Process for the synthesis of biaryl oxazolidinones
View Patent ↗The present invention relates to processes for the preparation of biaryl oxazolidinones. These compounds are useful as anti-infective, anti-proliferative, anti-inflammatory, and prokinetic agents.
1. A process for preparing a compound having the formula:
the process comprising the steps of:
combining a compound of formula (I):
with a compound of formula (II):
in a solvent in the presence of a base and a palladium catalyst, wherein
A is
phenyl;
B is
phenyl;
Het-CH 2 —R 3 is
M-L is
M-L 1 -X-L 2 ,
wherein
X is
—NR 4 —;
L 1 is
C 1-6 alkyl; and
L 2 is
C 1-6 alkyl;
M is selected from the group consisting of:
a) C 3-14 saturated, unsaturated, or aromatic carbocycle, b) 3-14 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, c) C 1-6 alkyl, d) C 2-6 alkenyl, e) C 2-6 alkynyl, and f) —CN,
wherein any of a)-e) optionally is substituted with one or more R 5 groups;
Q is a borane having the formula —BY 2 , wherein
Y, at each occurrence, independently is selected from the group consisting of:
a) —OH, b) —OC 1-6 alkyl, c) —OC 2-6 alkenyl, d) —OC 2-6 alkynyl, e) —OC 1-14 saturated, unsaturated, or aromatic carbocycle, f) C 1-6 alkyl, g) C 2-6 alkenyl, h) C 2-6 alkynyl, and i) C 1-14 saturated, unsaturated, or aromatic carbocycle,
wherein any of b)-i) optionally is substituted with one or more halogens;
alternatively, two Y groups taken together comprise a chemical moiety selected from the group consisting of:
a) —OC(R 4 )(R 4 )C(R 4 )(R 4 )O—, and b) —OC(R 4 )(R 4 )CH 2 C(R 4 )(R 4 )O—;
alternatively, Q is a BF 3 alkali metal salt or 9-borabicyclo[3.3.1]nonane;
Z is selected from the group consisting of:
a) I, b) Br, c) Cl, and d) —R 9 SO 3 —;
R 1 , at each occurrence, independently is selected from the group consisting of:
a) F, b) Cl, c) Br, d) I, e) —CF 3 , f) —OR 4 , g) —CN, h) —NO 2 , i) —NR 4 R 4 , j) —C(O)R 4 , k) —C(O)OR 4 , l) —OC(O)R 4 , m) —C(O)NR 4 R 4 , n) —NR 4 C(O)R 4 , o) —OC(O)NR 4 R 4 , p) —NR 4 C(O)OR 4 , q) —NR 4 C(O)NR 4 R 4 , r) —C(S)R 4 , s) —C(S)OR 4 , t) —OC(S)R 4 , u) —C(S)NR 4 R 4 , v) —NR 4 C(S)R 4 , w) —OC(S)NR 4 R 4 , x) —NR 4 C(S)OR 4 , y) —NR 4 C(S)NR 4 R 4 , z) —C(NR 4 )R 4 , aa) —C(NR 4 )OR 4 , bb) —OC(NR 4 )R 4 , cc) —C(NR 4 )NR 4 R 4 , dd) —NR 4 C(NR 4 )R 4 , ee) —OC(NR 4 )NR 4 R 4 , ff) —NR 4 C(NR 4 )OR 4 , gg) —NR 4 C(NR 4 )NR 4 R 4 , hh) —S(O) p R 4 , ii) —SO 2 NR 4 R 4 , and jj) R 4 ;
R 2 , at each occurrence, independently is selected from the group consisting of:
a) F, b) Cl, c) Br, d) I, e) —CF 3 , f) —OR 4 , g) —CN, h) —NO 2 , i) —NR 4 R 4 , j) —C(O)R 4 , k) —C(O)OR 4 , l) —OC(O)R 4 , m) —C(O)NR 4 R 4 , n) —NR 4 C(O)R 4 , o) —OC(O)NR 4 R 4 , p) —NR 4 C(O)OR 4 , q) —NR 4 C(O)NR 4 R 4 , r) —C(S)R 4 , s) —C(S)OR 4 , t) —OC(S)R 4 , u) —C(S)NR 4 R 4 , v) —NR 4 C(S)R 4 , w) —OC(S)NR 4 R 4 , x) —NR 4 C(S)OR 4 , y) —NR 4 C(S)NR 4 R 4 , z) —C(NR 4 )R 4 , aa) —C(NR 4 )OR 4 , bb) —OC(NR 4 )R 4 , cc) —C(NR 4 )NR 4 R 4 , dd) —NR 4 C(NR 4 )R 4 , ee) —OC(NR 4 )NR 4 R 4 , ff) —NR 4 C(NR 4 )OR 4 , gg) —NR 4 C(NR 4 )NR 4 R 4 , hh) —S(O) p R 4 , ii) —SO 2 NR 4 R 4 , and jj) R 4 ;
R 3 is
—NR 4 C(O)R 4 ;
R 4 , at each occurrence, independently is selected from the group consisting of:
a) H, b) —OR 6 , c) an amine protecting group, d) C 1-6 alkyl, e) C 2-6 alkenyl, f) C 2-6 alkynyl, g) C 3-14 saturated, unsaturated, or aromatic carbocycle, h) 3-14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, i) —C(O)—C 1-6 alkyl, j) —C(O)—C 2-6 alkenyl, k) —C(O)—C 2-6 alkynyl, l) —C(O)—C 3-14 saturated, unsaturated, or aromatic carbocycle, m) —C(O)-3-14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, n) —C(O)O—C 1-6 alkyl, o) —C(O)O—C 2-6 alkenyl, p) —C(O)O—C 2-6 alkynyl, q) —C(O)O—C 3-14 saturated, unsaturated, or aromatic carbocycle, and r) —C(O)O-3-14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur,
wherein any of d)-r) optionally is substituted with one or more R 5 groups;
R 5 , at each occurrence, is independently selected from the group consisting of:
a) F, b) Cl, c) Br, d) I, e) ═O, f) ═S, g) ═NR 6 , h) ═NOR 6 , i) ═N—NR 6 R 6 , j) —CF 3 , k) —OR 6 , l) —CN, m) —NO 2 , n) —NR 6 R 6 , o) —C(O)R 6 , p) —C(O)OR 6 , q) —OC(O)R 6 , r) —C(O)NR 6 R 6 , s) —NR 6 C(O)R 6 , t) —OC(O)NR 6 R 6 , u) —NR 6 C(O)OR 6 , v) —NR 6 C(O)NR 6 R 6 , w) —C(S)R 6 , x) —C(S)OR 6 , y) —OC(S)R 6 , z) —C(S)NR 6 R 6 , aa) —NR 6 C(S)R 6 , bb) —OC(S)NR 6 R 6 , cc) —NR 6 C(S)OR 6 , dd) —NR 6 C(S)NR 6 R 6 , ee) —C(NR 6 )R 6 , ff) —C(NR 6 )OR 6 , gg) —OC(NR 6 )R 6 , hh) —C(NR 6 )NR 6 R 6 , ii) —NR 6 C(NR 6 )R 6 , jj) —OC(NR 6 )NR 6 R 6 , kk) —NR 6 C(NR 6 )OR 6 , ll) —NR 6 C(NR 6 )NR 6 R 6 , mm) —S(O) p R 6 , nn) —SO 2 NR 6 R 6 , and oo) R 6 ;
R 6 , at each occurrence, independently is selected from the group consisting of:
a) H, b) —OR 8 , c) an amine protecting group, d) C 1-6 alkyl, e) C 2-6 alkenyl, f) C 2-6 alkynyl, g) C 3-14 saturated, unsaturated, or aromatic carbocycle, h) 3-14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, i) —C(O)—C 1-6 alkyl, j) —C(O)—C 2-6 alkenyl, k) —C(O)—C 2-6 alkynyl, l) —C(O)—C 3-14 saturated, unsaturated, or aromatic carbocycle, m) —C(O)-3-14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, n) —C(O)O—C 1-6 alkyl, o) —C(O)O—C 2-6 alkenyl, p) —C(O)O—C 2-6 alkynyl, q) —C(O)O—C 3-14 saturated, unsaturated, or aromatic carbocycle, and r) —C(O)O-3-14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur,
wherein any of d)-r) optionally is substituted with one or more R 7 groups;
R 7 , at each occurrence, independently is selected from the group consisting of:
a) F, b) Cl, c) Br, d) I, e) ═O, f) ═S, g) ═NR 8 , h) ═NOR 8 , i) ═N—NR 8 R 8 , j) —CF 3 , k) —OR 8 , l) —CN, m) —NO 2 , n) —NR 8 R 8 , o) —C(O)R 8 , p) —C(O)OR 8 , q) —OC(O)R 8 , r) —C(O)NR 8 R 8 , s) —NR 8 C(O)R 8 , t) —OC(O)NR 8 R 8 , u) —NR 8 C(O)OR 8 , v) —NR 8 C(O)NR 8 R 8 , w) —C(S)R 8 , x) —C(S)OR 8 , y) —OC(S)R 8 , z) —C(S)NR 8 R 8 , aa) —NR 8 C(S)R 8 , bb) —OC(S)NR 8 R 8 , cc) —NR 8 C(S)OR 8 , dd) —NR 8 C(S)NR 8 R 8 , ee) —C(NR 8 )R 8 , ff) —C(NR 8 )OR 8 , gg) —OC(NR 8 )R 8 , hh) —C(NR 8 )NR 8 R 8 , ii) —NR 8 C(NR 8 )R 8 , jj) —OC(NR 8 )NR 8 R 8 , kk) —NR 8 C(NR 8 )OR 8 , ll) —NR 8 C(NR 8 )NR 8 R 8 , mm) —S(O) p R 8 , nn) —SO 2 NR 8 R 8 , oo) C 1-6 alkyl, pp)C 2-6 alkenyl, qq) C 2-6 alkynyl, rr) C 3-14 saturated, unsaturated, or aromatic carbocycle, and ss) 3-14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur,
wherein any of oo)-ss) optionally is substituted with one or more moieties selected from the group consisting of R 8 , F, Cl, Br, I, —CF 3 , —OR 8 , —SR 8 , —CN, —NO 2 , —NR 8 R 8 , —C(O)R 8 , —C(O)OR 8 , —OC(O)R 8 , —C(O)NR 8 R 8 , —NR 8 C(O)R 8 , —OC(O)NR 8 R 8 , —NR 8 C(O)OR 8 , —NR 8 C(O)NR 8 R 8 , —C(S)R 8 , —C(S)OR 8 , —OC(S)R 8 , —C(S)NR 8 R 8 , —NR 8 C(S)R 8 , —OC(S)NR 8 R 8 , —NR 8 C(S)OR 8 , —NR 8 C(S)NR 8 R 8 , —C(NR 8 )R 8 , —C(NR 8 )OR 8 , —OC(NR 8 )R 8 , —C(NR 8 )NR 8 R 8 , —NR 8 C(NR 8 )R 8 , —OC(NR 8 )NR 8 R 8 , —NR 8 C(NR 8 )OR 8 , —NR 8 C(NR 8 )NR 8 R 8 , —SO 2 NR 8 R 8 , and —S(O) p R 8 ;
R 8 , at each occurrence, independently is selected from the group consisting of:
a) H, b) an amine protecting group, c) C 1-6 alkyl, d) C 2-6 alkenyl, e) C 2-6 alkynyl, f) C 3-14 saturated, unsaturated, or aromatic carbocycle, g) 3-14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, h) —C(O)—C 1-6 alkyl, i) —C(O)—C 2-6 alkenyl, j) —C(O)—C 2-6 alkynyl, k) —C(O)—C 3-14 saturated, unsaturated, or aromatic carbocycle, l) —C(O)-3-14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, m) —C(O)O—C 1-6 alkyl, n) —C(O)O—C 2-6 alkenyl, o) —C(O)O—C 2-6 alkynyl, p) —C(O)O—C 3-14 saturated, unsaturated, or aromatic carbocycle, and q) —C(O)O-3-14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur,
wherein any of c)-q) optionally is substituted with one or more moieties selected from the group consisting of F, Cl, Br, I, —CF 3 , —OH, —OC 1-6 alkyl, —SH, —SC 1-6 alkyl, —CN, —NO 2 , —NH 2 , —NHC 1-6 alkyl, —N(C 1-6 alkyl) 2 , —C(O)C 1-6 alkyl, —C(O)OC 1-6 alkyl, —C(O)NH 2 , —C(O)NHC 1-6 alkyl, —C(O)N(C 1-6 alkyl) 2 , —NHC(O)C 1-6 alkyl, —SO 2 NH 2 —, —SO 2 NHC 1-6 alkyl, —SO 2 N(C 1-6 alkyl) 2 , and —S(O) p C 1-6 alkyl;
R 9 is selected from the group consisting of:
a) C 1-6 alkyl, b) phenyl, and c) toluoyl;
wherein any of a)-c) optionally is substituted with one or more moieties selected from the group consisting of F, Cl, Br, and I;
m is 0, 1, 2, 3, or 4;
n is 0, 1, 2, 3, or 4; and
p, at each occurrence, independently is 0, 1, or 2.
2. The process according to claim 1 , wherein R 4 is —CH 3 .
3. The process according to claim 1 , wherein the compound of formula (II) has the formula:
4. The process according to claim 1 , wherein the compound of formula (I) has the formula:
5. The process according to claim 1 , wherein M-L is M-CH 2 —NR 4 —CH 2 —.
6. The process according to claim 5 , wherein R 4 is H.
7. The process according to claim 5 , wherein R 4 is an amine protecting group.
8. The process according to claim 7 , wherein the amine protecting group is selected from the group consisting of:
a) benzyl, b) t-butyldimethylsilyl, c) t-butdyldiphenylsilyl, d) t-butyloxycarbonyl, e) p-methoxybenzyl, f) methoxymethyl, g) tosyl, h) trifluoroacetyl, i) trimethylsilyl, j) fluorenyl-methyloxycarbonyl, k) 2-trimethylsilyl-ethyoxycarbonyl, l) 1-methyl-1-(4-biphenylyl)ethoxycarbonyl, m) allyloxycarbonyl, and n) benzyloxycarbonyl.
9. The process according to claim 7 , further comprising the step of removing the amine protecting group.
10. The process according to claim 5 , wherein M comprises a 5-6 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.
11. The process according to claim 10 , wherein M is selected from the group consisting of triazole, tetrazole, oxazole, and isoxazole.
12. The process according to claim 11 , wherein M is [1,2,3]triazol-4-yl.
13. The process according to claim 5 , wherein M is selected from the group consisting of:
a) C 1-6 alkyl, b) C 2-6 alkenyl, c) C 2-6 alkynyl, and d) —CN,
wherein
i) any of a)-c) is substituted with one or more moieties selected from the group consisting of F, Cl, Br, I, and —CN; and
ii) any of a)-c) optionally is further substituted with one or more R 5 groups.
14. The process according to claim 13 , wherein M is C 1-6 alkyl substituted with one or more atoms selected from the group consisting of F, Cl, Br, and I.
15. The process according to claim 14 , wherein M is —CH 2 CH 2 CH 2 F.
16. The process according to claim 1 , wherein Z is selected from the group consisting of I, trifluoromethanesulfonate, and p-toluenesulfonate.
17. The process according to claim 16 , wherein Z is I.
18. The process according to claim 1 , wherein Q is —B(OH) 2 .
19. The process according to claim 1 , wherein Q is:
20. The process according to claim 1 , wherein Q is —BF 2 .KF.
21. The process according to claim 1 , wherein the base is selected from the group consisting of alkali metal hydroxides, alkali metal carbonates, alkali metal fluorides, trialkyl amines, and mixtures thereof.
22. The process according to claim 21 , wherein the base is potassium carbonate.
23. The process according to claim 21 , wherein the ratio of equivalents of base to equivalents of the compound of formula (I) is about 3:1.
24. The process according to claim 1 , wherein the palladium catalyst is a ligand coordinated palladium (0) catalyst.
25. The process according to claim 24 , wherein the palladium catalyst is tetrakis(triphenylphosphine) palladium (0).
26. The process according to claim 25 , wherein the ratio of the equivalents of tetrakis(triphenylphosphine) palladium (0) to the equivalents of the compound of formula (I) is about 1:20.
27. The process according to claim 1 , wherein the solvent comprises an aqueous solvent.
28. The process according to claim 27 wherein the solvent comprises a mixture of water, toluene, and ethanol.
29. The process according to claim 28 wherein the solvent comprises a mixture of water, toluene, and ethanol in a ratio of about 1:3:1 by volume.
30. The process according to claim 1 , wherein the process is carried out at a temperature between about 20° C. and about 100° C.
31. The process according to claim 1 , wherein the process is carried out at the reflux temperature of the solvent.
32. A process for preparing a compound having the formula:
the process comprising the steps of:
combining a compound of formula (I):
with a compound of formula (II):
in a solvent in the presence of a base and a palladium catalyst, wherein
A is
phenyl;
B is:
phenyl;
Het-CH 2 —R 3 is
M-L is
M-L 1 -X-L 2 , wherein
X is
—NR 4 —
L 1 is
C 1-6 alkyl; and
L 2 is
C 1-6 alkyl;
M is selected from the group consisting of:
a) C 3-14 saturated, unsaturated, or aromatic carbocycle, b) 3-14 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, c) C 1-6 alkyl, d) C 2-6 alkenyl, e) C 2-6 alkynyl, and f) —CN,
wherein any of a)-e) optionally is substituted with one or more R 5 groups;
Q is a borane having the formula —BY 2 , wherein
Y, at each occurrence, independently is selected from the group consisting of:
a) —OH, b) —OC 1-6 alkyl, c) —OC 2-6 alkenyl, d) —OC 2-6 alkynyl, e) —OC 1-14 saturated, unsaturated, or aromatic carbocycle, f) C 1-6 alkyl, g) C 2-6 alkenyl, h) C 2-6 alkynyl, and i) C 1-14 saturated, unsaturated, or aromatic carbocycle,
wherein any of b)-i) optionally is substituted with one or more halogens;
alternatively, two Y groups taken together comprise a chemical moiety selected from the group consisting of:
a) —OC(R 4 )(R 4 )C(R 4 )(R 4 )O—, and b) —OC(R 4 )(R 4 )CH 2 C(R 4 )(R 4 )O—;
alternatively, Q is a BF 3 alkali metal salt or 9-borabicyclo[3.3.1]nonane;
Z is selected from the group consisting of:
a) I, b) Br, c) Cl, and d) —R 9 SO 3 —;
R 1 , at each occurrence, independently is selected from the group consisting of:
a) F, b) Cl, c) Br, d) I, e) —CF 3 , f) —OR 4 , g) —CN, h) —NO 2 , i) —NR 4 R 4 , j) —C(O)R 4 , k) —C(O)OR 4 , l) —OC(O)R 4 , m) —C(O)NR 4 R 4 , n) —NR 4 C(O)R 4 , o) —OC(O)NR 4 R 4 , p) —NR 4 C(O)OR 4 , q) —NR 4 C(O)NR 4 R 4 , r) —C(S)R 4 , s) —C(S)OR 4 , t) —OC(S)R 4 , u) —C(S)NR 4 R 4 , v) —NR 4 C(S)R 4 , w) —OC(S)NR 4 R 4 , x) —NR 4 C(S)OR 4 , y) —NR 4 C(S)NR 4 R 4 , z) —C(NR 4 )R 4 , aa) —C(NR 4 )OR 4 , bb) —OC(NR 4 )R 4 , cc) —C(NR 4 )NR 4 R 4 , dd) —NR 4 C(NR 4 )R 4 , ee) —OC(NR 4 )NR 4 R 4 , ff) —NR 4 C(NR 4 )OR 4 , gg) —NR 4 C(NR 4 )NR 4 R 4 , hh) —S(O) p R 4 , ii) —SO 2 NR 4 R 4 , and jj) R 4 ;
R 2 , at each occurrence, independently is selected from the group consisting of:
a) F, b) Cl, c) Br, d) I, e) —CF 3 , f) —OR 4 , g) —CN, h) —NO 2 , i) —NR 4 R 4 , j) —C(O)R 4 , k) —C(O)OR 4 , l) —OC(O)R 4 , m) —C(O)NR 4 R 4 , n) —NR 4 C(O)R 4 , o) —OC(O)NR 4 R 4 , p) —NR 4 C(O)OR 4 , q) —NR 4 C(O)NR 4 R 4 , r) —C(S)R 4 , s) —C(S)OR 4 , t) —OC(S)R 4 , u) —C(S)NR 4 R 4 , v) —NR 4 C(S)R 4 , w) —OC(S)NR 4 R 4 , x) —NR 4 C(S)OR 4 , y) —NR 4 C(S)NR 4 R 4 , z) —C(NR 4 )R 4 , aa) —C(NR 4 )OR 4 , bb) —OC(NR 4 )R 4 , cc) —C(NR 4 )NR 4 R 4 , dd) —NR 4 C(NR 4 )R 4 , ee) —OC(NR 4 )NR 4 R 4 , ff) —NR 4 C(NR 4 )OR 4 , gg) —NR 4 C(NR 4 )NR 4 R 4 , hh) —S(O) p R 4 , ii) —SO 2 NR 4 R 4 , and jj) R 4 ;
R 3 is
—NR 4 C(O)R 4 ;
R 4 , at each occurrence, independently is selected from the group consisting of:
a) H, b) —OR 6 , c) an amine protecting group, d) C 1-6 alkyl, e) C 2-6 alkenyl, f) C 2-6 alkynyl, g) C 3-14 saturated, unsaturated, or aromatic carbocycle, h) 3-14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, i) —C(O)—C 1-6 alkyl, j) —C(O)—C 2-6 alkenyl, k) —C(O)—C 2-6 alkynyl, l) —C(O)—C 3-14 saturated, unsaturated, or aromatic carbocycle, m) —C(O)-3-14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, n) —C(O)O—C 1-6 alkyl, o) —C(O)O—C 2-6 alkenyl, p) —C(O)O—C 2-6 alkynyl, q) —C(O)O—C 3-14 saturated, unsaturated, or aromatic carbocycle, and r) —C(O)O-3-14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur,
wherein any of d)-r) optionally is substituted with one or more R 5 groups;
R 5 , at each occurrence, is independently selected from the group consisting of:
a) F, b) Cl, c) Br, d) I, e) ═O, f) ═S, g) ═NR 6 , h) ═NOR 6 , i) ═N—NR 6 R 6 , j) —CF 3 , k) —OR 6 , l) —CN, m) —NO 2 , n)—NR 6 R 6 , o) —C(O)R 6 , p) —C(O)OR 6 , q) —OC(O)R 6 , r) —C(O)NR 6 R 6 , s) —NR 6 C(O)R 6 , t) —OC(O)NR 6 R 6 , u) —NR 6 C(O)OR 6 , v) —NR 6 C(O)NR 6 R 6 , w) —C(S)R 6 , x) —C(S)OR 6 , y) —OC(S)R 6 , z) —C(S)NR 6 R 6 , aa) —NR 6 C(S)R 6 , bb) —OC(S)NR 6 R 6 , cc) —NR 6 C(S)OR 6 , dd) —NR 6 C(S)NR 6 R 6 , ee) —C(NR 6 )R 6 , ff) —C(NR 6 )OR 6 , gg) —OC(NR 6 )R 6 , hh) —C(NR 6 )NR 6 R 6 , ii) —NR 6 C(NR 6 )R 6 , jj) —OC(NR 6 )NR 6 R 6 , kk) —NR 6 C(NR 6 )OR 6 , ll) —NR 6 C(NR 6 )NR 6 R 6 , mm) —S(O) p R 6 , nn) —SO 2 NR 6 R 6 , and oo) R 6 ;
R 6 , at each occurrence, independently is selected from the group consisting of:
a) H, b) —OR 8 , c) an amine protecting group, d) C 1-6 alkyl, e) C 2-6 alkenyl, f) C 2-6 alkynyl, g) C 3-14 saturated, unsaturated, or aromatic carbocycle, h) 3-14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, i) —C(O)—C 1-6 alkyl, j) —C(O)—C 2-6 alkenyl, k) —C(O)—C 2-6 alkynyl, l) —C(O)—C 3-14 saturated, unsaturated, or aromatic carbocycle, m) —C(O)-3-14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, n) —C(O)O—C 1-6 alkyl, o) —C(O)O—C 2-6 alkenyl, p) —C(O)O—C 2-6 alkynyl, q) —C(O)O—C 3-14 saturated, unsaturated, or aromatic carbocycle, and r) —C(O)O-3-14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur,
wherein any of d)-r) optionally is substituted with one or more R 7 groups;
R 7 , at each occurrence, independently is selected from the group consisting of:
a) F, b) Cl, c) Br, d) I, e) ═O, f) ═S, g) ═NR 8 , h) ═NOR 8 , i) ═N—NR 8 R 8 , j) —CF 3 , k) —OR 8 , l) —CN, m) —NO 2 , n) —NR 8 R 8 , o) —C(O)R 8 , p) —C(O)OR 8 , q) —OC(O)R 8 , r) —C(O)NR 8 R 8 , s) —NR 8 C(O)R 8 , t) —OC(O)NR 8 R 8 , u) —NR 8 C(O)OR 8 , v) —NR 8 C(O)NR 8 R 8 , w) —C(S)R 8 , x) —C(S)OR 8 , y) —OC(S)R 8 , z) —C(S)NR 8 R 8 , aa) —NR 8 C(S)R 8 , bb) —OC(S)NR 8 R 8 , cc) —NR 8 C(S)OR 8 , dd) —NR 8 C(S)NR 8 R 8 , ee) —C(NR 8 )R 8 , ff) —C(NR 8 )OR 8 , gg) —OC(NR 8 )R 8 , hh) —C(NR 8 )NR 8 R 8 , ii) —NR 8 C(NR 8 )R 8 , jj) —OC(NR 8 )NR 8 R 8 , kk) —NR 8 C(NR 8 )OR 8 , ll) —NR 8 C(NR 8 )NR 8 R 8 , mm) —S(O) p R 8 , nn) —SO 2 NR 8 R 8 , oo) C 1-6 alkyl, pp) C 2-6 alkenyl, qq) C 2-6 alkynyl, rr) C 3-14 saturated, unsaturated, or aromatic carbocycle, and ss) 3-14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur,
wherein any of oo)-ss) optionally is substituted with one or more moieties selected from the group consisting of R 8 , F, Cl, Br, I, —CF 3 , —OR 8 , —SR 8 , —CN, —NO 2 , —NR 8 R 8 , —C(O)R 8 , —C(O)OR 8 , —OC(O)R 8 , —C(O)NR 8 R 8 , —NR 8 C(O)R 8 , —OC(O)NR 8 R 8 , —NR 8 C(O)OR 8 , —NR 8 C(O)NR 8 R 8 , —C(S)R 8 , —C(S)OR 8 , —OC(S)R 8 , —C(S)NR 8 R 8 , —NR 8 C(S)R 8 , —OC(S)NR 8 R 8 , —NR 8 C(S)OR 8 , —NR 8 C(S)NR 8 R 8 , —C(NR 8 )R 8 , —C(NR 8 )OR 8 , —OC(NR 8 )R 8 , —C(NR 8 )NR 8 R 8 , —NR 8 C(NR 8 )R 8 , —OC(NR 8 )NR 8 R 8 , —NR 8 C(NR 8 )OR 8 , —NR 8 C(NR 8 )NR 8 R 8 , —SO 2 NR 8 R 8 , and —S(O) p R 8 ;
R 8 , at each occurrence, independently is selected from the group consisting of:
a) H, b) an amine protecting group, c) C 1-6 alkyl, d) C 2-6 alkenyl, e) C 2-6 alkynyl, f) C 3-14 saturated, unsaturated, or aromatic carbocycle, g) 3-14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, h) —C(O)—C 1-6 alkyl, i) —C(O)—C 2-6 alkenyl, j) —C(O)—C 2-6 alkynyl, k) —C(O)—C 3-14 saturated, unsaturated, or aromatic carbocycle, l) —C(O)-3-14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, m) —C(O)O—C 1-6 alkyl, n) —C(O)O—C 2-6 alkenyl, o) —C(O)O—C 2-6 alkynyl, p) —C(O)O—C 3-14 saturated, unsaturated, or aromatic carbocycle, and q) —C(O)O-3-14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur,
wherein any of c)-q) optionally is substituted with one or more moieties selected from the group consisting of F, Cl, Br, I, —CF 3 , —OH, —OC 1-6 alkyl, —SH, —SC 1-6 alkyl, —CN, —NO 2 , —NH 2 , —NHC 1-6 alkyl, —N(C 1-6 alkyl) 2 , —C(O)C 1-6 alkyl, —C(O)OC 1-6 alkyl, —C(O)NH 2 , —C(O)NHC 1-6 alkyl, —C(O)N(C 1-6 alkyl) 2 , —NHC(O)C 1-6 alkyl, —SO 2 NH 2 —, —SO 2 NHC 1-6 alkyl, —SO 2 N(C 1-6 alkyl) 2 , and —S(O) p C 1-6 alkyl;
R 9 is selected from the group consisting of:
a) C 1-6 alkyl, b) phenyl, and c) toluoyl;
wherein any of a)-c) optionally is substituted with one or more moieties selected from the group consisting of F, Cl, Br, and I;
m is 0, 1, 2, 3, or 4;
n is 0, 1, 2, 3, or 4; and
p, at each occurrence, independently is 0, 1, or 2.
33. The process of claim 1 , wherein R 2 is selected from the group consisting of F, Cl, Br, and I.
34. The process of claim 1 , wherein R 2 is F.
35. The process of claim 1 , wherein n is 1.
36. The process of claim 1 , wherein m is 0.
37. The process of claim 1 , wherein the compound of formula (I) has the formula:
38. The process of claim 1 , wherein the compound is
39. The process according to claim 32 , wherein M-L is M-CH 2 —NR 4 —CH 2 —.
40. The process according to claim 39 , wherein M comprises a 5-6 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.
41. The process according to claim 40 , wherein M is selected from the group consisting of triazole, tetrazole, oxazole, and isoxazole.
42. The process according to claim 41 , wherein M is [1,2,3]triazol-4-yl.
43. The process of claim 32 , wherein R 2 is selected from the group consisting of F, Cl, Br, and I.