IP Library › Granted Patent US 8,895,741

Granted Patent B2

US 8,895,741 · App. 13/618,091 · Granted Nov 25, 2014

Process for the synthesis of biaryl oxazolidinones

Inventors: Yusheng Wu (New Haven, CT); Shili Chen (Cheshire, CT); Yi Chen (Chestnut Hill, MA); Roger Hanselmann (Branford, CT); Rongliang Lou (Cheshire, CT); Jiacheng Zhou (Newark, DE)

Assignee: Melinta Therapeutics, Inc.

C07D263/20 C07D417/14 C07D413/12 C07D417/10 C07D413/06 C07D487/04 C07D263/32 C07D417/12 C07D473/00 C07D413/10 C07D413/14 C07D453/02

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Quick Facts

Patent No.: US 8,895,741
App. No.: 13/618,091
Granted: Nov 25, 2014
Kind: B2

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Abstract

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.

Claims (142)

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 selected from the group consisting of:

phenyl, pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl;

B is selected from the group consisting of:

phenyl, pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl;

Het-CH 2 —R 3 is selected from the group consisting of:

M-L is selected from the group consisting of:

a) M-X, b) M-L 1 , c) M-L 1 -X, d) M-X-L 2 , e) M-L 1 -X-L 2 , f) M-X-L 1 -X-L 2 , g) M-L 1 -X-L 2 -X, h) M-X—X—, i) M-L 1 -X—X—, j) M-X—X-L 2 , and k) M-L 1 -X—X-L 2 , wherein

X, at each occurrence, independently is selected from the group consisting of:

a) —O—, b) —NR 4 —, c) —N(O)—, d) —N(OR 4 )—, e) —S(O) p —, f) —SO 2 NR 4 —, g) —NR 4 SO 2 —, h) —NR 4 —N═, i) ═N—NR 4 —, j) —O—N═, k) ═N—O—, l) —N═, m) ═N—, n) —NR 4 —NR 4 —, o) —NR 4 C(O)O—, p) —OC(O)NR 4 —, q) —NR 4 C(O)NR 4 — r) —NR 4 C(NR 4 )NR 4 —, and

L 1 is selected from the group consisting of:

a) C 1-6 alkyl, b) C 2-6 alkenyl, and c) C 2-6 alkynyl,

wherein any of a)-c) optionally is substituted with one or more R 5 groups; and

L 2 is selected from the group consisting of:

a) C 1-6 alkyl, b) C 2-6 alkenyl, and c) C 2-6 alkynyl,

wherein any of a)-c) optionally is substituted with one or more R 5 groups;

alternatively, L in M-L is a bond;

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:

R 3 is selected from the group consisting of:

a) —OR 4 , b) —NR 4 R 4 , c) —C(O)R 4 , d) —C(O)OR 4 , e) —OC(O)R 4 , f) —C(O)NR 4 R 4 , g) —NR 4 C(O)R 4 , h) —OC(O)NR 4 R 4 , i) —NR 4 C(O)OR 4 , j) —NR 4 C(O)NR 4 R 4 , k) —C(S)R 4 , l) —C(S)OR 4 , m) —OC(S)R 4 , n) —C(S)NR 4 R 4 , o) —NR 4 C(S)R 4 , p) —OC(S)NR 4 R 4 , q) —NR 4 C(S)OR 4 , r) —NR 4 C(S)NR 4 R 4 , s) —C(NR 4 )R 4 , t) —C(NR 4 )OR 4 , u) —OC(NR 4 )R 4 , v) —C(NR 4 )NR 4 R 4 , w) —NR 4 C(NR 4 )R 4 , x) —OC(NR 4 )NR 4 R 4 , y) —NR 4 C(NR 4 )OR 4 , z) —NR 4 C(NR 4 )NR 4 R 4 , aa) —S(O) p R 4 , bb) —SO 2 NR 4 R 4 , and cc) 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 , 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 the compound of formula (II) has the formula:

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 —X—CH 2 —.

6. The process according to claim 5 , wherein X is —NR 4 —.

7. The process according to claim 6 , wherein R 4 is H.

8. The process according to claim 6 , wherein R 4 is an amine protecting group.

9. The process according to claim 8 , 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.

10. The process according to claim 8 , further comprising the step of removing the amine protecting group.

11. 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.

12. The process according to claim 11 , wherein M is selected from the group consisting of triazole, tetrazole, oxazole, and isoxazole.

13. The process according to claim 12 , wherein M is [1,2,3]triazol-4-yl.

14. The process according to claim 1 , wherein M-L is M-X—CH 2 —.

15. The process according to claim 14 , wherein X is —NR 4 —.

16. The process according to claim 15 , wherein R 4 is H.

17. The process according to claim 15 , wherein R 4 is an amine protecting group.

18. The process according to claim 17 , wherein the amine protecting group is selected from the group consisting of:

19. The process according to claim 14 , 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.

20. 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 selected from the group consisting of:

phenyl, pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl;

B is selected from the group consisting of:

phenyl, pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl;

Het-CH 2 —R 3 is selected from the group consisting of:

M-L is selected from the group consisting of:

a) M-X, b) M-L 1 , c) M-L 1 -X, d) M-X-L 2 , e) M-L 1 -X-L 2 , f) M-X-L 1 -X-L 2 , g) M-L 1 -X-L 2 -X, h) M-X—X—, i) M-L 1 -X—X—, j) M-X—X-L 2 , and k) M-L 1 -X—X-L 2 , wherein

X, at each occurrence, independently is selected from the group consisting of:

a) —O—, b) —NR 4 —, c) —N(O) 13 , d) —N(OR 4 )—, e) —S(O) p —, f) —SO 2 NR 4 —, g) —NR 4 SO 2 —, h) —NR 4 —N═, i) ═N—NR 4 —, j) —O—N═, k) ═N—O—, l) —N═, m) ═N—, n) —NR 4 —NR 4 —, o) —NR 4 C(O)O—, p) —OC(O)NR 4 —, q) —NR 4 C(O)NR 4 — r) —NR 4 C(NR 4 )NR 4 —, and

L 1 is selected from the group consisting of:

a) C 1-6 alkyl, b) C 2-6 alkenyl, and c) C 2-6 alkynyl,

wherein any of a)-c) optionally is substituted with one or more R 5 groups; and

L 2 is selected from the group consisting of:

a) C 1-6 alkyl, b) C 2-6 alkenyl, and c) C 2-6 alkynyl,

wherein any of a)-c) optionally is substituted with one or more R 5 groups;

alternatively, L in M-L is a bond;

M is selected from the group consisting of:

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:

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:

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)O R 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 selected from the group consisting of:

R 4 , at each occurrence, independently is selected from the group consisting of:

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:

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,

R 8 , at each occurrence, independently is selected from the group consisting of:

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.

Assignments (7)

TERMINATION AND RELEASE OF INTELLECTUAL PROPERTY SECURITY AGREEMENT (PATENTS) AT REEL 054836 AND FRAME 0824, REEL 061314 AND FRAME 0572 AND REEL 068260 AND FRAME 0283 Recorded Aug 29, 2025

From: SILICON VALLEY BANK, A DIVISION OF FIRST-CITIZENS BANK & TRUST COMPANY

To: MELINTA SUBSIDIARY CORP.

Reel/Frame 074576/0471 →

AMENDED AND RESTATED INTELLECTUAL PROPERTY SECURITY AGREEMENT Recorded Aug 25, 2022

From: MELINTA SUBSIDIARY CORP.

To: SILICON VALLEY BANK

Reel/Frame 061314/0572 →

INTELLECTUAL PROPERTY SECURITY AGREEMENT Recorded Dec 22, 2020

From: MELINTA SUBSIDIARY CORP.

To: SILICON VALLEY BANK

Reel/Frame 054836/0824 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 16, 2019