Oxygen linked pyrimidine derivatives
View Patent ↗The present invention relates to pyrimidine compounds that are useful as anti-proliferative agents. More particularly, the present invention relates to oxygen linked and substituted pyrimidine compounds, methods for their preparation, pharmaceutical compositions containing these compounds and uses of these compounds in the treatment of proliferative disorders. These compounds may be useful as medicaments for the treatment of a number of proliferative disorders including tumors and cancers as well as other disorders or conditions related to or associated with kinases.
1. A compound of formula I:
wherein:
R 1 and R 2 are each independently selected from the group consisting of: H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkylkoxy, heterocycloalkyloxy, aryloxy, arylalkyloxy, phenoxy, benzyloxy, heteroaryloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, sulfonylamino, sulfinylamino, —COOH, —COR 3 , —COOR 3 , —CONHR 3 , —NHCOR 3 , —NHCOOR 3 , —NHCONHR 3 , alkoxycarbonyl, alkylaminocarbonyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, —SR 3 , R 4 S(O)R 6 —, R 4 S(O) 2 R 6 —, R 4 C(O)N(R 5 )R 6 —, R 4 SO 2 N(R 5 )R 6 —, R 4 N(R 5 )C(O)R 6 —, R 4 N(R 5 )SO 2 R 6 —, R 4 N(R 5 )C(O)N(R 5 )R 6 — and acyl, each of which may be optionally substituted;
each R 3 , R 4 , and R 5 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl, each of which may be optionally substituted;
each R 6 is independently selected from the group consisting of a bond, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl, each of which may be optionally substituted;
Z 2 is selected from the group consisting of a bond, O, S, —N(R 7 )—, —N(R 7 )C 1-2 alkyl-, and —C 1-2 alkylN(R 7 )—;
each R 7 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, hetero alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl, each of which may be optionally substituted;
Ar 1 and Ar 2 are independently selected from the group consisting of aryl and heteroaryl, each of which may be optionally substituted, with the proviso that Ar 1 and Ar 2 are not both phenylene;
L is a group of formula:
—X 1 —Y—X 2 —
wherein X 1 is attached to Ar 1 and X 2 is attached to Ar 2 , and wherein X 1 , X 2 and Y are selected such that the group L has between 5 and 15 atoms in the normal chain,
X 1 and X 2 are each independently a heteroalkyl group containing at least one oxygen atom in the normal chain,
Y is a group of formula —CR a ═CR b — or an optionally substituted cycloalkyl group,
wherein R a and R b are each independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl, each of which may be optionally substituted, or
R a and R b are joined such that when taken together with the carbon atoms to which they are attached they form a cycloalkenyl or cycloheteroalkenyl group;
or a pharmaceutically acceptable salt, N-oxide, or ester thereof.
2. A compound according to claim 1 wherein Z 2 is —N(H)—.
3. A compound according to claim 1 wherein Ar 1 is selected from the group consisting of:
wherein V 1 , V 2 , V 3 and V 4 are each independently selected from the group consisting of N, and C(R 10 );
W is selected from the group consisting of O, S and N(R 10 );
W 1 and W 2 are each independently selected from the group consisting of N and C(R 10 );
wherein each R 10 is independently selected from the group consisting of: H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkylkoxy, heterocycloalkyloxy, aryloxy, arylalkyloxy, phenoxy, benzyloxy, heteroaryloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, sulfonylamino, sulfinylamino, —COOH, —COR 3 , —COOR 3 , —CONHR 3 , —NHCOR 3 , —NHCOOR 3 , —NHCONHR 3 , alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, —SR 3 , R 4 S(O)R 6 —, R 4 S(O) 2 R 6 —, R 4 C(O)N(R 5 )R 6 —, R 4 SO 2 N(R 5 )R 6 —, R 4 N(R 5 )C(O)R 6 —, R 4 N(R 5 )SO 2 R 6 —, R 4 N(R 5 )C(O)N(R 5 )R 6 — and acyl, each of which may be optionally substituted.
4. A compound according to claim 3 wherein Ar 1 is selected from the group consisting of:
5. A compound according to claim 1 wherein Ar 1 is selected from the group consisting of:
wherein each R 10 is independently selected from the group consisting of: H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkylkoxy, heterocycloalkyloxy, aryloxy, arylalkyloxy, phenoxy, benzyloxy, heteroaryloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, sulfonylamino, sulfinylamino, —COOH, —COR 3 , —COOR 3 , —CONHR 3 , —NHCOR 3 , —NHCOOR 3 , —NHCONHR 3 , alkoxycarbonyl, alkylaminocarbonyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, —SR 3 , R 4 S(O)R 6 —, R 4 S(O) 2 R 6 —, R 4 C(O)N(R 5 )R 6 —, R 4 SO 2 N(R 5 )R 6 —, R 4 N(R 5 )C(O)R 6 —, R 4 N(R 5 )SO 2 R 6 —, R 4 N(R 5 )C(O)N(R 5 )R 6 — and acyl, each of which may be optionally substituted;
k is an integer selected from the group consisting of 0, 1, 2, 3, and 4;
n is an integer selected from the group consisting of 0, 1, 2, and 3, and
q is an integer selected from the group consisting of 0, 1, and 2.
6. A compound according to claim 5 wherein Ar 1 is selected from the group consisting of:
7. A compound according to claim 1 wherein Ar 2 is selected from the group consisting of:
wherein V 5 , V 6 , V 7 and V 8 are each independently selected from the group consisting of N, and C(R 11 );
wherein each R 11 is independently selected from the group consisting of: H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkylkoxy, heterocycloalkyloxy, aryloxy, arylalkyloxy, phenoxy, benzyloxy, heteroaryloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, sulfonylamino, sulfinylamino, —COOH, —COR 3 , —COOR 3 , —CONHR 3 , —NHCOR 3 , —NHCOOR 3 , —NHCONHR 3 , alkoxycarbonyl, alkylaminocarbonyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, —SR 3 , R 4 S(O)R 6 —, R 4 S(O) 2 R 6 —, R 4 C(O)N(R 5 )R 6 —, R 4 SO 2 N(R 5 )R 6 —, R 4 N(R 5 )C(O)R 6 —, R 4 N(R 5 )SO 2 R 6 —, R 4 N(R 5 )C(O)N(R 5 )R 6 — and acyl, each of which may be optionally substituted.
8. A compound according to claim 1 wherein Ar 2 is selected from the group consisting of:
wherein each R 11 is independently selected from the group consisting of: H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkylkoxy, heterocycloalkyloxy, aryloxy, arylalkyloxy, phenoxy, benzyloxy, heteroaryloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, sulfonylamino, sulfinylamino, —COOH, —COR 3 , —COOR 3 , —CONHR 3 , —NHCOR 3 , —NHCOOR 3 , —NHCONHR 3 , alkoxycarbonyl, alkylaminocarbonyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, —SR 3 , R 4 S(O)R 6 —, R 4 S(O) 2 R 6 —, R 4 C(O)N(R 5 )R 6 —, R 4 SO 2 N(R 5 )R 6 —, R 4 N(R 5 )C(O)R 6 —, R 4 N(R 5 )SO 2 R 6 —, R 4 N(R 5 )C(O)N(R 5 )R 6 — and acyl, each of which may be optionally substituted;
o is an integer from 0 to 4; and
p is an integer from 0 to 3.
9. A compound according to claim 1 wherein Ar 2 is a group selected from the group consisting of:
wherein each R 11 is independently selected from the group consisting of: H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkylkoxy, heterocycloalkyloxy, aryloxy, arylalkyloxy, phenoxy, benzyloxy, heteroaryloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, sulfonylamino, sulfinylamino, —COOH, —COR 3 , —COOR 3 , —CONHR 3 , —NHCOR 3 , —NHCOOR 3 , —NHCONHR 3 , alkoxycarbonyl, alkylaminocarbonyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, —SR 3 , R 4 S(O)R 6 —, R 4 S(O) 2 R 6 —, R 4 C(O)N(R 5 )R 6 —, R 4 SO 2 N(R 5 )R 6 —, R 4 N(R 5 )C(O)R 6 —, R 4 N(R 5 )SO 2 R 6 —, R 4 N(R 5 )C(O)N(R 5 )R 6 — and acyl, each of which may be optionally substituted.
10. A compound according to claim 1 wherein the compound is selected from the group consisting of:
wherein each R 10 is independently selected from the group consisting of: H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkylkoxy, heterocycloalkyloxy, aryloxy, arylalkyloxy, phenoxy, benzyloxy, heteroaryloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, sulfonylamino, sulfinylamino, —COOH, —COR 3 , —COOR 3 , —CONHR 3 , —NHCOR 3 , —NHCOOR 3 , —NHCONHR 3 , alkoxycarbonyl, alkylaminocarbonyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, —SR 3 , R 4 S(O)R 6 —, R 4 S(O) 2 R 6 —, R 4 C(O)N(R 5 )R 6 —, R 4 SO 2 N(R 5 )R 6 —, R 4 N(R 5 )C(O)R 6 —, R 4 N(R 5 )SO 2 R 6 —, R 4 N(R 5 )C(O)N(R 5 )R 6 — and acyl, each of which may be optionally substituted;
each R 11 is independently selected from the group consisting of: H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkylkoxy, heterocycloalkyloxy, aryloxy, arylalkyloxy, phenoxy, benzyloxy, heteroaryloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, sulfonylamino, sulfinylamino, —COOH, —COR 3 , —COOR 3 , —CONHR 3 , —NHCOR 3 , —NHCOOR 3 , —NHCONHR 3 , alkoxycarbonyl, alkylaminocarbonyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, —SR 3 , R 4 S(O)R 6 —, R 4 S(O) 2 R 6 —, R 4 C(O)N(R 5 )R 6 —, R 4 SO 2 N(R 5 )R 6 —, R 4 N(R 5 )C(O)R 6 —, R 4 N(R 5 )SO 2 R 6 —, R 4 N(R 5 )C(O)N(R 5 )R 6 — and acyl, each of which may be optionally substituted;
o is an integer from 0 to 4; and
q is an integer from 0 to 2;
or a pharmaceutically acceptable salt thereof.
11. A compound according to claim 1 wherein X 1 and X 2 are each independently selected from the group consisting of:
(a) —OC 1-5 alkyl-,
(b) —C 1-5 alkylO—, and
(c) —C 1-5 alkylOC 1-5 alkyl.
12. A compound according to claim 1 wherein X 1 is selected from the group consisting of:
(a) —OCH 2 —
(b) —CH 2 O—,
(c) —OCH 2 CH 2 —,
(d) —CH 2 CH 2 O—,
(e) —CH 2 OCH 2 —, and
(f) —CH 2 CH 2 OCH 2 —.
13. A compound according to claim 1 wherein X 2 is selected from the group consisting of:
(a) —OCH 2
(b) —CH 2 O—,
(c) —OCH 2 CH 2 —,
(d) —CH 2 CH 2 O—,
(e) —CH 2 OCH 2 —, and
(f) —CH 2 CH 2 OCH 2 —.
14. A compound according to claim 1 selected from the group consisting of:
wherein each R 10 is independently selected from the group consisting of: H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkylkoxy, heterocycloalkyloxy, aryloxy, arylalkyloxy, phenoxy, benzyloxy, heteroaryloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, sulfonylamino, sulfinylamino, —COOH, —COR 3 , —COOR 3 , —CONHR 3 , —NHCOR 3 , —NHCOOR 3 , —NHCONHR 3 , alkoxycarbonyl, alkylaminocarbonyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, —SR 3 , R 4 S(O)R 6 —, R 4 S(O) 2 R 6 —, R 4 C(O)N(R 5 )R 6 —, R 4 SO 2 N(R 5 )R 6 —, R 4 N(R 5 )C(O)R 6 —, R 4 N(R 5 )SO 7 R 6 —, R 4 N(R 5 )C(O)N(R 5 )R 6 — and acyl, each of which may be optionally substituted;
each R 11 is independently selected from the group consisting of: H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkylkoxy, heterocycloalkyloxy, aryloxy, arylalkyloxy, phenoxy, benzyloxy, heteroaryloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, sulfonylamino, sulfinylamino, —COOH, —COR 3 , —COOR 3 , —CONHR 3 , —NHCOR 3 , —NHCOOR 3 , —NHCONHR 3 , alkoxycarbonyl, alkylaminocarbonyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, —SR 3 , R 4 S(O)R 6 —, R 4 S(O) 7 R 6 —, R 4 C(O)N(R 5 )R 6 —, R 4 SO 2 N(R 5 )R 6 —, R 4 N(R 5 )C(O)R 6 —, R 4 N(R 5 )SO 2 R 6 —, R 4 N(R 5 )C(O)N(R 5 )R 6 — and acyl, each of which may be optionally substituted;
o is an integer from 0 to 4; and
q is an integer from 0 to 2;
or a pharmaceutically acceptable salt thereof.
15. A compound according to claim 1 wherein R 1 and R 2 are independently selected from the group consisting of H and methyl.
16. A compound according to claim 14 wherein R 10 is selected from the group consisting of H, halogen, amino, alkyl, haloalkyl, haloalkenyl, heterocycloalkyl, aryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, and alkoxyalkyl, each of which may be optionally substituted.
17. A compound according to claim 14 wherein R 10 is selected from the group consisting of H, hydroxyl, methoxy, fluoro, methyl, ethyl, propyl, butyl, pentyl, hexyl, phenyl, and 2-morpholino-ethoxy, each of which may be optionally substituted.
18. A compound according to claim 14 wherein each R 11 is independently selected from the group consisting of H, alkoxy, heteroalkyl, heterocycloalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, and arylsulfonyloxy, each of which may be optionally substituted.
19. A compound according to claim 14 wherein each R 11 is independently selected from the group consisting of:
20. A compound according to claim 1 wherein Y is selected from the group consisting of:
21. A compound according to claim 1 wherein the optional substituent is selected from the group consisting of: halogen, ═O, ═S, —CN, —NO 2 , —CF 3 , —OCF 3 , alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, -amino, alkylamino, acylamino, aminoalkyl, arylamino, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, —COOH, —COR 5 , —C(O)OR 5 , —SH, —SR 5 , —OR 6 and acyl.
22. A compound according to claim 1 selected from the group consisting of:
or a pharmaceutically acceptable salt or ester thereof.
23. A pharmaceutical composition including comprising a compound according to claim 1 and a pharmaceutically acceptable diluent, excipient or carrier.
24. A method of synthesis of a compound of formula I as defined in claim 1 the method including the steps of:
(a) providing a compound of the formula
(b) subjecting the compound to ring closing metathesis;
(c) optionally reacting the double bond thus formed to form a cycloalkyl group.
25. A method according to claim 24 wherein step (b) involves treating the trifluoroacetic acid (TFA) or hydrochloric acid (HCl) salt of the compound with 5-10 mole % of Grubbs 2 nd generation catalyst in dichloromethane at 40° C.
26. A method according to claim 24 or 25 wherein step (c) includes treating the metathesis product with a freshly prepared ethereal solution of diazomethane (CH 2 N 2 ) in dichloromethane/dioxane at 0° C.
27. A compound according to claim 22 of the formula:
or a pharmaceutically acceptable salt or ester thereof.
28. A pharmaceutical composition comprising a compound according to claim 27 and a pharmaceutically acceptable diluent, excipient or carrier.