 mL.) at -78°C was added t-butyllithium (4.4 mL., 7.5 ramol., 1.7M in pentane). After 10 min. a solution of BiCl3 (375 mg., 1.2 mmol.) in THF (4 mL.) was added and the cooling batli removed. The reaction inixture stirred for 4 hr then poured into ice water and extracted with CH2CI2. The extracts were combined, backwashed with water, dried with Na2S04, filtered, and concentrated in vacuo to a dark oil. The product was crystallized from methanol to afford 290 mg. of the title compound as a tan solid. LV 10450 30 208 EXAMPLE 44 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(l-methylindol-6-yl)oxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]-23,25-diinethoxy-13,19,21,27-tetramethyl-ll, 28-dioxa-4-aza-trΐονο1οΓ22.3.1.04» 91octacos-18-ene-2.3.10.16-tetraone To a solution of tri[l-methylindol-6~yl]-bismuthine (200 mg., 0.33 mmol.) in CH2CI2 (2mL.) at room temperature was added peracetic acid (0.070 mL., 327. in acetic acid) folloved in 15 minūtes by 17-ethyl-l,14-dihydroxy-12-[2·-(4&quot;-hydroxy-3''-methoxy-cyclohexyl)-l'-methylvinyl]-23,25-diraethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo-[22.3.1.04»9]octacos-18-ene-2,3,10,16-tetraone (150 mg., 0.19 mmol.) and Cu(0Ac&gt;2 (30 mg.). The reaction mixture was stirred for 4 days. The reaction was then quenched with saturated NaHCŪ3 and the mixture extracted with CH2CI2. The organic extracts were combined, dried over Na2S04, filtered, and concentrated in vacuo . The product was isolated and purified by preparative TLC on silica gel (2:1, hexane/acetone) to give 76 mg. of the title compound. Partial 1H NMR (CDC1, 400 MHz) d: 7.44 (d, J=7Hz, 1H); 6.91 (d, J=3Hz, 1H) 6.88 (d, J=2Hz, 1H); 6.81 (m, III); 6.37 (d, J=3, 1H); 3.68 (s, 3H); 3.51 (s, 3H) . 30 LV 10450 - 209 -EXAMPLE 45 17- Ethyl-1,14-diliydroxy-12-[2 ’-(4&quot;-(l-dibenzyl-phosphonoxy-ethylindol-5-yl)oxy-3&quot;-methoxycyclohexyl)-1' -inethylvinyl]-23,25-dimethoxy-13,19,21,27-tetra-methyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^*^ļoctacos- 18- ene-2.3.10.16-betraone_'·

To a solution of 17-ethyl-l,14-dihydroxy-12-[2 '-(4&quot;-(^-hydl·oxyethylindol-5-yl)oxy-3&quot;-methoxy-cyclohexyl )-l’-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo-[22.3.1.04 &gt; ^]octacos-18-ene-2,3,10,16-tetraone (202 ing, azeotroped with toluene) in dry THF was added dibenzyl phosphate (88.6 mg) followed by triphenylpliosphine (83.5 mg). The reaction mixTure was cooled down to 0eC, then added diethyl azodicarboxylate (50 mL). The reaction mixture was stirred at 0®C for 5 minūtes, removed the ice bath, and stirred at room temperature for 2h. The crude reaction mixture was loaded directly onto the silica gel column and purified (ethyl acetate:hexane (2:3) + 17, MeOH) to give the title compound (197 mg).

Partial NMR (CDCl3)d: 7.29 (m, 6H); 7.18 (m, 5H); 7.12 (d, J = 9Hz, 1H); 7.0 (d, J = 4Hz, 1H); 6.89 (dd, J = 9, 2Hz, 1H); 6.36 (d, J = 4Hz, 1H); 4.82 (m, 4H); 4.40 (brd, J = 14Hz, 1H); 4.20 (m, 4H). 210

Monopotassiura salt of 17-Ethyl-l,14-dihydroxy-12-[2'-(4&quot;-(l-phosphonoxy-ethylindol-5-yl)oxy-3&quot;-methoxy-5 cyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13, 19 21.27- tetraraethyl-ll,28-dioxa-4-azatricyclo[22.3 1. Q4 ’ 9~loctacos-18-ene-2.3.10.16-tetraone_

To a solution of 17-ethyl-l,14-dihydroxy-12-[2'-(4&quot;-(l-dibenzylphosphate-ethylindol-5-yl)oxy-10 3&quot;-methoxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy- 13.19.21.27- tetramethyl-ll,28-dioxa-4-azatricyclo-[22.3.1.0^&gt; ^]octacos-18-ene-2,3,10,16-tetraone (197 mg) in inethanol (3.2 mL) was added potassium bicarbonate (16.3 mg) dissolved in water (200 mL). 15 Added palladium hydroxide over carbon, then charged the reaction mixture with hydrogen via balloon.

After the reaction was complete (10 min. by TLC analysis) , it was filtered over Celite and rinsed with methanol and small amount of water. The solvent 20 was reinoved in vacuo, and the crude material was purified on HP-20 column to give the title compound (69 mg).

Partial 1fl NMR (CD3OD) d: 7.34 (d, J = 9Hz, 1H); 7.27 (d, J = 4Hz, 1H); 7.12 (d, J= 2Hz, 1H); 6.85 25 (dd, J = 9, 2Hz, 1H); 6.31 (d, J = 4Hz, 1H); 5.23 (m, 2H); 4.35 (m, 2H); 4.13 (m, 2H). 30 LV 10450 - 211-EXAMPLE 47 17- Etliyl-1,14-dihydroxy-12-[2' -(4&quot;-(l-(N,N-dimethyl-glycyloxy)ethylindol-5-yl)oxy-3&quot;-methoxycyclohexyl)- 5 1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetra- methyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^»9]octacos- 18- ene-2.3.10.16-tetraone_

To a solution of 17-ethyl-l,14-dihydroxy-12-[2'-(4&quot;-(l-hydroxyethylindol-5-yl)oxy-3&quot;-methoxy-10 cyclohexyl)-l 1-methylvinyl]-23,25-dimethoxy- 13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo-[22.3.1.0^ *^]octacos-18-ene-2,3,10,16-tetraone &lt;26.6 mg) in dry methylene chloride (0.3 mL) was added hydrochloride salt of N,N-dimethylglycine (5.8 mg), 15 Dl’lAP (3.4 rag) and EDC (8 mg), Tespectively at room temperature. The reaction mixture was stirred for 4h, then diluted*with ethyl acetate and washed with saturated sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate, and the 20 solvent was removed in vacuo. The crude material was purified by flash chromatography (1:2/acetone:hexane). to give 23mg of the title compound.

Partial 1H NI1R (CDC13) d: 7.21 (m, 2H); 7.04 (d, J = 25 4Hs, III); 6.91 (dd, J = 9, 2Hz, 1H); 6.49 (d, J = 4Hz, 1H); 4.41 (m, 2H); 4.32 (m, 2H); 3.07 (s, 3H); 2.26 (s, 3H). 30 212 - EXAMPLE 48 17-Etliyl-1,14-dihydroxy-12-[2 ' -(4&quot;-(l-succinyloxy-ethylindol-5-yl)oxy-3&quot;-methoxycyclohexyl)-l1-methyl-vinyl]-23f 25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^ * ^]octacos-18-ene-2,3,10, 16-tetraone_

To a solution of 17-ethyl-l,14-dihydroxy-12-[2'-(4&quot;-(l-hydroxyethylindol-5-yl)oxy-3&quot;-methoxy-cycloliexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo-[22.3.1.0^'^]octacos-18-ene-2,3,10,16-tetraone (109 mg) in dry inethylene chloride was added succinic anyhydride (11.5 mg) and triethylamine (19 ml).

Added DI1AP (7 mg) to the reaction mixture and folloued the reaction by TLC. After 1.5h, the reaction inixture was diluted with ethyl acetate and* adjusted to pH 4 with 1N HC1. It was poured into the separatory funnel and the layers were separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layer was washed with brine. It was dried over magnesium sulfate, and the crude material was purified by flash chromatography (37. methanol/CIl2Cl2) to give 66 mg of the title compound. Partial NI1R (CDC13) d: 7.19 (m, 2H) ; 7.04 (d, J = 4Hz, 1H); 6.91 &lt;dd, J = 9, 2Hz , 1H); 6.39 (d, J » 4Hz, 1H); 4.32 (m, 4H); 2.49 (brs, 4H). LV 10450 - 213 -EXAMPLE 49 17-Ethyl-1,14-dihydroxy-12-[2' -(4M-(l-methyl-3-phenyl-indol-5-yl )oxy-3&quot;-inethoxycyclohexyl)-l1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^»9]octacos-18-ene-2,3,10,16-tetraone____ S_te.ļ)_A: 5-I3romo-3-phenvli satin

To a stirred mixture of 5-bromoisatin (5g., 22,1 mmol., 1 eq.) in dry THF (150 mL.) was added phenylmagnesium bromide (14.7 mL., 44.2 mmol., 2 eq. , 311 solution in diethyl ether)(The addition of Grignard reaģent was initiated at -78°C. The reaction mixture became too viscous to stir after addition of approximately 5 mL. of the Grignard reaģent. The cooling bath was removed and the remainder of the Grignard reaģent was added by quick dropwise addition.). The reaction mixture was i. stirred overniglit. Analysis by TLC showed a small amount of unreacted starting material. An additional 1.5 inL. of the Grignard reaģent was added and the reaction mixture was stirred an additional 6 hours. The reaction mixture was poured into a separatory funnel containing saturatēd aqueous ammonium chloride and was extracted 4x with diethyl ether. The organic extracts were combined, dried over anhydrous MgSO^, filtered and concentrated in vacuo. The product was carried on without further purification. 214 - SLeo B: 5-Bromo-3-phenvlindole

To a stirred solution of 5-bromo-3-phenylisatin (6.39 g. , 21 mmol., 1 eq.) in dry THF-(50 ml.) at 0°C was added lithium aluminum hydride (2.0g., 52.5 mmol., 2.5 eq.) portionwise over 1.5 hours. The cooling bath was removed and the reaction was allowed to stir overnight. The mixture was cooled to 0°C and carefully quenched with 1N aqueous HC1. The mixture was filtered through CeliteT&quot; and the Celite™ was washed with THF. The filtrate was concentrated in vacuo, dissolved in EtOAc and washed with water. The organic layer was dried over anhydrous MgSO^ , filtered and concentrated in vacuo.

Step C: 5-bromo-l-methvl-3-phenylindole

To a stirred solution of 5-broino-3-phenylindole (2.4 g., 8.78 mmol., 1 eq.) in dimethylformamide (20 mL.) was added NaH (422 mg. of a 60% dispersion in oil, 10.54 mmol., 1.2 eq.). The mixture was stirred 15 minūtes. Methyl iodide (0.6 ml, 9.66 mmol, 1.1 eq) was added via syringe and the reaction mixture was stirred 3 hours. The reaction was quenched with water and extracted 4x with EtOAc. The organic extracts were combined,dried over anhydrous llģS04, filtered and concentrated in vacuo The product was purified by flash column chromatography (2:1 hexanes/acetone) giving 1.63 g. 5-bromo-l-methyl-3-phenylindole. - 215 - - 215 - LV 10450 S_tep_JD: l£ii.ļ.-methYl-3-phenvlindol-5-vl’)bismuthine

To a stirred solution of 5-bromo-l-methyl-3-phenylindole (1.63 g. , 5.7 mmol., 1 eq.) in Et£Ū (35 mL.) at -78°C under N£ atmosphere was added t-buLi (6.7 mL. of a 1.7M solution in hexanes, 11.4 ininol., 2 eq.) dropwise via syringe. The reaction was stirred 10 minūtes at -78°C. To this mixture was added a solution of BiCl3 (540 mg., 1.71 nunol., 0.3 eq.) in THF (7 mL.) dropwise quickly. The reaction was stirred 10 minūtes at -78°C and the cooling bath was reinoved and the mixture allowed to warm to room temperature. After 3 hours the mixture was poured into a separatory funnel containing water and extracted 4x with CKļClļ· The organic extracts were combined, dried over anhydrous Na£S04, filtered and concentrated in vacuo. The residue was triturated with Et£0 and the solīds collected and washed with Et£0 giving 710 mg of

Tri(l-methyl-3-phenylindol-5-yl)bismuthine. 216

Step_E: 17-Ethyl-l,14-dihydroxy-12-[2'-(4&quot;-(l- methyl-3-phenylindol-5-yl)oxy-3&quot;-methoxy-cyclohexyl)-l'-methylvinyl]-23,25-dimethoxy -13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^» ^]octacos-18-ene- 2.3.10.16-tetraone_

To a stirred solution of tri(l-methyl-3-phenylindol-5-yl)bisinuthine (645 rag., 0.78 mmol., 1.2 eq.) in CH2C12 (10 mL.) and THF (3 mL. ) was added peracetic acid (0.514 mL. of a 32% solution in dilute acetic acid, 0.858 mmol., 1.3 eq.). The mixture was stirred 5 minūtes and 17-ethyl-l,14-dihydroxy-12-[2'-(4&quot;-hydroxy-3&quot;-methoxycyclohexyl)-l’-methylvinyl]-23,25-diinethoxy-13,19,21,27-tetramethyl-ll, 28-dioxa-4-azatricyclo[22.3.1.0^»^]octacos-18-ene-2,3,10,16-tetraone (514 ing., 0.65 mmol., 1 eq.) was added. Cu(0Ac)2 (12 mg., 0.065 mmol., 0.1 eq) was added.

The flask was capped and the mixture stirred. After 48 hours the reaction was quenched with saturated aqueous NaIIC03 and extracted 4x with CH2C12· The organic extracts were combined, dried over anhydrous NapSO/ļ, filtered and concentrated in vacuo. The product was purified by flash column chromatography on silica gel (2:1 hexanes/acetone) and again (3.5% CH30H/CI12C12) giving 78 mg 17-ethyl-l, 14-dihydroxy-12-[2'-(4&quot;-(l-methyl-3-phenylindol-5-yl)oxy-3&quot;-methoxy-cyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo-[22.3.1.0^»^]octacos-18-ene-2,3,10,16-tetraone.

Mass (FAB) 1003 (M++Li); 996 (M+).

Partial 1II NMR (CDC13, 400MHz) d: 7.59 (d, J=7Hz, 211); 7.50 (m, 1H); 7.41 (t, J=7Hz, 2H); 7.25-7.15 (m, 3H); 6.99 (dd. J=9Hz, J=2Hz, 1H); 4.57 (d, J=6Hz, 1H); 4.39 (bd, J=13 Hz, 1H); 3.78 (s, 3H). \ LV 10450 - 217 -EXAMPLE 50 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(l-methyl-3-(2-hydroxyethyl)indol-5-yl)oxy-3M-methoxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0^&gt;^]octacos-18-ene-2.3.1U.16-tetraone___

Sk ej)__A: 5-Bronio-3-livdroxyethylindole

To a stirred solution of 5-bromoindole-3-acetic acid (1.9g., 7.48 mmol., 1 eq.) in dry ΤΗΓ (17 mL.) at 0°C was added lithium aluminum hydride (570 rag. 14.96 mmol·, 2 eq.) portionwise over 30 minūtes. The reaction mixture coagulated. THF (20 mL.) was added and the cooling bath was removed. The mixture was stirred vigorously. Let stir overnight. The reaction mixture was carefully quenched with 1N aqueous HC1 and then acidified with 2N aqueous HC1. The mixture was filtered through Celite™ and the Celitem was washed with THF. The filtrate was concentrated in vacuo, dissolved in EtOAc, and washed with water.

The organic layer was dried over anhydrous MgS04, filtered and concentrated in vacuo. TLC analysis of the residue showed unreacted starting material. The residue was dissolved in Et£0 and extracted with 0.25N aqueous NaOH. The organic layer was dried over anhydrous MgS04, filtered and concentrated in vacuo giving 1.16g 5-bromo-3-hydroxyethylindole. 218

Step B: 5-Bromo-3-(2-t-butyldimethylsilyloxy)ethyl- indole___

To a stirred solution of 5-bromo-3-hydroxyethylindole (1.16g., 4.83 mmol., 1 eq.) in CH2CI2 (12inL.) was added triethylamine &lt;1.0mL., 7.25 īrnnol., 1.5eq.) followed by addition of t-butyldimethylchlorosilane (875mg., 1.2nunol., 1.2eq.) and dimethylaminopyridine(catalytic). The mixture was stirred overniglīt, poured into a separatory funnel containing water and extracted 4x with CH2Cl2· The organic extracts were combined, dried over anhydrous Na2SC&gt;4, filtered and concentrated in vacuo giving 1.66g. 5-bromo-3-(2-t-butyldimethylsilyloxy)ethylindole.

Sten C: 5-Bromo-l-methyl-3-(2-t-butyldimethy1sily1- oxv)ethylindole_

To a stirred solution of 5-bromo-3-(2-t-butyldimethylsilyloxy)ethylindole (1.66g., 4.66mmol., leq.) in DI1F (15mL.) was added NaH (225mg. of a 607o dispersion in oil, 5.6mmol. , 1.2eq.). After 15 minūtes iodomethane (0.320mL.f 5,13πυηο1., l.leq.) was added. The mixture was stirred 4 hours and then poured into a separatory funnel containing water and extracted 2x with EtOAc. The organic extracts were combined, dried over anhydrous MgSO^, filtered and concentrated in vacuo giving 1.49g. 5-bromo-l-methyl-3-(2-t-butyldimethyls ilyloxy)ethylindole. - 219 - - 219 - LV 10450

Step D: Tri(l-methyl-3-(2-t-butyldimethylsilyloxy)- ethvlindQl-5-vl)bismuthine_

To a stirred solution of 5-bromo-l-methyl-3-(2-t-butyldimethylsilyloxy)ethylindole (1.49g., 4.03mmol., leq.) in ΕΪ£θ &lt;15mL.) at -78*C under nitrogen atmosphere was added t-butyllithium (4.8mL. of a 1.7M solution in pentanes, 8.06mmol., 2eq.) dropwise via syringe. The mixture was stirred 10 minūtes at -78°C and then a solution of B1CI3 (381mg., 1.21mmol., 0.3eq.) in THF (5mL.) was added quichly dropwise via syringe. The mixture was stirred for 7 minūtes at -78°C under nitrogen. The cooling bath was removed and the mixture was allowed to warm to room temperature. After 1 hour the mixture was poured into a separatory funnel containing water and extracted 4x with CH2CI2. The organic extracts were combined, dried over anhydrous Na2S04, filtered and concentrated in vacuo giving 554 mg. crude product. NMR analysis of the residue indicates mixture of aproximately 2:1 of the desired bismuthine to reduced indole. Used the mixture crude in subsequent reaction.

Step E: 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(l- methyl-3-(2-t-butyldimethylsilyloxyethyl&gt;-indol-5-yl)oxy-3&quot;~methoxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3. l^-0-^O-Q-tĀCojs-18-ene-2.3.10.16-tetraone To a stirred solution of tri(l-methyl-3-(2-t-butyldiinethylsilyloxy)ethylindol-5-yl) bismuthine (554 mg. crude ) in CH2CI2 (10 mL.) and THF (3 mL.) 220 220 10 15 20 was added peracetic acid (0.120mL. of a 32% solution in dilute acetic acid, 0.571 mmol.). To this mixture was added 17-ethyl-l,14-dihydroxy-12-[2'-(4&quot;-hydroxy-3&quot;-methoxycyclohexyl)-l ’-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo-[22.3.1.0^*^]octacos-18-ene-2,3,10,16-tetraone &lt;347mg., 0.439nunol.) folloved by addition of Cu(0Ac)£ (24mg., 0.13minol.). The reaction mixture was allowed to stir overnight. The mixture was poured into a separatory funnel containing saturated agueous NaHC03 and extracted 4x with CH2CI2· The organic extracts were combined, dried over anhydrous Na2SŪ4, filtered and concentrated in vacuo. The product was purified by flasli column chromatography on silica gel (2:1 hexanes/acetone) giving 200mg. 17-ethyl-l,14-dihydroxy-12-[2'-(4&quot;-(l-methyl-3-(2-t-butyldimethyl-silyloxyethyl)indol-5-yl)oxy-3&quot;-raethoxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0^»^]octacos-18-ene-2,3,10,16-tetraone as a brown oil.

Step F: 17-Etliyl-1,14-dihydroxy-12-[2'-(4&quot;-(l- 25 methyl-3-(2-hydroxyethyl)indol-5-yl)oxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^*^]octacos-18- ene-2.3.10.16-tetraone_

To a stirred solution of 17-ethyl-l,14-dihydroxy-12-[2 *-(4M-(l-methyl-3-(2-t-butyldimethylsil yloxyethyl)indol-5-yl)oxy-3&quot;-methoxycyclohexyl)-l'-met hylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,2 8-dioxa-4-azatricyclo[22.3.1.0^*^]octacos-18-ene-2,3,1 30 - 221 - - 221 - LV 10450 Ο,16-tetraone (200mg.) in CH2CI2 (6mL.) and CH3OH (6mL.) was added p-toluenesulfonic acid monohydrate &lt;30ing.). The reaction mixture was allowed to stir 3 hours. The reaction was quenched with saturated agueous NaHC03 and extracted 4x with CH2CI2· The organic extracts were combined, dried over anhydrous Na2S0/f, filtered and concentrated in vacuo. The product was purified by preparative TLC on silica gel (1:1 hexanes/acetone) and again (77. CH3OH/CH2CI2) giving 75 mg. 17-ethyl-l,14-dihydroxy-12-[2'-(4U-(l-me thyl-3-(2-hyd roxyethyl)i ndol-5-yl)oxy-3n-methoxy-cyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo-[22.3.1.0^» 9]octacos-18-ene-2,3,10,16-tetraone.

Mass (FAB) 972 (M++Li).

Partial XH NMR (CDCI3, 400 MHz) d: 7.17-7,13 (m, 210; 6.94 (dd, J=9Hz, J=2Hz, 1H); 6.88 (s, 1H); 4.58 (d, J-6Hz, 1H); 4.39 (bd, J=13Hz, 1H); 3.84 (t, J=6Hz, 2H); 3.70 (s, 3H); 2.94 (t, J=7Hz, 2H). 30 222 EXAMPLE 51 17-Ethyl-1,14-dihydroxy-12-[2'-&lt;4&quot;-(l,3-dimethylindol-5-yl)oxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]-23,25-diinethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-aza-tļ Lcy.clor22.3.1.0^’ ^1octacos-18-ene-2.3.10.16-tetraone

Step A: 5-Bromo-3-inethvlindole

To a stirred mixture of 5-bromoisatin (5g., 22.1 mmol., 1 eq.) in dry THF (150 mL.) was added raethylmagnesium bromide (32 mL. of a 1.4M solution in toluene, 44.2 mrnol., 2 eq.) dropwise via syringe. After 45 minūtes TLC analysis showed small amount of unreacted bromoisatin. Added 3.2 mL. of methylraagnesium bromide solution. Let stir 1 hour. Cooled reaction mixture to 0°C. Added lithium aluminum hydride (1.26g., 33.15 mmol., 1.5 eq.) portionwise. Let stir 30 minūtes at 0°C. Removed cooling bath and let stir overnight. Cooled mixture to 0°C and carefully quenched reaction with IN aqueous HC1. Acidified with 2N aqueous HC1. Removed cooling bath. Let stir for 3 hours. Filtered mixture through Celite™. Washed Celite™ with THF. Concentrated filtrate in vacuo. Diluted residue with water and extracted 4x with CH2CI2· The organic extracts were combined, dried over anhydrous Na2SŪ4, filtered and concentrated in vacuo. Loaded residue onto a silica gel plug in a fritted filter and eluted with 4:1 hexanes/acetone. Collected fractions containing the desired product and concentrated in vacuo giving 2.85g. 5-bromo-3-methylindole. - 223 - - 223 -LV 10450

Step B: 5-Bromo-l.3-dimethvlindole

To a stirred solution of 5-bromo-3-methylindole (2.85g., 13.6 mmol., leq.) in D1IF (35 mL.) was added NaH (651 mg. of a 607. 5 dispersion in oil, 16.28 mmol., 1.2 eq.). The mixture was stirred 15 minūtes. To this mixture was added iodomethane (0.930 mL., 14.93 mmol., 1.1 eq.). The mixture was stirred for 2 hours. The DMF was removed in vacuo. The residue was diluted with water 10 and extracted 4x with Et20. The organic extracts were combined, dried over anhydrous MgSŪ4, filtered and concentrated in vacuo giving 3.‘04g. 5-bromo-l,3-dimethylindole as a reddish liquid. 15 Step C: TriCl. 3-dimethvlindol-5-vl)_bjLsmuthin£

To a stirred solution of 5-bromo-l,3-dimethylindole (3.04g., 13.57 mmol., 1 eq.) in Et20 (50 mL.) at -78°C under nitrogen atmosphere was added t-butyllithium (16 mL. of a 1.7M 20 solution in hexanes, 27.2 mmol., 2 eq.) dropvise via syringe. The mixture was stirred for 10 minūtes at -78°C. To the reaction was added a solution of BiCl3 (1.28g., 4.07mmol., 0.3 eq.) in THF (17 mL.) quickly dropv/ise via syringe. The mixture was stirred 5 25 minūtes at -78°C. The cooling bath was removed and the reaction was allowed to warm to room temperature. The reaction mixture was poured into a separatory funnel containing ice water and extracted 4x with CH2Cl2· The organic extracts were combined, 30 dried over anhydrous Na2S04» filtered and concentrated in vacuo. The residue was triturated 224 with Et2Ū. The solids were filtered off. The filtrate was concentrated in vacuo. giving 1.28g. brown oil. NMR analysis of the residue indicates material is a mixture of approximately 1:2 desired 5 tri(1,3-dimethylindol-5-yl)bismuthine: dimetliylindole. Material was used crude in subsequent Step D. SLeu D: 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(l,3-di- l o methylindol-5-yl)oxy-3”-methoxycyclohexyl)- 1'-methylvinyl]-23,25-dimethoxy-13,19,21,-27-tetramethyl-ll,28-dioxa-4-azatricyclo[22 .3.1.0^» ^1octacos-18-ene-2.3.10.16-tetraone To a stirred solution of tr i (1,3-dimethy.l-15 indol-5-yl)bismuthine (approximately 420 mg.[based on 1.28 g. of material containing one third bismuthine, .7 mmol., 1.2 eq.) in CH2CI2 (12 mL.) and THF (4 mL.) was added peracetic acid (0.193 mL. of a 32% solution in acetic acid, 0.916 mmol., 1.3 eq.). To this 20 mixture was added 17-ethyl-l,14-dihydroxy-12- [2(4&quot;-hydroxy-3&quot;-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl~ll,28-dioxa-4-azatricyclo[22.3.1.0^·^]octacos-18-ene-2,3,10,16-tetraone (464 mg., 0.59 mmol., 1 eq.) folloved by 25 addition of Cu(0Ac&gt;2 (30mg., 0.176 mmol., 0.3 eq.).

The mixture was stirred 4 days. The reaction was quenched with saturated aqueous NaHC03 and extracted 4x with CH2CI2· The organic extracts were combined, dried over anhydrous Na2S04» filtered and concentrated in vacuo. The product was purified by 30 - 225 - - 225 - LV 10450 flash column chromatography (2:1 hexanes/acetone) and again (3.5% CH3OH/CH2CI2) followed by preparative TLC (eluted 6x with 4:1 hexanes/acetone) giving 117 mg. of 17-ethyl-l,14-dihydroxy-12-[2'-(4&quot;-(l,3-dimethyl-indol-5-yl)oxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]-23,25-dimetlioxy-13,19,21,27-tetramethyl-ll, 28-dioxa-4-azatricyclo[22.3.1.0^»^]octacos-18-ene-2,3,10,16-tetraone.

Mass (FAB) 934 (M+).

Partial 1H NMR (CDCI3, 400 MHz) d: 7.14-7.10 (m, 2H); 6.91 (dd, J=9Hz, J=2Hz, III); 6.76 (s, 1H); 4.57 (d, J=6Hz, 1H); 4.39 (bd, J=13Hz, 1H); 3.66 (s, 3H); 2.24 (s, 3H). EXAMPLE 52 I. 17-Ethyl-1,14-dihydroxy-12-[2,-(4”-(l-benzylindol-5-yl)oxy-3&quot;-hydroxycyclohexyl)-l'-methylvinyl]-23,25-di-methoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatri- cvcloT22.3.1.04»91octacos-18-ene-2.3.10.16-tetraonfi_

To a stirred solution of tri(l-benzylindol-5-yl)bismuthine (1.28g., 1.54 mmol., 1.2eq.) in CH2C12 (9 mL.) and THF (3 mL.) was added peracetic acid (0.357 mL. of a 32% solution in dilute acetic acid, 1.69 mmol., 1.3 eq.). To this mixture was added 17-ethyl-l,14-dihydroxy-12-[2'-(3&quot;,4&quot;-dihydroxy-cyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo- [22.3.1.0^ *9]octacos-18-ene-2,3,10,16-tetraone (lg., 1.28 mmol., 1 eq.) followed by addition of Cu(0Ac)2 (23 mg.). The mixture was stirred 2 days. The 226 reaction was quenched with saturated agueous NaHCOj aml extracted 4x with CII2CI2· The organic extracts were coīnbined, dried over anhydrous Na2S04, filtered and concentrated in vacuo. The product was purified by flash coluran chromatography on silica gel (2:1 hexanes/acetone) and again (3.5% CH3OH/CH2CI2 ) and again (2:1 hexanes/acetone) giving 253 mg. 17-ethyl-l,14-dihydroxy-12-[2'-(4&quot;-(l-benzylindol-5-yl )oxy-3&quot;-hydroxycyclohexyl)-l' -methylvinyl]-23,25-dimet hoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo [22.3.1.0^»9]octacos-18-ene-2 , 3(10,16-tetraone.

Mass (FAB) 990(M++Li)..

Partial 1H NMR (CDCI3, 400MHz): 7.30-7.05'(m, 8H) ; 6^82 (dd, J=2Hz, J=8Hz, 1H); 6.43 (d, J=3Hz, 1H); 5.27 (s, 2H); 4.58 (d, J=6Hz, 1H); 4.40 (bd, J=13 Hz, 1H) . EXAMPLE 53 17-Ethyl-1,14-dihydroxy-12-[21-(4&quot;-(l-(3-hydroxy-propyl)indol-6-yl)oxy-3&quot;-methoxycyclohexyl)-1'-&quot; methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0^1^]octacos-18-ene-2.3.10.16-tetraone_

Step A: 2-t-Butvldimethylsilvloxyethyl bromide

To a solution of 2-bromoethanol (50 g, 0.40 mol) in CH2CI2 (50 mL) was added t-butyldimethylchlorosilane (63.4 g, 0.42 mol), triethylamine (45.4 g, 0.45 mol) and dimethylaminopyridine (0.5 g). After stirring overnight the reaction mixture was washed 3X with water. The organic fraction was dried with Na2S0^, filtered, and concentrated in vacuo to provide 85 g - 227 - - 227 - LV 10450 of the title corapound as a light yellow oil. 1- H NMR (CDC13) δ: 3.85 (t, 2H); 3.36 (t, 2H); 0.86 (s, 9H); 0.05 (s, 6H).

Step B: l-(2-Butyldimethylsilyloxyethyl)-5- bromoindole__

To a slurry of sodium hydride (12 g, 0.3 mol, 607o dispersion in oil) in DHF (200 mL) was added dropwise a solution of 5-bromoindole (50 g, 0.255 mol) in DHF (300 mL). After stirring for 15 minūtes 2- t-butyldimethylsilyloxyethyl bromide (60 g, 0.255 mol, neat) was added dropwise and the reaction mixture stirred for 1 hour. The reaction mixture was partitioned between ice water and ethyl ether. The organic fraction was washed with water, dried over Na2S04» filtered and concentrated in vacuo. The product was purified by column chromatography (silica, 3:1 hexane/acetone) to give 68.6 g of the title compound as a light yellow oil. ^ NMR (CDCI3) δ: 7.72 (s, 1H); 7.1-7.3 (m, 3H); 6.4 (d, 1H); 4.18 (t, 2H); 3.86 (t, 2H); 0.8 (s, 9H); -0.18 (s, 6H).

Step C: 17-Ethyl-1,14-dihydroxy-12-[21-(4&quot;-(l-(3-t- buty ld imethy.l s i lyloxypropyl) indol-6-yl)oxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]~23,-25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22,3.1.0^r 9]0ctacos-18- ene-2.3.10.16-tetraone_

To a solution of tri[l-(3-t-butyldimethyl-silyloxypropyl)-indol-6-yl]bismuthine (0.917 gm, crude) in CH2C12 (7 inL) at room temperature was added peracetic acid (0.10 inL, 327. in acetic acid) followed 228 in 15 minūtes by 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-hydroxy-3&quot;-methoxycyclohexyl)-l'raethylvinyl]-23,25-diinethoxy-13,19,21,27-tetramethyl-ll, 28-dioxa-4-aza-tricyclo[22.3.1.0^»^]octacos-18-ene-2,3,10,16-5 tetraone (500 mg,. 0.63 mmol) and Cu(0Ac&gt;2 (50 mg). The reaction mixture was stirred for 2 days. The reaction was then quenched with saturated NaHC03 and the mixture extracted with CH2CI2. The organic extracts were combined, dried over Na2SŪ4, filtered, 10 and concentrated in vacuo. The product was isolated and purified by preparative TLC on silica gel (3:1 ,hexane/acetone) to give 318 mg o.f the title compound. 15 Step D: 17-Ethyl-1,14-dihydroxy-12-[2’-(4&quot;-(l- (3-hydroxypropyl)indol-6-yl)oxy-3&quot;-inethoxycyclohexyl)-l' -methylvinyl]-23 25-dimethoxy-13,19,21,27-tetramethyl-.U r 28-dioxa-4-azatricyclo[22,3.1.0^*^ļoctacou- 20 18-ene-2.3.10.16-tetraone_

To a solution of 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(l-(3-t-butyldimethylsilyloxypropyl)indol-6-yl)oxy-3&quot;-inethoxycyclohexyl)-l' -methylvinyl]-23,25-dimetlioxy-13,19,21,27-tetramethyl-ll, 28-dioxa-4-aza-25 tricyclo[22.3.1.0^* ^]octacos-18-ene-2,3,10,16-tetra-one (318 mg) in CH2CI2 (5 mL) at rt was added a“ solution of p-toluene sulfonic acid (25 mg) in CH3OH (5 mL). The reaction mixture was stirred for 3 hours quenched with saturated NaHCC^ , then extracted with 30 - 229 - - 229 - LV 10450 CII2C.I2· The extracts were combined, dried over Wa2S04, filtered and concentrated in vacuo. The product was purified by preparative TLC on silica gel (2:1,hexane/acetone) to give 190 mg of the title compound.

Partial 1H NMR (CDCI3, 200 MHz) δ: 7.43 (d, J=9 Hz, 1H); 7.02 (d, J=2 Hz, 1H); 6.98 (d, J=3 Hz, 1E); 6.78 (dd, J=2 Hz and J=9 Hz, 1H); 6.38 (d, J=3 Hz, 1H); 4.20 (t, J = 6.5 Hz, 2H); 2.00 (πι, 2H). EXAMPLE 54 17-Ethyl-1,14-dihydroxy-12-[2,-(4,,-((2' 1 * »-(3' ' &quot; ·-diethylaminopropionyloxy)ethyl)indol-5''*-yl)oxy-3&quot;-methoxycyclohexyl)-l1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo- Γ22.3.1.0^ * ^1octacos-18-ene-2.3.10.16-tetraone_

To a stirred solution of 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(l'''-(2''''-hydroxyethyl)indol-5'''-yl)oxy-3&quot;-methoxycyclohexyl)-l,-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo-[22.3.1.0^ *^]octacos-18-ene-2,3,10,16-tetraone (200ing., 0.210 mmol. , 1 eq.) in CH2CI2 (2 mL.) under nitrogen was added 3-N,N-diethylamino-propionic acid hydrochloride (57 mg., 0.315 mmol., 1.5 eq.), dimethylaminopyridine (26 mg., 0.210 mmol., 1 eq.) and EDC (60 mg., 0.315 mmol., 1.5 eq.). The reaction was stirred for 1 hour. The mixture was diluted with ethyl acetate, washed with IN aq. HC1, saturated aqueous NaHC03 and then brine. The organic layer was dried over anhydrous MgSŪ4, filtered and concentrated in vacuo. The product was purified by 230 flash coluinn chromatography (3:2 hexanes/acetone) to give 194 mg. 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-((2''''-(3'1'''-dietliylaminopropionyloxy)ethyl)indol-5'''-yl)oxy-3&quot;-methoxycyclohexyl)-l1-methylvinyl]-23, 25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatr icyclo[22.3.1.0^»^Joctacos-18-ene-2,3,10,16-tetraone. Mass (FAB) 1079 (M++ 1). EXAMPLE 55 10 15 17-Ethyl-1,14-dihydroxy-12-[2 *-(4&quot;-((2'·*'-(3''· ”-diinethylaminopropionyloxy)ethyl)indol-5' ’ ,-yl)oxy-3&quot;-methoxycyclohexyl)-l’-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo-J122^1Jl·Λ^LL?JiELίL5^LQSJχl8^IlĒI^JiJJLJ16^

The title compound is prepared in the manner of Example 54 employing 3-N,N-dimethylamino-propionic acid. 20 EXAMPLE 56 17-Ethyl-1,14-dihydroxy-12-[2 '- (4&quot;-((2' · &quot;-(3&quot; 1 &quot;-arainopropionyloxy)ethyl)indol-5'1'-yl)oxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo-r22.3.1.0^,^loctacos-18-ene-2.3.10.16-tetraone

The title compound is prepared in the manner of Example 54 employing 3-aminopropionic acid in suitably protected form followed by deprotection of the amino group. 30 LV 10450 231 -EXAMPLE 57 17-Ethyl-1,14-dihydroxy-l2-[2'-(4&quot;-((2'·''-(3''·''-benzyloxycarbonyl-2' ' ’ ' ' -benzyloxycarbonylami.no-5 propionyloxy)ethyl)indol-5'''-yl)oxy-3&quot;-raethoxycyclo- hexyl)-l 1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^»9]- octacos-18-ene-2.3.10.16-tetraone_

To a stirred solution of 17-Ethyl-1,14-10 dihydroxy-12-[2’-(4&quot;-(l'·'-(2·'''-hydroxyethyl)indol- 5'''-yl)oxy-3&quot;-raethoxycyclohexyl)-l'-methylvinyl]-23, 25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo-[22.3.1.0^»^]octacos-18-ene-2,3,10,16-tetraone (500mg., 0.526 mmol., 1 eq.) in CH2CI2 (5 15 mL.) under nitrogen was added N-Cbz-aspartic acid -P-benzyl ester (225 mg., 0.631 mmol., 1.2 eq.), dimethyl-aminopyridine (64 mg., 0.526 mmol., 1 eq.) and EDC (120 mg., 0.631 mmol., 1.2 eq.). The reaction was stirred for 2 hours. TLC analysis 20 indicated reaction complete. The mixture was diluted with ethyl acetate, washed with 1N aq. HC1, saturated aqueous NaHCOg and then brine. The organic layer was dried over anhydrous MgSO^, filtered and concentrated in vacuo. The product was purified by flash column 25 chromatography (70:30 hexanes/acetone) to give 687 mg 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-((2''1'-(3'''''-benzyloxycarbonyl-2'1'''-benzyloxycarbonyl-aminopropionyloxy)ethyl)indol-5'''-yl)oxy-3&quot;-methoxy-cycloliexyl)-l' -inethylvinyl]-23,25-dimethoxy-13,19,21, 27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.04»^]-octacos-J.8-ene-2,3,10,16-tetraone. 30 232 EXAMPLE 58 17-Ethyl-1,14-dihydroxy-12-[2-(4&quot;-((21’''-(aspartyl-oxy)ethyl)indol-5' ' *-yl)oxy-3&quot;-raethoxycyclohexyl)-l'-methylvinyl]-23,25-diinethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0^&gt; 9]octacos-18-ene- 2.3.10.10-tetraone_

To a solution of 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-((2''1'-(3'''''-benzyloxycarbonyl-2' benzyloxy-carbonylaminopropionyloxy)ethyl)indol-5'' yl )oxy-3&quot;-inethoxycyclohexyl)-l' -methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatr icyclo-[22.3.1.0^ *^]octacos-18-ene-2,3,10,16-tetraone (125 mg. 0.093 minol., 1 eq.) in methanol (2 mL.) was added palladium hydroxide on carbon (25 mg.). The flask was charged with hydrogen and allowed to stir for 30 minūtes. The reaction was filtered through a 0.45 jim PTFE membrane and concentrated in vacuo. The product was purified by flash coluran chromatography (100:10:5:0.5 / CHCI3: MeOH:forinic acid:H20) to give 95 mg J. /—Etliyl — 1,14-dihydroxy-12-[2 '-(4&quot;-( (2' 1 ' (aspartyloxy)ethyl)indol-5'''-yl)oxy-3&quot;-methoxycyclo-hexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^»^]-ocLacos-18-ene-2,3,10,16-tetraone. Mass (FAB) 1067 (M+). - 233 - - 233 -LV 10450 17-Ethyl-l,14-dihydroxy-12-[2'-(4&quot;-((2''''-(1' ' ' ' *-imidazolylcarbonyloxy)ethyl)indol-5''1-yl)oxy-3&quot;-5 methoxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy- 13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo- ί 22^3^1,..0-1_

To a stirred solution of 17-Ethyl-1,14-diliydroxy-12-[2'-(4&quot;-(l1 ' ’ — &lt;2 * ' ' ' -hydroxyethyl)indol-5 10 ii·-yl)oxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]-23,- 25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo-[22.3.1.04,9Joctacos-18-ene-2,3,10,16-tetraone (1.5 g., 1.58 mmol., 1 eq.) in CH2CI2 (15 mL.) under nitrogen was added carbonyl diimidazole 15 (256 mg., 1.58 mmol., 1 eq.). After 45 minūtes thē reaction mixture was diluted with ethyl acetate, washed with 1N aq. HC1 and then brine. The organic layer was dried over anhydrous MgSO^., filtered and concentrated in vacuo. The residue was used vithout 20 furtlier purification EXAMPLE 60 17-Ethyl-l,14-dihydroxy-12-[2'-(4&quot;-(&lt;2''·'-(1· &quot; ''-25 piperazinocarbonyloxy)ethyl)indol-5' ’ '-yl)oxy-3&quot;- methoxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo- Γ 2 2.3.1.Q4,91octacos-18-ene-2.3.10.16-tetraone_

To a stirred solution of 17-Ethyl-1,14-30 dihydroxy-12-[2'-(4&quot;-((2''''-(!''''1-imidazolyl- 234 carbonyloxy)ethyl)-indol-5'''-yl)oxy-3&quot;-methoxycyclo-hexyl)-l'-methyl-vinyl]-23,25-dimethoxy-13,19,21,27-tetrainethyl-ll, 28-dioxa-4-azatricyclo[22.3.1.0^»^]-octacos-18-ene-2,3,10,16-tetraone &lt;100 mg., 0.096-minol. , 1 eq.) in THF (1 mL.) at room temperature under nitrogen was added piperazine (82 mg., 0.956 inmol., 10 eq.). The mixture was stirred for 2 hours at room temperature, stored overnight in freezer then stirred for an additional 6 hours at room temperature. The reaction was diluted with ethyl acetate, washed with IN HC1, saturated NaHCŪ3, and brine. The product was purified by flash column chromatography on silica gel (.57, methanol/ČI^C^ and then 57. methanol/CI^C^ plus 1% NH4OH) to give 74 mg. Mass (FAB) 1064 (M++l). EXAMPLE 61 17-Ethyl-1,14-dihydroxy-12-[2’-(4&quot;-(l'·'-(2· &quot; (2f''''-hydroy)ethylaminocarbonyloxy)ethyl)indol-5'''-yl)oxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-aza-tricvclor22.3.1.0^·^1octacos-18-ene-2.3.10.16-tetraone To a stirred solution of 17-Ethyl-1,14-dihydroxy-12-[2'-&lt;4&quot;-(l'''-(2'''-(1'''''-imidazolyl-carbonyloxy)-ethyl)indol-5'1'-yl)oxy-3&quot;-methoxycyclo-hexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^»^]-octacos-18-ene-2,3,10,16-tetraone (100 mg., 0.096 mmol., 1 eq.) in THF (1 mL.) at room temperature under nitrogen vjas added ethanolamine (29 μ.1*. , 0.4/8 - 235 - - 235 - LV 10450 mmol., 5 eq.). The reaction was stirred for 30 minūtes at room temperature. The reaction was diluted with ethyl acetate, washed with 1N HC1, saturated NaHC03, and brine. The product was 5 purified by flash column chromatography on silica gel (45/65 acetone/hexanes) to give 50 mg. 17-Ethyl-l,14-dihydroxy-12-[2'-(4&quot;-(l' ' «-(2' ' ' '-(2' ' 1 ' *-hydroy)-ethylaminocarbonyloxy)ethyl)indol-511'-yl)oxy-3M-methoxycyclohexyl)-lc-methylvinyl]-23,25-dimethoxy-10 13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo- [22.3.1.0^’ 9]octacos-18-ene-2,3,10,16-tetraone. Mass (FAB) 1061 (M++Na); 1038 (M++l). EXAMPLE 62 15 ~ 17-Ethyl-1,14-dihydroxy-12-[2,-(4,,-(l'1 '-(2·' · (isopropyaminocarbonyloxy)ethyl)indol-51 ' '-yl)oxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo- 20 122.3.1.04&gt; 91octacos-18-ene-2.3.10.16-tetraone_

To a stirred solution of 17-Ethyl-1,14-dihydroxy-12-[2,-(4&quot;-(l'''-(2''''-(1'·'1'-imidazolyl-carbonyloxy)ethyl)indol-5'''-yl)oxy-3&quot;-methoxycyclo-hexyl)-l'methylvinyl]-23,25-dimethoxy-13,19,21,27-25 tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^»^]- octacos-18-ene-2,3,10,16-tetraone (116 mg., 0.111 mmol., 1 eq.) in THF (1 mL.) at room temperature under nitrogen was added isopropylamine (48 μΕ., 0.555 mmol., 5 eq.). The reaction was stirred for 30 overnight. The reaction was diluted with ethyl acetate, washed with 1N HC1 and brine. The product - 236 - was purified by flash column chromatography on silica gel (2:3 acetone/hexanes) to give 50 mg. 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;~(1'1*-(2·'1’-(isopropyamino-carbonyloxy)ethyl)indol-5'''-yl)oxy-3&quot;-methoxycyclo-5 hexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27- tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^»9]-octacos-18-ene-2,3,10,16-tetraone. Mass (FAB) 1043 (M++Li). 10 EXAMPLE 63 17-Ethyl-l,14-dihydroxy-12-C2,-(4&quot;-(l'''-(2f·* (1'''''-piperidinocarbonyloxy)ethyl)indol-51·'-yl)oxy-3&quot;-methoxycyciohexyl)-l'-methylvinyl]-23,25-dimethoxy- . 15 13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo- Γ22.3.1.04» 91octacos-18-ene-2.3.10.16-tetraone_

To a stirred solution of 17-Ethyl-1,14-dihydroxy-12-[2 ,-(4,'-(l' ' '-(2' » ' ’-(l' ' · ' '-imidazolyl-carbonyloxy)ethyl)indol-5'''-yl)oxy-3&quot;-methoxycyclo-20 hexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27- tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^*^]-octacos-18-ene-2,3,10,16-tetraone (150 mg., 0.143 mmol.,’1 eq.) in THF (1 mL.) at room temperature under nitrogen was added piperidine (42 μΕ., 0.717 25 īrnnol., 5 eq.). The reaction was stirred 1 hour. The reaction was diluted with ethyl acetate, washed with 1N HC1 and brine. The product was purified by flash column chromatography on silica gel (4:1 hexanes/ acetone) to give 115 mg. 17-Ethyl-1,14-dihydroxy-30 12—[2'-(4&quot;-(l'''-(2''1'-(!·''''-piperidinocarbonyl- - 237 - LV 10450 oxy)ethyl)indol-5'1'-yl)oxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04* ^]octacos-18-ene-2,3,10,16-tetraone. Mass (FAB) 1062 (M+). EXAMPLE 64 17-Ethyl-1,14-dihydroxy-12-[2'-(4M-(1'''-(2''''- (1'’'''-morphilinocarbonyloxy)ethyl)indol-5'1'-yl)oxy- 3&quot;-methoxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy- 13.19.21.27- tetramethyl-ll,28-dioxa-4-azatricyclo- Γ 22.3·1.04 &gt; 91octacos-18-ene-2.3.10.16-tetraone_

To a stirred solution of 17-Ethyl-l,14-dihydroxy-12-[2'-(4&quot;-(l'''-(2'1''-(1*'«·'-imidazolyl-carbonyloxy)ethyl)indol-5 ’' '-yl)oxy-3&quot;-methoxycyclo-hexyl)-l1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.04»9]-octacos-18-ene-2,3,10,16-tetraone (100 mg., 0.096 nunol., 1 eq.) in THF (1 mL.) at room temperature under nitrogen was added morphiline (42 μΙ*. , 0.478 mmol., 5 eq.). The reaction was stirred 4 hours.

The reaction was diluted with ethyl acetate, washed with 1N HC1, saturated aqueous NaHC03 and brine.

The product was purified by preparative TLC on silica gel (4% MeOH/CH2Cl2) to give 85 mg. product. The compound was further purified by preparative TLC on silica gel (47. MeOH/CH2Cl2) to give 67 mg. 17-Ethyl-l,14-dihydroxy-12-[2'-(4&quot;-(l»''-(2&quot; ''-(1' &quot; &quot;-morphilinocarbonyloxy)ethyl)indol-5‘',-yl)oxy-3&quot;-methoxycyclohexyl)-l’-methylvinyl]-23,25-dimethoxy-13, 19.21.27- tetraraethyl-ll,28-dioxa-4-azatricyclo- [22.3.1.04 *9]octacos-18-ene-2,3,10,16-tetraone. Mass (FAB) 1064 (M+). EXAMPLE 65 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(l'''-(2'’' (diphenylaminocarbonyloxy)ethyl)indol-5·',-yl)oxy-3&quot;-methoxycyclohexyl)-1'-methylvinylj-23,25-d imethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo- Γ22.3.1.O4»91octacos-18-ene-2.3.10.16-tetraone_

To a stirred solution of 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(l'·* —&lt;2''''-hydroxyethyl)indol-5'',-yl)oxy-3&quot;-methoxycyclohexyl)-l,-methylvinyl]-23, 25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.04,^]octacos-18-ene-2,3,10,16-tetraone (lOOmg., 0.105 mmol., 1 eq.) in CH2CI2 (1 mL.) under nitrogen was added diphenylcarbamyl-chloride (29 rag., 0.13mmol., 1.2 eq.), triethylamine (22μ1,. , 0.16 mmol., 1.5 eq.) and dimethylamino-pyridine ( 3mg., 0.021 mmol., 0.2 eq.). The reaction was stirred overnight. More diphenylcarbamylchloride (15 mg.) and triethylamine (ΙΙμΕ.) were added. After 3 hours the reaction mixture was diluted with ethyl acetate, washed with 1N aq. HC1, water and then brine. The organic layer was dried over anhydrous MgSO^, filtered and concentrated in vacuo. The product was purified by preparative TLC (3% MeOH/ CH2CI2) to give 50 mg. 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(l'1'-(2''''-(diphenylaminocarbonyloxy)ethyl)-indol-5'''-yl)oxy-3&quot;-methoxycyclohexyl)-l1-methyl-vinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.04·9]octacos-18-ene-2,3,10, 16-tetraone. Mass (FAB) 1046 (M+). 239 - 239 - LV 10450 mrei«g-66 17-Ethyl-1,14-dihydroxy-12-[21-&lt;4M-(11'»-(2''''-(diethylaminocarbonyloxy)ethyl)indol-5'''-yl)oxy-3&quot;-5 methoxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy- 13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo- Γ22.3.1.04 &gt;9loctacos-18-ene-2.3.10.16-tetraone_

To a stirred solution of 17-Ethyl-l,14-dihydroxy-12-[2'-(4&quot;-&lt;l'''-(2''''-hydroxyethyl)indol-10 511'_yi)oxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]-23, 25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0419]octacos-18-ene-2,3,10,16-tetraone (100mg., 0.105 mmol., 1 eq.) in CH2CI2 (1 mL.) under nitrogen was added diethylcarbamylchloride 15 &lt;16 μΙ-,. , 0.13 mmol., 1.2 eq.), triethylamine (22μ1.. , 1.5 eq.), and dimethylaminopyridine (13 mg.f 1.0 eq.). The reaction was stirred overnight. The mixture was heated and maintained at reflux for 4 days. The mixture was cooled, diluted with ethyl 20 acetate, washed with 1N aq. HC1 and then brine. The organic layer was dried over anhydrous MgSO^., filtered and concentrated in vacuo. The product was purified by preparative TLC &lt;3% MeOH/ CH2CI2) to give 16 mg. 17-Ethyl-l,14-dihydroxy-12-[2’-(4&quot;-(l&quot; 25 (2'''·-&lt;diethyaminocarbonyloxy)ethyl)indol-5'1'-yl&gt;- oxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.04» 9]octacos-18-ene-2,3,10,16-tetraone. Mass (FAB) 1057 (M++Li). 30 EXAMPLE 67 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(l' ' '-(2’ 1 ' methanesulfonyloxyethyl)indol-5111-yl)oxy-3&quot;-methoxy-cyclohexyl)-l1-methylvinyl]-23,25-dimethoxy-13,19,21, 27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^·9]_ octacos-18-ene-2.3.10.16-tetraone_

To a stirred solution of 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(l'’'-(2''''-hydroxyethyl)indol-5'''-yl)oxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]-23, 25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^» ^]octacos-18-ene-2,3,10,16-tetra one (500mg., 0.526 mmol., 1 eq.) in CH2CI2·(20 mL.) under nitrogen at 0°C was added triethylamine (147μΙ,. , 1.053 mmol., 2 eq.), foliowed Έγ methanesulf onylchloride (54μί., 0.579 mmol., 1.1 eq.). The reaction was stirred 10 minūtes and the cooling bath was removed. The reaction was stirred at room temperature for three hours. The mixture was stored in the freezer overnight. The solvent was removed in vacuo. The product was used without purification EXAMPLE 68 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(l'1'-(2'1''-azido-ethyl)indol-5''1-yl)oxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0^'^]octacos-18-ene- 2.3.10.16-tetraone_

To a stirred solution of 17-Ethyl-1,14-dihydroxy-12-[2'-(4”-(l'''-(2''1'-methanesulfonyloxy-ethyl)indol-5111-yl)oxy-3&quot;-methoxycyclohexyl)-l1 - - 241 - - 241 - LV 10450 methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0^» ^]octacos-18-ene-2 ,3,10,16-tetraone ( 0.526 mmol., 1 eq.) in DMF (10 mL.) under nitrogen was added sodium azide (171 mg., 2.63 mmol., 5 eq.).,The reaction was heated to 60eC for 2 hours The solvent was removed in vacuo- The residue was diluted with ethyl acetate and washed with brine. The aqueous layer was extracted 3x with ethyl acetate. The organic extracts were dried over anhydrous MgSO^ filtered and concentrated in vacuo. The product was purified by flash column chromatography on silica gel (2:1 hexanes/acetone) giving 310 mg. 17-Ethyl-1,14-dihydroxy-12-{2'-(4&quot;-(1*''-(2''''-azidoethyl)indol-51'’-yl)oxy-3&quot;-methoxy-cyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21, 27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^^3-octacos-18-ene-2,3,10,16-tetraone. Mass (FAB) 975 (M+). 17-Ethyl-l,14-dihydroxy-12-[2,-(4',-(l' ' '-(2' * ' ’-amino-ethyl)indol-5'''-yl)oxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0^ *^]octacos-18-ene- 2,3 ,.lCh16-tetraone_

To a stirred solution of 17-Ethyl-l,14-dihydroxy-12-[2’-(4&quot;-(l'''-(2''1'-azidoethyl)indol-5' ' '-yl)oxy-3&quot;-methoxycyclohexyl)-l’-methylvinyl]-23, 25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.04» ^]octacos-18-ene-2,3,10,16- 242 tetraone (260 mg., 0.27 nunol.t 1 eq.) in THF (6 mL.) was added water (7 drops) followed by triphenyl-phosphine (87 mg., .33 mmol., 1.25 eq.). The reaction was stirred at room temperature for 16 hours The solvent was removed in vacuo. The product was purified by flash column chromatography on silica gel (10% MeOH/CH2Cl2) giving 227 mg. 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(ļ'''-(2''''-aminoethyl)indol-5'''-yl)oxy-3&quot;-methoxycyclohexyl)-l,-methylvinyl]-23, 25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^* ^]octacos-18-ene-2,3,10,16-tetraone. Mass (FAB) 956(M++ Li). EXAMPLE 70 15 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(l1·'-t-butyldi-methylsilyloxyethoxyethylindol-511'-yl)oxy-3&quot;-methoxy-cyclohexyl)-l,-methylvinyl]-23,25-dimethoxy-13,19,21, 27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^* octacos-18-ene-2.3.10.16-tetraone_

To a solution of triCl-(2-t-butyldi-methylsilyloxy-ethoxyethyl)-indol-5-yl] bismuthine (360 mg., 0.31 mmol.) in CH2C12 (3mL.) at rt was added peracetic acid ( 0.05 mL., 32% in acetic acid) followed in 10 minūtes by 17-Ethyl-1,14-dihydr03ty-12-[2'-(3&quot;,4&quot;-dihydroxycyclohexyl)-l'-methylvinyl]~ 23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo-C22.3.1.0^» ^]-octacos-18-ene-2,3,10,16-tet raone (200mg, 0.25 mmol) and Cu(0Ac)2 (20 mg.). The reaction mixture was stirred for 18 hrs. The reaction 30 - 243 - - 243 - LV 10450 was then quenched with saturated NaHC03 and extracted with CH2Cl2· The organic extracts were combined, dried with Na2SŪ4, filtered and concentrated in vacuo. The product was isolated and purified by preparative TLC &lt;3:1, hexane/acetone) to afford 120 mg. of the title compound as a dark oil. EKAMPLB. 71 17-Ethyl-1,14-dihydroxy-12-[2'-^&quot;^l1''-hydroxy-ethoxyethylindol-5' ' '-yl)oxy-3,,-methoxycyclohexyl)-l,-methylvinyl]-23 ,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0^»9]octacos-18-ene- 2.3.10.16- tetraone_

To a solution of 17-Ethyl-l,14-dihydroxy-12-[2'-(4M-&lt;111'-t-butyldimethylsilyloxyethoxy-ethyl-indol-5* ' '-yl)oxy-3&quot;-methoxycyclohexyl)-l'-methyl-vinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^»^]octacos-18-ene- 2.3.10.16- tetraone &lt;120mg) in CEļClļ &lt;3 mL.) at rt was added a solution of p-toluene sulfonic acid &lt;20 mg.) in CH3OH &lt;3 mL.). The reaction mixture was stirred for 3 hr., quenched with saturated NaHC03, then extracted with CH2CI2· The extracts were combined, dried over Na2S04, filtered and concentrated in vacuo. The product was purified by preparative TLC on silica gel &lt;2:1, hexane/acetone) to give 51 mg of the title compound. Partial NMR &lt;CDC13, 200 MHz) 6: 7.19 &lt;d, J=9Hz, 1H); 7.17 &lt;d, J=2 244

Hz, 1H); 7.08 (d, J=3.5 Hz, 1H); 6.89 (dd, J=2 and J=9 Hz, 1H); 6.34 (d, J=3.5 Hz, 1H) ; 4.22 (t, J=5 Hz, 2H); 3.73 (t, J=5 Hz, 2H); 3.57 (t, J=5 Hz, 2H); 3.39 (t, J=5 Hz, 2H) EXAMPLE 72 17- Ethyl-1,14-dihydroxy-12-[21 -(3,,-methoxy-4&quot;-(l1 · 1 -(1''''-oxoprop-3''''-yl)indol-5'''-yl)oxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetra-methyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^·^]octacos- 18- ene-2.3.10.16-tetraone_

To a solution of 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(l'''-&lt;3 *''*-hydroxypropyl)indol-5''*-yl)-oxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]-23,25-d imethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^»^Joctacos-18-ene-2,3,10,16-tetraone (700 rag., 0.726 mmol.) in CH2CI2 (25 mL) was added DMSO (2 mL.) and diisopropylethylamine ( 3.7 mL.) followed by pyridine sulfur trioxide (650 mg., 4.1 mmol.). The mixture was stirred for 20 min. then poured into saturated agueous NaHC03. The product was extracted into CH2CI2 which was then dried with Na2SŪ4, filtered, and concentrated in vacuo. The product was purified by column chromatography (silica gel, 4:1 hexane/acetone) to give 457mg. of the title compound. Partial ^H NMR (CDCI3, 200 MHz) δ: 9.77 (s, 1H); 7.19 (d, J=2Hz, 1H); 7.15 (d, J=9 Hz, 1H); 7.04 (d, J=3.5 Hz, 1H); 6.89 (dd, J=2 and J=9 Hz, 1H); 6.33 (d, J=3.5 Hz, 1H); 4.39 (t, J=5 Hz, 2H); 2.94 (t, J=5 Hz, 2H). EXAMPLE 73 17-Ethyl-1,14-dihydroxy-12-[2'-(3M-methoxy-4&quot;-(l1'' -(1''''-carboxyeth-2''11-yl)indol-5'''-yl)oxycyclo-hexyl)-l*-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll, 28-dioxa-4-azatricyclo[22.3.1.0^··^]- octacos-18-ene-2.3,10.16-tetraone_

To a stirred solution of 17-Ethyl-1,14-dihydroxy-12-[21-(3&quot;-methoxy-4&quot;-(l1'* —&lt;1'1''-οχορτορ-3»ii'-yl)indol-5''1-yl)oxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^* ^]octacos-18-ene-2,3,10,16-tetraone (100 mg.), 5-bromoindole (300 mg.) and 2-methyl-2-butene (0.80 mL.) in t-butanol (4mL.) was added a solution of sodium chlorite (15 mg.) and sodium dihydrogen phosphate (15 mg.) in water (0.15 mL.). The reaction mixture was stirred for 0.5 hr. then concentrated in vacuo. The residue was partioned between 10 ml. water containing 2 drops of 2N HC1 and diethyl ether. The organic extract was dried with Na2S04, filtered, and concentrated in vacuo. The product was purified by preparative TLC 2X first with 2:1 hexane/acetone then 77· CH3OH in CH2CI2 and finally flash column chromatography on C^g column &gt; packing with 60% CH3CN in water to give 11 mg. of the title compound. Mass (FAB) 1001 (M+ Na).

Utilizing the general procedures described in Examples 1 to 73, the following compounds of Formula I (wherein is hydrogen, R^ is methyl, ethyl, propyl or allyl; R^ is hydrogen and n is 2) are prepared from the appropriately substituted starting materiāls and reaģents. 5 24610 15 20 25 EXAMPLE NO. r1 R2 R3 R9

77

OH CHļCHj

30 T-Cell Proliferation Assav 1. sampie„P.r..eparation

The compounds to be assayed were dissolved in absolute ethanol at 1 mg/ml. 2. Assav

Spleens from C57B1/6 mice were taken under sterile conditions and gently dissociated in ice-cold RPMI 1640 culture medium (GIBC), Grand Island, N. Y.) supplemented with 10% heat-inactivated fetal calf serum (GIBO)). Celis were pelleted by centrifugation at 1500 rpm for 8 minūtes. Contaminating red celis were removed by treating the peliet with ammonium chloride lysing buffer (GIBO)) for 2 minūtes at 4eC. Cold medium was added and celis were again centrifuged at 1500 rpm for 8 minūtes. T lymphocytes were then isolated by separation of the celi suspension on nylon wool columns as follovs: Nylon wool columns were prepared by packing approximately 4 grams of vashed and dried nylon wool into 20 ml plastic syringes. The columns were sterilized by autoclaving at 25*F for 30 minūtes. Nylon wool columns were wetted with warm (37eC) culture medium and rinsed with the same medium. Washed spleen celis resuspended in warm medium were slowly applied to the nylon wool. The columns were then incubated in an upright position at 37eC for 1 hour. Non-adherent T lymphocytes were eluted from the columns with warm culture medium and the celi suspensions were spun as above. 248

Purified T lymphocytes were resuspended at 2.5 x 105 cells/ml in complete culture medium composed of RPMI 1640 medium with 10% heat-inactivated fetal calf serum, 100 mM glutamine, 1 mM 5 sodium pyruvate, 2 x 10~5 M 2-mercaptoethanol and 50 μg/ml gentamycin. Ionomycin was added at 250 ng/ml and PMA at 10 ng/ml. The celi suspension was immediately distributed into 96 well flat-bottom microculture plates (Costar) at 200 μΐ/νεΐΐ. The 1° various dilutions of the compound to be tested were then added in triplicate wells at 20 μΐ/νεΐΐ. The compound 17-allyl-l,14-dihydroxy-12-[2'-(4''— hydroxy-3'1 -methoxycyclohexyl)-l' -methylviiiyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-aza-15 tricyclo[22.3.1.0^»9]octacos-18-ene-2,3,10,16-tetraone was used as a Standard. The culture plates were then incubated at 37eC in a humidified atmosphere of 5% C02~95% air for 44 hours. The proliferation of T lyraphocytes was assessed by measurement of tritiated '20 thymidine incorporation. After 44 hours of culturing, the celis were pulse-labelled with 2 ļ.tCi/well of tritiated thymidine (NEN, Cambridge, MA). After another 4 hours of incubation, cultures were harvested on glass fiber filters using a 25 multiple sample harvester. Radioactivity of filter discs corresponding to individual wells was measured by Standard liquid scintillation counting methods (Betacounter). Mean counts per minūte of replicate wells were calculated and the results expressed as 30 concentration of compound required to inhibit tritiated thymidine uptake of T-cells by 50%. A selection of compounds were tested according to the previous procedure. The title compounds of the following Examples had activity in inhibiting the proliferation of T-cells in the aforementioned assay: 1,2.3,4,5,6,7,8,9,10,11,12,13, 14,15,16,17,18,19,20,21,23,26,28,31,32,33,34, 35, 37, 39, 42, 44, 46, 47, 48, 49, 50, 51, 52, 53, 54, 57, 58, 60, 61, 62, 63, 64, 65, 66, 69, 71, 72 and 73.

The results of thjLs assay are representative of the intrinsic immunosuppressive activity of the compounds of the present invention.

For determining antagonist activity, the foregoing procedure is modified in that dilutions of compounds are cultured with 17-ally-l,14-dihydroxy-12-[2'-(4&quot;-hydroxy-3' ’-methoxycyclohexy1)-1'-methyl-vinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^* 9]octacos-18-ene-2,3,10, 16-tetraone (as a Standard) at a concentration of 1.2 nM, a concentration which inhibits T celi prolife-ration by 100%, the concentration of compound reguired to reverse the inhibition obtained by the Standard alone by 50% is measured, and the ED50 value is determined.

While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses ali of the casual variations, adaptations, modifications, deletions, or additions of procedures and protocols described herein, as come within the scope of the following claims and its equivalents. - 250 -

- 250 - LV WHAT IS CLAIMED IS: 1. A compound of Formula I:

I or a pharmaceutically acceptable salt thereof, wherein: R-*- is selected from: (1) heteroaryl; (2) substituted heteroaryl in whic.h the substituents are X, Y and Z; (3) heteroaryl-Cļ_]_oalkyl; (4) substituted heteroaryl-C]__]_Qalkyl in which the heteroaryl group is substituted by X, I and Z and the alkyl portion may be substituted with one or more of the substituent(s) selected from: 5 251 (a) hydroxy, (b) oxo, (o) C1_6-alkoxy, (d) aryl-C]__3alkoxy, (e) substituted aryl-Cļ_3alkoxy, in vhich the substituents on aryl are X, Y and Z, (f) unsubstituted or substituted aryloxy, in which the substituents on aryl are X, Y and Z, 10 (g) -0C0-C1_6alkyl, (h) -NR^R?, vrherein R^ and R^ are independently selected from (i) hydrogen, 15 (ii) Cļ_]_oai^yi- unsubstituted or substituted with one or more of the substituent(s) selected from: (a*) aryl, which is unsubstituted or substituted with X, Y and Z, 20 (b') heteroaryl, which is unsubstituted or substituted with X, Y and Z, (c1) -0H, (d') C1_6alkoxy, 25 (e-) -C02H, (f'&gt; -C02-C1_6alkyl, (g') -C3_7cycloalkyl, and (h') -OR11, (iii) C3_ļQalkenyl unsubstituted or substituted with one or more of the substituent(s) selected from: 30 252 - 5 10 15 20 25 (a') aryl, which is unsubstituted or substituted with X, Y and 2, (b’&gt; heteroaryl, which is unsubstituted or substituted with X, Y and Z,(c') -0H, (d’) C1_6alkoxy, (e1) -C02H, (f&gt;) -C02-C1_6alkyl, (g’&gt; -C3_7cycloalkyl, and (h') -OR11, (iv)or where R^ and R7 and the N to which they are attached may form an unsubstituted or substituted 3-7-membered heterocyclic ring which may include one or two „ additional heteroatoms independently selected from the group consisting of 0, S(0&gt;p, NR14, wherein R14 is hydrogen or Cļ_£ alkyl unsubstituted or substituted by phenyl, and p is 0, 1 or 2, (i) -NR^CO-Cļ_^alkyl-R^, wherein R^ and R7 are as defined above, (j) -NR6C02-C1_6alkyl-R7. (k) -NR6C0NR6R7, (l) -0C0NR6R7,' (ra) -C00R6, (n) -CEO, (o) aryl, LV 10450 30 253 (p) substituted aryl in which the substituents are X, Y and Z, (q) -OR^·1, and (r) -S(0)p-C1_6alkyl; &lt;5) heteroaryl-Cļ_]_oalkyl wherein one or more of the alkyl carbons is replaced by a group selected from: -NR^-, -0-, -S(0)p-, -C02-, -02C-, -C0NR6-, -NR6C0-, -NR6CONR7-; (6) substituted heteroaryl-Cļ_ļQalkyl wherein one or more of the alkyl carbons is replaced by a group selected from: -NR6-, -0-, -S(0)p-, -C02-, -02C-, -CONR6-, -NR6C0-, and -NR^CONR7-, the heteroaryl group is substituted with X, Y, and Z, and the alkyl group may be substituted with one or more of the substituent(s) selected from: &lt;a) hydroxy, (b) ΟΧΟ, (c) Cļ_£alkoxy, .. (d) aryl-Cļ_3alkoxy, (e) substituted aryl-Cļ_3alkoxy, in which the substituents on aryl are X, Y and Z, (f) unsubstituted or substituted aryloxy, in which the substituents on X, Y and Z, aryl are (g) -0C0-C]__g(alkyl, (h&gt; -NR^R7, wherein R^ and R7 are defined above, i as (i) -NR6CO-C1_6alkyl-R7, (j) -NR6C02-C1_6alkyl-R7, - 254 - 5 10 15 20 25 (k) -NR6CONR6R7, (l) -OCONR6R7, (m) -C00R6, (n) -CHO, (o) aryl, (p) substituted aryl in which the substituents are X, Y and Z, (q) -OR·^, and (r) -SiOJp-C^al^l; (7) heteroaryl-C3_ļQalkenyl wherein alkenyl contains one to four double bonds; (8) heteroaryl-C3_]_Qalk.enyl vherein alkenyl contains one to four double bonds and wherein one or more of the alkyl carbons is replaced by a group selected from: -NR^-, -0-, -S(0)p-, -C02-, -02C-, -C0NR6-, -NR6C0-, and -NR6CONR7-; &lt;9) substituted heteroaryl-C3_3_Qalkenyl wherein alkenyl contains one to four double bonds and vherein one or more of the alkyl carbons may be replaced by a group selected from: -NR6-, -0-, -S(0)p-, -C02-, -02C-, -C0NR6-, -NR^CO-, and -NR^CONR7, the heteroaryl ..group is substituted with X, Y, and Z, and the alkyl group may be substituted with one or more of the substituent(s) selected from: (a) hydroxy, (b) oxo, (c) Cļ_6alkoxy, (d) aryl-Cļ_3alkoxy, (e) substituted aryl-C]__3alkoxy, in which the substituents on aryl are X, Y and Z, LV 10450 30 5 255 10 15 (f) unsubstituted or substituted aryloxy, in which the substituents on aryl are X, Y and Z, (g&gt; -0C0-Cļ_^alkyl, &lt;h&gt; -NR^R^, wherein R^ and R7 as defined above, (i) -NR^C0-Cļ_5alkyl, vherein R^ is as defined above, (j) -NR6C02-C1_6alkyl, OO -NR6C0NR6R7, (1) -OCONR6R7, &lt;m) -C00R6, (n) -CEO, (o) aryl, (p) substituted aryl in which the substituents are X, Y and Z, and &lt;s&gt; -OR-*·^-, and (r) -S(0)p-C1_5alkyl; 20 r2 j ls selected from: (1) the definitions of R^; (2) hydrogen; &lt;3) phenyl; (4) substituted phenyl in which the substituents are X, Y and Z; 25 ¢5) 1- or 2-naphthyl; (6) substituted 1- or 2-naphthyl in which the substituents are X, Y and Z; (7) biphenyl; (8) substituted biphenyl in which the substituents are X, Y and Z; (9) C1_10alkyl; 30 - 256 - 5 10 15 20 25 (10) substituted-Cļ_2Qalkyl in which one or more substituent(s) is(are) selected from: (a) hydroxy, (b) oxo, (0) C1_5alkoxy, (d) aryl-Cļ_3alkoxy, (e) substituted aryl-C2_3alkoxy, in which the substituents on aryl are X, Y and Z, (f) unsubstituted or substituted aryloxy, in which the substituents on aryl are X, Y and Z, &lt;g) -0C0-C1_6alkyl, (h) -NR^R?, wherein R^ and R^ are as defined above (1) -NR^CO-C2_0alkyl-R'r, vherein and R^ is as defined above, (j) -COOR^, wherein R^ is as defined above, (k) -CHO, (l) phenyl, (m) substituted phenyl in which the substituents are X, Y and Z, (η) 1- or 2-naphthyl, (o) substituted 1- or 2-naphthyl in which the substituents are X, Y and Z, (p) biphenyl, (q) substituted biphenyl in which the substituents are X, Y and Z, (r) -OR·^, and (s) -S(0)p-C1_6alkyl; (11) C3_10alkenyl; (12) substituted C3_ļQalkenyl in which one or more substituent(s) is(are) selected from: (a) hydroxy, LV 10450 30 257 (b) οχο, (c) Cļ.galkoK^·, (d) phenyl-Cļ_3alkoxy, (e) substituted phenyl-Cļ_3alkoxy, in which the substituents on phenyl are X, Y and Z, (f) -OCO-C1_galkyl, (g) -NR^R?, vherein R^ and are as defined above (h) -NR^CO-Cj__galkyl, wherein R^ is as defined above, (i) -COOR^, wherein R^ is as defined above, (j) -CHO, (k) phenyl, (l) substituted phenyl in which the substituents are X, Y and Z, (m) 1- or 2-naphthyl, (n) substituted 1- or 2-naphthyl in which the substituents are X, Y and Z, (o) biphenyl, (p) substituted biphenyl in which the substituents are X, Y and Z, (q) -OR11, and (r) -S(0)p-C1_6alkyl; (13) C3_10alkynyl; (14) substituted C3_ļ0all&lt;yny3- in which one or more substituent(s) is(are) selected from: (a) hydroxy, (b) oxo, (c) C1_6alkoxy, (d) phenyl-Cļ_3alkoxy, LV 10450 - 258 - (e) substituted phenyl-Cļ_3alkoxy, in which the substituents on phenyl are X, Y and Z, (f) -0C0-Cļ_£alkyl, 5 &lt;8) -NR^R^, wherein R^ and R^ are as defined above, (h) -NR^CO-Cļ_galkyl, wherein R^ is as defined above, (i) -COOR^, wherein R^ is as defined above, 10 (j) -CEO, (k) phenyl, (1) substituted phenyl in whicb the substituents are X, Y and Z,' (m) 1- or 2-naphthyl, 15 (n) substituted 1- or 2-naphthyl in which the substituents are X, Y and Z, (o) biphenyl, (P) substituted biphenyl in which the substituents are X, Y and Σ, 20 (q) -OR·^; and (15) -R11; r3 is hydrogen, hydroxy, -0R^, or Cļ_^alkoxy; R^ is hydrogen, or R^ and R1^ taken together form a double bond; 25 R5 is methyl, ethyl, propyl or allyl; R^-0 is hydro gen, hydroxy, -0R11 or fluoro; rH is selected from: (a) -P0(0H)0 M+, wherein M+ is a positively charged inorganic or organic counterion, 30 (b) -S03“M+, ( c) -C0(CH2)qC02~M+, wherein q is 1-3, and 5 259 &lt;d) -CO-C1_6alkyl-NR6R7&gt; vherein R6 and R7 are as defined above and the alkyl is unsubstituted or substituted with one or more substituents selected from: (i) hydroxy, (ii) Cļ_^alkoxy, (iii) -NR^R^-7, wherein R·^ and R·^-7 are independently selected from: 10 (a') hydrogen, and &lt;b«) C1_$alkyl, (iv) -COOR^, wherein R^ is as defined above, (v) phenyl, 15 (iv) substituted phenyl in which the substituents are X, Y and Z, (vii) heteroaryl, (viii) -SH, and (ix) -S-Cļ_£alkyl; W is 0 or (Η, 0H); 20 X, Y and Z independently are selected from: (a) hydrogen, (b) C]__]_Qalkyl, unsubstituted or substituted with one or more substituents selected from: 25 (i) aryl, (ii) substituted aryl in which the substituents are X’, Υ1 and Z1, (iii) heteroaryl, (iv) substituted heteroaryl in vhich the substituents are X1, Υ1, and Z’ , (v) unsubstituted or substituted aryloxy, in which the substituents 30 - 260 - - 260 - LV 10450 on aryl are X', Y' and Z', (vi) -OR6, (vii) -OR11, (viii) -0C0R6, (ix) -0C02R6, (x) -NR6R7, (xi) -CHO, (xii) -NR6COC1_6alkyl-R7, &lt;xiii) -NR6C02C1_6alkyl-R7, (xiv) -NR6CONR6R7, (xv) -OCONR6R7, (xvi ) -CONR6R7, (c) Cļ_ļQalkyl wherein one or more of the alkyl carbons is replaced by a group selected from -NR6-, -0-, -S(0)p-, -C02-, -02C-, -CONR6-, -NR6C0-, -NR6CONR7-, -C0-, -CH(OH)-, alkenyl or alkynyl and the aikyl may be unsub-stituted or substituted with one or more substituents selected from: (i) aryl, (ii) substituted aryl in which the substituents are X', Y' and Z', (iii) heteroaryl, (iv) substituted heteroaryl in which the substituents are X', Y', and Z', (v) unsubstituted or substituted aryloxy, in which the substituents on aryl are X' , Y' , and Z' , (vi) -OR6, (vii) -OR11, (viii) -0C0R6, 261 (ix) -0C02R6, (x) -NR6R7,

(xi)'-CHO (xii) -NR6COC1_6allcyl-R7, (xiii) -NR8C02Cj__galkyl-R7, (xiv) -NR6CONR6R7, (xv) -0C0NR6R7, (xvi) -CONR6R7, 10 &lt;d) halogen, (e) -NR6R7, (f) -CN, (s) -CHO, 00 -cf3, 15 (i) -SR8, wherein R8 is hydrogen, Cļ_6alkyl, trifluoromethyl, or phenyl, &lt;j) -SOR8, OO -so2r8, (1) -conr6r7, 20 (m) R90(CH2)m- wherein R9 is hydrogen, Cļ_6alkyl, hydroxy-C2_3alkyl, -CF3, phenyl, R·^ or naphthyl and na is 0, 1, 2, or 3, (n) -CH(0R·^)(OR-*-8), wherein R-*-8 and R.-*-8 25 are Cļ_3alkyl or taken tcgether form. an ethyl or propyl bridge, 0 R9CO(CH2)rn- vherein R9 and m are as defined above, (o) 30 0 (p) R9OC(CH2)m- vherein R9 and m are as defined above, and &lt;q&gt; -Rll; - 264 -LV 10450 3. The coiapound of Claira 1, wherein the heteroaryl is selected from the group consisting of:

Y Z

( Pvrimidine)

265

(Quinoline)

X (Quinoxal±ne) wherein Q is -N(X)-, -0-, or S . - 262 -LV 10450 or any two of X, Y and Z may be joined to form a saturated ring having 5, 6 or 7 ring atoms, said ring atoms comprising 1 or 2 oxygen atoms, the remaining ring atoms being carbon, X' , Τ' and Z' independently are selected from: (a) hydrogen, (b) C1_7alkyl, (o) C2_6alkenyl, (d) halogen, (e) -(CH2)m-NR8R^, wherein E.8, and m are as defined abcve, (f) -CN, (g) -CH0, (h) -CF3, (i) -SR8, wherein R8 is hydrogen, C]__glalkyl, tr if lnoromethyl, or phenyl, (j) -SOR8, wherein R8 is as defined above, (k) -S02R8, wherein R8 is as defined above, (l) -CONR^R?, vherein R^ and ?J are as defined above, (m) R^0(CH2)m- wherein R^ and m are as defined above, (n) -CE(0R12)(0R13), vherein R12 and R13 are as defined above, 0 (o) R^C0(CH2)m- wherein R^ and m are as defined above, 0 (p) R^0C(CH2&gt;in- wherein R^ and m are as defined above, and (q&gt; -R11; n is 1 or 2. 263 2. The compound according to Claira 1 wherein the absolute configuration of Formula I is as defined in Formula III:

III LV 10450 - 266 - 4. The corupound of Claim 3, wherein the heteroarvl is selected from the group consisting of:

267 267

wherein X is defined in Claim 1. 5. The compound of Cl&amp;im 1, wherein heteroaryl is:

- 268 -LV 10450 R&quot; is selected from: (1) hydrogen, (2) methyl, (3) ethyl, (4) propyl, (5) allyl, (6) R11, (7) -C2_3alRyl-' (8) -C2_3alRyl-1 is selected from: (1)&lt;2) hydrogen, hydroxy, (3) -OR11, or and R4 taRen together form a R10 is hydrogen, hydroxy, fluoro, or -0R W is 0; and n is 2. aouble11. &gt; bond; 269 6. A compound which is selected from the grcrnp consisting of: I7-Ethyl-1,14-dihydroxy-12-[2 ’-(4,!-(2-furanyl)irethoxy-3&quot;-n:ethoxycyclchexyl)-l '-methylvinyl]-23, 25-dini8thoxy- 13.19.21.27- tetrametiiyl-il, 28-dioxa-4-azatricyclo-[22.3.1.C4·9]octacos-lS-ene-2,3,10,16-tetraone; 17-Ethyl-i,14-dihydroxy-12-[2' - (4&quot;-(2-furanyl)πletiloxy-3,,-hydΓOxycyclohexyl)-l '-methylvinyl]-23,25-dimethoxy- 13.19.21.27- tetramethyl-ll,28-dicxa-4-azatricyclo-[22.3.1.04 &gt;9]octacos-lS-ene-2,3,10,16-tetraone; 17-=Ethyl-l, 14-dihydroxy-12-[2 '-(4&quot;-hydroxy-3&quot;-(2-f-uranyl):nethoxycyclohexyl)-l1 -methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramč:thyl-ll, 28-dioxa-4-aza-tricyclo[22.3.1.04,9]octacos-18-sne-2,3,10,16-tetraone ; 17-Ethyl-i,14-dihydroxy-12-[2'-(4&quot;-(2-thicphene)-metnoxy-3!'-methoxycyclohexyI)-I ’ -nethylvinyl]-23,25-dimethoxy-13,19,21,27-tetraaethyl-ll, 23-dioxa-4-aza-tricyclo[22.3.1.04 *9]octacos-18-ene-2,3,10,16-tetraone ; 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(2-thiophene)-methoxy-3''-hydroxycyclohexyl)-l1 -methyivinyl]-23 ,·25-dimethoxy-13,19,21,27-tetrarnsthyl-ll, 28-dioxa-4-aza-tricyclo[22.3.1.04,9]octacos-13-ene-2,3,10,16-tetraone ; ---- - 270 - ---- - 270 -LV 10450 17-Ethyl-1,14-difcydroxy-12-[2' - (4&quot;-(3-tiiiophene)-methoxy-3&quot;-hydroxy&lt;:yclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-li,23-dioxa-4-aza-5 tricyclo[22.3.1.04&gt;9]octacos-18-ene-2,3,10,16- tetraone; 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-hydroxy-3&quot;-(2-thio-phene)inethoxy cyc lohexyl)-1'-methylvinyl]-23,25-10 dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-aza- tricyclo[22.3.1. O^- &gt; ^]octacos-18-ene-2,3,10,16-tetraone ; 17-Ethyl-1,14-dihydroxy-1.2-[2' -(4&quot;-hydroxy-3&quot;-(3-15 thiophene)methoxycyclohexyl')-l' -methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-aza-tricyclo[22.3.1.0^&gt; 9]octacos-18-ene-2,3,10,16-tetracne; 20 17-Ethyl-1,14-dihydroxy-12-[2'-(4H-(2-thiophene)oxy- 3&quot;-methoxycyclohexyl)-l' -methylvinyl]-23,25-dinethoxy- 13.19.21.27- tetramethyl-ll,28-dioxa-4-azatricyclo-[22.3.1.0^&gt; ^]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[21-(4&quot;-(2-benzothienyl)-oxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]-23,25-dime-thoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatri-cyclo-[22.3.1.0^»^]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[21-(4&quot;-(5-indolyl)oxy-3n-methoxycyclohexyi)-i'-methylvinyl]-23,25-dimethoxy- 13.19.21.27- tetramethyl-ll,28-dioxa-4-azatricyclo-[22.3.1.0^1^]octacos-18-ene-2,3,10,16-tetraone; 30 - 271 - 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(5-indolyl)oxy-3M-hydroxycyclohexy±)-l' -msthylvir.yl]-23,25-dimethoxy- 13,19,21,27-tetranethyl-ll,28-dioxa-4-azatricyclo-[22. 3.1.04» 9]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14,20-trihydroxy-12-[21-(4&quot;-(5-indolyl)-oxy-3&quot;-nethoxycyclohexyl)-l1 -methylvinyl]-23,25-di-methoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatri-cyclo-[22.3.1.04&gt; 9]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,20-dihydroxy-12-[2'-(4!,-(5-indolyl)oxy-3&quot;-methoxycyclchexyl)-l1-methylvinyl]-23,25-dimethoxy- 13.19.21.27- tetramethyl-ll,28-dioxa-4-azatricyclo-— [22.3.1.04,^3octacos—18—ene—2,3,10,16-tetraone; 17-Ethyl-l-hydroxy-12-[21-(4&quot;-(5-indolyl)oxy-3&quot;-methoxycyclohexyl)-l! -metIiylvinyl]-23,25-dimethoxy- 13.19.21.27- tetramethyl-ll, 23-dioxa-4-azatricyclo-[22.3.1.04&gt; 9]octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14-dihydroxy-i2-[2'-(4&quot;-(5-indolyl)oxy-3”-uiethoxycyclohexyl )-l1 -methylvinyl]-23,25-dinethcxy- 13.19.21.27- tstramethyl-ll,28-dioxa-4-azatricyclo-[22.3.1.04&gt;9]octaco2-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14-dihydroxy-12-[2'-&lt;4&quot;-(5-indolyl)oxy-3&quot;-hydroxycyciohexyl)-i' -methvlvinvl] -23 &gt; 25-dimethoxy- 13.19.21.27- tetramethyl-ll,28-dioxa-4-azatricyclo-[22.3.1.G4-9]octacos-13-ene-2,3,10,16-tetraone; 17-Allyl-1,14,20-tr ihydroxy-12-[2' -(4,,-(5-indoiyl)-oxy-3-&quot;-methoxycyclohexyl)-l1 -ne‘ehylvinyi]-25,25-di-methoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatri-cyclo-[22.3.1.0419]octacos-lc&gt;-ene-2,3,10,16-tetraone; - 272 - - 272 -LV 10450 17-Allyl-I,20-dihydroxy-12-[2'-(4&quot;-(5-indolyl)oxy-3M-methoxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy- 13.19.21.27- tetramethyl-ll,28-dioxa-4-azatricyclo-[22.3.1.0^» ^]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(5-indolyl)oxy-3&quot;-ethoxycyclohexyl)-l' -methylvinylj-23,25-dimethoxy- 13.19.21.27- tetram8thyl-ll,28-dioxa-4-azatricyclo-[22.3.1.0^’ ^]octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14-dihydroxy-12-[21-(4&quot;-(5-indolyl)oxy-3&quot;-ethoxycyclohexyl)-l! -methylvinyl ]-23,25-di:aethoxy- 13.19.21.27- tetramethyl-ll,28-dioxa-4-azatricyclo-[22.3.1.0^» ^]octacos-18-ene-2,3,10,16^-tetraone; 17-Allyl-l-hydroxy-12-[2 ,-(4,,-(5-indclyl)oxy-3,,-methoxycyclohexyl)-l1-methylvinyl]-23,25-dimethoxy- 13.19.21.27- tetramethyl-ll,28-dioxa-4-azatricyclo-[22.3.1.0^ &gt;9]octacos-18-ene-2,3,10,16-tetraone; 17-Eth3^1-1,14-dihydrcxy-12-[2 1 -(4&quot;-(l-N-rnethyl-5-indolyl)oxy-3&quot;-met2iOxycyciohexyl)-i1 -methylvinyl]-23,25-diaiethoxy-13,19,21,27-tetramethyl-ll, 28-dioxa-4-azatricyclo[22.3.1.0^&gt; ^]octacos-18-sne-2,3,10,16-tetraone ; 17-Ethyl-1,14-dihydroxy-12-[2'-(4”-(l-N-methyl-5-indolyl)oxy-3&quot;-hydroxyeyclohexyl)-l1 -methylvinyl]-23,25-dimethoxy-13,19, 21,27-tetran-ethyl-ll, 28-dioxa-4-azatricyclo[22.3.1.04&gt; 9]octacos-18~ene-2,3,10,16-tetraone ; 273 17-Ethyl-1,14,20-tr ihydroxy-12-[2 1 -(4’:-(l-N-methyl-5-indolyl)oxy-3M-m5tho:xycycioīiexyl)-l' -aethylvinyl]- 23.25- dimatho:..y-13,19,21,27-tatramethyl-il, 2o-dicxa-4-azatricyclo[22.3.1.0^ &gt; octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14,20-tr ihyaro&gt;y-12-[2 '-(4&quot;-(l-N-niethyl-5-indolyl)oxy-3&quot;-hydroxycyclohe:yl)-l1 -methylvinyl]- 23.25- dimethoxy-13,19,21,27-tetrametiiyl-ll, 28-dio::a-4-azatricyclo[22.3.1.0^’^]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,2C-dih3rdroxy-i2-[2 '-(4”-(l-N-aethyl-5-indolyl)oxy-3&quot;-aetho:cycyclohe:tyl)~l1 -methylvinyl]- 23.25- diaethoxy-13,19,21,27-tetramethyl-ll,23-dioxa-4-azatricyclo[22.3.1.O^’°]octacos-18-ene-2,3,10,16-tatraone; 17-Ethyl-1,20-dihydroxy-12-[2 '-(4&quot;-(l-N-methyl-5-indolyl)oxy-3&quot;-hydroxycyclohexyi)-l'-methylvinyl]- 23.25- dimethoxy-13,19,21,27-tetransthyi-ll,28-dioxa-4-azatr icyclo[22.3.1.0^ ’.^]octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-l,14-dihydroxy-12-[2 1-(4&quot;-(l-N-Inethyl-5-indolyί )oxy-3''-aetho:xycyclchexyl)-l'-methyivinyl]- 23.25- dimethoxy-13,19,21,27-tetramethyl-li,28-dioxa-4-azatri Cj^clo[22.3.1.0^’ ^]octacos-18-ene-2,3,10,16-tetraone; 274 - 274 -LV 10450 17-Ailyl-1,14,20-trihydroxy-12-[2'-(4&quot;-(l-N-methyl-5-ixidolyl)oxy-3n-methoxycyclohs:'yrl)-l' -methylvinyl]- 23.25- dimethoxy-13,19,21,27-tetramethyl-ll, 28-dioxa-4-azatricyclo[22.3.1.0^ &gt;9]octacos-18-sne-2,3,10,16-tstraone; 17-Allyl-1,20-dihydrcxy-12-[21-(4&quot;-(l-N-methyl-5-indolyl)oxy-3,,-ciethoxycyclohe2cyl)-l' -methylvinyl]- 23.25- dimetīioxy-13,19,21,27-tetramethyl-ll, 28-dioxa-4-azatricyclo[22.3.1.0^ &gt; 9]octacos-18-er±e-2,3,10,16-tetraone; 17-Ethyl-l-hydroxy-12-[2 ’ -(4&quot;-(l-N-;netliyl-5-indolyl)-oxy-3&quot;-methoxycyclohexyl)-l1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-aza-tricyclo[22.3.1.0^»9]octacos-lS-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[21-(4&quot;-(l-N-methyl-5-indolyl)oxy-3M-ethoxycyclohexyl)-l'-nethylvinylΙΣΟ ,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^·9]octacos-lS-ene-2,3,10,16-tetraone; 17-Allyl-1,14-dihydroxy-12-[2'-(4&quot;-(l-N-methyl-5-indolyl)oxy-3&quot;-ethoxycyclohexyl)-l1-methylvinyl]- 23.25- dimethoxy-13,19,21,27-tetracethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^&gt; 9]octacos-18-ene-2,3,10,16-tetraone; - 275 17-Ethyl-1,14-dihydroxy-12-[2'-(4n-(l-N-ethyl-5-indolyl)oxy-3&quot;-ethoxycyclohexyl)-l' -m2triylvinyl]- 23.25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dicxa-4-

5 azatricyclo[22.3.1.0^&gt; ^]octacos-18-ene-2,3,10,16T tetraone; 17-Allyl-l-hydroxy-12-[2' -(4&quot;-(l-N-iasthyl-5-indolyl)-oxy-3&quot;-methoxycyclohexyl)-l1 -ir.ethylvinyl]-23,25-10 dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-aza- tricyclo[22.3.1.04,^]octacos-lS-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(l-N-methyl-5-15 indolyl)oxy-3&quot;-allyloxycyclohexyl)-l1 -metnylvinyl]- 23.25- dinethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.04-* ^]octacos-18-ene-2,3,10,16-tetraone; 20 17-Sthyl-l-hydroxy-12-[2,-(4,,-(l-N-nethyl-5-indolyl)-oxy-3M-aliyloxycyclohexyl)-i'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tatramethyl-ll,28-dicxa-4-aza-tricyclo[22.3.1.04&gt; octacos-18-ene-2,3,10,16-tetraone; 25 17-Ethyl-1,14-dihydroxy-12-[2 ' -(4&quot;-(l-I\-aethyl-5-indolyl)oxy-3,,-n-propylo;cycycloriexyl)-i1 -nathylvinyl J- 23.25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1. C4-1 ^]octacos-13-ene-2,3,10,16-tetraone; 30 - 276 - - 276 -LV 10450 17-Ethyl-l-hydroxy-12-[2 ,-(4,,-(l-N-methyl-5-indolyl)-oxy-3&quot;-n-propyloxycyclohexyl)-l ,-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-aza-5 tricyclo[22.3.1.0^·^]octacos-18-ene-2,3,10,16- tetraone; 17-Ethyl-1,14-dihydroxy-12-[2,-(4&quot;-(l-N-methyl-5-indolyl)oxy-3!,-i-propyloxycyclohexyl)-l '-methylvinyl]-10 23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4- azatricyclo[22.3.1.04 &gt; ^]octacos-18-ene-2,3,10,16-tetraone ,* 17-Ethyl-1,14-dihydroxy-12-[2'-(4”-(l-N-ethyl-5-15 indOiyl)oxy-3&quot;-nethoxycycloh.exyi)-l,-iaethylvinyl]- 23.25- dimethoxy-13,19,21,27-tetramethyi-ll,28-dioxa-4-azatricyclo[22.3.1.0^·^]oCwacos-18-ene-2,3,10,16-tetraone; 20 17-Ethyl-1,14,20-trihydroxy-12-[2 '-(4&quot;-(l-N-ethyl-5- indolyl)oxy-3&quot;-siethoxycyclohexyl)-l * -methylvinyl]- 23.25- dimethoxy-13,19,21 , 27-tetraaethyl-ll, 28-dicxa-4-azatricyclo[22.3.1.0^»^]octacos-18-ene-2,3,10,16-tetraone; 25 17-Ethyi-1,20-dihydroxy-12-[2'-(4&quot;-(l-N-ethyl-5-indol3'l)oxy-3&quot;-ffiethoxycyclohexyl)-l' -methylvinyl]- 23.25- dimethoxy-13,19,21,27-te^raāiethyl-il, 28-dioxa-4-azatricyclo[22.3.1.04 &gt;^]octacos-18-eae-2,3,10,16-tetraone; 30 277 17-Ethyl-1,14-dihydroxy-12-[21-(4&quot;-(l-N-ethyl-5-indolyl)oxy-3''-hydroxycyciohexyl)-l' -msthylvinyl]- 23.25- dimetIioxy-13,19,21,27-tetramethyl-ll, 28-dicxa-4-azatricyclo[22.3.1.04» 5]octacos-18-eae-2,3,10,16- t et r aone; 17-Allyl-1,14-dihydroxy-12-[2'-(4&quot;-(l-N-ethyl-5-indolyl)oxy-3&quot;-mathoxycyclohexyl)-l1 -methylvirlyl]~ 23.25- dimathoxy-13,19,21,27-tetramethyl-il,28-dioxa-4-azatricyclo[22.3.1.04» 9]octacos-18-ene-2,3,10,16-tetraone; 17-Aliyl-1,14·, 20-tr iīiydroxy-12-[2 '-(4”-(l-N-ethyl-5-indolyl)oxy-3&quot;-niethoxycyclohexyl)-l1 -methylvinyl]- 23.25- dimethoxy-13,19,21,27-tetraz:ethyl-ll, 28-dioxa-4-azatricyclo[22.3.1.04» 9]octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,20-dihydroxy-12-[2'-(4&quot;-(l-N-ethyl-5-indolyl)oxy-3M-methoxycyciofc.exyl)-l1-methylvinyl]- 23.25- diaiethoxy-13,19,21,27-tetramethyl-ll, 28-aioxa-4-azatricyclo[22.3.1.04 &gt; 9]octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-I, 14-dihydroxy-12-[2 »-(4&quot;-(l-N-ethyl-5-indolyl)oxy-3&quot;-hydroxycyclohe5cyl)-l ’ -methylvinyl]- 23,25-dimethoxy-13,19,21,27-tetra:neĪh3ri-ll, 28-dioxa-4-azatricyclo[22.3.1.04&gt; 9]octacos-18-ene-2,3,10,16-tetraone; - 278 - - 278 - LV 10450 17-Ethyl-l-hydroxy-12-[2 '-(4&quot;-(l-N-etliyl-5-indolyl)-oxy-3&quot;-iaethoxycyclo'hesyl)-l' -aethylvinyl]-23,25-dimethoxy-13,19,21,27-tetran‘ethyl-ll, 28-dioxa-4-aza-tricyclo[22.3.1.0^» ^]octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-l-hydroxy-12-[2'-(4&quot;-(l-N-ethyl-5-indolyl)-oxy-3&quot;-methoxycyclohexyl)-l1-methylvinyl]-23,25-d im3thcxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-aza-tricyclo[22.3.1.0^ &gt; ^]octacos-18-ene-2,3,10,16-tetraone; 4· 17-Allyl-1,14-dihydroxy-12-[2'-(4&quot;-(l-N-ethyi-5-indolyl)oxy-3n-ethoxycyclohexyl)-l!-methylvinyl3- 23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^»^]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(l-N-propyl-5-iadolyl)oxy-3,,-methoxycyclOiiexyl)-l '-methylvinyl]- 23.25- dimethoxy-13,19,21,27-tetzamethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^» ^]octacos-18-er.2-2,3,10,16-tetraone; 17-Ethyl-1,14,20-trihydroxy-12-[2'-(4M-(l-N-propyl-5-indoly1)oxy-3&quot;-methoxycyclohexyl)-11-methylvinyl]- 23.25- dimethoxy-13,19,21,27-tetraniethyl-il, 28-dioxa-4-azatricyclo[22.3.1.0^ &gt; ^]octacos-18-ene-2,3,10,16-tetraone; - 279 - 17-Ethyl-1,20-dihydroxy-12-[2'-(4&quot;-(l-N-propyl-5-indolyl)oxy-3&quot;-nethoxycyclohexyl)-ī'-raithylvinyl]- 23,25-dimethGxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^·9]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(l-N-propyl-5-indolyl)oxy-3!’-hydroxycyclohexyi)-i1 -methylvinyl]- 23.25- dimeth.oxy-13,19,21, 27-tetramethyi-ll, 28-dioxa-4-azatricyclo[22.3.1.0^» 9]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14,20-tri!iydroxy-12-[ 2 1 -(4&quot;-(l-N-propyl-5-indolyl)oxy-3&quot;-hydroxycyclohexyl)-l l-n:ethylvinyl]- 23.25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0&lt;:!‘»9]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,20-diiiydroxy-12-C2'-(4&quot;-(l-N-propyl-5-indolyl)oxy-3&quot;-hydroxycyclohexyl)-l'-methylvinyl]- 23.25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.04&gt; 9]octacos-lS-ene-2,3,10,16-tetraone; 17-Allyl-1,l4-dihydroxy-12-[2'-(4&quot;-(l-N-propyl-5-indolyi )oxy-3:'-ii:ethoxycyclohexyl)-l * -ir.ethylvi.nyl]- 23.25- dimethoxy-13,19,21,27-tetraEetnyl-li,28-dioxa-4-azatricyclo[22.3.1.0^»9joctacos-i8-ene-2,3,10,16-tetraone; - 280 - - 280 - LV 10450 17-Allyl-1,14,20-trihydroxy-12-[2,-(4&quot;-(l-N-propyl-5-indolyl) oxy-3 M-methoxycyclohexyl) -1 ’ -methylvinyl ] - 23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^'» ^]octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-l,20-diIiydroxy-12-[2'-(4&quot;-(l-N-propyl-5-indolyl)oxy-3&quot;-inethoxycyclohexyl)-l1 -methylvinyl]- 23.25- dimethoxy-13,19, 21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.04»9]octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14-dihydroxy-12-[2'-(4&quot;-(l-N-propyl-5-ind oly1)oxy-3' ’-hyd roxycyclohexyl)-1'-methylvi nyl]- 23.25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^»^]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-l-hydroxy-12-[2'-(4&quot;-(l-M-propyl-5-indolyl)-oxy-3,,-methoxycyclohexyl)-l' -methylvinyl]-23,25-dimethoxy-13,19,21,27-tstramethyl-ll,28-dioxa-4-asa-tricyclo[22,3.1.0^&gt; ^]octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-l-hydroxy-12-[21-(4M-(l-N-propyl-5-indoiyl)-oxy-3M-methoxycyclohexyl)-l'-msthyIvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-aza-tricyclo[22.3.1.0^ &gt; ^]octaccs-18-ene-2,3,10,16-tetraone; 281 17-Ethyl-1,14-dihydro:cy-i2-[2 '-(4&quot;-(l-N-propyi-5-indolyl)oxy-3&quot;-ethoxycyclohexyl)-l1 -iaei:īiyivinyl]- 23.25- dimethoxy-13,19,21,27-tetramethyl-ll, 23-dioxa- 5 azatricyclo[22.3.1.°]octacos-18-ene-2,3,10,16- tetraone; 17-Allyl-1,14-dihydroxy-12-[2 ’-(4&quot;-(l-N-propyl-5-indolyl)oxy-3&quot;-ethoxycyclohexyl)-l' -nethylvinyl]-10 23,25-dimethoxy-13,19,21,27-tetramethyl-ll,2S-dioxa- 4-azatricyclo[22.3.1.0^»^]octacos-18-ene-2,3,10,16-tetraone; 17-Sthyl-1,14-dihydroxy-12-[2'-(4&quot;-(l-N-allyl-5-15 indolyl)oxy-3&quot;-methoxycyclohexyl)-l'-methylvinylj- 23.25- dimethcxy-13,19,21,27-tetramethjrl-ll,28-dioxa-4-azatr icyclo [22.3.1.0^»^ joctacos-lS-ens-2,3,10, j.6-tetraona; 20 17-Ethyl-l,14,20-triliydrc;cy-12-[2‘-(4&quot;-&lt;l-N-allyl-5- indolyl )o&gt;ry-3&quot;-methoxycyclohexyl )-l' -:aethyr7inyl]- 23.25- dir-:athoxy-13,19,21,27-tetramethyl-ll, 28-dioxa-4-azatric3^clo[22.3.1.0^»^]cctacos-18-ens-2,3,10,16-tatraone; 25 17-Ethyl-1,20-dihydroxy-12-[2'-(4&quot;-(l-N-aiiyl-5-indolyl )oxy-3&quot;-!nethoxycyclohexyl)-l' -methylvinyl]- 23.25- dimethoxy-13,19,21,27-tetramethyl-H,28-aioxa-4-azatricyclo[22.3.1.0^·']octacos-I8~ene~2,3,10,16-tetraone; 30 - 282 - - 282 -LV 10450 17-Ethyl-1,14-dihydroxy-12-[21-&lt;4&quot;-(l-N-allyl-5-indolyl)oxy-3M-hydroxyc3'cloh.exyl)-l' -methylvinyl]- 23.25- dimethoxy-13,19,2i,27-tetrasethyl-ll,28-dioxa- 5 4-azatricyclo[22.3.1.0^&gt; ^]octacos-18-exie-2,3,10,16- tetraone; 17-Etīiyl-l,14,20-trihydroxy-12-[2'-(4&quot;-(l-N-allyl-5-i nd oly 1) oxy-3' '-hy ά r oxy cj'-c lohexyl) -1 · -met hy Īvi ny 1 ] -10 23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa- 4-azatricyclo[22.3.1.0^* ^]octacos-I8-ene-2,3,10,16-tetraone; 17-Ethyl-1,20-dihydroxy-12-[2 ' -(4&quot;-(l-N-allyl-5-15 ~indclyl)oxy-3M-hydrcxycyclohexyl)-l’-nethylvinyl]- 23.25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^»']octacos-18-ene-2,3,10,16-tetraone; 20 17-Allyl-1,14-dihydroxy-12-[21-(4n-(l-N-allyl-5- ind o ly 1) oxy-3 &quot;-me thoxycyc 1 oh.exy 1) -11 -me t hy 1 vi nyl ] - 23.25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricycio[22.3.1.0^’^]octacos-18-ene-2,3,10,16-tetraone; 25 17-Allyl-i,14,20-trihydroxy-12-[2«-(4&quot;-(l-N-allyl-5-indoly1)oxy-3&quot;-methoxycyclohexyl)-11-methylvinyl]- 23.25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^»^]octacos-18-ene-2,3,10,16-tetraone; 30 - 283 - 17-Allyl-1,20-dihydrcxy-12-[2’-(4&quot;-(l-N-allyl-5-indolyl)oxy-3&quot;-Eiethoxycyclohexyl)-l' -izethylvinyl]- 23,25-disethoxy-13,19,21,27-tetrametr.yI-il,28-dioxa-4-azatricyclo[22.3.1.0^·°]cctacos-18-ene-2,3,10,16-tetraone; 17-Allyl-i,14-dihydroxy-12-[2 !-(4n-(l-N-allyl-5-indolyl)oxy-3&quot;-hydroxycyclohexyl)-l ’ -iaethylvinyl]- 23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^» ^]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-l-hyd£oxy-12-[2'-(4&quot;-(l-N-allyl-5-indolyl)-oxy-3&quot;-meĪhoxycycloīiexyl)-l' -ir.ethylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-aza-tricyclo[22.3.1.0^» octacos-18-er.a-2,3,10,16-tetraone; 17-Allyl-l-hydroxy-12-[2'-(4&quot;-(l-N-allyl-5-indolyl)-oxy-3&quot;-methoxycyclohexyl)-l1-Eethylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-aza-tricyclo[22.3.1.0^’ ^]octacos-18-er.e-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(l-N-allyl-5-indolyl )oxy-3&quot;-etliOxycyclohexyl)-l1 -raethylvir.yl]- 23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^’^]octacos-18-ane-2,3,10,Ϊ6-tetraone; - 284 - - 284 - LV 10450 17-Allyl-1,14-dihydroxy-12-[2'-(4&quot;-(l-N-allyl-5-indolyi)oxy-3&quot;-ethoxycyclohexyl)-l'-methyivinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^ *^]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-l,14-dihydroxy-12-[2'-(4&quot;-(l-N-2-hydroxy-ethyl-5-indolyl)oxy-3&quot;-īEetliOxycyclohexyl)-l1 -methyl-vinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll, 28-dioxa-4-azatricyclo[22.3.1.0^»9]octacos-18-ene- 2.3.10.16- tetraone; 17-Ethyl-1,14,2’0-trihydroxy-12-[2,-(4&quot;-(l-N-2-hydroxy-ethyl^3-indolyl)oxy-3&quot;-m8thoxycyclohexyl)-l1-methyl-vinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^&gt;^]octacos-18-ene- 2.3.10.16- tetraone; 17-Ethyl-1,20-dihydroxy-12-[2’-(4M-(l-N-2-hydroxy-ethyl-5-indolyl)oxy-3&quot;-methoxycyclohexyi)-l'-msthyl-vinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,23-dioxa-4-azatricyclo[22.3.1.0^»^]octacos-18-ene- 2.3.10.16- tetraone; 17-Eth3^1-1,14-dihydroxy-12-[2'-(4&quot;-(l-N-2-hydroxy-ethyi-5-indolyi)oxy-3',-hydroxycyclohexyl)-l ’-methyl-vir.yl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll, 28-dioxa-4-azatricyclo[22.3.1.0^&gt;9]octacos-18-ene- 2.3.10.16- tetraone; 285 17-Ethyl-1,14,20-trihydro&gt;ry-12-[2 1 -(4&quot;-(l-N-2-hydroxy-etl.yl-5-indolyl)oxy-3&quot;-hydroxycyclohexyl)-l' -aethyl-vinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-5 dioxa-4-azatricyclo[22.3.1.*^]cctacos-18-ene- 2.3.10.16- tetraone; 17-Ethyl-1&gt; 20-dihydroxy-12-[21-(4&quot;-(l-N-2-hydroxy-e t iiy 1 - 5 - i nd o ly 1) oxy- 3' ’ -hy d r oxy cy c 1 ohexy 1) -1' -ma t hy 1-10 vinyl]-23,25-diEetho:-cy-13,19,21,27-tetrametnyl-li, 23- dioxa-4~azatricyclo[22.3.1.0^· ^]octaccs-13-ene- 2.3.10.16- tetraone; 17-Allyl-1,14-dihydroxy-12-[2 ‘-(4&quot;-(l-N-2-nydroxy-15 . ethyl-5-ir*dolyl)oxy-3&quot;-metiio:-r/cyclohexyl)-l' -methyl- vinyl]-23,25-dinetho2^-13,19,21,27-tetramethyl-ll, 23-dioxa-4-azatricycIo[22.3.1.0^ »^]octacos-18-ene- 2.3.10.16- tetraone; 17-Allyl-1,14-dihydroxy-12-[2'-(4&quot;-(l-N-2-hydroxy-ethyl-5-indolyl)oxy-3&quot;-hydroxycyclohexyl)-l1 -methyl-vinyl]-23,25-diāiethoiiy-13,19,21,27-tetramethyl-ll, 28-dioxa-4-asatricyclo[22.3.1.0^ &gt;^]octacos-18-ene- 2.3.10.16- tetraone; 17-Ethyl-1,14-dihydrcry-12-[2 ' -(4&quot;-( l-N-bē'nzyl-5-indolyl)oxy-3&quot;-metho3cycyclohexyl)-l1 -nethylvinyi]~ 23,25-dimethoxy-13,19,21,27-tetramethyl-li,28-dioxa-4-azatricyclo[22.3.1.0^»^]octacos-I8-ene~2,3,10,16-tetraone ; 30 - 286 - - 286 -LV 10450 17-Ethyl-1,14,20-trihydro:sy-12-[2 ' -(4&quot;-(l-N-benzyl-5-indolyl)oxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]- 23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa~4-azatricyclo[22.3.1.04,9]octacos-18-ens-2,3,10,16-tetraone; 17-Ethyl-i,20-dihydroxy-12-[2'-(4&quot;-(l-N-benzyl-5-indolyl)oxy-3&quot;-msthoxycyclohexyl)-l'-nethylvinyl]- 23.25- dimethoxy-13,19,21,27-tetranethyl-ll, 28-dioxa-4-azatricyclo[22.3.1.04»^]cctacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-l,14-diliydroxy-12-[2,-(4,'-(l-H-beiizyl-5-indolyl)osy-3&quot;-hydrosycyclohexyi)-l '-inethylvinyl]- 23.25- diiaethoxy-13,19,21,27-tGtrāmsthyl-Il, 28-dioxa-4-azatricyclo[22.3.1.04,°]octacos-18-ene-2,3,10,16-tetraons; 17-Ethyl-1,14,20-trihydroxy-12-[2'-(4&quot;-(l-N-benzyl-5-indclyl)oxy-3&quot;-hydroxycyclohexyl)-l'-methylvinyl]- 23.25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.04,^]octacos-18-ene-2,3,10,16-retraone; 17-Ethyl-1,20-dihydroxy-12-[2'-(4&quot;-(l-N-benzyl-5-i nd olyl)oxy-3 ’ ’-hyd roxycy c1ohexy1)-11-methy1vinyl]- 23.25- diraethoxy-13,19,21,27-tetramethyl-ll, 28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-13-ene-2,3,10,16-tetraone; - 287 17-Allyl-1,14-dihydroxy-12-[2'-(4&quot;-(l-N-benzyl-5-indolyl)oxy-3M-niethoxycyclohexyl)-l'-msthylvir.yl]-23,25-diūiethoxy-13,19,21,27-tetranieth3/l-ll, 28-dioxa-4-azatricyclo[22.3.1.04&gt;9]octaccs-13~ene-2,3,10,16-tetraone; 17-Allyl-1,14,20-trihydroxy-12-[2'-(4&quot;-(l-N-benzyl-5-indolyl)oxy-3''-methoxycycloh.exyl)-l1-methylvinyl]~ 23.25- diiūethoxy-13,19,21,27-tetraaiethyl-ll, 28-dioxa-4-azatricyclo[22. 3.1.04 &gt; 9]octacos-18-ene-2,3,10,16-tetraone; 17-A.llyl-1,20-dihydroxy-12-[2 ’-(4”-(l-N-benzyl-5-indolyl)oxy-3,'-methoxycyclohexyl)-l '-nethylvinyl]- 23.25- dimethcxy-13,19,21,27-tetramethyI-ll, 28-dioxa-4-azatricyclo[22.3.1.04» 9]octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14-dihydroxy-12-[2'-(4&quot;-(l-N-benzyl-5-indolyl)oxy-3u-hydroxycyclohexyl)-l1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0419]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-l-hydroxy-12-[2'-(4&quot;-(l-N-benzyl-5-indolyl)-oxy-3&quot;-mathoxycyclohexyl)-l’-methylvinyi]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-aza-tricyclo[22.3.1.C4,9]octacos-18-ene-2,3,10,16-tetraone; 4. - 288 - 4. - 288 -LV 10450 17-Allyl-l-hydroxy-12-[2 ,-(4&quot;-(l-N-benzyl-5-indolyl)-oxy-3&quot;-methoxycyclohexyl)-l1-mathylvinyi]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-aza-tricyclo[22.3.1.04,^]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[21-(4M-(l-N-benzyl-5-indolyl)oxy-3&quot;-ethoxycyclohexyl)-l'-methylvinyl]- 23.25- dimethoxy-13,19,21,27-tetramethyl-il,28-dioxa-4-azatricyclo[22.3.1.04,^]octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14-dihydroxy-12-[2'-(4&quot;-(l-N-benzyl-5-indoTyl) oxy-3 *'-e thoxy cyclohexyl) -11 -methy lvinyl ] - 23.25- dimethoxy-13,19,21,27-tetra:aethyl-ll, 28-dioxa- 4- azatricyclo[22.3.1.Q4·9]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(l-N-cyclopropyl- 5- indolyl)oxy-3&quot;-methoxycyclohexyl)-l’-methylvinyl]- 23.25- dimsthoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.04,^]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[2’-(4&quot;-(l-N-cyclopropyl-5-indolyl)oxy-3&quot;-hydroxycyclohexyl)-l'-nethylvinyl]- 23.25- dimethoxy-13,19,21,27-tetra;sethyl-ll, 28-dioxa-4-azatricyclo[22.3.1.04 &gt; 9]octacos-18-ene-2,3,10,16-tetraone; - 239 - 17-Allyl-1,14-dihydroxy-12-[2,-(4”-(l-N-cyclopropyl-5-indolyl)oxy-3&quot;-ni3tlīoxycyclohexyl)-l ‘ -methylvinyl]- 23.25- dimethoxy-13,19,21,27-tetram£tīiyl-ll, 28-dioxa-4-azatricyclo[22.3.1.04 ·'^joctacos-lS-ene-2,3,10,16-tetraone; 17-Allyl-1,l4-dihydroxy-12-[21-(4&quot;-(l-N-cyclopropyl-5-indolyl)oxy-3&quot;-hydroxycyclohexyl)-l1 -aiethylvinyl]- 23.25- dimethoxy-13,19,21,27-tetramethyl-Il,28-dioxa-4-azatricyclo[22.3.1.04 &gt; ^]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[21~(4&quot;-(l-N-cyclopropyl-5-indolyl)oxy-3,,-ethoxycyclohexyl)-i'-methylvinyl]- 23.25- dimethoxy-13,19,21,27-tstramethyl-ll,28-dioxa-4-azatricycio[22.3.1.04»5]octacos-13-ene-2,3,10,16-tetraone; 17-Allyl-1,14-dihydzcxy-12-[21-(4&quot;-(l-N-cyclopropyl-5-indolyl)oxy-3&quot;-ethoxycyclohexyl)-l1-nsthylvinyl]- 23,25-dimethoxy-13,19,21,27-tetramethyl-ll,2S-dioxa-4-azatricyclo[22. 3.1.04 &gt; ^]octacos-lS-ene-2,3,10,16-tetraone; 17-Ethyl-l-hydroxy-12-[21-(4&quot;-(i-N-cyclopropyl-5-indolyl) oxy-3 ''-methoxycycloh8xyl) -1' -nethylvinyl ] -23,25-dimethoxy-13,15,21,27-tetrasiethyi-ll, 28-dic:-:a-4-azatr icyclo[22.3.1.04 &gt; ^]octacos-18-erie-2,3,10,16- tetraone; - 250 - - 250 -LV 10450 17-Allyl-l-hydroxy-12-[2'-(4,,-(l-N-cyclopropyl-5-indolyl)oxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]- 23.25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^»^]octacos-18-ene-2,3,10,16-tetraone; »· 17-Ethyl-l-hydroxy-12-[2'-(4&quot;-methoxy-N-tryptophanyl-carbonylmstii02^-3&quot;-n:3thoxycyclohexyl)-l' -raethylvinyl]- 23.25- dimethoxy-13,19,21,27-tetramethyl-lI,28-dioxa-4-a2atricyclo[22.3.1.0^&gt; ^]octacos-18-ene-2,3,10,16-tetraona; 17-Ethyl-l-hydroxy-12-[2 ' -(4&quot;-3-indoiylethylaniino-carbonyimethoxy-3&quot;-!nethoxycyclofcexyl)-l' -methylvinyl]- 23,25-diE.ethoxy-13,19,21,27-tetramethyl-ll, 28-dioxa-4-azatricyclo[22.3.1.0^»^]octacos-18-ene-2,3,10,16-tetraone ; 17-Ethyl-1,14-difcydroxy-12-[2'-(4&quot;-(l-(3-hydroxy-propyl)indol-5-yl)oxy-3&quot;-nethoxycyclohexyl)-l1 -nethyl-vir.yl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll, 28-dioxa-4-asatricyclo[22.3.1.0^&gt;^]octacos-13-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[2 f-(3&quot;-hydroxy-4&quot;-(l-hy d r oxy e t hy 1 i r.d ο 1 - 5 -y 1) oxycyc 1ohexy1)-11 -me t hy 1 v i nyi]- 23,25-diaethcxy-13,19,21,27-tetramethyl-ll,28-dioxa~4-azatri cycio[22.3.1.0^’^]octacos-18-ens-2,3,10,16-tetraone ; 291 - 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(l-hydroxyethyl-indol-6-yl)oxy-3&quot;-iī:etho:Īycyclohe^l)-l1 -methylvinyl]-23,25-diniethoxy-13,19,21,27-tetramethyl-il,28-&lt;iioxa-4-azatricyclo[22.3.1.0Z·' &gt;9] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydro:sy-12-[2 1-(4&quot;-(l-methylindol-6-yl)oxy-3&quot;-methoxycyclohexyl)-l ’ -msthylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-aza-tricyclo[22.3.1.0^» ^ joctacos-lS-erie-2,3,10,16-tetraone; 17-Etiiyl-1,14-dihydroxy-12-[2 ' -(4”-&lt;l-dibenzyl-phosphono^-athylindol-5-yl)oxy-3,,-metho:tycyclohexyl)-11 -raethylvinyl]-23,25-dimethoxy-13,19,21,27-tetra-msthyl-ll,28-dioxa-4-azatricycic[22.3.1.0^'^]octacos-lS-ene-2,3,10,16-tetraone;

Monopotassiua salt of 17-Ethyl-l,14-dihydroxy-12-[2'-(4,,-(l-phosphcnoxy-ethylir.dol-5-yl)oxy-3&quot;-methoxy-cyclohexyl )-l' -nethylvinyl j —23,25-dimethoxy-13,19,21, 27-tetramethyl-ll,2S-dioxa-4-azatricyclo[22.3.1.0^’^]-octacos-18-ene-2,3,10,16-tetraone; 17- Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(l-(N,N-dimethyl-glycyloxy) ethylir.dol-5-yl )oxy-3&quot;-:nethoxycyclohexyl)-11 -methylvinyl] -23,25-dimethoxy-13,19,21,27-tetra-methyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^’^joctacos- 18- ene-2,3,10,16-tetraone; - 292 - - 292 - LV 10450 17-Ethyl-1,14-dihydroxy-12-[21-(4&quot;-(l-succinyloxy-ethylindol-5-yl )oxy-3&quot;-rii8thoxycyciohexyl )-l' -methyl-vinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-asatricyclo[22°]octacos-18-ene-2,3,10, 16- tetraone; 17- Ethyl-1,14-dihydroxy-12-[2,-(4”-(l-methyl-3-phenyl-indol-5-yl )oxy-3&quot;-methoxycycloīiexyl )-i ' -methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^» ^]octacos-18-ene-2,3,10,16-tetraone ; 17-Ethyl-i , 14-dihydroxy-12-[21 -(4&quot;-(l-inethyl-3-('2-hyd r oxyethyl) indol-5 -yl) oxy-3 &quot;-meth.oxy cyclohexy 1 )-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0^* ^]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[2 '-(4l'-(l, 3-dimethylindol-5-yl)oxy-3M-msthoxycyclohexyl)-l1-meth.ylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-aza-tricyclo[22.3.1.0^·^]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydrcxy-12-[2 ' -(4&quot;-(l, 3-dimethylindol-5-yl)oxy-3&quot;-methoxycyclohexyl)-l1-methylvinyl]-23,25-dimetho:cy-13,19,21,27-tetramethyl-ll, 28-dioxa-4-aza-tricyclo[22.3.1.0^&gt; ^]octacos-18-ene-2,3,10,16-tetraone ; - 293 - 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(91-methylcarbazol 31-yl)oxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]-23,25 diaiethoxy-13,19,21,27-tetramethyl-ll, 28-dio:ra-4-aza-tricyclo[22.3.1.04*9]octacos-18-ene-2,3,10,16-tetracne; 17-Ethyl-1,14-dihydroxy-12-[2!-(4&quot;-((2’1''-(3' diethylaminopropionyloxy)ethyl)indol-51'1-yl)oxy-3&quot;~ 10 methoxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy- 13.19.21.27- tetramethyl-ll,28-dioxa-4-azatricyclo-[22.3.1.04 &gt; 9]octacos-18-er.e-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[21-(4&quot;-((21'''-(3' &quot; ' 15 dimethylarainopropionyloxy)ethyl)indol-51''-yl)oxy-3&quot;-methoxycyclohexyl)-l'-nethylvinyl]-23,25-dimethoxy- 13.19.21.27- tetrameth.yl-li,28-dioxa-4-azatricyclo-[22.3.1.04»9]octacos-18-ene-2,3,10,16-tetraone; ·· 20 17-Ethyl-1,14-dihydroxy-12-[21-(4&quot;-((2'«»‘-(3'''« aiuinoproņionyloxy)ethyl)indol-5'''-yl)osy-3&quot;-methoxycyclohexyl)-l '-ciethylvinyl]-23,25-dimethoxy- 13,19,21,27-tetramethyl-ll,23-dicxa-4-azatricyclo-[22.3.1.O4 &gt;9]octacos-18-ene-2,3,10,16-tetraone; 25 17-Ethyl-1,14-dihydroxy-12-[2'-(4”-(&lt;2''’'-(3' &quot; · -benzyxoxycarbor.yl-2' ' ' ' ' -benzyloxycarbonylamino-propionyloxy)ethyl)indcl-51 ' ' -yl)cxy-3&quot;-niethoxycycIo-hexyl)-l1 -methylvinyl]-23,25-diniethoxy-I3,19,21,27- t et r airis thy 1-11,28-dioxa-4-azatricycio[22. 3.1.O4,9]- octacos-18-ene-2,3,10,16-tetraone; 30 - 294 - - 294 -LV 10450 17-Ethyl-1,14-difcydroxy-12-[2'-(4&quot;-((2'*'*-(aspartyl-oxy)ethyl)indol-5'''-yl)oxy-3&quot;-methoxycyclohexyl)-l methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04 &gt; ^]octacos-18-ene-2,3,10,16-tetracne; 17-Ethyl-l,14-dihydroxy-12-[2,-(4M-((2' ' ' '-(1' imidazolylcarbonylcxy)ethyl)indol-5'·*-yl)oxy-3&quot;-methoxycyclohexyl)-i'-raethylvinyl]-23,25-dimethoxy- 13.19.21.27- tetramethyi-ll,28-dicxa-4-azatricyclo-[22.3.1.0^ &gt; ^]octacos-18-8ne-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[21-(4M-(&lt;211''-(1''''·-piperazinocazbonyloxy)ethyl)indol-5'*'-yl)oxy-3M-methoxycyclohexyl)-l '-zaethylvinyl]-23,25-dimathoxy- 13.19.21.27- tetrajnethyl-Il, 28-dioxa-4-azatricyclo-[22.3.1.0^19]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyi-1,14-dihydroxy-12-[21-(4&quot;-(l1''-(2''' &lt; 21'''1-hydroy)ethylaminocarbonyloxy)ethyl)indol-5’1'-yl)oxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-aza-tricyclo[22.3.1.0^&gt; ^]octacos-18-ene-2,3,10,16-tetraone ; 17-Ethyl-1,14-dihydroxy-12-[21-(4&quot;-(l1·!-(2··’ (isopropyaminocarbonyloxy)ethyi)indol-51'1-yl)oxy-3&quot;-methoxycyclohexyl)-l'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetraaieth:/l-ll, 28-dioxa-4-azatricyclo-[22.3.1.0^»^loctacos-18-ene-2,3,10,16-tetraone; 295 - 17-Ethyl-1,14-dihydroxy-12-[2'-(4&quot;-(l'''-(2''' (1' ' ' ' 1 -piperidinocarbonyloxy)etliyl)indol-5 1 ’ ’-yl)oxy-3&quot;-methoAycyclohe:-^rl)-l '-n-3thylvinyl]-23,25-dimethoxy-5 13,19,21,27-tetramethyl-ll, 28-dioi:a-4-azatricyclo- [22.3.1.0^»']octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dih.ydroxy-12-[21’ ' * — (2* * ' '-(I!'''1-morphi±inocarbonyloxy)ethyl)indol-511'-yl)oxy-10 3&quot;-metiio2rycyciohe2yl )-l' -methylvinylj-23,25-dimethoxy- 13.19.21.27- tetrasiethyl-ll, 2S-dio:-:a-4-azatricyclo-[22.3.1.0^ &gt;9]octacos-18-ene-2,3,10,16-tetraone; * 17-Ethyl-l,14-dihydrozy-12-[2'-(4&quot;-(l'1'-(2''''-15 (dipn3nylaminocarbonyloxy)ethyl)indol-5''’-yl)oxy-3&quot;- metho3cycyclche&gt;:yl)-lr-methylvinyl]-23,25-dimethoxy- 13.19.21.27- t2tranethyl-ll, 23-dion:a-4-azatricyclo-[22.3.1.0^’°]octacos-18-ene-2,3,10,16-tetraone; 20 17-Ethyl-1,14-dibydroxy-12-[21-(4&quot;-(l'’'-&lt;2''''- (diethylaiainocazbonyloxy)ethyl) indol-5 ’ 1 '-yl)oxy-3&quot;-netho:vycyclohexyl)-l' -methylvinyl]-23,25-dimethoxy- 13.19.21.27- tetra:rethyl-il, 28-dioxa-4-azatricyclo-[22.3.1.0^ &gt; 9]ectacos-lS-ene-2,3,10,16-tetraone; 25 17-Ethyl-l,14-diTiydro:ry-12-[2'-(£,,-(l' ' '-&lt;2' ' 1 '-metbanesnlfonyloxyethyl)indol-5*',-yl)oxy-3&quot;-methoxy-cyclohe:-:yl)-l' -msthylvinyl]-23,25-din:ethoxy-13,19,21, 27-tetramethyi-ll, 23-dic?;a-4-azatr icyclo[22.3.1.04&gt; 9]~ cctacos-lS-ene-2,3,10,16-tetraone; 30 - 296 - - 296 - LV 10450 17-Ethyl-1,14-dihydroxy-12-[2 '-(4&quot;-(l1 &quot;-(2'&quot; ’-azido-ethyl)indol-5' ' '-yl)oxy-3,,-methoxycyclohexyl)-l'-msthylvinyl]-23,25-dimethoxy-13,19,21,27-tetraraethyl-11,2S-dioxa-4-azatricyclo[22.3.1. 0^’9]octacos-18-ene- 2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[21-(4&quot;-(l'''-&lt;2’''’-amino-etīiyi)indol-5' ' f-yl)oxy-3&quot;-methoxycyclohexyl)-l methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl- 11.28- dioxa-4-azatricyclo[22.3.1.0^ &gt;^]octacos-18-ene- 2.3.10.16- tetraone; 17-Et’nyl-1,14-dihydroxy-12-[21 -(4&quot;-(l1 1 '-t-butyldi-msthylsilyloxyethoxyethylindol-5'''-yl)oxy-3&quot;-methoxy-cyclohexyl)-l' -methyivinyl]-23,25-dimethoxy-13,19,21, 27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^’^]-octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[21-&lt;4n-(l·' r-hydroxy-ethoxyethy!indol-5! ’ ’ -yl)oxy-3&quot;-methoxycyclohexyl)-l' -methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl- 11.28- dioxa-ii-azatr icyclo[22.3.1.0^’^]octacos-18-ene- 2.3.10.16- tetraone; 17-Ethyl-1,14-dihydroxy-12-[2'-(3&quot;-iaethoxy-4&quot;-(l' ' ' -(1'it1-oxcprop-31''!-yl)indol-5'11-yl)oxycyclohexyl)-1'-methylvinyl]-23,25-dimsthoxy-13,19,21,27-tetra-methyl-ll,28-dioxa-4-azatricyclo[22.3.1.0^ &gt;9]octacos-13-ene-2,3,10,16-tetraone; and - 297 17-Ethyl-1,14-dihydroxy-12-[2'-(3&quot;-methcxy-4&quot;-(l'1'-(1' ' ' '-carboxyetfc-2' ' 1-3'l)indol-5' ' '-yl)o3ycyclo-hexyl)-l '-meth3'-ivinyl]-23,25-dimethoxy-13,19,21,27-tetram3thyl-ll, 2S-dio:-:a-A-azatricyclo[22.3.1.0^*^]-octacos-13-ene-2,3,10,16-tetraone; or a pharmaceutically acceptable salt thersof. 7. A pharnaceutical compositicn comprising a pharmaceutical carrier and a therapeutically effective amount of tha compound of Claim 1. 8. The use of the compound of Claim 1 for the manufacture of a medicament for the treatment of immunoregulatory discrders. 9. The use of the compound of Claim 1 for the manufacture of a medicament for tha treatment of resistance to transplantation. 10. The use of the compound of Claim 1 for the manufacture of a medicament for the topical treatment of inflammatory and hyperproliferative skin diseases and or cutaneous manifestations of immunologicaliy-mediated illnesses.

Claims (18)

FIELD OF THE INVENTION The invention relates to the preparation and use of macrolides or pharmaceutically acceptable salts thereof represented by Formula I: I and wherein A R is selected from the group consisting of: (1) heteroaryl; (2) substituted heteroaryl- wherein X, Y and Z are substituted; (3) heteroaryl-C 1-10 alkyl; (4) substituted heteroaryl-C 1-4 alkyl- wherein the heteroaryl is substituted with X, Y and Z and the alkyl moiety may be substituted with one or more substituents such as: (a) hydroxy, (b) oxo, (o) C 1-6 alkoxy, (d) aryl-C 1-3 alkoxy, (e) substituted aryl-C 1-4 alkoxy, the substituents on the aryl being X, Y and Z, (f) unsubstituted or substituted aryloxy, wherein the substituents are aryl is X, Y and Z, (g) -OCO-C 1-8 alkyl, (h) -NR 6 R wherein R 6 and R 7 are independently selected from: (i) hydrogen, (ii) C 1-6 galkyl, unsubstituted or substituted with one or more substituents such as: (a ') aryl- which is unsubstituted or substituted with X, Y and Z, (b') heteroaryl- which is unsubstituted or substituted with X, Y and Z , (o ') -OH, (d') C 1 -C 6 -alkoxy, (e ') -CO 2 H, (f') -CO 2 -C 1-4 alkyl, LV 10450 (g ') -C., 7cycloalkyl-1-and ( h ') - 0RT \ (iii) C3_1Qenalkenyl, unsubstituted or substituted by one or more substituents or (b ') heteroaryl, which is unsubstituted or substituted with X, Y and Z, (o') -OH, (a ') aryl-, unsubstituted or substituted with X, Y and Z; d ') G 1 -alkoxy, (e') -CO 2 H, (f ') -CO 8 -C 6 -alkyl, (g') -C 3 -C 10 cycloalkyl and (h ') -O R 11, c (iv) or wherein R and R and N to which they are attached may form an unsubstituted or substituted 3- to 7-membered heterocyclic ring which may have one or two additional heteroatoms selected from the group consisting of 0, NR 14, S (0), or 0 (i). ) -NR 6 CO 0 -Cr as reference (J) -N 6 CO 2 -C 00 -N 6 CO 2 R 6: (1) -oconr 6 R 7 (m) -C 00 R 6, P 1 -C 8 alkyl, -alkyl-R 1-6 r 7, alkyl-R 14. wherein R is hydrogen is an unsubstituted group, and p fi 7 wherein R and R are, 5 (η) —CHO, (ο) aryl, (ρ) substituted aryl, wherein X, Y and Z are substituted, (q) -O R 11 and (r) -S (O) -C 1-8 alkyl; 10 (5) heteroaryl-C 1-4 alkyl- where one or more alkyl carbons are substituted with groups such as: -NR 6 -, -O-, -S (O) ^ -, -COg-, -OgC-, - CONR 6 -, -NR 6 CO -, -NR 6 COO 7 -; (6) substituted heteroaryl-C 1-4 alkyl- where one or more alkyl carbons are substituted with groups such as: -NR 6 -, -O-, -S (O) -, -CO 8 -, -O-C 2 -, - CONR6-, -NR6C0-, -NR6C0NR7-, heteroaryl are substituted with X, Y and Z. and the alkyl group may be substituted with one or more substituents selected from the group consisting of (a) hydroxy, (b) oxo, 20 (O) C 1-3 alkoxy, (d) aryl-C 1-3 alkoxy, (e) substituted aryl-C (gal) -alkoxy-, wherein the aryl substituents are X, Y and Z, (f) unsubstituted or substituted aryloxy-, where the aryl substituents are X, Y and Z, (gj-OCO-C 1-6 alkyl, (h) -NR 6 R 7, wherein R6 and R7 are as defined above, (1) -NR6CO-C1-6alkyl-R7, (j) -NR6CO2-C1-6alkyl-R7, (k) -NR6C0NR6R7, (l) -OC0NR6R7, (m) -C00R6, 35 t (n) -CHO, LV 10450 (o) aryl, (p) substituted aryl, wherein X, Y and Z, (q) -O-R 11 and (r) -S (O) p -O- are substituted. (7) heteroaryl-C 3-10 alkenyl, Xr * L - wherein alkenyl contains one to four double bonds; (8) heteroaryl-C 3-10 alkenyl - wherein alkenyl contains one to four double bonds and wherein one or more alkyl carbons are substituted with groups such as: -NR 6 -, -O-, -S (O) -CO 2 -, -O 2 C-, -CO 6 NR 6 -, -NR 6 CO 0 -. , -NR600NR -; (9) substituted heteroaryl-C1-4 alkenyl, where alkenyl contains one to four double bonds and wherein one or more of the alkyl carbons c may be substituted with groups such as: -NR -, -O -, -S (O) -, -C0-, -O0C-, -OONR6-, -MR6C0-, -NRC0NR-, heteroaryl is substituted with X, Y and Z and alkyl may be substituted with one or more substituents selected from the group consisting of: (a) hydroxy, (b) oxo, (O) C 1-6 alkoxy, (d) aryl-C 1-4 alkoxy, (e) substituted aryl-C 1-3 alkoxy, wherein the substituents on the aryl group are X, Y and Z, (f) the unsubstituted or substituted aryloxy-, wherein the substituents on the aryl group are X, Y and Z, (g) -OCO-C 1-6 alkyl-, (h) -NR 6 R 7 where R 6 and R 7 are as defined above, (1) -NR 6 CO-C 1-6 alkyl, where R 6 is as defined above, (j) -N 1 -C 6 CO 8 -C 6 galkyl, (k) -NR 600 NR 6 R 7, (I) -OCONR 6 R 7. , (m) -C00R6, (n) -CHO, (o) aryl, (p) substituted aryl, wherein X, Y and Z are substituted, (q) -OR11 and (r) ) -S (O) -O-O-C6-6 alkyl; R11 is selected from: (1) R; (2) hydrogen, (3) phenyl, (4) substituted phenyl wherein X, Y and Z are substituted; (5) 1- or 2-naphthyl; (6) substituted 1- or 2-naphthyl wherein X, Y and Z are substituted; (7) diphenyl; (8) substituted diphenyl wherein X, Y and Z are substituted; (9) C 1-4 alkyl; (10) substituted -G1-4alkyl wherein one or more of the substituents is selected from: (a) hydroxy, (b) oxo, (o) C1-4alkoxy, (d) aryl-1-3alkoxy, (e) ) substituted aryl-C 1-3 alkoxy- wherein the aryl substituents are X, Y and Z, (f) unsubstituted or substituted aryloxy- where the aryl substituents are X, Y and Z, (g) -OCO-C 1-3 alkyl-, EN 10450 ( h) -NR 6 R 7 where R 6 and R 7 are as defined above, (i) -NR 6 CO 0 -C 1-6 alkyl-R 7 where R 6 and R 7 are as defined above, (3) -COOR® where R® is as defined above above, (k) -CHO, (l) phenyl, (m) substituted phenyl wherein X, Y and Z are substituted, (n) 1- or 2-naphthyl, (o) substituted 1- or 2- naphthyl- wherein X, Y and Z are substituted, (p) diphenyl-, (q) substituted diphenyl- wherein X, Y and Z are substituted, (r) -O-R 11 and (s) -S (O) p-C 1-6 alkyl- ; (11) 0-alkenyl; (12) substituted C 3-10 alkenyl wherein one or more substituents are selected from: (a) hydroxyl, (b) oxo, (O) C 1-4 alkoxy, (d) phenyl-C 1-4 alkoxy, ( e) substituted phenyl-C 1-3 alkoxy- wherein the substituents on the phenyl group are X, Y and Z, (f) -OCO-C 1-6 alkyl-, (g) -NR R 7 where R 6 and R 7 are as defined above, (h) -NR6CO-C1-6alkyl- wherein R6 and is as defined above, (1) -C00R6 wherein R® is as defined above, (j) -CHO, 5 (k) phenyl, (l) substituted phenyl - wherein the substituents are X, Y and Z, (m) 1- or 2-naphthyl, (n) substituted with 1 or 2-naphthyl, wherein the substituents are X, Y and Z, (o) diphenyl, (p) substituted diphenyl- wherein j * i is substituted with X, Y and Z, (q) -O-R 11 and (r) -S (O) p-01-6alkyl-; (13) C 3-10 alkynyl; (14) substituted C 1-4 alkynyl groups wherein one or more substituents are selected from the group consisting of (a) hydroxy, (b) oxo, (O) C 1-3 galoxy, (d) phenyl-C 1-3 alkoxy, (E) substituted phenyl-C 1-3 alkoxy- wherein the substituents on the phenyl are X, Y and Z, (f) -O-CO-G 1-6 alkyl-, (g) -NR 6 R 7 where R 6 and R 7 are as defined above; (h) -NR ^ OC ^ galkyl-. wherein R6 is as defined above, C β (1) -C00R, where R is as defined above, (u) -CHO, (k) phenyl, 30 · (l) substituted phenyl, wherein the substituent *! is X, Y and Z, (m) 1- or. 2-naphthyl-, (n) substituted 1- or 2-naphthyl- wherein the substituted j * i is X, Y and Z, (o) diphenyl-, 10450 (p) substituted diphenyl wherein the substituents are X, Y and Z, (q) -OR 11; and (15) -R 11; 11 is hydrogen, hydroxy, -OR or alkoxy; »3 j is hydrogen or R and R taken together to form a double bond; is methyl, ethyl, propyl or allyl; is hydrogen, hydroxy, -OR 11 or fluorine; is selected from: (a) (b) (o) (d) -PO (0H) 0 ~ M +, where M + is a positively charged inorganic or organic to ion, -SO 3'm +, -CO (CH 2) q CO 2 'M +, q is 1-3 and -C0-C1-6alkyl-NR6R7 wherein R6 and R7 are as defined above and the alkyl group is unsubstituted or substituted with one or more substituents such as groups • • (i) hydroxyl, (ii) ) C 1 -C 6 -alkoxy, (iii) NR 16 R 17, wherein R 16 and R 17 are independently selected from: 25 (a *) hydrogen, or (iv) (b *) 0, alkyl, S g -C00 R, wherein R is as defined as defined above, (v) phenyl, (vi) substituted phenyl, wherein the substituents are X, Y and Z, (vii) heteroaryl, (viii) -SH, and '(ii) -S-C 1-6 alkyl-; 0 or (Η, 0H); 35 W is X, Υ and Z are independently selected from: (a) hydrogen, (b) C 1-6 alkyl, unsubstituted or substituted with one or more substituents such as: (i) aryl, ( (ii) substituted aryl wherein X ', Y' and Z 'are substituted, (iii) heteroaryl, (10) (iv) substituted heteroaryl wherein X', Y 'and Z' are substituted, 15 (vi) - 0R6, (vii) -OR11, (viii) -OCO6, (is) -OCOgR6, (z) -NR6R7, 20 (zi) -CH0, (zii) (ziii) -NR6C0C1-6alkyl-R7, -NR6CO2C1-6alkyl-R7, ( fish) -NR6OONR6R7, (zv) -oconr6r7, (zvi) -C0NR6R7, (c) C 1-4 alkyl, wherein one of the alkyl carbons is replaced by groups such as: -NR -, -O -, (v) unsubstituted or substituted aryloxy, wherein the substituents on the aryl group are X ', Y' and Z ', "-S (O) 3 -, -CO 0 -, -0,0 -, -CONR 0 -, -NR ° C 0 -, ii c. -NRSC0NR7-; -CO-, -CH (OH) -, alkenyl or alkynyl and alkyl may be unsubstituted or substituted with one or more substituents such as: (i) a-yl, * aryl-substituted; with substituents X ', Y' and Z ', (iii) heteroaryl, (iv) substituted heteroaryl where X', Y * and Z 'are substituted, (v) unsubstituted or substituted aryloxy wherein the substituents on the aryl group are X ', Y' and Z ', (vi) -0R6, 10 (vii) -0R11, (viii) -0C0R6, (ix) -oco2r6, (ς) -nr6r7, (zi) -CH0, (Xii) (xiii) -NR6C0C1-6alkyl-R7, -NR6CO2C1-6alkyl-R7, (fish) -NR6C0NR6R7, (xv) -0C0NR6R7, (zvi) -conr6r7, 20 (d) halogen, (e) -NR6R7, (f) -CN, (g) -CH 0, 00 -cp3, 25 (i) ΟQ -SR where R is hydrogen, C1 trifluoromethyl or phenyl, (3) -SO08, (k) -SOpR8, (1) -C0NR6R7 , 30 (m) R 90 (CH 2) m -, wherein R 9 is hydrogen, kil, hydroxy-02-3 alkyl, -CP3 R11 or naphthyl and m is 0, (n) -CH (OR12) (OR13) where R12 and R13 , alkyl, alkyl groups taken together in the '1-3 group to form 1, 2 or 3 is C. var 35 (0) also ethyl or propyltyl, R 9 COO (CH 2) m -, where R 9 and m are as defined above, (p) R 90 CO (CH 2) m - wherein R 9 and m are as defined above and (q) -R 11; or any two of X, Y and Z can combine to form a saturated ring with 5, 6 or 7 ring atoms, of which 1 or 2 are oxygen and the other carbon atoms; Σ ', Y * and Z' are independently selected from: (a) hydrogen, (b) C 1-7 alkyl, (c) C 2-6 alkenyl, (d) halogen, (e). - (CH 2) m -NR 6 R 7 where R 6, R 7 and m are as defined above, (f) -CN, (') -CHO, (h) -CP 3, (i) -SR 9, wherein R 9 is hydrogen, C 1-6 galkyl, trifluoromethyl or phenyl, (j) -SO 2 R 9 where R 9 is as defined above, OQ (k) -SO 2 R where R is as above, (1) -CO 6 NR 7 where R 6 and R7 is as defined above, (m) R90 (CH2) m-, wherein R9 and m are as above, (n) -CH (0R12) (0R13), wherein R12 and R13 are as defined above, (o) R 9 CO 3 (CH 2) m - wherein R 9 and m are as defined above, (q) (p) R 90 CO (CH 2) - where R 9 and m are as defined above and -R 11; n is 1 or 2. LV 10450 2. A process according to claim 1, wherein the absolute configuration of the compounds is as shown in formula III: 5 10 15 III% 20 25 30 35 5 3. Invention according to claim 1, wherein the heteroaryl group is selected from the following: 10 15 Y Y 20 25 30th 35 10 15 20 25 Y Z ζι Quinoline) C-quinoxaline) EN 10450 wherein Q is -N (X) -, -O- or -S- 35 4. The process of claim 3, wherein the heteroaryl is selected from: LV 10450 5 N where X is as defined in p. 5. The process of claim 1, wherein the heteroaryl is selected from: R2 is selected from: (1) hydrogen, (2) methyl, (3) ethyl, (4) propyl, (5) allyl, (6) R11, (7) -C2.3 alkyl-OH; and (8) -C 2-3 alkyl-OR 11; R 3 is selected from: (1) hydrogen, (2) oxy, (3) -OR 11, or R 3 and R 6 taken together form a double bond; R 10 is hydrogen, oxy, fluoro or -OR 11 W is O; and n is 2 EN 10450 * 6. The invention according to claims 1-3, characterized in that the compounds are selected from the following: 17-Ethyl-1,14-dihydroxy-12- [2 * - (4 * '- (2-furyl) methoxy-3'1-methoxycyclohexyl) -11-methylvinyl] -3-23,25-dimethoxy -13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.04 * 9] octacos-18-ene-2,3,10,16-tetraone; Φ 17-Ethyl-1,14-dihydroxy-12- [2 * - (4 '' - (2-furyl) methoxy-3 '' -hydroxycyclohexyl) -! * -methylvinvinyl 3-2 3,25-di-10 methoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyl [22.3.1.04.9 3 octacos-18- en-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' '-hydroxy-3' '- (2-furyl) -methoxycyclohexyl) -1'-methyl-vinyl] -3-23,25-di. 15 methoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-triaclo [22.3.1.0 &gt; .0 &lt; 4 &gt;]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-1 2- [2 '- (4' '- (2-thiophene) -methoxy-3' * -methoxy-cyclohexyl) -1 * -methyl-vinyl] -2- 23,25-di- 20 methoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-triaclo [22.3.14.090] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' '- (2-thiophene) -methoxy-3' '-hydroxycyclohexyl) -1,3-methylvinyl] -3-23,25-di-25 methoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-triaclo [22.3.14.93,93] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2,1- (4'-O-thiophene-3-methoxy-3 '' -hydroxy-cyclohexyl) -1 * -methylvinvinyl] -23,25-di-30-methoxy -13,19,21,27-tetramethyl-11,28-dioxa-4-azatri-cyclo [22.3.1.04.93 octacos-18-ene-2,3,10,16-tetraone; 35 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' * -hydroxy-3 '' - (2-thiophene) methoxycyclohexyl) -1'-methyl vinyl] -23,25-dimethoxy-13 , 19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.04 * 9] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4', -hydroxy-3 &quot; - (3-thiophene) methoxycyclohexyl) -1'-methyl vinyl] -23,25-dimethoxy-13, 19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.04 * 9] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-C 2 - (4 * '- (2-thiophene) oxy-3' 'methoxycyclohexyl) -1 * -methyl vinyl] -23,25-dimethoxy-13,19, 21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.04 * 9] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4', - (2-benzthienyl) oxy-3 '' - methoxycyclohexyl) -1 * -methyl vinyl] -23,25-di -methoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.04 * 9] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' '- (5-indolyl) oxy-3'1-methoxycyclohexyl) -1'-methyl vinyl] -23,25-dimethoxy-13 , 19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.14.4 * 9] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 * - (4 '' - (5-indolyl) oxy-3 '' hydroxycyclohexyl) -1'-methyl vinyl] -23,25-dimethoxy-13 , 19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1 -0 4,9] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14,20-trihydroxy-12- [2 '- (4' '- (5-indolyl) oxy-3' '- methoxycyclohexyl) -1,11-methylvinyl] -23,25-di- methoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.04'9] octacos-18-ene-2,3,10,16-tetraone; LV 10450 17-Ethyl-1,20-dihydroxy-12- [2 '- (4' '- (5-indolyl-oxy-3' '-methoxycyclohexyl) -1' -methyl-vinyl] -S 5'S-dimethoxy-13, 19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.04 * 9] octacos-18-ene-2,3,10,16-tetraone; hydroxy-12- [2 * - (4 * '- (5-indolyl) oxy-3H-methoxycyclohexyl) -1'-methylvinyl] -23,25-dimethoxy-13,19, 21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &gt;.beta.-octacos-18-ene-2,3,10,16-tetraone; - [2 '- (4' * - (5-indolyl) oxy-3 '' -methoxycyclohexyl) -1'-methylvinyl] -3,23,25-dimethoxy-13,19,21,27-tetramethyl-11,28 -dioxa-4-aza-tricyclo [22.3.1.0 &gt; 04 * 9] 3-octaacos-18-ene-2,3,10,16-tetraone; 17-allyl-1,14-dihydroxy-12- [2, - ( 4 * (5-indolyl) oxy-3 '' -hydroxycyclohexyl) -1'-methyl vinyl-3,23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclic- lo [22.3.1.04,9,9] octocos-18-ene-2,3,10,16-tetraone; 20 17-Allyl-1,14-20-trihydroxy-12 ~ [2 '- (4' '- (5-indolyl) ) -cxi-3 '' - methoxycyclohexi) -1 '-met ilvinyl3-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; 4,9 &gt;16-tetraone; · 17 17-Allyl-1, 20-dihydroxy-12- [2 '- (4 *' - (5-indolyl) oxy-3 * '-methoxycyclohexyl) -1 * -methyl vinyl] -3-23,25-dimethoxy -13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &gt; .0 &lt; 4 &gt;]octacos-18-ene-2,3,10,16-tetraone; 17 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' '- (5-indolyl) oxy-3' '-ethoxycyclohexyl) -1 * -methyl vinyl] -23,25-dimethoxy- 13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1 .04 * 9,3-octacos-18-n-2,3,10,16-theta; 35 17-Allyl-1,14-dihydroxy-12- [2 * - (4 '' - (5-indolyl) oxy-3 '' - ethoxycyclohexyl) -1'-methyl vinyl] -23,25-dimethoxy- 13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.04 * 9] octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1-hydroxy-12- [2 '- (4' '- (5-indolyl) oxy-3' '- methoxycyclohexyl) -1'-methyl vinyl] -23,25-dimethoxy-13,19 21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.04,9] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-12-12 (4 '- (1-N-methyl-5-indolyl) oxy-3' '- methoxycyclohexyl) -1'-methylvinyl] -23.25 -dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo (22.3.14.9,9) octacos-18-ene-2,3,10,16-tetraone; Ethyl 1,14-dihydroxy-12- [2 '- (4'1- (1-N-methyl-5-indolyl) oxy-3' 'hydroxycyclohexyl) -1'-methyl vinyl] -23.25 -dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.04 * 9] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl; -1,14,20-trihydroxy-12- [2 '- (4' '- (1-N-methyl-5-indolyl) oxy-3' '- methoxycyclohexyl) -1'-methyl vinyl] -23,25- dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo (22.3.14.9,9) octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1 H- N-O-trihydroxy-4 '- (' - N '- (1-N-methyl-5-indolyl) oxy-3' '-hydroxycyclohexyl) -1'-methyl vinyl] -23,25-dimethoxy-13,19 , 21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.04 * 9] octacos-18-ene-2,3,10,16-tetraone; LV 10450 17-Ethyl-1,20-dihydroxy -12- [2 '- (4' '- (1-N-methyl-5-indolyl) oxy-3' '- methoxy) cyclohexyl) -1 * -methylvinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.04 * 9] octacos-18-ene-2, 3,10,16-tetraones; 17-Ethyl-1,20-dihydroxy-12- [2 '- (4' '- (1-N-methyl-5-indolyl) oxy-3' '-hydroxycyclohexyl) -1'-methylvinyl3-23 , 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatri-4,9-ollo [22.3.1.0 *] octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14-dihydroxy-12- [2 '- (4 *' - (1-N-methyl-5-indolyl) oxy-3 * '- methoxycyclohexyl) -1 * -methyl vinyl] -23 , 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.04 * 9] octacos-18-ene-2,3,10,16-thetone; 17-Allyl-1,14,20-trihydroxy-12- [2 '- (4' '- (1-N-methyl-5-indolyl) oxy-3' 'methoxycyclohexyl) -1'-methyl vinyl] -23 , 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.04,9] octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1, 20-dihydroxy-12- [2 '- (4' '- (1-N-methyl-5-indolyl) oxy-3' 'methoxycyclohexyl) -1'-methyl vinyl] -23 , 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1. 04 * 9] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1-hydroxy-12- [2 '- (4' - (1-N-methyl-5-indolyl) oxy-3 '' methoxycyclohexyl) -1'-methyl vinyl] -23,25-di -methoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.04'9] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 * - (4 '' - (1-N-methyl-5-indolyl) oxy-3 * '- ethoxycyclohexyl) -1' -methyl vinyl- 23,25-Dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.094 .9] octacos-18-ene-2,3,10,16- tetraone; 17 17-Allyl-1,14-dihydroxy-12- [2 '- (4' '- (1-N-methyl-5-indolyl) oxy-3' * ethoxycyclohexyl) -1'-methyl vinyl ] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.04.9] octacos-18-ene-2,3,10, 16-tetraone; 17 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' '- (1-N-ethyl-5-indolyl) oxy-3' '- ethoxycyclohexyl) -1'-methyl vinyl -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &gt; 04 * 9] octacos-18-ene-2,3,10,16- tetraone; 17-Allyl-1-hydroxy-12- [2 '- (4' - (1-N-methyl-5-indolyl) oxy-3 '' -methoxycyclohexyl) -1'-methylvinyl3-23 , 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &gt; .0 &lt; 4 &gt;; 17 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' '- (1-N-methyl-5-indolyl) oxy-3' 'allyloxycyclohexyl) -1'-methylvinyl3-23 , 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &gt; .0 &lt; 3 &gt; 17-Ethyl-1-hydroxy-12- [2 '- (4' '- (1-N-methyl-5-indolyl) oxy-3' 'allyloxycyclohexyl) -1'-methylvinyl 3-23,25 -dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; 4,9 &gt;]octacos-18-ene-2,3,10,16-tetraone; 17 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' '- (1-N-methyl-5-indolyl) oxy-3' '- n-propyloxycyclohexyl) -1'-methyl vinyl -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.104,59] octacos-18-ene-2,3,10,16-tetraone; 35 LV 10450 17-Ethyl-1-hydroxy-12- [2 '- (4' * - (1-N-methyl-5-indoyl) -oxy-3 * '- n-propyloxycyclohexyl) -1 * -methyl-vinyl-3- 23.25-Dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatrylcyclo [22.3.1.04 * 9] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 * - (4 '' - (1-N-methyl-5-indolyl) oxy-3 '' - i -propyloxycyclohexyl) -1'- methyl vinyl] - 23.25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.04 * 9] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2- (4 '* - (1-N-ethyl-5-indolyl) -oxy-5' -raethoxycyclohexyl) -1 * -methyl-vinyl-3-23,25-dimethoxy- 13,19,21,27-tetraethyl-1,1,28-dioxa-4-aza-trio-cyclo [22.3.1.0 &gt; .0 &lt; 4 &gt;]octacos-18-ene-2,3,10,16-tetraone; 17-ethyl -1,14,20-trihydroxy-12- [2 '- (4' * - (1-N-ethyl-5-indolyl) oxy-3 '' - methoxycyclohexyl) -1'-methyl vinyl-23, 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &gt; .0 &lt; 4 &gt;-Octacos-18-ene-2,3,10,16-tetraone; -1,20-dihydroxy-1 2- [2 '- (4' '- (1-N-ethyl-5-indolyl) oxy-3' 'methoxycyclohexyl) -1'-methyl vinyl 3-23, 25-Dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.04 * 9] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl; -1,14-Dihydroxy-12- [2 '- (4' '- (1-N-ethyl-5-indolyl) oxy-3' * -hydroxycyclohexyl) -1'-methylvinyl] -3-23,25-dimethoxy -13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo C 22.3.1 .04 * 9 3-octacos-18-ene-2,3,10,16-tetraone; -1,14-dihydroxy-12- [2 '- (4' '- (1-N-ethyl-5-indole) yloxy-S1 '-methoxycyclohexyl) -1'-methylvinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.04.4 * 9] octacos -18-en-2,3,10,16-tetraone; 17-Allyl-1,14,20-trihydroxy-12- [2 '- (4' '- (1-N-ethyl-5-indolyl) oxy-3' '-methoxycyclohexyl) -1'-methyl vinyl] -23,15-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-trio-cyclo [22.3.1.04'9] octacos-18-ene-2,3,10,16- tetraone; 17-Allyl-1, 20-dihydroxy-12- [2 * - (4 '' - (1-N-ethyl-5-indolyl) oxy-3 '' methoxycyclohexyl) -1'-methyl vinyl] -23 , 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-trio cyclo [22.3.1.04 * 9] octacos-18-ene-2,3,10,16-tetraone; 17-N -1-1,14-Dihydroxy-12- [2 '- (4' '- (1-N-ethyl-5-indolyl) oxy-3' 'hydroxycyclohexyl) -1'-methyl vinyl] -23 , 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-trio cyclo [22.3.1.04 * 9] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1-hydroxy-12- [2 '- (4 &quot; - (1-N-ethyl-5-indolyl-oxy-3' * -methoxy-cyclohexyl) -1 * -methyl-vinyl] -23,25- dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &gt; .0 &lt; 4 &gt;]octacos-18-ene-2,3,10,16-tetraone;17-allyl; -1-hydroxy-12- [2 '- (4' '- (1-N-ethyl-5-indolyl-oxy-3' '-methoxy-cyclohexyl) -1'-methyl-vinyl) -23,25-dimethoxy-13, 19,21,27-tetramethyl-11,28-dioxa-4-aza-trio cyclo [22.3.1.04,9] octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14- dihydroxy-12- [2 '- (4' '- (1-N-ethyl-5-indolyl) oxy-3' '-ethoxycyclohexyl) -1'-methylvinyl] -3-23,25-dimethoxy-13,19, 21,27-tetramethyl-11,28-dioxa-4-aza-trio-cyclo [22.3.1.0 &gt; 4.9 * 9] octacos-18-ene-2,3,10,16-tetraone; LV 10450 17-Ethyl-1, 14-dihydroxy-12- [2 '- (41' - (1-N-propyl-5-indolyl) oxy-3 '' - methoxycyclohexyl] -1-methylvinyl) - 23.25-dimethoxy-13,19,21, 27-Tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.04,9] octacos-18-ene-2,3,10,16-5-tetraone; 17-Ethyl-1,14,20-trihydroxy-12 - [2 '- (41 * - (1-N-propyl-5-indolyl) oxy-3' '- me) Toxicyclohexyl) -1'-methylvinyl] -23.25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &gt; .0 4] octacos-18-ene-2,3 , 10,16-10 tetraons; 17-Ethyl-1- (2-dihydroxy) -4'-te '- ^' '- (1-N-propyl-5-indolyl) oxy-3' * -methoxycyclohexyl) -1'-methylvinyl] - 23.25-dimethoxy -13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.04,9] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' '- (1N-propyl-5-indolyl) oxy-3 ** -hydroxycyclohexyl) -1'-methylvinyl] -20 23,25-Dimethoxy-13,19,21,27-tetramethyl-11,28 -loxa-4-aza-tricyclo [22.3.1.04 * 9] octacos-18-ene-2,3,10,16-1-tetraone; 17-Ethyl-1,14,20-trihydroxy-12- [2 '- (4' * - (1-N-propyl-5-25 indolyl) oxy-3 '' hydroxycyclohexyl) -1'-methyl vinyl] - 23.25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &gt; 4.9 * 9] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,20-dihydroxy-12- [2 '- (4' '- (1-N-propyl-5-indolyl) oxy-311-hydroxycyclohexyl) -1'-methyl vinyl] - 23.25-dimethoxy -13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.04 * 9] octacos-18-ene-2,3,10,16-tetraone; 35 17-Allyl-1,14-dihydroxy-12 - [. 2 '- (4' '- (1-N-propyl-5-indolyl) oxy-3' '-methoxycyclohexyl) -1'-methylvinyl- 23.25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.04'9] octacos-18-ene-2,3,10,16-tetraone; 17-A1U-1,14,20-trihydroxy-12- [2 '- (4' '- (1-N-propyl-5-indolyl) oxy-3' '-methoxycyclohexyl) -1'-methyl vinyl] - 23.25 - dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22. 3.1.04'9] octacos-18-ene-2,3,10,16-tetraone; 17-AlH-1,20-dihydroxy-12- [2 '- (4 *' - (1-N-propyl-5-indolyl) oxy-3 '' - methoxycyclohexyl) -1'-methylvinyl] -23.25- dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &gt; .0 4,9] octacos-18-ene-2,3,10,16-tetraone; 17-Al 11-1, 14-dihydroxy-12- [2 '- (4' '- (1-N-propyl-5-indolyl) oxy-3' 'hydroxycyclohexyl) -1'-rethyl vinyl] -23 , 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.04'9] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1-hydroxy-12-C2 * - (4 '* - (1-N-propyl-5-indolyl) oxy-3 * * -methoxycyclohexyl) -1' -πΐΘΪί1νίηϋ] -23,25- ( -Methoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.04 * 9] octacos-18-ene-2,3,10,16-tetraone; 17 -Alyl-1-hydroxy-12- [2 '- (4' '- (1-N-propyl-5-indolyl) oxy-3' 'methoxycyclohexyl) -1'-methyl vinyl] -23,25-di -methoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-triaclo [22.3.1.04.9] octacos-18-ene-2,3,10,16-tetraone; 10450 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' * - (1-N-propyl-5-indolylloxy-S * '- ethoxycyclohexyl) -1'-methyl vinyl] - 23.25- Dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-pyro-cyclo [22.3.1.04,9] octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1, 14-dihydroxy-12- [2 '- (4' '- (1-N-propyl-5-indolyl) oxy-3' '- ethoxycyclohexyl) -1'-methyl vinyl] - 23.25-dimethoxy-13,19 , 21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.04 * 9] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12 - [2 '- (4' '- (1-N-allyl-5-indolyl) oxy) -3''-methoxycyclohexyl) -1'-methyl vinyl-3-23,25-dimethoxy-13,19,21,27-tetramethyl-H, 28-dioxa-4-aza-tricyclo [22.3.1.04 * 9] octacos-18-ene -2,3,10,16-tetraones; 17-Ethyl-1,14,20-trihydroxy-12- [2 * - (4 '' - (1-N-allyl-5-indolyl) oxy-3 '' -methoxycyclohexyl) -1 '-methyl vinyl-23.25- dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &gt; .0 &lt; 3 &gt;]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,2-dihydroxy-12- [2 '- (4 *' - (1-N-allyl-5-indolyl) oxy-31'-methoxycyclohexyl) -1'-methyl vinyl] - 23.25- dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &gt; .0 4,9] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' '- (1-N-allyl-5-indolyl) oxy-3' 'hydroxycyclohexyl) -1'-methyl vinyl} - 23.25 - dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &gt; .0 &lt; 3 &gt;]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14,20-trito-di * oxy-12- [2 '- (4' (1-N-allyl-5-indolyl) oxy-3 * '-hydroxycyclohexyl) -1'-methyl vinyl] - 23.25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.04 * 9] octacos-18-ene-2,3,10,16-5-tetraone; 17-Ethyl-1,20-dihydroxy-12- [2 '- (4' * - (1-N-allyl-5-indolyl) oxy-3 '' hydroxycyclohexyl) -1'-methyl vinyl] -23.25- dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.04'9] octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14-di-hydroxy-12- [2 '- (4' '- (1-N-allyl-5-indolyl) oxy-3' '-methoxycyclohexyl) -1 * -methyl vinyl-3' 23,25-Dimethoxy-13,19,21,27-tetramethyl-1,1,28-dioxa-4-aza-tricyclo [22.3.1.0 &gt; 4 * 9] octacos-18-ene-2,3,10,16-tetraone ; 17-Allyl-1,14,20-trihydroxy-12- [2 '- (4' '- (1-N-allyl-5-20 indolyl) oxy-3' * methoxycyclohexyl) -1'-methyl vinyl - 23.25-dimethoxy-13,19,21,27-tethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.04,9] octacos-18-ß-2,3,10,16-tetraone; 17-Allyl-1, 20-dihydroxy-12- [2 '- (4' '- (1-N-allyl-5-indolyl) oxy-3' '- methoxycyclohexyl) -1'-methylvinyl] -3- , 25-dimethoxy-1,3,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 4,9] octacos-18-ene-2,3,10,16-tetraone; 17 17-Allyl-1,14-dihydroxy-12- [2 '- (4 *' - (1-N-allyl-5-in-clolyl) hydroxy-3 '' -hydroxycyclohexyl) -1'-methyl-vinyl] - 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.04,9] octacos-18-ene-2,3,10,16-tetraone; 35 LV 10450 17-Ethyl-1-hydroxy-12- [2 '- (4' '- (1-N-allyl-5-indolyl) oxy-3' '-methoxycyclohexyl) -1'-methylvinyl3-23, 25-Dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0 &gt; .0 &lt; 4 &gt;] octacos-18-ene-2,3,10,1.6- tetraone; 17-Allyl-1-hydroxy-12- [21- (4 '' - (1-N-allyl-5-indolyl) oxy-3 '' -methoxycyclohexyl) -1'-methylvinyl] -3-23,25-di- methoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatri-4,9-cyclo [22.3.1.0 * 3-octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' '- (1-N-allyl-5-indolyl) oxy-3'1-ethoxycyclohexyl) -1'-methyl vinyl} -23 , 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.04 * 9] octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14-dihydroxy-12- [2 '- (4' '- (1-N-allyl-5-indolyl) oxy-3' '- ethoxycyclohexyl) -1'-methylvinyl3-23, 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.04 * 9] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' '- (1-? -2-hydroxyethyl-5-indolyl) oxy-3' '- methoxycyclohexyl) -1'-methyl vinyl] - 23 , 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.04 * 9] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14,20-trihydroxy-12- [2 '- (4' '- (1- Ν-2-hydroxyethyl-5-indolyl) oxy-3' '- methoxycyclohexyl) -1'- methyl vinyl3-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.04 * 9] octacos-18-ene-2,3,10,16 -tetraone; ✓ 17-Ethyl-1,20-dihydroxy-12- [2 * - (4 '' - (1-N-2-hydroxyethyl-5-indolyl) oxy-3 '' - methoxycyclohexyl) -1'-methyl vinyl] - 23.25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.04 * 9] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1M-dichydroxy -? - te '- ^' * - (1- (2-hydroxyethyl-5-indolyl) oxy-3 '' - hydroxycyclohexyl) -1'-methyl vinyl] - 23.25-dimethoxy -13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; 4 &gt; -] - octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14,20-trihydroxy-12- [2 * - (4 '' - (1- Ν-2-hydroxyethyl-5-indolyl) oxy-3 '' -hydroxy cyclohexyl) -1 '- Methylvinyl3-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; 4 &gt;] octacos-18-ene-2,3,10 , 16-tetraone; 17-Ethyl-1,20-dihydroxy-12- [2 '- (4' * - (1-N-2-hydroxyethyl-5-indolyl) oxy-3 '' hydroxycyclohexyl) -1'-methyl vinyl] -23 , 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; 4 &gt; -] - octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14-dihydroxy-12- [2 '- (4' '- (1'N-2-hydroxyethyl-5-indolyl) oxy-3' '- methoxycyclohexyl) -1'-methyl vinyl] - 23.25-dimethoxy -13,19,21,27-tetramethyl-11,28-dioxa-4-aza-triethyl [22.3.1.0 &gt; .0 &lt; 4 &gt;]octacos-18-ene-2,3,10,16-tephrone; 17-A111-1,14-dihydroxy-12- [2 '- (41' - (1-N-2-hydroxyethyl-5-indolyl) oxy-3 '' - hydroxycyclohexyl] -N-methylvinyl-23.25-dimethoxy-13, 19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; 4 &gt;]]octacos-18-ene-2,3,10,16-tetraone; LV 10450 17-Ethyl-1 , 14-Dihydroxy-12- [2 '- (4' - (1-N-benzyl-5-indolyl) oxy-3 '' -methoxycyclohexyl) -1'-methylvinyl] -5S-dimethoxy-13 , 19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.04 * 9] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14 , 20-trihydroxy-12- [2 * - (4 '' - (1-N-benzyl-5-indolyl) oxy-3''-methoxy-cyclohexyl] -1'-methyl-vinyl) -23,25-dimethoxy-13,19 , 21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.04 * 9] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,20-dihydroxy-12. - [2 '- (4' '- (1-N-benzyl-5-indolyl) oxy-3' '-methoxycyclohexyl] -1 * -methyl vinyl) -3-23,25-dimethoxy-13,19,21,27- tetramethyl-11,28-dioxa-4-aza-triaclo [22.3.14909] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' * - ( 1-N-benzyl-5-indolyl) oxy-3 '' -hydroxycyclohexyl) -1'-methyl vinyl-3-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4- azatri-oxo [22.3.1 .04 * 9] octacos-18-ene-2,3,10,16-tetraone; '17-Ethyl-1,14,20-trihydroxy-12- [2' - (4 '' - (1-N-benzyl-5-indolyl) oxy-3 '' -hydroxycyclohexyl) -1'-methyl vinyl] - 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; 4 &gt; .0 &lt; 3 &gt;]octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,20-dihydroxy-12- [2 '- (4' '- (1-N-benzyl-5-indolyl) oxy-3' 'hydroxycyclohexyl) -1'-methyl vinyl] -23 , 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.04 * 9] octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14-dihydroxy-12- [2 '- (4' '- (1-N-benzyl-5-indolyl) oxy-3' '-methoxycyclohexyl) -1'-methylvinyl] -23 , 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.04 * 9] octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14,20-trihydroxy-12- [2 '- (4 * 1- (1-N-benzyl-5-indolyl) oxy-3' '-methoxycyclohexyl) -1'-methylvinyl] -23 , 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.04 * 9] octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1, 20-dihydroxy-12- [2 '- (4 *' - (1-N-benzyl-5-indolyl) oxy-3 * * -methoxycyclohexyl) -1'-methylvinyl] -23 , 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.04 * 9] octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14-dihydroxy-1 2- [2 '- (4' '- (1-N-benzyl-5-indolyl) oxy-3' '- hydroxycyclohexyl) -1'-methylvinyl3-23 , 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ** 9] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1-hydroxy-12- [2 '- (4' '- (1-N-benzyl-5-indolyl) oxy-3' '- methoxycyclohexyl) -1'-methyl vinyl] -3-23,25-di -methoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-triaclo [22.3.14.9,9] octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1-hydroxy-12- [2 '- (4' '- (1-N-benzyl-5-indolyl) oxy-3' '-methoxycyclohexyl) -1' -πιβίί1νίηίΐ3-23,25- ( α-Methoxy-1,3,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.04.9] octacos-18-ene-2,3,10,16-te 17-Ethyl-1,14-dihydroxy-12- [2 '- (4 *' - (1-N-benzyl-5-indolyl) oxy-3 '' - ethoxycyclohexyl) -1'-methyl vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &gt; 4 * 9] octacos-18-ene-2,3,10,16 LV 10450 17-Allyl-1,14-dihydroxy-12- [2 '- (4' '- (1-N-benzyl-5-indolyl) oxy-3' '- ethoxycyclohexyl) -1' -methyl-methyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &gt; .0 4] 9 octacos-18-ene-2,3 , 10,16-Tetraones; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' '- (1-N-cyclopropyl-5-indolyl) oxy-3''-methoxycyclohexyl-l) '-methylvinyl] - 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &gt; 4 * 9] octacos-18-ene-2,3,10 , 16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4 * * - (1-N-cyclic) lopropyl-5-indolyl) oxy-31'-hydroxycyclohexyl) -1'-methylvinyl] - 23.25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.04 * 9] octakcz-18-en-2,3,10,16-tetraone; 17-N -1-1,14-dihydroxy-12- [2 '- (4' '- (1'-cyclopropyl-5-indolyl) oxy-3' '- methoxycyclohexyl) -1'-methyl vinyl] - 23.25-dimethoxy-13 , 19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.04,9] octacos-18-ene-2,3,10,16-tetraone; 17β-1,1,11A-Dihydroxy - N - tert -N '- (1N-cyclopropyl-5-indolyl) oxy-3' '- hydroxycyclohexyl) -1'-methyl vinyl] - 23.25-dimethoxy-13,19 , 21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.04 * 9] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' '- (1-N-cyclopropyl-5-indolyl) oxy-3' '- ethoxycyclohexyl) -1'-methyl vinyl] -23,25- dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &gt; .0 4,9] octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14-dihydroxy-12- [2 '- (4' '- (1-N-cyclopropyl-5-indolyl) oxy-3' '-ethoxycyclohexyl) -1'-methylvinyl] - 23.25-dimethoxy -13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.04 * 9] octacos-18-ene-2,3,10,16-5-tetraone; 17-Ethyl-1-hydroxy-12- [2 '- (4' '- (1-N-cyclopropyl-5-indolyl) oxy-3' * methoxycyclohexyl) -1'-methyl vinyl] - 23.25-dimethoxy -13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.04 * 9] octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1-hydroxy-12- [2 '- (4' '- (1-N-cyclopropyl-5-indolyl) oxy-3' 'methoxycyclohexyl) -1'-methyl vinyl] -15 23, 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.04 * 9] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1-hydroxy-12- [2 '- (4 *' -methoxy-N-tryptoananyl-20 carbonylmethoxy-3 '' - methoxycyclohexyl) -1 * -methyl vinyl] - 23.25-dimethoxy-13,19,21 , 27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &gt; 4,9] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1-hydroxy-12- [2 '- (4' '- (3-indolylethylaminocarbonylmethoxy-3' '- methoxycyclohexyl) -1'-methyl vinyl) -23.25-dimethoxy-13,19,21,27- tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.04 * 9] octacos-18-ene-2,3,10,16-tetraone; 17 17-Ethyl-1,14-dihydroxy-12- [2 ' - (4 '' - (1- (3-Hydroxypropyl) indol-5-yl) oxy-3 '' methoxycyclohexyl) -1'-methylvinyl] - 23.25-dimethoxy-13,19,21,27-tetramethyl-11 , 28-dioxa-4-aza-tricyclo [22.3.1.04,9] octacos-18-ene-2,3,10,16-tetraone; 35 LV 10450 17-Ethyl-1,14-dihydroxy-12- [2 ' - (3 '' - Hydroxy-4 '' - (1-hydroxyethylindol-5-yl) oxycyclohexyl) -1'-methyl vinyl] - 23.25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa- 4-aza-tricyclo [22.3.1.04 * 9] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1 H -dihydroxy-4'-te '- ^' '- (1-hydroxyethyl) -6-yl) oxy-3 '' - methoxycyclohexyl) -1'-methyl vinyl] - 23.25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-nacyclo [22. 3.1.04 * 9] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4 *' - (1-methylindol-e-yl-oxy-3 '' -methoxycyclohexyl) -1 '- [beta] -1-bis-1] -23,25- &lt; 11 &gt; Bβ-oxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.04 * 9] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dlh.hydroxy-12- [2 '- (4 *' - (1-dibenzylphosphonooxy-ethylindol-5-yloxy-S * '-methoxycyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-9 9 -loxa-4-aza-tricyclo [22.3.1.0 * 3-octacos-18-ene-2.3.10.16-tetraone; 17-Ethyl-1 , 14-dihydroxy-12- [2 '- (4' '- (1-phosphonooxy-ethylindol-5-yl) oxy-3' '-methoxycyclohexyl) -1'-methyl-vinyl] -23,25- dimethoxy-13,19,21,27-tetramethyl-11,28-AQ dioxa-4-aza-tricyclo [22.3.1.0 *] octacos-18-ene-2.3.10.16-etraone monopotassium salt; 17-Ethyl-1,14 -di 2 -hydroxy-12- [2 '- (41 M- (N, N-diroethylglyloxy) ethylindol-5-yl) oxy-3' 'methoxycyclohexyl) -! '-methylvinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatrioylo [22.3.1.04.9] octacos-18-ene-2.3.10.16-tetraone ; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' '- (1-succinyloxy-ethylindol-5-yl) oxy-3' '-methoxycyclohexyl) -1'-methyl-vinyl] -23 , 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.04 * 9] octacos-18-ene-5,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' '- (1-methyl-3-phenylindol-5-yl) oxy-3' '- methoxycyclohexyl) -1'-methyl- vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-10-dioxa-4-aza-tricyclo [22.3.1.04 * 9] octacos-18-ene-2.3.10.16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' '- (1-methyl-3- (2-hydroxyethyl) indol-5-yl) oxy-3' * methoxycyclohexyl) - 1'-me-15 tilvinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatrioylo [22.3.1.04 * 9] octacos-18-ene 2.3.10.16 - tetraons; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' '- (1,3-dimethylindol-20,5-yl) oxy-3' '-methoxycyclohexyl) -1,11-methylvinyl-23.25-dimethoxy -13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.04 * 9] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' '- (9'-methylcarbazol-3'-yl) oxy-31'-methoxycyclohexyl) -1'-methyl vinyl] -23.25-dimethoxy- 13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.04 * 9] octacos-18-ene-2,3,10,16-tetraone; 17 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' '- ((2 &quot;' '- (3 &quot;' '- di-ethylaminopropionyloxy) ethyl) indol-5' '' - yl). ) oxy-3 '' - methoxycyclohexyl) -1 * -methylvinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.04.9] ] octacos-18-ene-2,3,10,16-tetraone; 35 LV 10450 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' * - ((2 '' '- (3' '*' '- dimethylaminopropionyloxy) ethyl) indole) 5 '' - yl) oxy-3 '' - methoxycyclohexyl) -1'-methylvinvinyl] -2,25-dimethoxy-13.19.21.27-tetramethyl-11,28-dioxa-4-aza-tricyclo- [22.3.1. 04- '9] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydro-bis-12- [2 '- (4' '- ((2 &quot;' '- (3 &quot; 11-aminopropionyloxy) ethyl) indole-5' '') - iDoxy-S 1 '-methyl). Toxicyclohexyl) -1'-methylvinyl-4S, 5S-dimethoxy-13.19.21.27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &gt; 4 * 9] octacos-18-ene-2,3,10 , 16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4 *' - ((2 &quot; '' - (3 &quot; ')' 'benzyloxycarbonyl-2' '' '' - benzyloxycarbonylamino) -propionyloxy) ethyl) indol-5 '' '- yl) oxy-3'1-methoxycyclohexyl) -1'-methyl vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28 -dioxa-4-aza-tricyclo [22.3.1.4 &lt; 4 &gt;]9-octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12- [2 '- (4 '' - ((2 &quot; 1 '- (aspartyloxy) ethyl) indol-5' '' -yl) oxy-3 '' -methoxycyclohexyl) - &lt; · 1 &apos; -methyl-vinyl-4S, 5S-dimethoxy-1S, 2S, 27-tetramethyl-11,28-dioxa-4-azatrioylo [22.3.1.04-9] octacos-18-ene-2,3 , 10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' * - ((2 ''% '- (1' '' '- imidazolylcarbonyloxy) ethyl) indol-5' '') yl ) oxy-3 '' - methoxy-cyclohexyl) -1'-methylvinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatrioyl [22.3.1.4 * 9] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' '- ((2' '*' - (1 '*' '' - piperazinecarbonyloxy) ethyl) indole-5 '') '-yl) oxy-3' '-methoxy-cyclohexyl) -1'-methyl vinyl-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dickssa-4-aza-tricyclo [22.3.1. 04,9] octa-5 koz-18-ene-2,3,10,15-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' '- (1' '' - (2 &quot; ') (2 *' * '' -hydroxyethylaminocarbonyloxy) ethyl] indol-5 '') oxy-3 ' '-methoxycyclohexyl) -1'-methyl vinyl-3-23,25-10 dimethoxy-13,19,21,27-tetraraethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.04.9] octacos-18 17-Ethyl-1,14-dihydroxy-12- [2 '- (1' '' - (2 '' '' - isopropylaminocarbonyloxy) ethyl) -en-2,3,10,16-tetraone; ) indol-5 '' - yl) oxy-15 3 '' -methoxycyclohexyl-1'-methylvinyl 3-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4 azatryl-oxo [22.3.1 .0 4,9] octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1,14-dihydroxy-12- [2 '- (4' '- ( 1 '' '- (2' '' '- 20 (1' '**' - piperidinecarbonyloxy) ethyl) indol-5 '' '- yl) oxy - 3' - methoxycyclohexyl) -1 '- methylvinyl3-23 , 25-Dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-triacyl [22.3.1 .04 * 9] octacos-18-ene-2,3,10,16 17-Ethyl-1,14-dihydroxy-12- [2 * - (4 '* - (1% - (2'1 * * - (2' '* -morpholinecarbonyloxy) ethyl) indole-5' ')) * -il) ok-si-3 ' -methoxycyclohexyl) -1'-methylvinyl-1, 23, 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1 .04 * 9,3-octacos-18 -en-2,3,10,16-tetraone; 17 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' '- (1'% '- (2' '' '- diphenylaminocarbonyloxy) ethyl) indol-5' '- yl) oxy -3 * '-methoxycyclohexyl) -1'-methylvinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1 .04 * 91 octacos-18-ene-2,3,10,16-tetraone; 35 LV 10450 17-Ethyl-1,14-dihydroxy-12- [2 '- (4 *' - (1 '' '- (2' '' '- diethylaminocarbonyloxy) ethyl) indol-5' '- yl) oxy-3 '' -methoxycyclohexyl) -1 '-ιηβΐϋν1ιιϋ] -23,25- &lt; ϋιηΘί-oxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-triaclo [22.3.1.0 &lt; 4 &gt;] octacos-18-ene-2,3,10,16-te traon; 17-Ethyl-1,14-dihydroxy-12- [2 * - (4 '' - (1 * '' - (2'1 '* -methanesulfonyloxyethyl) indol-5' '' - yl) oxy-31 * - methoxycyclohexyl) -11-methylvinyl 3 -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.04 * ®] -acta-18- shadow-2,3,10,16-te traon; 17-Ethyl-1,14-άίΜ &lt;! Γθ1β3ί-12- [2 * -ν (4 '' - (1 * 1 * - (2 '* 1' -azi-doethyl) indol-5 '' '-yl) oxy-3 *' - methoxycyclohexyl-1-methylvinyl3-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.04, 3'-octacos-18-ene-2,3,10,16- 17-Ethyl-1,14-dihydroxy-12- [2, - (4 ', - (1' '' - (2 '' '' - aminoethyl) indole-51 '') -doxy-S '); '-methoxycyclohexyl-1'-methylvinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11.28-dioxa-4-aza-tricyclo [22.3.1.04 * 9] octacos-18-ene-2.3.10.16-tetraone 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' '- (1' '' - t -butyldimethylsilyloxyethoxyethylindole-5 * '' - iDoxy-5 '' - methoxy-cyclohexyl) - 1 * -methylvinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; 4 &gt;] octacos-18-ene-2,3, 10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' '- (1' '-hydroxy-ethoxyethylindol-5' '* - yl) oxy-3' '- methoxycyclohexyl) ) -1'-methylvinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11.28-dioxa-4-aza-tricyclo [2 2.3.1.04'93oktakoz-18-ene-2.3.10.16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (3 &quot; -methoxy-4 &quot;-( 1' &quot;-( 1, ,,, - oxoprop-3 &quot; &quot; -yl) indol-5H, -yl) oxycyclohexyl) -1'-methyl vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28 -dioxa-4-azatricyclo [22.3.14] &lt; 9] -octacos-18-ene-2,3,10,16-tetraone; and 17-Ethyl-1,14-dihydroxy-12- [2, - (3 ', - methoxy-4 &quot; -), 1 M, - (1 M, - carboxy-2m, -yl) indole-5' &quot;; -yl) oxycyclohexyl) -1'-methylvinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0.4 &gt; 9] - octacos-18-ene-2,3,10,16-tetraone; or a pharmaceutically acceptable salt thereof. 7. The process of claim 1, wherein the pharmaceutical compositions comprise a therapeutically effective amount of a pharmaceutical carrier and the compounds described above. 8. A process according to claim 1, wherein the compounds disclosed below are used for the manufacture of a medicament for use in the prevention of immune dysregulation. 9. The process of claim 1, wherein the above compounds are used in the manufacture of a medicament for use in the prevention of transplant rejection. 10. A process according to claim 1, wherein the above compounds are used in the manufacture of medicaments for use as a topical agent for the treatment of inflammation and rapidly progressive skin diseases and / or immunological skin conditions.