11,13-modified saxitoxins for the treatment of pain
Provided herein are compounds, pharmaceutical compositions comprising the compounds, methods of preparing the compounds, and methods of using the compounds and compositions in treating conditions associated with voltage-gated sodium channel function where the compounds are 11,13-modified saxitoxins according to Formula (I): where R 1 , X 1 and X 3 are as described herein.
1. A Compound of Formula (I):
where
R 1 is H, OH, —OS(O) 3 − , —OS(O) 2 R 5 , —OC(O)R 6 , —NR 7 C(O)R 7a , —OC(O)NR 10 R 10a , —NR 11 R 11a , —NH 3 + , —NR 13 S(O) 2 R 13a , or —NR 14 C(O)NR 14a R 14b ;
X 1 is R 3 and X 2 is R 9 ; or
X 1 and X 2 together with the —NC(O)— to which they are attached form a 5 or 6-membered ring where X 1 , X 2 , and the one or two additional ring atoms are independently selected from —C(O)—, —O—, —S—, —NR 8 —, and —C(R 4 )(R 4a )— provided that only one is selected from —O—, —S—, and —NR 8 —; and where the 5 or 6-membered ring is optionally fused at two adjacent carbon atoms, or is optionally fused at one carbon atom and one nitrogen atom which are adjacent to each other, to a form a saturated or unsaturated 6-12 membered bicyclic ring; where the 1, 2, 3, 4, 5, or 6 additional bicyclic ring atoms are independently —CR 12 ═ or —C(R 12 ) 2 —; or
X 1 and X 2 together with the —NC(O)— to which they are attached form 1,3-dioxo-hexahydro-1H-4,7-methanoisoindolyl;
each R 4 and R 4a is independently H; C 1-6 alkyl; or when the 6-12 membered ring is fused at a —C(R 4 )(R 4a —, one or both of the R 4 and R 4a on the —C(R 4 )(R 4a )— form a single or double bond with an adjacent ring atom;
R 8 is hydrogen; C 1-6 alkyl; phenyl optionally substituted with 1, 2, or 3 groups independently selected from halo, C 1-6 alkyl, halo-C 1-6 alkyl, hydroxy, C 1-6 alkoxy, halo-C 1-6 alkoxy, nitro, and cyano; or when the 6-12 membered ring is fused at an —NR 8 —, the R 8 forms a single bond with an adjacent ring atom;
each R 12 is independently hydrogen, halo, C 1-6 alkyl, halo-C 1-6 alkyl, or aryl;
R 3 is —C(O)C 1-6 alkyl, —C(O)OC 1-6 alkyl, or —C(O)phenyl where the phenyl is optionally substituted with one or two groups independently selected from halo, C 1-6 alkyl, halo-C 1-6 alkyl, C 1-6 alkoxy, and aryl;
R 5 is H, C 1-6 alkyl, or aryl optionally substituted with 1, 2, 3, or 4 R 5a ;
each R 5a , when present, is independently halo, C 1-6 alkyl, halo-C 1-6 alkyl, hydroxy, C 1-6 alkoxy, halo-C 1-6 alkoxy, C 1-6 alkylthio, halo-C 1-6 alkylthio, C 1-6 alkylsulfinyl, halo-C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, halo-C 1-6 alkylsulfonyl, nitro, amino, C 1-6 alkylamino, di- C 1-6 alkylamino, phenyl, or cyano;
R 9 is C 1-6 alkyl, C 1-6 alkoxy, or phenyl where the phenyl is optionally substituted with one or two groups independently selected from halo, C 1-6 alkyl, halo-C 1-6 alkyl, C 1-6 alkoxy, and aryl;
R 6 is C 1-6 alkyl; aryl optionally substituted with 1, 2, 3, or 4 R 6a ; aralkyl where the aryl is optionally substituted with 1, 2, 3, or 4 R 6a ; heteroaryl optionally substituted with 1, 2, 3, or 4 R 6a ; heterocyclic optionally substituted with 1, 2, 3, or 4 R 6a ; biphenyl optionally substituted on either ring with 1, 2, or 3 R 6a ; or cycloalkyl optionally substituted with 1, 2, 3, or 4 groups independently selected from C 1-6 alkyl and halo-C 1-6 alkyl;
each R 6a , when present, is independently halo, C 1-6 alkyl, halo-C 1-6 alkyl, hydroxy, C 1-6 alkoxy, halo-C 1-6 alkoxy, nitro, C 1-6 alkylthio, halo-C 1-6 alkylthio, C 1-6 alkylsulfinyl, halo-C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, halo-C 1-6 alkylsulfonyl, amino, C 1-6 alkylamino, di-C 1-6 alkylamino, phenyl, or cyano;
R 7 is hydrogen or C 1-6 alkyl;
R 7 a is C 1-6 alkyl; aryl optionally substituted with 1, 2, 3, or 4 R 7 b; aralkyl where the aryl is optionally substituted with 1, 2, 3, or 4 R 7b ; heteroaryl optionally substituted with 1, 2, 3, or 4 R 7b ; heterocyclic optionally substituted with 1, 2, 3, or 4 R 7b ; biphenyl optionally substituted on either ring with 1, 2, or 3 R 7b ; or cycloalkyl optionally substituted with 1, 2, 3, or 4 groups independently selected from C 1-6 alkyl and halo-C 1-6 alkyl;
each R 7b , when present, is independently halo, C 1-6 alkyl, halo-C 1-6 alkyl, hydroxy, C 1-6 alkoxy, halo-C 1-6 alkoxy, nitro, C 1-6 alkylthio, halo-C 1-6 alkylthio, C 1-6 alkylsulfinyl, halo-C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, halo-C 1-6 alkylsulfonyl, amino, C 1-6 alkylamino, di-C 1-6 alkylamino, phenyl, or cyano;
R 10 is hydrogen or C 1-6 alkyl;
R 10a is C 1-6 alkyl; aryl optionally substituted with 1, 2, 3, or 4 R 10b ; aralkyl where the aryl is optionally substituted with 1, 2, 3, or 4 R 10b ; phenylcarbonyl where the phenyl is optionally substituted with 1, 2, or 3 R 10b ; heteroaryl optionally substituted with 1, 2, 3, or 4 R 10b ; heterocyclic optionally substituted with 1, 2, 3, or 4 R 10b ; biphenyl optionally substituted on either ring with 1, 2, 3, or 4 R 10b , or cycloalkyl optionally substituted with 1, 2, 3, or 4 groups independently selected from C 1-6 alkyl and halo-C 1-6 alkyl;
each R 10b , when present, is independently halo, C 1-6 alkyl, halo-C 1-6 alkyl, hydroxy, C 1-6 alkoxy, halo-C 1-6 alkoxy, nitro, C 1-6 alkylthio, halo-C 1-6 alkylthio, C 1-6 alkylsulfinyl, halo-C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, halo-C 1-6 alkylsulfonyl, amino, C 1-6 alkylamino, di-C 1-6 alkylamino, phenyl, or cyano;
R 11 is hydrogen or C 1-6 alkyl;
R 11a is C 1-6 alkyl; aryl optionally substituted with 1, 2, 3, or 4 R 11b ; aralkyl where the aryl is optionally substituted with 1, 2, 3, or 4 R 11b ; heteroaryl optionally substituted with 1, 2, 3, or 4 R 11b ; heterocyclic optionally substituted with 1, 2, 3, or 4 R 11b ; biphenyl optionally substituted on either ring with 1, 2, 3, or 4 R 11b ; or cycloalkyl optionally substituted with 1, 2, or 3 groups independently selected from C 1-6 alkyl and halo-C 1-6 alkyl; and
each R 11b , when present, is independently halo, C 1-6 alkyl, halo-C 1-6 alkyl, hydroxy, C 1-6 alkoxy, halo-C 1-6 alkoxy, nitro, C 1-6 alkylthio, halo-C 1-6 alkylthio, C 1-6 alkylsulfinyl, halo-C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, halo-C 1-6 alkylsulfonyl, amino, C 1-6 alkylamino, di-C 1-6 alkylamino, phenyl, or cyano;
R 13 is hydrogen or C 1-6 alkyl;
R 13a is C 1-6 alkyl; aryl optionally substituted with 1, 2, 3, or 4 R 13b ; aralkyl where the aryl is optionally substituted with 1, 2, 3, or 4 R 13b , heteroaryl optionally substituted with 1, 2, 3, or 4 R 13b ; heterocyclic optionally substituted with 1, 2, 3, or 4 R 13b , biphenyl optionally substituted on either ring with 1, 2, 3, or 4 R 13b ; or cycloalkyl optionally substituted with 1, 2, 3, or 4 groups independently selected from C 1-6 alkyl and halo-C 1-6 alkyl;
each R 13b , when present, is independently halo, C 1-6 alkyl, halo-C 1-6 alkyl, hydroxy, C 1-6 alkoxy, halo-C 1-6 alkoxy, C 1-6 alkylthio, halo-C 1-6 alkylthio, C 1-6 alkylsulfinyl, halo-C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, halo-C 1-6 alkylsulfonyl, nitro, amino, C 1-6 alkylamino, di-C 1-6 alkylamino, phenyl, or cyano;
R 14 is hydrogen or C 1-6 alkyl;
R 14a is hydrogen or C 1-6 alkyl;
R 14b ) is C 1-6 alkyl; aryl optionally substituted with 1, 2, 3, or 4 R 14c ; aralkyl where the aryl is optionally substituted with 1, 2, 3, or 4 R 14c ; heteroaryl optionally substituted with 1, 2, 3, or 4 R 14c ; heterocyclic optionally substituted with 1, 2, 3, or 4 R 14c ; biphenyl optionally substituted on either ring with 1, 2, 3, or 4 R 14c ; or cycloalkyl optionally substituted with 1, 2, 3, or 4 groups independently selected from C 1-6 alkyl and halo-C 1-6 alkyl; and
each R 14c , when present, is independently halo, C 1-6 alkyl, halo-C 1-6 alkyl, hydroxy, C 1-6 alkoxy, halo-C 1-6 alkoxy, C 1-6 alkylthio, halo-C 1-6 alkylthio, C 1-6 alkylsulfinyl, halo-C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, halo-C 1-6 alkylsulfonyl, nitro, amino, C 1-6 alkylamino, di-C 1-6 alkylamino, phenyl, or cyano; or
a pharmaceutically acceptable salt, stereoisomer, tautomer, or mixture thereof.
2. The Compound of claim 1 where the compound is according to Formula (Ia):
or a pharmaceutically acceptable salt, stereoisomer, tautomer, or mixture thereof.
3. The Compound of claim 1 where the compound is according to Formula (Ib):
or a pharmaceutically acceptable salt, stereoisomer, tautomer, or mixture thereof.
4. The Compound of claim 1 where
X 1 is R 3 and X 2 is R 9 ; or
X 1 and X 2 together with the —NC(O)— to which they are attached form
where X 1 a is —O—, —CH 2 —, or —C(O)—; X 2a is —S—, —NR 8 — or —C(R 4 )(R 4a )—, and X 3a is one or two groups independently selected from —O—, —S—, —NR 8 —, and —C(R 4 )(R 4a )— provided that only one atom of X 1a , X 2a , and X 3a is selected from —O—, —S—, and —NR 8 —; and where the
ring is optionally fused at X 2a and at the adjacent atom in X 3a to form a saturated or unsaturated, 6-12 membered bicyclic ring when 1) X 2a is —NR 8 — and X 3a is —C(R 4 )(R 4a )— or —C(R 4 )(R 4a )—C(R 4 )(R 4a )— or 2) X 2a is —C(R 4 )(R 4a )— and X 3a is —C(R 4 )(R 4a )—, —NR 8 —, —C(R 4 )(R 4a )—C(R 4 )(R 4a )—, —C(R 4 )(R 4a )—NR 8 —,or —NR 8 —C(R 4 )(R 4a )—; and where the 1, 2, 3, 4, 5, or 6 additional ring atoms are independently —CR 12 ═ or —C(R 12 ) 2 —; or
a pharmaceutically acceptable salt, stereoisomer, tautomer, or mixture thereof.
5. The Compound of claim 1 where X 1 is R 3 and X 2 is R 9 .
6. The Compound of claim 1 where X 1 and X 2 together with the —NC(O)— to which they are attached form
where X 1a is —O—, —CH 2 —, or —C(O)—; X 2a is —S—, —NR 8 —, or —C(R 4 )(R 4a )—; and X 3a is one or two groups independently selected from —O—, —S—, —NR 8 —, and —C(R 4 )(R 4a )— provided that only one atom of X 1a , X 2a , and X 3a is selected from —O—, —S—, and —NR 8 —; and where the
ring is optionally fused at X 2a and at the adjacent atom in X 3a to form a saturated or unsaturated, 6-12 membered bicyclic ring when 1) X 2a is —NR 8 — and X 3a is —C(R 4 )(R 4a )— or —C(R 4 )(R 4a )—C(R 4 )(R 4a ) 13 or 2) X 2a is —C(R 4 )(R 4a )— and X 3a is —C(R 4 )(R 4a )—, —NR 8 —, —C(R 4 )(R 4a )—C(R 4 )(R 4a ), —C(R 4 )(R 4a )—NR 8 —, or —NR 8 —C(R 4 )(R 4a )—; and where the three or four additional ring atoms are independently —CR 12 ═ or —C(R 12 ) 2 —;
each R 4 and R 4a is independently H; C 1-6 alkyl; or when the 6-12 membered ring is fused at a —C(R 4 )(R 4a )—, one or both of the R 4 and R 4a on the —C(R 4 )(R 4a )— form a single or double bond with an adjacent ring atom;
R 8 is hydrogen; C 1-6 alkyl; phenyl optionally substituted with 1, 2, or 3 groups independently selected from halo, C 1-6 alkyl, halo-C 1-6 alkyl, hydroxy, C 1-6 alkoxy, halo-C 1-6 alkoxy, nitro, and cyano; or when the 6-12 membered ring is fused at an —NR 8 —, the R 8 forms a single bond with an adjacent ring atom; and
each R 12 is independently hydrogen, halo, C 1-6 alkyl, halo-C 1-6 alkyl, or aryl; or
a pharmaceutically acceptable salt, stereoisomer, tautomer, or mixture thereof.
7. The Compound of claim 1 where X 1 and X 2 together with the —NC(O)— to which they are attached form a 5-membered ring where the 5-membered ring is optionally fused at two adjacent carbon atoms and is
or
a pharmaceutically acceptable salt, stereoisomer, tautomer, or mixture thereof.
8. The Compound of claim 1 where X 1 and X 2 together with the —NC(O)— to which they are attached form a 5-membered ring where the 5-membered ring is optionally fused at two adjacent carbon atoms and is
or
a pharmaceutically acceptable salt, stereoisomer, tautomer, or mixture thereof.
9. The Compound of claim 1 where X 1 and X 2 together with the —NC(O)— to which they are attached form a 5-membered ring which is
or
a pharmaceutically acceptable salt, stereoisomer, tautomer, or mixture thereof.
10. The Compound of claim 7 where
R 5 is C 1-6 alkyl or aryl optionally substituted with 1, 2, 3, or 4 R 5 ;
R 6 is aryl optionally substituted with 1, 2, 3, or 4 R 6a ; or heterocyclic optionally substituted with 1, 2, 3, or 4 R 6a ;
R 7 a is aryl optionally substituted with 1, 2, 3, or 4 R 7b ; or heterocyclic optionally substituted with 1, 2, 3, or 4 R 7b ;
R 10a is aryl optionally substituted with 1, 2, 3, or 4 R 10b ; or heterocyclic optionally substituted with 1, 2, 3, or 4 R 10b ;
R 11a is aryl optionally substituted with 1, 2, 3, or 4 R 11b ; or heterocyclic optionally substituted with 1, 2, 3, or 4 R 11b ;
R 13a is aryl optionally substituted with 1, 2, 3, or 4 R 13b ; or heterocyclic optionally substituted with 1, 2, 3, or 4 R 13b ; and
R 14b is aryl optionally substituted with 1, 2, 3, or 4 R 14c ; or heterocyclic optionally substituted with 1, 2, 3, or 4 R 14c .
11. The Compound of claim 1 where R 1 is —OS(O) 2 R 5 , —OC(O) 6 , —NR 7 C(O)NR 7a , —OC(O)NR 10 R 10a , —NR 11 R 11a , —NR 13 S(O) 2 R 13a , or —NR 14 C(O)NR 14a R 14b .
12. The Compound of claim 1 where R 1 is —OC(O)R 6 or —NR 7 C(O)R 7a .
13. The Compound of claim 1 where R 7 , R 10 , R 11 , R 13 , R 14 , and R 14a are hydrogen.
14. The Compound of claim 1 where the aryl in R 1 is phenyl, naphthyl, tetrahydronaphthyl, fluorenyl, or indanyl; each of which is optionally substituted with 1, 2, or 3 groups independently selected from halo, C 1-6 alkyl, halo-C 1-6 alkyl, hydroxy, C 1-6 alkoxy, halo-C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylsulfonyl, and amino.
15. The Compound of claim 1 where the heterocyclic in R 1 is benzo-1,4-dioxanyl, benzodioxolyl, indolinyl, 2-oxo-indolinyl, pyrrolidinyl, piperidinyl, 2,3-dihydrobenzofuranyl, or decahydroquinolinyl; each of which is optionally substituted with 1, 2, or 3 groups independently selected from halo, C 1-6 alkyl, halo-C 1-6 alkyl, hydroxy, C 1-6 alkoxy, halo-C 1-6 alkoxy, and phenyl.
16. The compound of claim 1 where the Compound is selected from the compounds of Formula 1-122:
or a pharmaceutically acceptable salt, stereoisomer, tautomer, or mixture thereof.
17. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient, carrier or diluent.
18. The pharmaceutical composition of claim 17 , wherein the composition is an oral or injectable formulation.
19. A method for the treatment of a condition associated with voltage-gated sodium channel function in a mammal, comprising the administration of a therapeutically effective amount of a compound of claim 1 .
20. The method of claim 19 , wherein the mammal is a human.
21. The method of claim 19 where the condition is pain.
22. The method of claim 19 where the condition is associated with pain.
23. The method of claim 22 where the condition is selected from erythromelalgia, diabetic peripheral neuropathy, paroxysmal extreme pain disorder, complex regional pain syndrome, trigeminal neuralgia, multiple sclerosis, osteoarthritis, postherpetic neuralgia, cancer pain, cluster headache, migraine, sciatica, endometriosis, fibromyalgia, and postsurgical pain.
24. The method of claim 19 where the condition is selected from epilepsy, Parkinson's disease, a mood disorder, psychosis, amyotropic lateral sclerosis, glaucoma, ischemia, a spasticity disorder, and obsessive compulsive disorder.
25. A compound of Formula Xe
or a salt thereof, where
PG 1 is a nitrogen-protecting group and is 9-fluorenylmethyloxycarbonyl (Fmoc), tert-butoxycarbonyl (Boc), benzyloxycarbonyl (CBz), acetyl, trichloroacetyl, trifluoroacetyl, —C(O)OCH 2 CCl 3 (Troc), p-methoxyphenyl, benzyl, p-methoxybenzyl, p-methoxybenzylcarbonyl, triphenylmethyl, benzylidenyl, 2,2,2-trichloroethoxysulfonyl (Tces), p-methoxybenzenesulfonyl (Mbs) or p-toluenesulfonyl (tosyl);
PG 2 is a nitrogen-protecting group and is 9-fluorenylmethyloxycarbonyl (Fmoc), tert-butoxycarbonyl (Boc), benzyloxycarbonyl (CBz), acetyl, trichloroacetyl, trifluoroacetyl, —C(O)OCH 2 CCl 3 (Troc), p-methoxyphenyl, benzyl, p-methoxybenzyl, p-methoxybenzylcarbonyl, triphenylmethyl, benzylidenyl, 2,2,2-trichloroethoxysulfonyl (Tces), p-methoxybenzenesulfonyl (Mbs) or p-toluenesulfonyl (tosyl);
R 1 is —OS(O) 2 R 5 , —OC(O)R 6 , —NR 7 C(O)R 7a , —OC(O)NR 10 R 10a ,—NR 11 R 11a , —NR 13 S(O) 2 R 13a , or —NR 14 C(O)NR 14a R 14b ;
X 1 is R 3 and X 2 is R 9 ; or
X 1 and X 2 together with the —NC(O)— to which they are attached form
where X 1a is —O—, —CH 2 —, or —C(O)—; X 2a is —S—, —NR 8 —, or —C(R 4 )(R 4a )—; and X 3a is one or two groups independently selected from —O—, —S—, —NR 8 —, and —C(R 4 )(R 4a )— provided that only one atom of X 1a , X 2a , and X 3a is selected from —O—, —S—, and —NR 8 —; and where the
ring is optionally fused at X 2a and at the adjacent atom in X 3a to form a saturated or unsaturated, 6-12 membered bicyclic ring when 1) X 2a is —NR 8 — and X 3a is —C(R 4 )(R 4a )— or —C(R 4 )(R 4a )—C(R 4 )(R 4a )— or 2) X 2a is —C(R 4 )(R 4a )— and X 3a is —C(R 4 )(R 4a )—, —NR 8 —, —C(R 4 )(R 4a )—C(R 4 )(R 4a )—, —C(R 4 )(R 4a )—NR 8 —, or —NR 8 —C(R 4 )(R 4a )—; and where the three or four additional bicyclic ring atoms are independently —CR 12 ═ or —C(R 12 ) 2 —;
each R 4 and R 4a is independently H; C 1-6 alkyl; or when the 6-12 membered ring is fused at a —C(R 4 )(R 4a )—, one or both of the R 4 and R 4a on the —C(R 4 )(R 4a )— form a single or double) bond with an adjacent ring atom;
R 8 is hydrogen; C 1-6 alkyl; phenyl optionally substituted with 1, 2, or 3 groups independently selected from halo, C 1-6 alkyl, halo-C 1-6 alkyl, hydroxy, C 1-6 alkoxy, halo-C 1-6 alkoxy, nitro, and cyano; or when the 6-12 membered ring is fused at an —NR 8 —, the R 8 forms a single bond with an adjacent ring atom;
each R 12 is independently hydrogen, halo, C 1-6 alkyl, halo-C 1-6 alkyl, or aryl;
R 3 is —C(O)C 1-6 alkyl, —C(O)OC 1-6 alkyl, or —C(O)phenyl where the phenyl is optionally substituted with one or two groups independently selected from halo, C 1-6 alkyl, halo-C 1-6 alkyl, C 1-6 alkoxy, and aryl;
R 9 is C 1-6 alkyl, C 1-6 alkoxy, or phenyl where the phenyl is optionally substituted with one or two groups independently selected from halo, C 1-6 alkyl, halo-C 1-6 alkyl, C 1-6 alkoxy, and aryl;
R 5 is H, C 1-6 alkyl, or aryl optionally substituted with 1, 2, 3, or 4 R 5a ;
each R 5a , when present, is independently halo, C 1-6 alkyl, halo-C 1-6 alkyl, hydroxy, C 1-6 alkoxy, halo-C 1-6 alkoxy, C 1-6 alkylthio, halo-C 1-6 alkylthio, C 1-6 alkylsulfinyl, halo-C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, halo-C 1-6 alkylsulfonyl, nitro, amino, C 1-6 alkylamino, di-C 1-6 alkylamino, phenyl, or cyano;
R 6 is C 1-6 alkyl; aryl optionally substituted with 1, 2, 3, or 4 R 6a ; aralkyl where the aryl is optionally substituted with 1, 2, 3, or 4 R 6a ; heteroaryl optionally substituted with 1, 2, 3, or 4 R 6a ; heterocyclic optionally substituted with 1, 2, 3, or 4 R 6a ; biphenyl optionally substituted on either ring with 1, 2, 3, or 4 R 6a ; or cycloalkyl optionally substituted with 1, 2, or 3 groups independently selected from C 1-6 alkyl and halo-C 1-6 alkyl;
each R 6a , when present, is independently halo, C 1-6 alkyl, halo-C 1-6 alkyl, hydroxy, C 1-6 alkoxy, halo-C 1-6 alkoxy, nitro, C 1-6 alkylthio, halo-C 1-6 alkylthio, C 1-6 alkylsulfinyl, halo-C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, halo-C 1-6 alkylsulfonyl, amino, C 1-6 alkylamino, di-C 1-6 alkylamino, phenyl, or cyano;
R 7 is hydrogen or C 1-6 alkyl;
R 7a is C 1-6 alkyl; aryl optionally substituted with 1, 2, 3, or 4 R 7b ; aralkyl where the aryl is optionally substituted with 1, 2, 3, or 4 R 7b ; heteroaryl optionally substituted with 1, 2, 3, or 4 R 7b ; heterocyclic optionally substituted with 1, 2, 3, or 4 R 7b ; biphenyl optionally substituted on either ring with 1, 2, 3, or 4 R 7b ; or cycloalkyl optionally substituted with 1, 2, 3, or 4 groups independently selected from C 1-6 alkyl and halo-C 1-6 alkyl;
each R 7b , when present, is independently halo, C 1-6 alkyl, halo-C 1-6 alkyl, hydroxy, C 1-6 alkoxy, halo-C 1-6 alkoxy, nitro, C 1-6 alkylthio, halo-C 1-6 alkylthio, C 1-6 alkylsulfinyl, halo-C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, halo-C 1-6 alkylsulfonyl, amino, C 1-6 alkylamino, di-C 1-6 alkylamino, phenyl, or cyano; and
R 10 is hydrogen or C 1-6 alkyl;
R 10a is C 1-6 alkyl; aryl optionally substituted with 1, 2, 3, or 4 R 10b ; aralkyl where the aryl is optionally substituted with 1, 2, 3, or 4 R 10b ; phenylcarbonyl where the phenyl is optionally substituted with 1, 2, 3, or 4 R 10b ; heteroaryl optionally substituted with 1, 2, 3, or 4 R 10b ; heterocyclic optionally substituted with 1, 2, 3, or 4 R 10b ; biphenyl optionally substituted on either ring with 1, 2, 3, or 4 R 10b ; or cycloalkyl optionally substituted with 1, 2, 3, or 4 groups independently selected from C 1-6 alkyl and halo-C 1-6 alkyl;
each R 10b , when present, is independently halo, C 1-6 alkyl, halo-C 1-6 alkyl, hydroxy, C 1-6 alkoxy, halo-C 1-6 alkoxy, nitro, C 1-6 alkylthio, halo-C 1-6 alkylthio, C 1-6 alkylsulfinyl, halo-C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, halo-C 1-6 alkylsulfonyl, amino, C 1-6 alkylamino, di-C 1-6 alkylamino, phenyl, or cyano;
R 11 is hydrogen or C 1-6 alkyl;
R 11a is C 1-6 alkyl; aryl optionally substituted with 1, 2, 3, or 4 R 11b ; aralkyl where the aryl is optionally substituted with 1, 2, 3, or 4 R 11b ; heteroaryl optionally substituted with 1, 2, 3, or 4 R 11b ; heterocyclic optionally substituted with 1, 2, 3, or 4 R 11a ; biphenyl optionally substituted on either ring with 1, 2, 3, or 4 R 11b ; or cycloalkyl optionally substituted with 1, 2, 3, or 4 groups independently selected from C 1-6 alkyl and halo-C 1-6 alkyl;
each R 11b , when present, is independently halo, C 1-6 alkyl, halo-C 1-6 alkyl, hydroxy, C 1-6 alkoxy, halo-C 1-6 alkoxy, nitro, C 1-6 alkylthio, halo-C 1-6 alkylthio, C 1-6 alkylsulfinyl, halo-C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, halo-C 1-6 alkylsulfonyl, amino, C 1-6 alkylamino, di-C 1-6 alkylamino, phenyl, or cyano;
R 13 is hydrogen or C 1-6 alkyl;
R 13a is C 1-6 alkyl; aryl optionally substituted with 1, 2, 3, or 4 R 13b ; aralkyl where the aryl is optionally substituted with 1, 2, 3, or 4 R 13b ; heteroaryl optionally substituted with 1, 2, 3, or 4 R 13b ; heterocyclic optionally substituted with 1, 2, 3, or 4 R 13b ; biphenyl optionally substituted on either ring with 1, 2, 3, or 4 R 13b ; or cycloalkyl optionally substituted with 1, 2, 3, or 4 groups independently selected from C 1-6 alkyl and halo-C 1-6 alkyl;
each R 13b , when present, is independently halo, C 1-6 alkyl, halo-C 1-6 alkyl, hydroxy, C 1-6 alkoxy, halo-C 1-6 alkoxy, C 1-6 alkylthio, halo-C 1-6 alkylthio, C 1-6 alkylsulfinyl, halo-C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, halo-C 1-6 alkylsulfonyl, nitro, amino, C 1-6 alkylamino, di-C 1-6 alkylamino, phenyl, or cyano;
R 14 is hydrogen or C 1-6 alkyl;
R 14a is hydrogen or C 1-6 alkyl;
R 14b is C 1-6 alkyl; aryl optionally substituted with 1, 2, 3, or 4 R 14c ; aralkyl where the aryl is optionally substituted with 1, 2, 3, or 4 R 14c ; heteroaryl optionally substituted with 1, 2, 3, or 4 R 14c ; heterocyclic optionally substituted with 1, 2, 3, or 4 R 14c ; biphenyl optionally substituted on either ring with 1, 2, 3, or 4 R 14c ; or cycloalkyl optionally substituted with 1, 2, 3, or 4 groups independently selected from C 1-6 alkyl and halo-C 1-6 alkyl; and
each R 14c , when present, is independently halo, C 1-6 alkyl, halo-C 1-6 alkyl, hydroxy, C 1-6 alkoxy, halo-C 1-6 alkoxy, C 1-6 alkylthio, halo-C 1-6 alkylthio, C 1-6 alkylsulfinyl, halo-C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, halo-C 1-6 alkylsulfonyl, nitro, amino, C 1-6 alkylamino, di-C 1-6 alkylamino, phenyl, or cyano.
26. A method of preparing a compound of Formula (I) comprising
a) deprotecting a compound of Formula Xe
where
PG 1 is a nitrogen-protecting group and is 9-fluorenylmethyloxycarbonyl (Fmoc), tert-butoxycarbonyl (Boc), benzyloxycarbonyl (CBz), acetyl, trichloroacetyl, trifluoroacetyl, —C(O)OCH 2 CCl 3 (Troc), p-methoxyphenyl, benzyl, p-methoxybenzyl, p-methoxybenzylcarbonyl, triphenylmethyl, benzylidenyl, 2,2,2-trichloroethoxysulfonyl (Tces), p-methoxybenzenesulfonyl (Mbs) or p-toluenesulfonyl (tosyl);
PG 2 is a nitrogen-protecting group and is 9-fluorenylmethyloxycarbonyl (Fmoc), tert-butoxycarbonyl (Boc), benzyloxycarbonyl (CBz), acetyl, trichloroacetyl, trifluoroacetyl, —C(O)OCH 2 CCl 1 (Troc), p-methoxyphenyl, benzyl, p-methoxybenzyl, p-methoxybenzylcarbonyl, triphenylmethyl, benzylidenyl, 2,2,2-trichloroethoxysulfonyl (Tces), p-methoxybenzenesulfonyl (Mbs) or p-toluenesulfonyl (tosyl);
R 1 is —OS(O) 2 R 5 , —OC(O)R 6 , —NR 7 C(O)R 7a , —OC(O)NR 10 R 10a , NR 11 R 11a , —NR 13 S(O) 2 R 13a , or —NR 14 C(O)NR 14a R 14b ;
X 1 is R 3 and X 2 is R 9 ; or
X 1 and X 2 together with the —NC(O)— to which they are attached form
where X 1a is —O—, —CH 2 —, or —C(O)—; X 2a is —S—, —NR 8 —, or —C(R 4 )(R 4a )—; and X 3a is one or two groups independently selected from —O—, —S—, —NR 8 —, and —C(R 4 )(R 4a )— provided that only one atom of X 1a , X 2a , and X 3a is selected from —O—, —S—, and —NR 8 —; and where the
ring is optionally fused at X 2a and at the adjacent atom in X 3a to form a saturated or unsaturated, 6-12 membered bicyclic ring when 1) X 2a is —NR 8 — and X 3a is —C(R 4 )(R 4a )— or —C(R 4 )(R 4a )—C(R 4 )(R 4a )— or 2) X 2a is —C(R 4 )(R 4a )— and X 3a is —C(R 4 )(R 4a )—, —NR 8 —, —C(R 4 )(R 4a )—C(R 4 )(R 4a )—, —C(R 4 )(R 4a )—NR 8 —, or —NR 8 —C(R 4 )(R 4a )—; and where the three or four additional ring atoms are independently —CR 12 ═ or —C(R 12 ) 2 —;
each R 4 and R 4a is independently H; C 1-6 alkyl; or when the 6-12 membered ring is fused at a —C(R 4 )(R 4a )—, one or both of the R 4 and R 4a on the —C(R 4 )(R 4a )— form a single or double bond with an adjacent ring atom;
R 8 is hydrogen; C 1-6 alkyl; phenyl optionally substituted with 1, 2, or 3 groups independently selected from halo, C 1-6 alkyl, halo-C 1-6 alkyl, hydroxy, C 1-6 alkoxy, halo-C 1-6 alkoxy, nitro, and cyano; or when the 6-12 membered ring is fused at an —NR 8 —, the R 8 forms a single bond with an adjacent ring atom;
each R 12 is independently hydrogen, halo, C 1-6 alkyl, halo-C 1-6 alkyl, or aryl;
R 3 is —C(O)C 1-6 alkyl, —C(O)OC 1-6 alkyl, or —C(O)phenyl where the phenyl is optionally substituted with one or two groups independently selected from halo, C 1-6 alkyl, halo-C 1-6 alkyl, C 1-6 alkoxy, and aryl;
R 9 is C 1-6 alkyl, C 1-6 alkoxy, or phenyl where the phenyl is optionally substituted with one or two groups independently selected from halo, C 1-6 alkyl, halo-C 1-6 alkyl, C 1-6 alkoxy, and aryl;
R 5 is H, C 1-6 alkyl, or aryl optionally substituted with 1, 2, 3, or 4 R 5a ;
each R 5a , when present, is independently halo, C 1-6 alkyl, halo-C 1-6 alkyl, hydroxy, C 1-6 alkoxy, halo-C 1-6 alkoxy, C 1-6 alkylthio, halo-C 1-6 alkylthio, C 1-6 alkylsulfinyl, halo-C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, halo-C 1-6 alkylsulfonyl, nitro, amino, C 1-6 alkylamino, di-C 1-6 alkylamino, phenyl, or cyano;
R 6 is C 1-6 alkyl; aryl optionally substituted with 1, 2, 3, or 4 R 6a ; aralkyl where the aryl is optionally substituted with 1, 2, 3, or 4 R 6a ; heteroaryl optionally substituted with 1, 2, 3, or 4 R 6a ; heterocyclic optionally substituted with 1, 2, 3, or 4 R 6a ; biphenyl optionally substituted on either ring with 1, 2, 3, or 4 R 6a ; or cycloalkyl optionally substituted with 1, 2, 3, or 4 groups independently selected from C 1-6 alkyl and halo-C 1-6 alkyl;
each R 6a , when present, is independently halo, C 1-6 alkyl, halo-C 1-6 alkyl, hydroxy, C 1-6 alkoxy, halo-C 1-6 alkoxy, nitro, C 1-6 alkylthio, halo-C 1-6 alkylthio, C 1-6 alkylsulfinyl, halo-C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, halo-C 1-6 alkylsulfonyl, amino, C 1-6 alkylamino, di-C 1-6 alkylamino, phenyl, or cyano;
R 7 is hydrogen or C 1-6 alkyl;
R 7a is C 1-6 alkyl; aryl optionally substituted with 1, 2, 3, or 4 R 7b ; aralkyl where the aryl is optionally substituted with 1, 2, 3, or 4 R 7b ; heteroaryl optionally substituted with 1, 2, 3, or 4 R 7b ; heterocyclic optionally substituted with 1, 2, 3, or 4 R 7b ; biphenyl optionally substituted on either ring with 1, 2, 3, or 4 R 7b ; or cycloalkyl optionally substituted with 1, 2, 3, or 4 groups independently selected from C 1-6 alkyl and halo-C 1-6 alkyl;
each R 7 b, when present, is independently halo, C 1-6 alkyl, halo-C 1-6 alkyl, hydroxy, C 1-6 alkoxy, halo-C 1-6 alkoxy, nitro, C 1-6 alkylthio, halo-C 1-6 alkylthio, C 1-6 alkylsulfinyl, halo-C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, halo-C 1-6 alkylsulfonyl, amino, C 1-6 alkylamino, di-C 1-6 alkylamino, phenyl, or cyano; and
R 10 is hydrogen or C 1-6 alkyl;
R 10a is C 1-6 alkyl; aryl optionally substituted with 1, 2, 3, or 4 R 10b ; aralkyl where the aryl is optionally substituted with 1, 2, 3, or 4 R 10b ; phenylcarbonyl where the phenyl is optionally substituted with 1, 2, 3, or 4 R 10b ; heteroaryl optionally substituted with 1, 2, 3, or 4 R 10b ; heterocyclic optionally substituted with 1, 2, or 3 R 10b ; biphenyl optionally substituted on either ring with 1, 2, 3, or 4 R 10b ; or cycloalkyl optionally substituted with 1, 2, 3, or 4 groups independently selected from C 1-6 alkyl and halo-C 1-6 alkyl;
each R 10b , when present, is independently halo, C 1-6 alkyl, halo-C 1-6 alkyl, hydroxy, C 1-6 alkoxy, halo-C 1-6 alkoxy, nitro, C 1-6 alkylthio, halo-C 1-6 alkylthio, C 1-6 alkylsulfinyl, halo-C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, halo-C 1-6 alkylsulfonyl, amino, C 1-6 alkylamino, di-C 1-6 alkylamino, phenyl, or cyano;
R 11 is hydrogen or C 1-6 alkyl;
R 11a is C 1-6 alkyl; aryl optionally substituted with 1, 2, 3, or 4 R 11b ; aralkyl where the aryl is optionally substituted with 1, 2, 3, or 4 R 11b ; heteroaryl optionally substituted with 1, 2, 3, or 4 R 11b ; heterocyclic optionally substituted with 1, 2, 3, or 4 R 11a ; biphenyl optionally substituted on either ring with 1, 2, 3, or 4 R 11b ; or cycloalkyl optionally substituted with 1, 2, 3, or 4 groups independently selected from C 1-6 alkyl and halo-C 1-6 alkyl;
each R 11b , when present, is independently halo, C 1-6 alkyl, halo-C 1-6 alkyl, hydroxy, C 1-6 alkoxy, halo-C 1-6 alkoxy, nitro, C 1-6 alkylthio, halo-C 1-6 alkylthio, C 1-6 alkylsulfinyl, halo-C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, halo-C 1-6 alkylsulfonyl, amino, C 1-6 alkylamino, di-C 1-6 alkylamino, phenyl, or cyano;
R 13 is hydrogen or C 1-6 alkyl;
R 13a is C 1-6 alkyl; aryl optionally substituted with 1, 2, 3, or 4 R 13b ; aralkyl where the aryl is optionally substituted with 1, 2, 3, or 4 R 13b ; heteroaryl optionally substituted with 1, 2, 3, or 4 R 13b ; heterocyclic optionally substituted with 1, 2, 3, or 4 R 13b ; biphenyl optionally substituted on either ring with 1, 2, 3, or 4 R 13b ; or cycloalkyl optionally substituted with 1, 2, 3, or 4 groups independently selected from C 1-6 alkyl and halo-C 1-6 alkyl;
each R 13b , when present, is independently halo, C 1-6 alkyl, halo-C 1-6 alkyl, hydroxy, C 1-6 alkoxy, halo-C 1-6 alkoxy, C 1-6 alkylthio, halo-C 1-6 alkylthio, C 1-6 alkylsulfinyl, halo-C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, halo-C 1-6 alkylsulfonyl, nitro, amino, C 1-6 alkylamino, di-C 1-6 alkylamino, phenyl, or cyano;
R 14 is hydrogen or C 1-6 alkyl;
R 14a is hydrogen or C 1-6 alkyl;
R 14b is C 1-6 alkyl; aryl optionally substituted with 1, 2, 3, or 4 R 14c ; aralkyl where the aryl is optionally substituted with 1, 2, 3, or 4 R 14c ; heteroaryl optionally substituted with 1, 2, 3, or 4 R 14c ; heterocyclic optionally substituted with 1, 2, 3, or 4 R 14c ; biphenyl optionally substituted on either ring with 1, 2, 3, or 4 R 14c ; or cycloalkyl optionally substituted with 1, 2, 3, or 4 groups independently selected from C 1-6 alkyl and halo-C 1-6 alkyl; and
each R 14c , when present, is independently halo, C 1-6 alkyl, halo-C 1-6 alkyl, hydroxy, C 1-6 alkoxy, halo-C 1-6 alkoxy, C 1-6 alkylthio, halo-C 1-6 alkylthio, C 1-6 alkylsulfinyl, halo-C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, halo-C 1-6 alkylsulfonyl, nitro, amino, C 1-6 alkylamino, di-C 1-6 alkylamino, phenyl, or cyano;
to yield a compound of Formula I; and
b) optionally isolating the compound of Formula I.
27. The Compound of claim 25 where PG 1 is Tces, Mbs, or tosyl and PG 2 is trichloroacetyl or —C(O)OCH 2 CCl 3 .
28. The method of claim 26 where PG 1 is Tces, Mbs, or tosyl and PG 2 is trichloroacetyl or —C(O)OCH 2 CCl 3 .
29. The Compound of claim 1 where X 1 and X 2 together with the —NC(O)— to which they are attached form a 5-membered ring which is
30. The Compound of claim 10 where X 1 and X 2 together with the —NC(O)— to which they are attached form a 5-membered ring which is
31. The Compound of claim 1 where X 1 and X 2 together with the —NC(O)— to which they are attached form a 5-membered ring which is
and R 1 is —OC(O)R 6 or —NR 7 C(O)R 7a .
32. The Compound of claim 31 where R 6 is aryl optionally substituted with 1, 2, 3, or 4 R 6a ; or heterocyclic optionally substituted with 1, 2, 3, or 4 R 6a ; R 7 is hydrogen; and R 7a is aryl optionally substituted with 1, 2, 3, or 4 R 7b ; or heterocyclic optionally substituted with 1, 2, 3, or 4 R 7b .