U.S. patent application number 15/558544 was filed with the patent office on 2018-02-22 for boronic acid derivatives and therapeutic uses thereof.
The applicant listed for this patent is Rempex Pharmaceuticals, Inc.. Invention is credited to Scott Hecker, Raja K. Reddy.
Application Number | 20180051041 15/558544 |
Document ID | / |
Family ID | 56920147 |
Filed Date | 2018-02-22 |
United States Patent
Application |
20180051041 |
Kind Code |
A1 |
Hecker; Scott ; et
al. |
February 22, 2018 |
BORONIC ACID DERIVATIVES AND THERAPEUTIC USES THEREOF
Abstract
Disclosed herein are antimicrobial compounds compositions,
pharmaceutical compositions, the use and preparation thereof. Some
embodiments relate to boronic acid derivatives and their use as
therapeutic agents.
Inventors: |
Hecker; Scott; (Del Mar,
CA) ; Reddy; Raja K.; (San Diego, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Rempex Pharmaceuticals, Inc. |
San Diego |
CA |
US |
|
|
Family ID: |
56920147 |
Appl. No.: |
15/558544 |
Filed: |
March 16, 2016 |
PCT Filed: |
March 16, 2016 |
PCT NO: |
PCT/US2016/022678 |
371 Date: |
September 14, 2017 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
62134329 |
Mar 17, 2015 |
|
|
|
62191221 |
Jul 10, 2015 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/69 20130101;
Y02A 50/483 20180101; Y02A 50/401 20180101; Y02A 50/30 20180101;
Y02A 50/471 20180101; Y02A 50/47 20180101; Y02A 50/473 20180101;
Y02A 50/478 20180101; A61K 45/06 20130101; C07F 5/025 20130101;
Y02A 50/475 20180101; A61P 31/04 20180101; A61K 31/69 20130101;
A61K 2300/00 20130101 |
International
Class: |
C07F 5/02 20060101
C07F005/02; A61K 31/69 20060101 A61K031/69; A61K 45/06 20060101
A61K045/06 |
Claims
1. A compound having the structure of the formula III' or IV':
##STR00148## or a pharmaceutically acceptable salt thereof,
wherein: A is a C.sub.6-10 aryl or 5-10 membered heteroaryl; m is
0, 1 or 2; Y.sup.7 is selected from the group consisting of
--CH.sub.2--, --O--, --S-- and --NR.sup.1--; n.sup.1 is 1, 2 or 3;
Q.sup.1 and Q.sup.2 are H; each R.sup.7 is independently selected
from the group consisting of OH, optionally substituted
--O--C.sub.1-6 alkyl, --NR.sup.1R.sup.2, and --N(OR.sup.1)R.sup.2;
and Y.sup.4 is selected from the group consisting of --O--, --S--,
and --NR.sup.1--; Y.sup.5 is selected from the group consisting of
--OH, --SH, and --NHR.sup.1; Y.sup.6 is selected from the group
consisting of --OH, optionally substituted --O--C.sub.1-6 alkyl,
--NR.sup.1R.sup.2, and --N(OR.sup.1)R.sup.2; each R.sup.1, R.sup.2,
R.sup.3 and R.sup.4 are independently selected from --H, halogen,
optionally substituted C.sub.1-4alkyl, optionally substituted
O--C.sub.1-4alkyl, optionally substituted C.sub.3-7 carbocyclyl,
optionally substituted 4-10 membered heterocyclyl, optionally
substituted C.sub.6-10aryl, and optionally substituted 5-10
membered heteroaryl; R.sup.5 is present 1 to 5 times and each
R.sup.5 is independently selected from the group consisting of H,
OH, halogen, --C(O)OR.sup.1; --C(O)NR.sup.1R.sup.2;
--C(O)NR.sup.1OR.sup.2; --C(.dbd.NR.sup.1)R.sup.2;
--C(.dbd.NR.sup.1)NR.sup.2R.sup.3; --NR.sup.1C(O)R.sup.2;
--NR.sup.1C(O)NR.sup.2R.sup.3; --NR.sup.1C(O)OR.sup.2;
--NR.sup.1S(O).sub.2R.sup.2; --NR.sup.1S(O).sub.2NR.sup.2R.sup.3;
--NR.sup.1CR.sup.2(.dbd.NR.sup.3);
--NR.sup.1C(.dbd.NR.sup.2)NR.sup.3R.sup.4;
--S(O)(CH.sub.2).sub.1-3R.sup.4, --S(O).sub.2NR.sup.1R.sup.2,
--S(O).sub.2NR.sup.1OR.sup.3, --NR.sup.1S(O).sub.2NR.sup.1OR.sup.3,
optionally substituted C.sub.2-C.sub.6 alkenyl, optionally
substituted C.sub.2-C.sub.6 alkynyl, optionally substituted
C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.7
carbocyclyl, optionally substituted 5-10 membered heterocyclyl,
optionally substituted C.sub.6-10aryl, optionally substituted 5-10
membered heteroaryl, cyano, C.sub.1-C.sub.6
alkoxy(C.sub.1-C.sub.6)alkyl, aryloxy, sulfhydryl (mercapto), and
--(CH.sub.2).sub.p--Y.sup.3--(CH.sub.2).sub.qM'; p and q are each
independently 0, 1, or 2; Y.sup.3 is selected from the group
consisting of --S--, --S(O)--, --S(O).sub.2--, --O--,
--CR.sup.1R.sup.2--, and --NR.sup.1--; M' is selected from the
group consisting of halogen, cyano, --OH, --C(O)NR.sup.1R.sup.2;
--C(O)NR.sup.1OR.sup.2; --NR.sup.1C(O)R.sup.2;
--NR.sup.1C(O)NR.sup.2R.sup.3; --NR.sup.1C(O)OR.sup.2;
--NR.sup.1S(O).sub.2R.sup.2; --NR.sup.1S(O).sub.2NR.sup.2R.sup.3;
--C(.dbd.NR.sup.1)R.sup.2; --C(.dbd.NR.sup.1)NR.sup.2R.sup.3;
--NR.sup.1CR.sup.2(.dbd.NR.sup.3);
--NR.sup.1C(.dbd.NR.sup.2)NR.sup.3R.sup.4; --S(O).sub.2R.sup.1,
--S(O).sub.2NR.sup.1R.sup.2, --S(O).sub.2NR.sup.1OR.sup.3,
C.sub.1-4 alkyl optionally substituted with 0-2 substituents
selected from the group consisting of --OR.sup.1, --CN,
--NR.sup.1R.sup.2, -heterocyclyl, halogen, --C(O)NR.sup.1R.sup.2,
and --NR.sup.1C(O)R.sup.2; C.sub.2-4 alkenyl optionally substituted
with 0-2 substituents selected from the group consisting of
C.sub.1-4 alkyl, --(CH.sub.2).sub.0-4OR.sup.1,
--(CH.sub.2).sub.0-4CN, --(CH.sub.2).sub.0-4NR.sup.1R.sup.2,
--(CH.sub.2).sub.0-4-heterocyclyl, halogen, --C(O)NR.sup.1R.sup.2,
and --NR.sup.1C(O)R.sup.2; C.sub.2-4 alkynyl optionally substituted
with 0-2 substituents selected from the group consisting of
C.sub.1-4 alkyl, --(CH.sub.2).sub.0-4OR.sup.1,
--(CH.sub.2).sub.0-4CN, --(CH.sub.2).sub.0-4NR.sup.1R.sup.2,
--(CH.sub.2).sub.0-4-heterocyclyl, halogen, --C(O)NR.sup.1R.sup.2,
and --NR.sup.1C(O)R.sup.2; C.sub.6-10 aryl optionally substituted
with 0-2 substituents selected from the group consisting of
C.sub.1-4 alkyl, --(CH.sub.2).sub.0-4OR.sup.1,
--(CH.sub.2).sub.0-4CN, --(CH.sub.2).sub.0-4NR.sup.1R.sup.2,
--(CH.sub.2).sub.0-4-heterocyclyl, halogen, --C(O)NR.sup.1R.sup.2,
and --NR.sup.1C(O)R.sup.2; C.sub.3-7 carbocyclyl optionally
substituted with 0-2 substituents selected from the group
consisting of C.sub.1-4 alkyl, --(CH.sub.2).sub.0-4OR.sup.1,
--(CH.sub.2).sub.0-4CN, --(CH.sub.2).sub.0-4NR.sup.1R.sup.2,
--(CH.sub.2).sub.0-4-heterocyclyl, halogen, --C(O)NR.sup.1R.sup.2,
and --NR.sup.1C(O)R.sup.2; 5-10 membered heteroaryl optionally
substituted with 0-2 substituents selected from the group
consisting of C.sub.1-4 alkyl, --(CH.sub.2).sub.0-4OR,
--(CH.sub.2).sub.0-4CN, --(CH.sub.2).sub.0-4NR.sup.1R.sup.2,
--(CH.sub.2).sub.0-4-heterocyclyl, halogen, --C(O)NR.sup.1R.sup.2,
and --NR.sup.1C(O)R.sup.2; and 3-10 membered heterocyclyl
optionally substituted with 0-2 substituents selected from the
group consisting of C.sub.1-4 alkyl, --(CH.sub.2).sub.0-4OR.sup.1,
--(CH.sub.2).sub.0-4CN, --(CH.sub.2).sub.0-4NR.sup.1R.sup.2,
--(CH.sub.2).sub.0-4-heterocyclyl, halogen, --C(O)NR.sup.1R.sup.2,
and --NR.sup.1C(O)R.sup.2; R.sup.6 is selected from the group
consisting of H, halogen, substituted --C.sub.1-6 alkyl, --OH,
--C(O)OR, --P(O)(OR).sub.2, P(O)(OR)R.sup.1 optionally substituted
--O--C.sub.1-6 alkyl, --NR.sup.1R.sup.2, --N(OR.sup.1)R.sup.2,
optionally substituted --S--C.sub.1-6 alkyl, --C(O)NR.sup.1R.sup.2,
--S(O).sub.2NR.sup.1R.sup.2, CN, optionally substituted
--S(O)--C.sub.1-6 alkyl, optionally substituted
--S(O).sub.2--C.sub.1-6 alkyl, and a carboxylic acid isostere; R is
selected from --H, alkali metal, NH.sub.4.sup.+, --C.sub.1-9alkyl,
--CR.sup.10R.sup.11OC(O)C.sub.1-9alkyl,
--CR.sup.10R.sup.11OC(O)OC.sub.1-9alkyl,
--CR.sup.10R.sup.11OC(O)C.sub.6-10aryl,
--CR.sup.10R.sup.11OC(O)OC.sub.6-10aryl,
--CR.sup.10R.sup.11OC(O)NR.sup.10C.sub.1-9-alkyl,
--CR.sup.10R.sup.11OC(O)NR.sup.10C.sub.6-10aryl, and ##STR00149##
R.sup.10 and R.sup.11 are independently selected from the group
consisting of --H, optionally substituted C.sub.1-4alkyl,
optionally substituted C.sub.3-7 carbocyclyl, optionally
substituted 5-10 membered heterocyclyl, optionally substituted
C.sub.6-10aryl, and optionally substituted 5-10 membered
heteroaryl.
2. The compound of claim 1, having the structure of the formula Ill
or IV: ##STR00150## or a pharmaceutically acceptable salt thereof,
wherein: Y.sup.7 is selected from the group consisting of CH.sub.2,
O, S and NH; each R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are
independently selected from --H, optionally substituted
C.sub.1-4alkyl, optionally substituted C.sub.3-7 carbocyclyl,
optionally substituted 4-10 membered heterocyclyl, optionally
substituted C.sub.6-10aryl, and optionally substituted 5-10
membered heteroaryl; R.sup.5 is present 1 to 5 times and each
R.sup.5 is independently selected from the group consisting of H,
OH, halogen, --CF.sub.3, optionally substituted C.sub.2-C.sub.6
alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally
substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted
C.sub.3-C.sub.7 carbocyclyl, optionally substituted 5-10 membered
heterocyclyl, optionally substituted C.sub.6-10aryl, optionally
substituted 5-10 membered heteroaryl, cyano, C.sub.1-C.sub.6
alkoxy(C.sub.1-C.sub.6)alkyl, aryloxy, sulfhydryl (mercapto), and
--(CH.sub.2).sub.p--Y.sup.3--(CH.sub.2).sub.qM'; p and q are each
independently 0 or 1; Y.sup.3 is selected from the group consisting
of --S--, --S(O)--, --S(O).sub.2--, --O--, --CH.sub.2--, and
--NR.sup.1--; M' is selected from the group consisting of
--C(O)NR.sup.1R.sup.2; --C(O)NR.sup.1OR.sup.2;
--NR.sup.1C(O)R.sup.2; --NR.sup.1C(O)NR.sup.2R.sup.3;
--NR.sup.1C(O)OR.sup.2; --NR.sup.1S(O).sub.2R.sup.2;
--NR.sup.1S(O).sub.2NR.sup.2R.sup.3; --C(.dbd.NR)R.sup.2;
--C(.dbd.NR.sup.1)NR.sup.2R.sup.3;
--NR.sup.1CR.sup.2(.dbd.NR.sup.3);
--NR.sup.1C(.dbd.NR.sup.2)NR.sup.3R.sup.4; C.sub.1-4 alkyl
optionally substituted with 0-2 substituents selected from the
group consisting, --OR.sup.1, --NR.sup.1R.sup.2, halogen,
--C(O)NR.sup.1R.sup.2, and --NR.sup.1C(O)R.sup.2; C.sub.6-10 aryl
optionally substituted with 0-2 substituents selected from the
group consisting of C.sub.1-4 alkyl, --OR.sup.1, --NR.sup.1R.sup.2,
halogen, --C(O)NR.sup.1R.sup.2, and --NR.sup.1C(O)R.sup.2;
C.sub.3-7 carbocyclyl optionally substituted with 0-2 substituents
selected from the group consisting of C.sub.1-4 alkyl, --OR.sup.1,
--NR.sup.1R.sup.2, halogen, --C(O)NR.sup.1R.sup.2, and
--NR.sup.1C(O)R.sup.2; 5-10 membered heteroaryl optionally
substituted with 0-2 substituents selected from the group
consisting of C.sub.1-4 alkyl, --OR.sup.1, --NR.sup.1R.sup.2,
halogen, --C(O)NR.sup.1R.sup.2, and --NR.sup.1C(O)R.sup.2; and 3-10
membered heterocyclyl optionally substituted with 0-2 substituents
selected from the group consisting of C.sub.1-4 alkyl, --OR.sup.1,
--NR.sup.1R.sup.2, halogen, --C(O)NR.sup.1R.sup.2, and
--NR.sup.1C(O)R.sup.2; R.sup.6 is selected from the group
consisting of H, halogen, substituted --C.sub.1-6 alkyl, --OH,
--C(O)OR, optionally substituted --O--C.sub.1-6 alkyl,
--NR.sup.1R.sup.2, --N(OR.sup.1)R.sup.2, optionally substituted
--S--C.sub.1-6 alkyl, --C(O)NR.sup.1R.sup.2,
--S(O).sub.2NR.sup.1R.sup.2, CN, optionally substituted
--S(O)--C.sub.1-6 alkyl, optionally substituted
--S(O).sub.2--C.sub.1-6 alkyl, and a carboxylic acid isostere; and
R is selected from --H, alkali metal, NH.sub.4.sup.+,
--C.sub.1-9alkyl, --CR.sup.10R.sup.11OC(O)C.sub.1-9alkyl,
--CR.sup.10R.sup.11OC(O)OC.sub.1-9alkyl,
--CR.sup.10R.sup.11OC(O)C.sub.6-10aryl,
--CR.sup.10R.sup.11OC(O)OC.sub.6-10aryl and ##STR00151##
3. The compound of claim 1 or 2, having the structure of Formula
(IIIa) ##STR00152## or a pharmaceutically acceptable salt
thereof.
4. The compound of claim 1 or 2, having the structure of Formula
(IIIb) ##STR00153## or a pharmaceutically acceptable salt
thereof.
5. The compound of claim 1 or 2, having the structure of Formula
(IIIc) ##STR00154## or a pharmaceutically acceptable salt thereof,
wherein: m is 0, 1, or 2; and J, L, and M are each independently
selected from the group consisting of CR.sup.5 and N.
6. The compound of claim 1, 2, or 5, having the structure of
Formula (IIId) ##STR00155## or a pharmaceutically acceptable salt
thereof.
7. The compound of claim 1 or 2, having the structure of Formula
(IVa) ##STR00156## or a pharmaceutically acceptable salt thereof
wherein: m is 0, 1, or 2; and J, L, and M are each independently
selected from the group consisting of CR.sup.5 and N.
8. The compound of claim 1, 2, or 7, having the structure of
Formula (IVb) ##STR00157## or a pharmaceutically acceptable salt
thereof.
9. The compound of any one of claims 1 to 8, wherein Y.sup.7 is
CH.sub.2, O, or S.
10. The compound of claim 1 or 2, having the structure of (III-1)
or (IV-1): ##STR00158## or a pharmaceutically acceptable salt
thereof, wherein: J, L, and M are each independently selected from
the group consisting of CR.sup.5 and N.
11. The compound of claim 10, having the structure of (III-2) or
(IV-2): ##STR00159## or a pharmaceutically acceptable salt
thereof.
12. The compound of claim 1, wherein n.sup.1 is 1 and Q.sup.1 and
Q.sup.2 are deuterium.
13. The compound of any one of claims 1-2, 4-5, 7, and 12, wherein
Y.sup.7 is O, n.sup.1 is 1, and m is 1.
14. The compound of any one of claims 10 to 13, wherein M is
CR.sup.5.
15. The compound of any one of claims 10 to 13, wherein M is N.
16. The compound of any one of claims 10 to 15, wherein J and L are
each independently CR.sup.5.
17. The compound of claim 16, wherein J and L are CH.
18. The compound of any one of claims 10 to 13, wherein J is N.
19. The compound of any one of claims 10 to 15 and 18, wherein L
and M are each independently CR.sup.5.
20. The compound of claim 19, wherein L and M are CH.
21. The compound of any one of claims 10 to 13, wherein L is N.
22. The compound of any one of claims 10 to 13 and 21, wherein J
and M are each independently CR.sup.5.
23. The compound of claim 22, wherein J and M are CH.
24. The compound of any one of claims 10 to 15 and 21, wherein M is
CH.
25. The compound of any one of claims 1 to 24, wherein each R.sup.5
is independently selected from the group consisting of
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.3-C.sub.7 carbocyclyl, C.sub.1-C.sub.6 heteroalkyl,
5-10 membered heterocyclyl, C.sub.6-C.sub.10 aryl, 5-10 membered
heteroaryl, cyano, hydroxy, --OR.sup.3, --SR.sup.3, --S(O).sub.2M',
--P(O)R.sup.1M', and halogen.
26. The compound of claim 25, wherein R.sup.5 is halogen.
27. The compound of claim 26, wherein R.sup.5 is F.
28. The compound of claim 25, wherein R.sup.5 is alkoxy.
29. The compound of claim 28, wherein R.sup.5 is --OCH.sub.3.
30. The compound of claim 28, wherein R.sup.5 is
--OCH.sub.2CH.sub.3.
31. The compound of any one of claims 1 to 25, wherein R.sup.5 is
--OH.
32. The compound of any one of claims 1 to 25, wherein R.sup.5 is
--SH.
33. The compound of any one of claims 1 to 25, wherein R.sup.5 is
--SCH.sub.3.
34. The compound of any one of claims 1 to 25, wherein R.sup.5 is
--S(O).sub.2M'.
35. The compound of claim 34, wherein R.sup.5 is
--S(O).sub.2CH.sub.3.
36. The compound of any one of claims 1 to 25, wherein R.sup.5 is
--SOM'.
37. The compound of claim 36, wherein R.sup.5 is --SOCH.sub.3.
38. The compound of any one of claims 1 to 25, wherein R.sup.5 is
cyano.
39. The compound of any one of claims 1 to 25, wherein R.sup.5 is
--C.ident.CH.
40. The compound of any one of claims 1 to 24, wherein R.sup.5 is
--CHF.sub.2.
41. The compound of any one of claims 1 to 24, wherein R.sup.5 is
--CF.sub.3.
42. The compound of any one of claims 1 to 24, wherein R.sup.5 is
--C(O)NR.sup.1R.sup.2.
43. The compound of claim 42, wherein R.sup.5 is
--C(O)NH.sub.2.
44. The compound of any one of claims 1 to 24, wherein R.sup.5 is
--C(.dbd.NR)R.sup.2.
45. The compound of claim 44, wherein R.sup.5 is
--CH.dbd.N--OCH.sub.3.
46. The compound of any one of claims 1 to 24, wherein R.sup.5 is
--COOR.sup.1.
47. The compound of claim 46, wherein R.sup.5 is --COOH.
48. The compound of any one of claims 1 to 24, wherein R.sup.5 is a
C.sub.2-4 alkynyl, triazole, or diazole, optionally substituted
with 0-2 substituents selected from --(CH.sub.2).sub.0-4OR.sup.1,
--(CH.sub.2).sub.0-4CN, --(CH.sub.2).sub.0-4NR.sup.1R.sup.2,
--(CH.sub.2).sub.0-4-heterocyclyl, halogen, --C(O)NR.sup.1R.sup.2,
and --NR.sup.1C(O)R.sup.2.
49. The compound of claim 48, wherein R.sup.5 is ##STR00160##
50. The compound of any one of claims 1 to 24, wherein R.sup.5 is
--(CH.sub.2).sub.p--Y.sup.3--(CH.sub.2).sub.qM'.
51. The compound of claim 50, wherein Y.sup.3 is --S--, --O--, or
--NH--.
52. The compound of claim 50 or 51, wherein M' is a 5-10 membered
heteroaryl or 3-10 membered heterocyclyl, each optionally
substituted with 0-2 substituents selected from the group
consisting of C.sub.1-4 alkyl, --(CH.sub.2).sub.0-4OR.sup.1,
--(CH.sub.2).sub.0-4CN, --(CH.sub.2).sub.0-4NR.sup.1R.sup.2,
--(CH.sub.2).sub.0-4-heterocyclyl, halogen, --C(O)NR.sup.1R.sup.2,
and --NR.sup.1C(O)R.sup.2.
53. The compound of claim 52, wherein M' is azetine, thiadiazole,
triazole, dioxolane, pyridine, morpholine, or cyclopropyl, each
optionally substituted with 0-2 substituents selected from the
group consisting of C.sub.1-4 alkyl, --(CH.sub.2).sub.0-4OR.sup.1,
--(CH.sub.2).sub.0-4CN, --(CH.sub.2).sub.0-4NR.sup.1R.sup.2,
--(CH.sub.2).sub.0-4-heterocyclyl, halogen, --C(O)NR.sup.1R.sup.2,
and --NR.sup.1C(O)R.sup.2.
54. The compound of claim 53, wherein M' is ##STR00161## each
optionally substituted with 0-2 substituents selected from the
group consisting of C.sub.1-4 alkyl, --(CH.sub.2).sub.0-4OR.sup.1,
--(CH.sub.2).sub.0-4CN, --(CH.sub.2).sub.0-4NR.sup.1R.sup.2,
--(CH.sub.2).sub.0-4-heterocyclyl, halogen, --C(O)NR.sup.1R.sup.2,
and --NR.sup.1C(O)R.sup.2.
55. The compound of claim 54, wherein M' is ##STR00162##
56. The compound of claim 50 or 51, wherein M' is cyano.
57. The compound of claim 50 or 51, wherein M' is --OH.
58. The compound of claim 50 or 51, wherein M' is --S(O).sub.2R or
--S(O).sub.2NR.sup.1R.sup.2.
59. The compound of claim 58, wherein M' is --S(O).sub.2CH.sub.3 or
--S(O).sub.2NH.sub.2.
60. The compound of claim 50 or 51, wherein M' is
--C(O)NR.sup.1R.sup.2.
61. The compound of claim 60, wherein M' is --C(O)NH.sub.2.
62. The compound of claim 50, wherein Y.sup.3 is --S(O)-- or
--S(O).sub.2--.
63. The compound of any one of claims 50-51 and 62, wherein M' is
C.sub.1-4 alkyl optionally substituted with 0-2 substituents
selected from the group consisting of --OR.sup.1, --CN,
--NR.sup.1R.sup.2, -heterocyclyl, halogen, --C(O)NR.sup.1R.sup.2,
and --NR.sup.1C(O)R.sup.2; C.sub.2-4 alkenyl optionally substituted
with 0-2 substituents selected from the group consisting of
C.sub.1-4 alkyl, --(CH.sub.2).sub.0-4OR.sup.1,
--(CH.sub.2).sub.0-4CN, --(CH.sub.2).sub.0-4NR.sup.1R.sup.2,
--(CH.sub.2).sub.0-4-heterocyclyl, halogen, --C(O)NR.sup.1R.sup.2,
and --NR.sup.1C(O)R.sup.2; or C.sub.2-4 alkynyl optionally
substituted with 0-2 substituents selected from the group
consisting of C.sub.1-4 alkyl, --(CH.sub.2).sub.0-4OR.sup.1,
--(CH.sub.2).sub.0-4CN, --(CH.sub.2).sub.0-4NR.sup.1R.sup.2,
--(CH.sub.2).sub.0-4-heterocyclyl, halogen, --C(O)NR.sup.1R.sup.2,
and --NR.sup.1C(O)R.sup.2.
64. The compound of claim 63, wherein M' is --C.ident.CH.
65. The compound of claim 63, wherein M' is
--C.ident.C--(CH.sub.2).sub.0-4OR.sup.1,
--C.ident.C--(CH.sub.2).sub.0-4NR.sup.1R.sup.2, or
--C.ident.C--(CH.sub.2).sub.0-4-heterocyclyl.
66. The compound of claim 65, wherein M' is
--C.ident.C--(CH.sub.2)--OCH.sub.3, --C.ident.C--(CH.sub.2)--OH,
--C.ident.C--(CH.sub.2)--NH.sub.2, or ##STR00163##
67. The compound of claim 63, wherein M' is
--(CH.sub.2).sub.3NH.sub.2, CH.sub.2F, CHF.sub.2, CF.sub.3,
CH(CH.sub.2OH).sub.2, or CH.sub.2N(CH.sub.3).sub.2.
68. The compound of claim 63, wherein M' is C.sub.1-4 alkyl.
69. The compound of any one of claims 10 to 12, wherein R.sup.5 is
present twice.
70. The compound of any one of claims 10 to 12, wherein: L and M
are each independently CR.sup.5; J is CH; and each R.sup.5 is
independently selected from the group consisting of OH, halogen,
CN, --C(O)OR.sup.1; --C(O)NR.sup.1R.sup.2; --C(O)NR.sup.1OR.sup.2;
--NR.sup.1C(O)R.sup.2; --NR.sup.1C(O)NR.sup.2R.sup.3;
--NR.sup.1C(O)OR.sup.2; --NR.sup.1S(O).sub.2R.sup.2;
--NR.sup.1S(O).sub.2NR.sup.2R.sup.3; --C(.dbd.NR.sup.1)R.sup.2;
--C(.dbd.NR.sup.1)NR.sup.2R.sup.3;
--NR.sup.1CR.sup.2(.dbd.NR.sup.3);
--NR.sup.1C(.dbd.NR.sup.2)NR.sup.3R.sup.4;
--S(O)(CH.sub.2).sub.1-3R.sup.4, --S(O).sub.2NR.sup.1R.sup.2,
--S(O).sub.2NR.sup.1OR.sup.3, --NR.sup.1S(O).sub.2NR.sup.1OR.sup.3,
optionally substituted C.sub.2-C.sub.6 alkenyl, optionally
substituted C.sub.2-C.sub.6 alkynyl, optionally substituted
C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.7
carbocyclyl, optionally substituted 5-10 membered heterocyclyl,
optionally substituted C.sub.6-10aryl, optionally substituted 5-10
membered heteroaryl, cyano, C.sub.1-C.sub.6
alkoxy(C.sub.1-C.sub.6)alkyl, aryloxy, sulfhydryl (mercapto), and
--(CH.sub.2).sub.p--Y.sup.3--(CH.sub.2).sub.qM'.
71. The compound of any one of claims 69 to 70, wherein each
R.sup.5 is independently halogen or --OM'
72. The compound of claim 71, wherein each R.sup.5 is independently
F or --OCH.sub.3.
73. The compound of claim 71, wherein each R.sup.5 is independently
Cl or --OCH.sub.3.
74. The compound of any one of claims 1 to 73, wherein R.sup.6 is
--COOR or --P(O)(OR).sub.2.
75. The compound of claim 74, wherein R.sup.6 is --COOH or
--P(O)(OH).sub.2.
76. The compound of claim 1, having the structure selected from the
group consisting of ##STR00164## and pharmaceutically acceptable
salts thereof.
77. The compound of claim 1, having the structure selected from the
group consisting ##STR00165## ##STR00166## ##STR00167##
##STR00168## ##STR00169## ##STR00170## ##STR00171## and
pharmaceutically acceptable salts thereof.
78. A compound having the structure selected from the group
consisting of ##STR00172## and pharmaceutically acceptable salts
thereof.
79. A compound having the structure of the formula I' or II':
##STR00173## or a pharmaceutically acceptable salt thereof,
wherein: each G is independently selected from the group consisting
of --C(O)R.sup.4, --C(O)(CH.sub.2).sub.0-3SR.sup.3,
--C(O)(CH.sub.2).sub.1-3R.sup.4, --C(O)OR.sup.3,
--C(O)NR.sup.1R.sup.2, --C(O)NR.sup.1OR.sup.3,
--NR.sup.1C(O)R.sup.4, --NR.sup.1C(O)NR.sup.1R.sup.2,
--NR.sup.1C(O)OR.sup.3, --NR.sup.1S(O).sub.2R.sup.3,
--NR.sup.1S(O).sub.2NR.sup.1R.sup.2, --C(.dbd.NR.sup.1)R.sup.4,
--C(.dbd.NR.sup.1)NR.sup.1R.sup.2,
--NR.sup.1CR.sup.4(.dbd.NR.sup.2),
--NR.sup.1C(.dbd.NR.sup.2)NR.sup.1R.sup.2, --S(O).sub.2R.sup.3,
--S(O)(CH.sub.2).sub.1-3R.sup.3, --S(O).sub.2NR.sup.1R.sup.2,
--S(O).sub.2NR.sup.1OR.sup.3, --NR.sup.1S(O).sub.2NR.sup.1OR.sup.3,
--CN, --OR.sup.1, --SR.sup.1, --NR.sup.1R.sup.2, optionally
substituted C.sub.1-10 alkyl, optionally substituted
C.sub.2-10alkenyl, optionally substituted C.sub.2-10alkynyl,
optionally substituted C.sub.3-7 carbocyclyl, optionally
substituted 5-10 membered heterocyclyl, optionally substituted
C.sub.6-10aryl, optionally substituted 5-10 membered heteroaryl,
optionally substituted C.sub.3-7carbocyclyl-C.sub.1-6alkyl,
optionally substituted 5-10 membered heterocyclyl-C.sub.1-6alkyl,
optionally substituted C.sub.6-10aryl-C.sub.1-6alkyl, and
optionally substituted 5-10 membered heteroaryl-C.sub.1-6alkyl;
Y.sup.1 is selected from the group consisting of CR.sup.1 and N;
each Y.sup.2 is independently selected from the group consisting of
--S--, --S(O)--, --S(O).sub.2--, --O--, --CR.sup.1R.sup.2--, and
--NR.sup.2--, or Y.sup.2--(CH.sub.2).sub.n-G is CH.sub.3; Y.sup.4
is selected from the group consisting of --O--, --S--, and
--NR.sup.1--; Y.sup.5 is selected from the group consisting of
--OH, --SH, and --NHR.sup.1; Y.sup.6 is selected from the group
consisting of --OH, optionally substituted --O--C.sub.1-6 alkyl,
--NR.sup.1R.sup.2, and --N(OR.sup.3)R.sup.2, Q.sup.1 and Q.sup.2 is
each independently H or --Y.sup.2--(CH.sub.2).sub.n-G; each n is
independently an integer from 0 to 3; m is 0 or 1; A is selected
from the group consisting of C.sub.3-10 carbocyclyl, C.sub.6-10
aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl;
each R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are independently
selected from --H, halogen, optionally substituted C.sub.1-4alkyl,
optionally substituted O--C.sub.1-4alkyl, optionally substituted
C.sub.3-7 carbocyclyl, optionally substituted 4-10 membered
heterocyclyl, optionally substituted C.sub.6-10aryl, and optionally
substituted 5-10 membered heteroaryl; R.sup.5 is present 1 to 5
times and each R.sup.5 is independently selected from the group
consisting of H, OH, halogen, CN, --C(O)OR.sup.1;
--C(O)NR.sup.1R.sup.2; --C(O)NR.sup.1OR.sup.2;
--NR.sup.1C(O)R.sup.2; --NR.sup.1C(O)NR.sup.2R.sup.3;
--NR.sup.1C(O)OR.sup.2; --NR.sup.1S(O).sub.2R.sup.2;
--NR.sup.1S(O).sub.2NR.sup.2R.sup.3; --C(.dbd.NR.sup.1)R.sup.2;
--C(.dbd.NR.sup.1)NR.sup.2R.sup.3;
--NR.sup.1CR.sup.2(.dbd.NR.sup.1);
--NR.sup.1C(.dbd.NR.sup.2)NR.sup.3R.sup.4;
--S(O)(CH.sub.2).sub.1-3R.sup.4, --S(O).sub.2NR.sup.1R.sup.2,
--S(O).sub.2NR.sup.1OR.sup.3, --NR.sup.1S(O).sub.2NR.sup.1OR.sup.3,
optionally substituted C.sub.2-C.sub.6 alkenyl, optionally
substituted C.sub.2-C.sub.6 alkynyl, optionally substituted
C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.7
carbocyclyl, optionally substituted 5-10 membered heterocyclyl,
optionally substituted C.sub.6-10aryl, optionally substituted 5-10
membered heteroaryl, cyano, C.sub.1-C.sub.6
alkoxy(C.sub.1-C.sub.6)alkyl, aryloxy, sulfhydryl (mercapto), and
--(CH.sub.2).sub.p--Y.sup.3--(CH.sub.2).sub.qM'; p and q are each
independently 0, 1, or 2; Y.sup.3 is selected from the group
consisting of --S--, --S(O)--, --S(O).sub.2--, --O--,
--CR.sup.1R.sup.2--, and --NR.sup.1--; M' is selected from the
group consisting of halogen, cycano, --OH, --C(O)NR.sup.1R.sup.2;
--C(O)NR.sup.1OR.sup.2; --NR.sup.1C(O)R.sup.2;
--NR.sup.1C(O)NR.sup.2R.sup.3; --NR.sup.1C(O)OR.sup.2;
--NR.sup.1S(O).sub.2R.sup.2; --NR.sup.1S(O).sub.2NR.sup.2R.sup.3;
--C(.dbd.NR.sup.1)R.sup.2; --C(.dbd.NR.sup.1)NR.sup.2R.sup.3;
--NR.sup.1CR.sup.2(.dbd.NR.sup.3);
--NR.sup.1C(.dbd.NR.sup.2)NR.sup.3R.sup.4; --S(O).sub.2R.sup.1,
--S(O).sub.2NR.sup.1R.sup.2, --S(O).sub.2NR.sup.1OR.sup.3,
C.sub.1-4 alkyl optionally substituted with 0-2 substituents
selected from the group consisting of --OR.sup.1, --CN,
--NR.sup.1R.sup.2, -heterocyclyl, halogen, --C(O)NR.sup.1R.sup.2,
and --NR.sup.1C(O)R.sup.2; C.sub.2-4 alkenyl optionally substituted
with 0-2 substituents selected from the group consisting of
C.sub.1-4 alkyl, --(CH.sub.2).sub.0-4OR.sup.1,
--(CH.sub.2).sub.0-4CN, --(CH.sub.2).sub.0-4NR.sup.1R.sup.2,
--(CH.sub.2).sub.0-4-heterocyclyl, halogen, --C(O)NR.sup.1R.sup.2,
and --NR.sup.1C(O)R.sup.2; C.sub.2-4 alkynyl optionally substituted
with 0-2 substituents selected from the group consisting of
C.sub.1-4 alkyl, --(CH.sub.2).sub.0-4OR.sup.1,
--(CH.sub.2).sub.0-4CN, --(CH.sub.2).sub.0-4NR.sup.1R.sup.2,
--(CH.sub.2).sub.0-4-heterocyclyl, halogen, --C(O)NR.sup.1R.sup.2,
and --NR.sup.1C(O)R.sup.2; C.sub.6-10 aryl optionally substituted
with 0-2 substituents selected from the group consisting of
C.sub.1-4 alkyl, --(CH.sub.2).sub.0-4OR.sup.1,
--(CH.sub.2).sub.0-4CN, --(CH.sub.2).sub.0-4NR.sup.1R.sup.2,
--(CH.sub.2).sub.0-4-heterocyclyl, halogen, --C(O)NR.sup.1R.sup.2,
and --NR.sup.1C(O)R.sup.2; C.sub.3-7 carbocyclyl optionally
substituted with 0-2 substituents selected from the group
consisting of C.sub.1-4 alkyl, --(CH.sub.2).sub.0-4OR.sup.1,
--(CH.sub.2).sub.0-4CN, --(CH.sub.2).sub.0-4NR.sup.1R.sup.2,
--(CH.sub.2).sub.0-4-heterocyclyl, halogen, --C(O)NR.sup.1R.sup.2,
and --NR.sup.1C(O)R.sup.2; 5-10 membered heteroaryl optionally
substituted with 0-2 substituents selected from the group
consisting of C.sub.1-4 alkyl, --(CH.sub.2).sub.0-4OR.sup.1,
--(CH.sub.2).sub.0-4CN, --(CH.sub.2).sub.0-4NR.sup.1R.sup.2,
--(CH.sub.2).sub.0-4-heterocyclyl, halogen, --C(O)NR.sup.1R.sup.2,
and --NR.sup.1C(O)R.sup.2; and 3-10 membered heterocyclyl
optionally substituted with 0-2 substituents selected from the
group consisting of C.sub.1-4 alkyl, --(CH.sub.2).sub.0-4OR,
--(CH.sub.2).sub.0-4CN, --(CH.sub.2).sub.0-4NR.sup.1R.sup.2,
--(CH.sub.2).sub.0-4-heterocyclyl, halogen, --C(O)NR.sup.1R.sup.2,
and --NR.sup.1C(O)R.sup.2; R.sup.6 is selected from the group
consisting of is selected from the group consisting of --H,
halogen, optionally substituted --C.sub.1-6 alkyl, --OH, --C(O)OR,
--P(O)(OR).sub.2, P(O)(OR)R.sup.1, optionally substituted
--O--C.sub.1-6 alkyl, --NR.sup.1R.sup.2, --N(OR.sup.3)R.sup.2,
optionally substituted --S--C.sub.1-6 alkyl, --C(O)NR.sup.1R.sup.2,
--S(O).sub.2NR.sup.1R.sup.2, CN, optionally substituted
--S(O)--C.sub.1-6 alkyl, optionally substituted
--S(O).sub.2--C.sub.1-6 alkyl, and a carboxylic acid isostere; R is
selected from --H, --C.sub.1-9alkyl,
--CR.sup.10R.sup.11OC(O)C.sub.1-9alkyl,
--CR.sup.10R.sup.11OC(O)OC.sub.1-9alkyl,
--CR.sup.10R.sup.11OC(O)C.sub.6-10aryl,
--CR.sup.10R.sup.11OC(O)OC.sub.6-10aryl,
--CR.sup.10R.sup.11OC(O)NR.sup.10C.sub.1-9alkyl,
--CR.sup.10R.sup.11OC(O)NR.sup.10C.sub.6-10aryl, and ##STR00174##
R.sup.7 is selected from the group consisting of OH, optionally
substituted --O--C.sub.1-6 alkyl, --NR.sup.1R.sup.2, and
--N(OR.sup.3)R.sup.2; and R.sup.10 and R.sup.11 are independently
selected from the group consisting of --H, optionally substituted
C.sub.1-4alkyl, optionally substituted C.sub.3-7 carbocyclyl,
optionally substituted 5-10 membered heterocyclyl, optionally
substituted C.sub.6-10aryl, and optionally substituted 5-10
membered heteroaryl.
80. The compound of claim 79 having the structure of formula I or
II: ##STR00175## each G is independently selected from the group
consisting of --C(O)R.sup.4, --C(O)(CH.sub.2).sub.0-3SR.sup.3,
--C(O)(CH.sub.2).sub.1-3R.sup.4, --C(O)OR.sup.3,
--C(O)NR.sup.1R.sup.2, --C(O)NR.sup.1OR.sup.3,
--NR.sup.1C(O)R.sup.4, --NR.sup.1C(O)NR.sup.1R.sup.2,
--NR.sup.1C(O)OR.sup.3, --NR.sup.1S(O).sub.2R.sup.3,
--NR.sup.1S(O).sub.2NR.sup.1R.sup.2, --C(.dbd.NR.sup.1)R.sup.4,
--C(.dbd.NR.sup.1)NR.sup.1R.sup.2,
--NR.sup.1CR.sup.4(.dbd.NR.sup.2),
--NR.sup.1C(.dbd.NR.sup.2)NR.sup.1R.sup.2, --S(O).sub.2R.sup.3,
optionally substituted C.sub.1-10 alkyl, optionally substituted
C.sub.2-10alkenyl, optionally substituted C.sub.2-10alkynyl,
optionally substituted C.sub.3-7 carbocyclyl, optionally
substituted 5-10 membered heterocyclyl, optionally substituted
C.sub.6-10aryl, optionally substituted 5-10 membered heteroaryl,
optionally substituted C.sub.3-7carbocyclyl-C.sub.1-6alkyl,
optionally substituted 5-10 membered heterocyclyl-C.sub.1-6alkyl,
optionally substituted C.sub.6-10aryl-C.sub.1-6alkyl, and
optionally substituted 5-10 membered heteroaryl-C.sub.1-6alkyl; Q
is H or --Y.sup.2--(CH.sub.2).sub.n-G; each R.sup.1, R.sup.2,
R.sup.3, and R.sup.4 are independently selected from --H,
optionally substituted C.sub.1-4alkyl, optionally substituted
C.sub.3-7 carbocyclyl, optionally substituted 4-10 membered
heterocyclyl, optionally substituted C.sub.6-10aryl, and optionally
substituted 5-10 membered heteroaryl; R.sup.5 is present 1 to 5
times and each R.sup.5 is independently selected from the group
consisting of H, OH, halogen, --CF.sub.3, optionally substituted
C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6
alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl,
optionally substituted C.sub.3-C.sub.7 carbocyclyl, optionally
substituted 5-10 membered heterocyclyl, optionally substituted
C.sub.6-10aryl, optionally substituted 5-10 membered heteroaryl,
cyano, C.sub.1-C.sub.6 alkoxy(C.sub.1-C.sub.6)alkyl, aryloxy,
sulfhydryl (mercapto), and
--(CH.sub.2).sub.p--Y.sup.3--(CH.sub.2).sub.qM'; p and q are each
independently 0 or 1; Y.sup.3 is selected from the group consisting
of --S--, --S(O)--, --S(O).sub.2--, --O--, --CH.sub.2--, and
--NR.sup.1--; M' is selected from the group consisting of
--C(O)NR.sup.1R.sup.2; --C(O)NR.sup.1OR.sup.2;
--NR.sup.1C(O)R.sup.2; --NR.sup.1C(O)NR.sup.2R.sup.3;
--NR.sup.1C(O)OR.sup.2; --NR.sup.1S(O).sub.2R.sup.2;
--NR.sup.1S(O).sub.2NR.sup.2R.sup.3; --C(.dbd.NR.sup.1)R.sup.2;
--C(.dbd.NR.sup.1)NR.sup.2R.sup.3;
--NR.sup.1CR.sup.2(.dbd.NR.sup.3);
--NR.sup.1C(.dbd.NR.sup.2)NR.sup.3R.sup.4; C.sub.1-4 alkyl
optionally substituted with 0-2 substituents selected from the
group consisting, --OR.sup.1, --NR.sup.1R.sup.2, halogen,
C(O)NR.sup.1R.sup.2, and --NR.sup.1C(O)R.sup.2; C.sub.6-10 aryl
optionally substituted with 0-2 substituents selected from the
group consisting of C.sub.1-4 alkyl, --OR.sup.1, --NR.sup.1R.sup.2,
halogen, --C(O)NR.sup.1R.sup.2, and --NR.sup.1C(O)R.sup.2;
C.sub.3-7 carbocyclyl optionally substituted with 0-2 substituents
selected from the group consisting of C.sub.1-4 alkyl, --OR.sup.1,
--NR.sup.1R.sup.2, halogen, --C(O)NR.sup.1R.sup.2, and
--NR.sup.1C(O)R.sup.2; 5-10 membered heteroaryl optionally
substituted with 0-2 substituents selected from the group
consisting of C.sub.1-4 alkyl, --OR.sup.1, --NR.sup.1R.sup.2,
halogen, --C(O)NR.sup.1R.sup.2, and --NR.sup.1C(O)R.sup.2; and 3-10
membered heterocyclyl optionally substituted with 0-2 substituents
selected from the group consisting of C.sub.1-4 alkyl, --OR.sup.1,
--NR.sup.1R.sup.2, halogen, --C(O)NR.sup.1R.sup.2, and
--NR.sup.1C(O)R.sup.2; and R is selected from --H,
--C.sub.1-9alkyl, --CR.sup.10R.sup.11OC(O)C.sub.1-9alkyl,
--CR.sup.10R.sup.11OC(O)OC.sub.1-9alkyl,
--CR.sup.10R.sup.11OC(O)C.sub.6-10aryl,
--CR.sup.10R.sup.11OC(O)OC.sub.6-10aryl and ##STR00176##
81. The compound of claim 79 or 80, wherein the compound has the
structure of formula I ##STR00177## or a pharmaceutically
acceptable salt thereof.
82. The compound of any one of claims 79 to 81, wherein Q is
--Y.sup.2--(CH.sub.2).sub.n-G.
83. The compound of any one of claims 79 to 81, wherein the
compound has the structure of formula I-1 ##STR00178## or a
pharmaceutically acceptable salt thereof, wherein: G is selected
from the group consisting of --C(O)R.sup.4,
--C(O)(CH.sub.2).sub.0-3SR.sup.3, --C(O)OR.sup.3,
--C(O)NR.sup.1R.sup.2, --C(O)NR.sup.1OR.sup.3,
--NR.sup.1C(O)R.sup.4, --NR.sup.1C(O)NR.sup.1R.sup.2,
--NR.sup.1C(O)OR.sup.3, --NR.sup.1S(O).sub.2R.sup.3,
--NR.sup.1S(O).sub.2NR.sup.1R.sup.2, --C(.dbd.NR.sup.1)R.sup.4,
--C(.dbd.NR.sup.1)NR.sup.1R.sup.2,
--NR.sup.1CR.sup.4(.dbd.NR.sup.2),
--NR.sup.1C(.dbd.NR.sup.2)NR.sup.1R.sup.2, --S(O).sub.2R.sup.3,
optionally substituted C.sub.1-10 alkyl, optionally substituted
C.sub.2-10alkenyl, optionally substituted C.sub.2-10alkynyl,
optionally substituted C.sub.3-7 carbocyclyl, optionally
substituted 5-10 membered heterocyclyl, optionally substituted
C.sub.6-10aryl, optionally substituted 5-10 membered heteroaryl,
optionally substituted C.sub.3-7carbocyclyl-C.sub.1-6alkyl,
optionally substituted 5-10 membered heterocyclyl-C.sub.1-6alkyl,
optionally substituted C.sub.6-10aryl-C.sub.1-6alkyl, and
optionally substituted 5-10 membered heteroaryl-C.sub.1-6alkyl;
each R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are independently
selected from --H, optionally substituted C.sub.1-4alkyl,
optionally substituted C.sub.3-7 carbocyclyl, optionally
substituted 5-10 membered heterocyclyl, optionally substituted
C.sub.6-10aryl, and optionally substituted 5-10 membered
heteroaryl; and R is selected from --H, --C.sub.1-9alkyl,
--CR.sup.10R.sup.11OC(O)C.sub.1-9alkyl,
--CR.sup.10R.sup.11OC(O)OC.sub.1-9alkyl, and ##STR00179##
84. The compound of any one of claims 79-81 and 83, having the
structure of formula Ia: ##STR00180## or a pharmaceutically
acceptable salt thereof, wherein: n is 0 or 1; and J, L, and M are
each independently selected from the group consisting of CR.sup.3
and N.
85. The compound of any one of claims 79-81 and 83, having the
structure of (Ib): ##STR00181## or pharmaceutically acceptable salt
thereof.
86. The compound of any one of claims 79-81 and 83, having the
structure of (Ic): ##STR00182## or pharmaceutically acceptable salt
thereof.
87. The compound of claim 79 or 80 having the structure of formula
IIa: ##STR00183## or a pharmaceutically acceptable salt thereof,
wherein: n is 0 or 1; and J, L, and M are each independently
selected from the group consisting of CR.sup.5 and N.
88. The compound of claim 87, having the structure of (IIb):
##STR00184## or pharmaceutically acceptable salt thereof.
89. The compound of claim 87, having the structure of (IIc):
##STR00185## or pharmaceutically acceptable salt thereof.
90. The compound of any one of claims 79-89, wherein Y.sup.2 is
selected from the group consisting of --S--, --SO.sub.2--, --O--,
or --NH--.
91. The compound of any one of claims 79-90, wherein M is N.
92. The compound of any one of claims 79-90, wherein M is
CR.sup.5.
93. The compound of any one of claims 79-92, wherein J and L are
each independently CR.sup.5.
94. The compound of any one of claims 79-83, wherein Y.sup.4 is
--O--.
95. The compound of any one of claims 79-83 wherein R.sup.7 is
--OH.
96. The compound of any one of claims 79-81 and 83, having the
structure of Formula (Id): ##STR00186## or pharmaceutically
acceptable salt thereof.
97. The compound of any one of claims 79-90, wherein: Y.sup.2 is
--O-- or --S--; G is selected from the group consisting of
C.sub.1-4alkyl, phenyl, imidazole, pyrazole, triazole, tetrazole,
thiazole, thiadiazole, oxazole, oxadiazole, isoxazole, isothiazole,
pyridine, pyrazine, pyrimidine, pyridazine, and pyrazine, each
optionally substituted by 0-2 substituents selected from the group
consisting of hydroxy, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
alkoxy(C.sub.1-C.sub.6)alkyl, aryloxy, halo(C.sub.1-C.sub.6)alkoxy,
amino, C-amido, and N-amido; and J, L and M are CR.sup.5.
98. The compound of claim 97, wherein G is C.sub.1-4alkyl.
99. The compound of claim 98, wherein G is --CH.sub.3.
100. The compound of claim 97, wherein G is thiadiazole optionally
substituted with amino.
101. The compound of claim 18, wherein G is ##STR00187##
102. The compound of any one of claims 79-90, wherein: M is
CR.sup.5; and each R.sup.5 is independently selected from the group
consisting of --H, --C.sub.1-4alkyl, and halogen, --CF.sub.3, and
--(CH.sub.2).sub.p--Y.sup.3--(CH.sub.2).sub.qM'.
103. The compound of claim 102, wherein R.sup.5 is halogen.
104. The compound of claim 103, wherein R.sup.5 is F.
105. The compound of any one of claims 79-90, wherein: R.sup.5 is
--(CH.sub.2).sub.p--Y.sup.3--(CH.sub.2).sub.qM'; m is 0; p is 0;
Y.sup.3 is S or O; and M' is hydrogen; hydroxyl; C.sub.1-C.sub.4
alkyl optionally substituted with one or more substituents selected
from the group consisting of --O--C.sub.1-C.sub.6alkyl,
--S--C.sub.1-C.sub.6alkyl, amino, --C(O)-amino, --S(O).sub.2-amino,
hydroxy, cyano, azido, and halogen; C.sub.3-10 cycloalkyl
optionally substituted with one or more substituents selected from
the group consisting of C.sub.1-C.sub.6alkyl,
--O--C.sub.1-C.sub.6alkyl, --S--C.sub.1-C.sub.6alkyl, amino,
--C(O)-amino, --S(O).sub.2-amino, hydroxy, cyano, azido, and
halogen; C.sub.6-C.sub.10 aryl optionally substituted with one or
more substituents selected from the group consisting of
C.sub.1-C.sub.6alkyl, --O--C.sub.1-C.sub.6alkyl,
--S--C.sub.1-C.sub.6alkyl, amino, --C(O)-amino, --S(O).sub.2-amino,
hydroxy, cyano, azido, and halogen; 5 to 10 membered heteroaryl
optionally substituted with one or more substituents selected from
the group consisting of C.sub.1-C.sub.6alkyl,
--O--C.sub.1-C.sub.6alkyl, --S--C.sub.1-C.sub.6alkyl, amino,
--C(O)-amino, --S(O).sub.2-amino, hydroxy, cyano, azido, and
halogen; and 4 to 10 membered heterocyclyl optionally substituted
with one or more substituents selected from the group consisting of
C.sub.1-C.sub.6alkyl, --O--C.sub.1-C.sub.6alkyl,
--S--C.sub.1-C.sub.6alkyl, amino, --C(O)-amino, --S(O).sub.2-amino,
hydroxy, cyano, azido, and halogen.
106. The compound of claim 105, wherein R.sup.5 is
--S--C.sub.1-C.sub.6alkyl, --S--C.sub.1-C.sub.6 cycloalkyl, or
--S-4 to 10 membered heterocyclyl.
107. The compound of claim 106, wherein R.sup.5 is
--S--CH.sub.3.
108. The compound of claim 105, wherein R.sup.5 is
--O--C.sub.1-C.sub.6alkyl, --O--C.sub.1-C.sub.6 cycloalkyl, or
--O-4 to 10 membered heterocyclyl.
109. The compound of claim 108, wherein R.sup.5 is ##STR00188##
110. The compound of claim 108, wherein R.sup.5 is --OCH.sub.3.
111. The compound of any one of claims 79-17 and 23-31, wherein: n
is 0 or 1; Y.sup.2 is --NH--; G is selected from the group
consisting of --C(O)R.sup.4, --C(O)(CH.sub.2).sub.0-3SR.sup.3,
--C(O)(CH.sub.2).sub.1-3R.sup.4, --C(O)OR.sup.3,
--C(O)NR.sup.1R.sup.2, --S(O).sub.2R.sup.3,
--C(.dbd.NR.sup.1)R.sup.4, and --C(.dbd.NR)NR.sup.1R.sup.2.
112. The compound of claim 111, wherein G is selected from the
group consisting of --C(O)R.sup.4,
--C(O)(CH.sub.2).sub.0-3SR.sup.3, --C(O)OR.sup.3,
--C(O)NR.sup.1R.sup.2, --S(O).sub.2R.sup.3,
--C(.dbd.NR.sup.1)R.sup.4, and
--C(.dbd.NR.sup.1)NR.sup.1R.sup.2.
113. The compound of claim 111 or 112, wherein G is
--C(O)R.sup.4.
114. The compound of claim 111 or 112, wherein G is
--C(O)(CH.sub.2)R.sup.4.
115. The compound of any one of claims 111 to 114, wherein R.sup.4
is optionally substituted C.sub.1-4alkyl.
116. The compound of claim 115, wherein R.sup.4 is C.sub.1-4alkyl
substituted with C.sub.1-C.sub.4 alkylthio.
117. The compound of claim 116, wherein R.sup.4 is
--CH.sub.2SCH.sub.3
118. The compound of claim 115, wherein R.sup.4 is C.sub.1-4alkyl
substituted with 5-10 membered heteroaryl optionally substituted
with halo, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 haloalkyl, and C.sub.1-C.sub.6 haloalkoxy.
119. The compound of claim 118, wherein R.sup.4 is ##STR00189##
120. The compound of claim any one of claims 111 to 114, wherein R
is optionally substituted 5-10 membered heteroaryl.
121. The compound of claim 120, wherein R.sup.4 is 5-10 membered
heteroaryl substituted with amino.
122. The compound of claim 120, wherein R.sup.4 is ##STR00190##
123. The compound of any one of claims 1 to 96, wherein G is
--C(O)CH.sub.2SR.sup.3.
124. The compound of claim 123, wherein R.sup.3 is
C.sub.1-4alkyl.
125. The compound of claim 123, wherein R.sup.3 is 5-10 membered
heterocyclyl.
126. The compound of any one of claims 79 to 96 and 23-31, wherein
G is --C(O)(CH.sub.2)SCH.sub.3.
127. The compound of any one of claims 79 to 96 and 23-31, wherein
G is ##STR00191##
128. The compound of any one of claims 79 to 96 and 23-31, wherein
G is ##STR00192##
129. The compound of any one of claims 79-96 and 102-110, wherein
Y.sup.2 is --S(O).sub.2--.
130. The compound of claim 129, wherein G is optionally substituted
C.sub.6-10aryl.
131. The compound of any one of claims 79-130, wherein Y.sup.1 is
CH.
132. The compound of any one of claims 79-130, wherein Y.sup.1 is
N.
133. The compound of claim 79-81 and 83-132, wherein Q.sup.1 and
Q.sup.2 are deuterium.
134. The compound of claim 79, having the structure selected from
the group consisting of: ##STR00193## ##STR00194## and
pharmaceutically acceptable salts thereof.
135. The compound of any one of claims 1-134, wherein the
pharmaceutically acceptable salt is an alkaline metal salt or
ammonium salt.
136. The compound of claim 135, wherein the pharmaceutically
acceptable salt is a sodium salt.
137. A pharmaceutical composition comprising a therapeutically
effective amount of a compound of any one of claims 1-136 and a
pharmaceutically acceptable excipient.
138. The pharmaceutical composition of claim 137, further
comprising an additional medicament.
139. The composition of claim 138, wherein the additional
medicament is selected from an antibacterial agent, an antifungal
agent, an antiviral agent, an anti-inflammatory agent, or an
anti-allergic agent.
140. The composition of claim 139, wherein the additional
medicament is a .beta.-lactam antibacterial agent.
141. The composition of claim 140, wherein the .beta.-lactam
antibacterial agent is selected from Amoxicillin, Ampicillin
(Pivampicillin, Hetacillin, Bacampicillin, Metampicillin,
Talampicillin), Epicillin, Carbenicillin (Carindacillin),
Ticarcillin, Temocillin, Azlocillin, Piperacillin, Mezlocillin,
Mecillinam (Pivmecillinam), Sulbenicillin, Benzylpenicillin (G),
Clometocillin, Benzathine benzylpenicillin, Procaine
benzylpenicillin, Azidocillin, Penamecillin,
Phenoxymethylpenicillin (V), Propicillin, Benzathine
phenoxymethylpenicillin, Pheneticillin, Cloxacillin (Dicloxacillin,
Flucloxacillin), Oxacillin, Meticillin, Nafcillin, Faropenem,
Tomopenem, Razupenem, Cefazolin, Cefacetrile, Cefadroxil,
Cefalexin, Cefaloglycin, Cefalonium, Cefaloridine, Cefalotin,
Cefapirin, Cefatrizine, Cefazedone, Cefazaflur, Cefradine,
Cefroxadine, Ceftezole, Cefaclor, Cefamandole, Cefininox,
Cefonicid, Ceforanide, Cefotiam, Cefprozil, Cefbuperazone,
Cefuroxime, Cefuzonam, Cefoxitin, Cefotetan, Cefmetazole,
Loracarbef, Cefixime, Ceftriaxone, Cefcapene, Cefdaloxime,
Cefdinir, Cefditoren, Cefetamet, Cefinenoxime, Cefodizime,
Cefoperazone, Cefotaxime, Cefpimizole, Cefpiramide, Cefpodoxime,
Cefsulodin, Cefteram, Ceftibuten, Ceftiolene, Ceftizoxime,
Flomoxef, Latamoxef, Cefepime, Cefozopran, Cefpirome, Cefquinome,
Ceftobiprole, Ceftaroline, CXA-101, RWJ-54428, MC-04,546, ME 1036,
Ceftiofur, Cefquinome, Cefovecin, RWJ-442831, RWJ-333441, or
RWJ-333442.
142. The composition of claim 140 wherein the .beta.-lactam
antibacterial agent is selected from Ceftazidime, Biapenem,
Doripenem, Ertapenem, Imipenem, Meropenem, Tebipenem, Tebipenem
pivoxil, Apapenem, or Panipenem.
143. The composition of claim 140, wherein the .beta.-lactam
antibacterial agent is selected from Aztreonam, Tigemonam,
BAL30072, SYN 2416, or Carumonam.
144. A method of treating a bacterial infection, comprising
administering to a subject in need thereof, a compound according
any one of claims 1-136.
145. The method of claim 144, further comprising administering to
the subject an additional medicament.
146. The method of claim 145, wherein the additional medicament is
selected from an antibacterial agent, an antifungal agent, an
antiviral agent, an anti-inflammatory agent, or an antiallergic
agent.
147. The method of claim 146, wherein the additional medicament is
a .beta.-lactam antibacterial agent.
148. The method of claim 147, wherein the .beta.-lactam
antibacterial agent is selected from Amoxicillin, Ampicillin
(Pivampicillin, Hetacillin, Bacampicillin, Metampicillin,
Talampicillin), Epicillin, Carbenicillin (Carindacillin),
Ticarcillin, Temocillin, Azlocillin, Piperacillin, Mezlocillin,
Mecillinam (Pivmecillinam), Sulbenicillin, Benzylpenicillin (G),
Clometocillin, Benzathine benzylpenicillin, Procaine
benzylpenicillin, Azidocillin, Penamecillin,
Phenoxymethylpenicillin (V), Propicillin, Benzathine
phenoxymethylpenicillin, Pheneticillin, Cloxacillin (Dicloxacillin,
Flucloxacillin), Oxacillin, Meticillin, Nafcillin, Faropenem,
Tomopenem, Razupenem, Cefazolin, Cefacetrile, Cefadroxil,
Cefalexin, Cefaloglycin, Cefalonium, Cefaloridine, Cefalotin,
Cefapirin, Cefatrizine, Cefazedone, Cefazaflur, Cefradine,
Cefroxadine, Ceftezole, Cefaclor, Cefamandole, Cefininox,
Cefonicid, Ceforanide, Cefotiam, Cefprozil, Cefbuperazone,
Cefuroxime, Cefuzonam, Cefoxitin, Cefotetan, Cefmetazole,
Loracarbef, Cefixime, Ceftriaxone, Cefcapene, Cefdaloxime,
Cefdinir, Cefditoren, Cefetamet, Cefinenoxime, Cefodizime,
Cefoperazone, Cefotaxime, Cefpimizole, Cefpiramide, Cefpodoxime,
Cefsulodin, Cefteram, Ceftibuten, Ceftiolene, Ceftizoxime,
Flomoxef, Latamoxef, Cefepime, Cefozopran, Cefpirome, Cefquinome,
Ceftobiprole, Ceftaroline, CXA-101, RWJ-54428, MC-04,546, ME 1036,
Ceftiofur, Cefquinome, Cefovecin, RWJ-442831, RWJ-333441, or
RWJ-333442.
149. The method of claim 147, wherein the .beta.-lactam
antibacterial agent is selected from Ceftazidime, Biapenem,
Doripenem, Ertapenem, Imipenem, Meropenem, Tebipenem, Tebipenem
pivoxil, Apapenem, or Panipenem.
150. The method of claim 147, wherein the .beta.-lactam
antibacterial agent is selected from Aztreonam, Tigemonam,
BAL30072, SYN 2416, or Carumonam.
151. The method of any one of claims 144-150, wherein the subject
is a mammal.
152. The method of claim 151, wherein the mammal is a human.
153. The method of any one of claims 144-152, wherein the infection
comprises a bacteria selected from Pseudomonas acidovorans,
Pseudomonas alcaligenes, Pseudomonas putida, Burkholderia cepacia,
Aeromonas hydrophilia, Francisella tularensis, Morganella morganii,
Proteus mirabilis, Proteus vulgaris, Providencia alcalifaciens,
Providencia rettgeri, Providencia stuartii, Acinetobacter
baumannii, Bordetella pertussis, Bordetella para pertussis,
Bordetella bronchiseptica, Haemophilus ducreyi, Pasteurella
multocida, Pasteurella haemolytica, Branhamella catarrhalis,
Borrelia burgdorferi, Kingella, Gardnerella vaginalis, Bacteroides
distasonis, Bacteroides 3452A homology group, Clostridium
difficile, Mycobacterium tuberculosis, Mycobacterium avium,
Mycobacterium intracellulare, Mycobacterium leprae, Corynebacterium
diphtheriae, Corynebacterium ulcerans, Streptococcus pneumoniae,
Streptococcus agalactiae, Streptococcus pyogenes, Enterococcus
faecalis, Enterococcus faecium, Staphylococcus aureus,
Staphylococcus epidermidis, Staphylococcus saprophyticus,
Staphylococcus intermedius, Staphylococcus hyicus subsp. hyicus,
Staphylococcus haemolyticus, Staphylococcus hominis, or
Staphylococcus saccharolyticus.
154. The method of any one of claims 144-152, wherein the infection
comprises a bacteria selected from Pseudomonas aeruginosa,
Pseudomonas fluorescens, Stenotrophomonas maltophilia, Escherichia
coli, Citrobacter freundii, Salmonella typhimurium, Salmonella
typhi, Salmonella paratyphi, Salmonella enteritidis, Shigella
dysenteriae, Shigella flexneri, Shigella sonnei, Enterobacter
cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiella
oxytoca, Serratia marcescens, Acinetobacter calcoaceticus,
Acinetobacter haemolyticus, Yersinia enterocolitica, Yersinia
pestis, Yersinia pseudotuberculosis, Yersinia intermedia,
Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus
haemolyticus, Haemophilus parahaemolyticus, Helicobacter pylori,
Campylobacter fetus, Campylobacter jejuni, Campylobacter coli,
Vibrio cholerae, Vibrio parahaemolyticus, Legionella pneumophila,
Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria
meningitidis, Moraxella, Bacteroides fragilis, Bacteroides
vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron,
Bacteroides uniformis, Bacteroides eggerthii, or Bacteroides
splanchnicus.
Description
BACKGROUND
Field of the Invention
[0001] The present invention relates to the fields of chemistry and
medicine. More particularly, the present invention relates to
boronic acid antimicrobial compounds, compositions, their
preparation, and their use as therapeutic agents.
Description of the Related Art
[0002] Antibiotics have been effective tools in the treatment of
infectious diseases during the last half-century. From the
development of antibiotic therapy to the late 1980s there was
almost complete control over bacterial infections in developed
countries. However, in response to the pressure of antibiotic
usage, multiple resistance mechanisms have become widespread and
are threatening the clinical utility of antibacterial therapy. The
increase in antibiotic resistant strains has been particularly
common in major hospitals and care centers. The consequences of the
increase in resistant strains include higher morbidity and
mortality, longer patient hospitalization, and an increase in
treatment costs.
[0003] Various bacteria have evolved .beta.-lactam deactivating
enzymes, namely, .beta.-lactamases, that counter the efficacy of
the various .beta.-lactam antibiotics. .beta.-lactamases can be
grouped into 4 classes based on their amino acid sequences, namely,
Ambler classes A, B, C, and D. Enzymes in classes A, C, and D
include active-site serine .beta.-lactamases, and class B enzymes,
which are encountered less frequently, are Zn-dependent. These
enzymes catalyze the chemical degradation of .beta.-lactam
antibiotics, rendering them inactive. Some .beta.-lactamases can be
transferred within and between various bacterial strains and
species. The rapid spread of bacterial resistance and the evolution
of multi-resistant strains severely limits .beta.-lactam treatment
options available.
[0004] The increase of class D .beta.-lactamase-expressing
bacterium strains such as Acinetobacter baumannii has become an
emerging multidrug-resistant threat. A. baumannii strains express
A, C, and D class .beta.-lactamases. The class D .beta.-lactamases
such as the OXA families are particularly effective at destroying
carbapenem type .beta.-lactam antibiotics, e.g., imipenem, the
active carbapenems component of Merck's Primaxin.RTM. (Montefour,
K.; et al. Crit. Care Nurse 2008, 28, 15; Perez, F. et al. Expert
Rev. Anti Infect. Ther. 2008, 6, 269; Bou, G.; Martinez-Beltran, J.
Antimicrob. Agents Chemother. 2000, 40, 428. 2006, 50, 2280; Bou,
G. et al, J. Antimicrob. Agents Chemother. 2000, 44, 1556). This
has imposed a pressing threat to the effective use of drugs in that
category to treat and prevent bacterial infections. Indeed the
number of catalogued serine-based 3-lactamases has exploded from
less than ten in the 1970s to over 300 variants. These issues
fostered the development of five "generations" of cephalosporins.
When initially released into clinical practice, extended-spectrum
cephalosporins resisted hydrolysis by the prevalent class A
.beta.-lactamases, TEM-1 and SHV-1. However, the development of
resistant strains by the evolution of single amino acid
substitutions in TEM-1 and SHV-1 resulted in the emergence of the
extended-spectrum .beta.-lactamase (ESBL) phenotype.
[0005] New .beta.-lactamases have recently evolved that hydrolyze
the carbapenem class of antimicrobials, including imipenem,
biapenem, doripenem, meropenem, and ertapenem, as well as other
.beta.-lactam antibiotics. These carbapenemases belong to molecular
classes A, B, and D. Class A carbapenemases of the KPC-type
predominantly in Klebsiella pneumoniae but now also reported in
other Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter
baumannii. The KPC carbapenemase was first described in 1996 in
North Carolina, but since then has disseminated widely in the US.
It has been particularly problematic in the New York City area,
where several reports of spread within major hospitals and patient
morbidity have been reported. These enzymes have also been recently
reported in France, Greece, Sweden, United Kingdom, and an outbreak
in Germany has recently been reported. Treatment of resistant
strains with carbapenems can be associated with poor outcomes.
[0006] The zinc-dependent class B metallo-.beta.-lactamases are
represented mainly by the VIM, IMP, and NDM types. IMP and
VIM-producing K. pneumonia were first observed in 1990s in Japan
and 2001 in Southern Europe, respectively. IMP-positive strains
remain frequent in Japan and have also caused hospital outbreaks in
China and Australia. However dissemination of IMP-producing
Enterobacteriaceae in the rest of the word appears to be somewhat
limited. VIM-producing enterobacteria can be frequently isolated in
Mediterranean countries, reaching epidemic proportions in Greece.
Isolation of VIM-producing strains remains low in Northern Europe
and in the United States. In stark contrast, a characteristic of
NDM-producing K. pneumonia isolates has been their rapid
dissemination from their epicenter, the Indian subcontinent, to
Western Europe, North America, Australia and Far East. Moreover,
NDM genes have spread rapidly to various species other than K.
pneumonia.
[0007] The plasmid-expressed class D carbapenemases belong to
OXA-48 type. OXA-48 producing K. pneumonia was first detected in
Turkey, in 2001. The Middle East and North Africa remain the main
centers of infection. However, recent isolation of OXA-48-type
producing organisms in India, Senegal and Argentina suggest the
possibility of a global expansion. Isolation of OXA-48 in bacteria
other than K. pneumonia underlines the spreading potential of
OXA-48.
[0008] Treatment of strains producing any of these carbapenemases
with carbapenems can be associated with poor outcomes.
[0009] Another mechanism of 1-lactamase mediated resistance to
carbapenems involves combination of permeability or efflux
mechanisms combined with hyper production of beta-lactamases. One
example is the loss of a porin combined in hyperproduction of ampC
beta-lactamase results in resistance to imipenem in Pseudomonas
aeruginosa. Efflux pump over expression combined with
hyperproduction of the ampC .beta.-lactamase can also result in
resistance to a carbapenem such as meropenem.
[0010] Thus, there is a need for improved .beta.-lactamase
inhibitors.
SUMMARY
[0011] Some embodiments relate to a compound having the structure
of structure of the formula I' or II':
##STR00001## [0012] or a pharmaceutically acceptable salt thereof,
wherein: [0013] each G is independently selected from the group
consisting of --C(O)R.sup.4, --C(O)(CH.sub.2).sub.0-3SR.sup.3,
--C(O)(CH.sub.2).sub.1-3R.sup.4, --C(O)OR.sup.3,
--C(O)NR.sup.1R.sup.2, --C(O)NR.sup.1OR.sup.3,
--NR.sup.1C(O)R.sup.4, --NR.sup.1C(O)NR.sup.1R.sup.2,
--NR.sup.1C(O)OR.sup.3, --NR.sup.1S(O).sub.2R.sup.3,
--NR.sup.1S(O).sub.2NR.sup.1R.sup.2, --C(.dbd.NR.sup.1)R.sup.4,
--C(.dbd.NR.sup.1)NR.sup.1R.sup.2,
--NR.sup.1CR.sup.4(.dbd.NR.sup.2),
--NR.sup.1C(.dbd.NR.sup.2)NR.sup.1R.sup.2, --S(O).sub.2R.sup.3,
--S(O)(CH.sub.2).sub.1-3R.sup.3, --S(O).sub.2NR.sup.1R.sup.2,
--S(O).sub.2NR.sup.1OR.sup.3, --NR.sup.1S(O).sub.2NR.sup.1OR.sup.3,
--CN, --OR.sup.1, --SR.sup.1, --NR.sup.1R.sup.2, optionally
substituted C.sub.1-10 alkyl, optionally substituted
C.sub.2-10alkenyl, optionally substituted C.sub.2-10alkynyl,
optionally substituted C.sub.3-7 carbocyclyl, optionally
substituted 5-10 membered heterocyclyl, optionally substituted
C.sub.6-10aryl, optionally substituted 5-10 membered heteroaryl,
optionally substituted C.sub.3-7carbocyclyl-C.sub.1-6alkyl,
optionally substituted 5-10 membered heterocyclyl-C.sub.1-6alkyl,
optionally substituted C.sub.6-10aryl-C.sub.1-6alkyl, and
optionally substituted 5-10 membered heteroaryl-C.sub.1-6alkyl;
[0014] Y.sup.1 is selected from the group consisting of CR.sup.1
and N; [0015] each Y.sup.2 is independently selected from the group
consisting of --S--, --S(O)--, --S(O).sub.2--, --O--,
--CR.sup.1R.sup.2--, and --NR.sup.2--, or
Y.sup.2--(CH.sub.2).sub.n-G is CH.sub.3; [0016] Y.sup.4 is selected
from the group consisting of --O--, --S--, and --NR.sup.1--; [0017]
Y.sup.5 is selected from the group consisting of --OH, --SH, and
--NHR.sup.1; [0018] Y.sup.6 is selected from the group consisting
of --OH, optionally substituted --O--C.sub.1-6 alkyl,
--NR.sup.1R.sup.2, and --N(OR.sup.3)R.sup.2, [0019] Q.sup.1 and
Q.sup.2 is each indecently H or --Y.sup.2--(CH.sub.2).sub.n-G;
[0020] each n is independently an integer from 0 to 3; [0021] m is
0 or 1; [0022] A is selected from the group consisting of
C.sub.3-10 carbocyclyl, C.sub.6-10 aryl, 5-10 membered heteroaryl,
and 5-10 membered heterocyclyl; [0023] each R.sup.1, R.sup.2,
R.sup.3, and R.sup.4 are independently selected from --H, halogen,
optionally substituted C.sub.1-4alkyl, optionally substituted
O--C.sub.1-4alkyl, optionally substituted C.sub.3-7 carbocyclyl,
optionally substituted 4-10 membered heterocyclyl, optionally
substituted C.sub.6-10aryl, and optionally substituted 5-10
membered heteroaryl; [0024] R.sup.5 is present 1 to 5 times and
each R.sup.5 is independently selected from the group consisting of
H, OH, halogen, CN, --C(O)OR.sup.1; --C(O)NR.sup.1R.sup.2;
--C(O)NR.sup.1OR.sup.2; --NR.sup.1C(O)R.sup.2;
--NR.sup.1C(O)NR.sup.2R.sup.3; --NR.sup.1C(O)OR.sup.2;
--NR.sup.1S(O).sub.2R.sup.2; --NR.sup.1S(O).sub.2NR.sup.2R.sup.3;
--C(.dbd.NR.sup.1)R.sup.2; --C(.dbd.NR.sup.1)NR.sup.2R.sup.3;
--NR.sup.1CR.sup.2(.dbd.NR.sup.3);
--NR.sup.1C(.dbd.NR.sup.2)NR.sup.3R.sup.4;
--S(O)(CH.sub.2).sub.1-3R.sup.4, --S(O).sub.2NR.sup.1R.sup.2,
--S(O).sub.2NR.sup.1OR.sup.3, --NR.sup.1S(O).sub.2NR.sup.1OR.sup.3,
optionally substituted C.sub.2-C.sub.6 alkenyl, optionally
substituted C.sub.2-C.sub.6 alkynyl, optionally substituted
C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.7
carbocyclyl, optionally substituted 5-10 membered heterocyclyl,
optionally substituted C.sub.6-10aryl, optionally substituted 5-10
membered heteroaryl, cyano, C.sub.1-C.sub.6
alkoxy(C.sub.1-C.sub.6)alkyl, aryloxy, sulfhydryl (mercapto), and
--(CH.sub.2).sub.p--Y.sup.3--(CH.sub.2).sub.qM'; [0025] p and q are
each independently 0, 1, or 2; [0026] Y.sup.3 is selected from the
group consisting of --S--, --S(O)--, --S(O).sub.2--, --O--,
--CR.sup.1R.sup.2--, and --NR.sup.1--; [0027] M' is selected from
the group consisting of halogen, cycano, --OH,
--C(O)NR.sup.1R.sup.2; --C(O)NR.sup.1OR.sup.2;
--NR.sup.1C(O)R.sup.2; --NR.sup.1C(O)NR.sup.2R.sup.3;
--NR.sup.1C(O)OR.sup.2; --NR.sup.1S(O).sub.2R.sup.2;
--NR.sup.1S(O).sub.2NR.sup.2R.sup.3; --C(.dbd.NR.sup.1)R.sup.2;
--C(.dbd.NR.sup.1)NR.sup.2R.sup.3;
--NR.sup.1CR.sup.2(.dbd.NR.sup.3);
--NR.sup.1C(.dbd.NR.sup.2)NR.sup.3R.sup.4; --S(O).sub.2R.sup.1,
--S(O).sub.2NR.sup.1R.sup.2, --S(O).sub.2NR.sup.1OR.sup.3,
C.sub.1-4 alkyl optionally substituted with 0-2 substituents
selected from the group consisting of --OR.sup.1, --CN,
--NR.sup.1R.sup.2, -heterocyclyl, halogen, --C(O)NR.sup.1R.sup.2,
and --NR.sup.1C(O)R.sup.2; C.sub.2-4 alkenyl optionally substituted
with 0-2 substituents selected from the group consisting of
C.sub.1-4 alkyl, --(CH.sub.2).sub.0-4OR.sup.1,
--(CH.sub.2).sub.0-4CN, --(CH.sub.2).sub.0-4NR.sup.1R.sup.2,
--(CH.sub.2).sub.0-4-heterocyclyl, halogen, --C(O)NR.sup.1R.sup.2,
and --NR.sup.1C(O)R.sup.2; C.sub.2-4 alkynyl optionally substituted
with 0-2 substituents selected from the group consisting of
C.sub.1-4 alkyl, --(CH.sub.2).sub.0-4OR.sup.1,
--(CH.sub.2).sub.0-4CN, --(CH.sub.2).sub.0-4NR.sup.1R.sup.2,
--(CH.sub.2).sub.0-4-heterocyclyl, halogen, --C(O)NR.sup.1R.sup.2,
and --NR.sup.1C(O)R.sup.2; C.sub.6-10 aryl optionally substituted
with 0-2 substituents selected from the group consisting of
C.sub.1-4 alkyl, --(CH.sub.2).sub.0-4OR.sup.1,
--(CH.sub.2).sub.0-4CN, --(CH.sub.2).sub.0-4NR.sup.1R.sup.2,
--(CH.sub.2).sub.0-4-heterocyclyl, halogen, --C(O)NR.sup.1R.sup.2,
and --NR.sup.1C(O)R.sup.2; C.sub.3-7 carbocyclyl optionally
substituted with 0-2 substituents selected from the group
consisting of C.sub.1-4 alkyl, --(CH.sub.2).sub.0-4OR.sup.1,
--(CH.sub.2).sub.0-4CN, --(CH.sub.2).sub.0-4NR.sup.1R.sup.2,
--(CH.sub.2).sub.0-4-heterocyclyl, halogen, --C(O)NR.sup.1R.sup.2,
and --NR.sup.1C(O)R.sup.2; 5-10 membered heteroaryl optionally
substituted with 0-2 substituents selected from the group
consisting of C.sub.1-4 alkyl, --(CH.sub.2).sub.0-4OR.sup.1,
--(CH.sub.2).sub.0-4CN, --(CH.sub.2).sub.0-4NR.sup.1R.sup.2,
--(CH.sub.2).sub.0-4-heterocyclyl, halogen, --C(O)NR.sup.1R.sup.2,
and --NR.sup.1C(O)R.sup.2; and 3-10 membered heterocyclyl
optionally substituted with 0-2 substituents selected from the
group consisting of C.sub.1-4 alkyl, --(CH.sub.2).sub.0-4OR.sup.1,
--(CH.sub.2).sub.0-4CN, --(CH.sub.2).sub.0-4NR.sup.1R.sup.2,
--(CH.sub.2).sub.0-4-heterocyclyl, halogen, --C(O)NR.sup.1R.sup.2,
and --NR.sup.1C(O)R.sup.2; [0028] R.sup.6 is selected from the
group consisting of is selected from the group consisting of --H,
halogen, optionally substituted --C.sub.1-6 alkyl, --OH, --C(O)OR,
--P(O)(OR).sub.2, P(O)(OR)R.sup.1, optionally substituted
--O--C.sub.1-6 alkyl, --NR.sup.1R.sup.2, --N(OR.sup.3)R.sup.2,
optionally substituted --S--C.sub.1-6 alkyl, --C(O)NR.sup.1R.sup.2,
--S(O).sub.2NR.sup.1R.sup.2, CN, optionally substituted
--S(O)--C.sub.1-6 alkyl, optionally substituted
--S(O).sub.2--C.sub.1-6 alkyl, and a carboxylic acid isostere;
[0029] R is selected from --H, --C.sub.1-9alkyl,
--CR.sup.10R.sup.11OC(O)C.sub.1-9alkyl,
--CR.sup.10R.sup.11OC(O)OC.sub.1-9alkyl,
--CR.sup.10R.sup.11OC(O)C.sub.6-10aryl,
--CR.sup.10R.sup.11OC(O)OC.sub.6-10aryl,
--CR.sup.10R.sup.11OC(O)NR.sup.10C.sub.1-9alkyl,
--CR.sup.10R.sup.11OC(O)NR.sup.10C.sub.6-10aryl, and
[0029] ##STR00002## [0030] R.sup.7 is selected from the group
consisting of OH, optionally substituted --O--C.sub.1-6 alkyl,
--NR.sup.1R.sup.2, and --N(OR.sup.3)R.sup.2; and
[0031] R.sup.10 and R.sup.11 are independently selected from the
group consisting of --H, optionally substituted C.sub.1-4alkyl,
optionally substituted C.sub.3-7 carbocyclyl, optionally
substituted 5-10 membered heterocyclyl, optionally substituted
C.sub.6-10aryl, and optionally substituted 5-10 membered
heteroaryl.
[0032] A compound having the structure of the Formula (I) or
(II):
##STR00003## [0033] or a pharmaceutically acceptable salt thereof,
wherein: [0034] each G is independently selected from the group
consisting of --C(O)R.sup.4, --C(O)(CH.sub.2).sub.0-3SR.sup.3,
C(O)(CH.sub.2).sub.1-3R.sup.4, --C(O)OR.sup.3,
--C(O)NR.sup.1R.sup.2, --C(O)NR.sup.1OR.sup.3,
--NR.sup.1C(O)R.sup.4, --NR.sup.1C(O)NR.sup.1R.sup.2,
--NR.sup.1C(O)OR.sup.3, --NR.sup.1S(O).sub.2R.sup.3,
--NR.sup.1S(O).sub.2NR.sup.1R.sup.2, --C(.dbd.NR.sup.1)R.sup.4,
--C(.dbd.NR.sup.1)NR.sup.1R.sup.2,
--NR.sup.1CR.sup.4(.dbd.NR.sup.2),
--NR.sup.1C(.dbd.NR.sup.2)NR.sup.1R.sup.2, --S(O).sub.2R.sup.3,
optionally substituted C.sub.1-10 alkyl, optionally substituted
C.sub.2-10alkenyl, optionally substituted C.sub.2-10alkynyl,
optionally substituted C.sub.3-7 carbocyclyl, optionally
substituted 5-10 membered heterocyclyl, optionally substituted
C.sub.6-10aryl, optionally substituted 5-10 membered heteroaryl,
optionally substituted C.sub.3-7carbocyclyl-C.sub.1-6alkyl,
optionally substituted 5-10 membered heterocyclyl-C.sub.1-6alkyl,
optionally substituted C.sub.6-10aryl-C.sub.1-6alkyl, and
optionally substituted 5-10 membered heteroaryl-C.sub.1-6alkyl;
[0035] Y.sup.1 is selected from the group consisting of CR.sup.1
and N; [0036] each Y.sup.2 is independently selected from the group
consisting of --S--, --S(O)--, --S(O).sub.2--, --O--,
--CR.sup.1R.sup.2--, and --NR.sup.2--; [0037] Y.sup.4 is selected
from the group consisting of --O--, --S--, and --NR.sup.1--; [0038]
Y.sup.5 is selected from the group consisting of --OH, --SH, and
--NHR.sup.1; [0039] Y.sup.6 is selected from the group consisting
of --OH, optionally substituted --O--C.sub.1-6 alkyl,
--NR.sup.1R.sup.2, and --N(OR.sup.3)R.sup.2, Q is H or
--Y.sup.2--(CH.sub.2).sub.n-G; [0040] each n is independently an
integer from 0 to 3; [0041] m is 0 or 1; [0042] A is selected from
the group consisting of C.sub.3-10 carbocyclyl, C.sub.6-10 aryl,
5-10 membered heteroaryl, and 5-10 membered heterocyclyl; [0043]
each R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are independently
selected from --H, optionally substituted C.sub.1-4alkyl,
optionally substituted C.sub.3-7 carbocyclyl, optionally
substituted 4-10 membered heterocyclyl, optionally substituted
C.sub.6-10aryl, and optionally substituted 5-10 membered
heteroaryl; [0044] R.sup.5 is present 1 to 5 times and each R.sup.5
is independently selected from the group consisting of H, OH,
halogen, --CF.sub.3, optionally substituted C.sub.2-C.sub.6
alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally
substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted
C.sub.3-C.sub.7 carbocyclyl, optionally substituted 5-10 membered
heterocyclyl, optionally substituted C.sub.6-10aryl, optionally
substituted 5-10 membered heteroaryl, cyano, C.sub.1-C.sub.6
alkoxy(C.sub.1-C.sub.6)alkyl, aryloxy, sulfhydryl (mercapto), and
--(CH.sub.2).sub.p--Y.sup.3--(CH.sub.2).sub.qM'; [0045] p and q are
each independently 0 or 1; [0046] Y.sup.3 is selected from the
group consisting of --S--, --S(O)--, --S(O).sub.2--, --O--,
--CH.sub.2--, and --NR.sup.1--; [0047] M' is selected from the
group consisting of --C(O)NR.sup.1R.sup.2; --C(O)NR.sup.1OR.sup.2;
--NR.sup.1C(O)R.sup.2; --NR.sup.1C(O)NR.sup.2R.sup.3;
--NR.sup.1C(O)OR.sup.2; --NR.sup.1S(O).sub.2R.sup.2;
--NR.sup.1S(O).sub.2NR.sup.2R.sup.3; --C(.dbd.NR.sup.1)R.sup.2;
--C(.dbd.NR.sup.1)NR.sup.2R.sup.3;
--NR.sup.1CR.sup.2(.dbd.NR.sup.3);
--NR.sup.1C(.dbd.NR.sup.2)NR.sup.3R.sup.4; C.sub.1-4 alkyl
optionally substituted with 0-2 substituents selected from the
group consisting, --OR.sup.1, --NR.sup.1R.sup.2, halogen,
--C(O)NR.sup.1R.sup.2, and --NR.sup.1C(O)R.sup.2; C.sub.6-10aryl
optionally substituted with 0-2 substituents selected from the
group consisting of C.sub.1-4 alkyl, --OR.sup.1, --NR.sup.1R.sup.2,
halogen, --C(O)NR.sup.1R.sup.2, and --NR.sup.1C(O)R.sup.2;
C.sub.3-7 carbocyclyl optionally substituted with 0-2 substituents
selected from the group consisting of C.sub.1-4 alkyl, --OR.sup.1,
--NR.sup.1R.sup.2, halogen, --C(O)NR.sup.1R.sup.2, and
--NR.sup.1C(O)R.sup.2; 5-10 membered heteroaryl optionally
substituted with 0-2 substituents selected from the group
consisting of C.sub.1-4 alkyl, --OR.sup.1, --NR.sup.1R.sup.2,
halogen, --C(O)NR.sup.1R.sup.2, and --NR.sup.1C(O)R.sup.2; and 3-10
membered heterocyclyl optionally substituted with 0-2 substituents
selected from the group consisting of C.sub.1-4 alkyl, --OR.sup.1,
--NR.sup.1R.sup.2, halogen, --C(O)NR.sup.1R.sup.2, and
--NR.sup.1C(O)R.sup.2; [0048] R.sup.6 is selected from the group
consisting of is selected from the group consisting of --H,
halogen, optionally substituted --C.sub.1-6 alkyl, --OH, --C(O)OR,
optionally substituted --O--C.sub.1-6 alkyl, --NR.sup.1R.sup.2,
--N(OR.sup.3)R.sup.2, optionally substituted --S--C.sub.1-6 alkyl,
--C(O)NR.sup.1R.sup.2, --S(O).sub.2NR.sup.1R.sup.2, CN, optionally
substituted --S(O)--C.sub.1-6 alkyl, optionally substituted
--S(O).sub.2--C.sub.1-6 alkyl, and a carboxylic acid isostere;
[0049] R is selected from --H, --C.sub.1-9alkyl,
--CR.sup.10R.sup.11OC(O)C.sub.1-9alkyl,
--CR.sup.10R.sup.11OC(O)OC.sub.1-9alkyl,
--CR.sup.10R.sup.11OC(O)C.sub.6-10aryl,
--CR.sup.10R.sup.11OC(O)OC.sub.6-10aryl and
[0049] ##STR00004## [0050] R.sup.7 is selected from the group
consisting of OH, optionally substituted --O--C.sub.1-6 alkyl,
--NR.sup.1R.sup.2, and --N(OR.sup.3)R.sup.2; and [0051] R.sup.10
and R.sup.11 are independently selected from the group consisting
of --H, optionally substituted C.sub.1-4alkyl, optionally
substituted C.sub.3-7 carbocyclyl, optionally substituted 5-10
membered heterocyclyl, optionally substituted C.sub.6-10aryl, and
optionally substituted 5-10 membered heteroaryl.
[0052] Some embodiments relate to compound having the structure of
the formula III' or IV':
##STR00005## [0053] or a pharmaceutically acceptable salt thereof,
wherein: [0054] A is selected from the group consisting of
C.sub.3-10 carbocyclyl, C.sub.6-10 aryl, 5-10 membered heteroaryl,
and 5-10 membered heterocyclyl; [0055] m is 0, 1 or 2; [0056]
Y.sup.7 is selected from the group consisting of --CH.sub.2--,
--O--, --S-- and --NR.sup.1--; [0057] n is 1, 2 or 3; [0058]
Q.sup.1 and Q.sup.2 are H; [0059] each R.sup.7 is independently
selected from the group consisting of OH, optionally substituted
--O--C.sub.1-6 alkyl, --NR.sup.1R.sup.2, and --N(OR)R.sup.2; and
[0060] Y.sup.4 is selected from the group consisting of --O--,
--S--, and --NR.sup.1--; [0061] Y.sup.5 is selected from the group
consisting of --OH, --SH, and --NHR.sup.1; [0062] Y.sup.6 is
selected from the group consisting of --OH, optionally substituted
--O--C.sub.1-6 alkyl, --NR.sup.1R.sup.2, and --N(OR.sup.1)R.sup.2;
[0063] each R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are independently
selected from --H, halogen, optionally substituted C.sub.1-4alkyl,
optionally substituted O--C.sub.1-4alkyl, optionally substituted
C.sub.3-7 carbocyclyl, optionally substituted 4-10 membered
heterocyclyl, optionally substituted C.sub.6-10aryl, and optionally
substituted 5-10 membered heteroaryl; [0064] R.sup.5 is present 1
to 5 times and each R.sup.5 is independently selected from the
group consisting of H, OH, halogen, --C(O)OR.sup.1;
--C(O)NR.sup.1R.sup.2; --C(O)NR.sup.1OR.sup.2;
--C(.dbd.NR.sup.1)R.sup.2; --C(.dbd.NR.sup.1)NR.sup.2R.sup.3;
--NR.sup.1C(O)R.sup.2; --NR.sup.1C(O)NR.sup.2R.sup.3;
--NR.sup.1C(O)OR.sup.2; --NR.sup.1S(O).sub.2R.sup.2;
--NR.sup.1S(O).sub.2NR.sup.2R.sup.3;
--NR.sup.1CR.sup.2(.dbd.NR.sup.3);
--NR.sup.1C(.dbd.NR.sup.2)NR.sup.3R.sup.4;
--S(O)(CH.sub.2).sub.1-3R.sup.4, S(O).sub.2NR.sup.1R.sup.2,
--S(O).sub.2NR.sup.1OR.sup.3, --NR.sup.1S(O).sub.2NR.sup.1OR.sup.3,
optionally substituted C.sub.2-C.sub.6 alkenyl, optionally
substituted C.sub.2-C.sub.6 alkynyl, optionally substituted
C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.7
carbocyclyl, optionally substituted 5-10 membered heterocyclyl,
optionally substituted C.sub.6-10aryl, optionally substituted 5-10
membered heteroaryl, cyano, C.sub.1-C.sub.6
alkoxy(C.sub.1-C.sub.6)alkyl, aryloxy, sulfhydryl (mercapto), and
--(CH.sub.2).sub.p--Y.sup.3--(CH.sub.2).sub.qM'; [0065] p and q are
each independently 0, 1, or 2; [0066] Y.sup.3 is selected from the
group consisting of --S--, --S(O)--, --S(O).sub.2--, --O--,
--CR.sup.1R.sup.2, and --NR.sup.1--; [0067] M' is selected from the
group consisting of halogen, cyano, --OH, --C(O)NR.sup.1R.sup.2;
--C(O)NR.sup.1OR.sup.2; --NR.sup.1C(O)R.sup.2;
--NR.sup.1C(O)NR.sup.2R.sup.3; --NR.sup.1C(O)OR.sup.2;
--NR.sup.1S(O).sub.2R.sup.2; --NR.sup.1S(O).sub.2NR.sup.2R.sup.3;
--C(.dbd.NR.sup.1)R.sup.2; --C(.dbd.NR.sup.1)NR.sup.2R.sup.3;
--NR.sup.1CR.sup.2 (.dbd.NR.sup.3);
--NR.sup.1C(.dbd.NR.sup.2)NR.sup.3R.sup.4; --S(O).sub.2R.sup.1,
--S(O).sub.2NR.sup.1R.sup.2, --S(O).sub.2NR.sup.1OR.sup.3,
C.sub.1-4 alkyl optionally substituted with 0-2 substituents
selected from the group consisting of --OR.sup.1, --CN,
--NR.sup.1R.sup.2, -heterocyclyl, halogen, --C(O)NR.sup.1R.sup.2,
and --NR.sup.1C(O)R.sup.2; C.sub.2-4 alkenyl optionally substituted
with 0-2 substituents selected from the group consisting of
C.sub.1-4 alkyl, --(CH.sub.2).sub.0-4OR.sup.1,
--(CH.sub.2).sub.0-4CN, --(CH.sub.2).sub.0-4NR.sup.1R.sup.2,
--(CH.sub.2).sub.0-4-heterocyclyl, halogen, --C(O)NR.sup.1R.sup.2,
and --NR.sup.1C(O)R.sup.2; C.sub.2-4 alkynyl optionally substituted
with 0-2 substituents selected from the group consisting of
C.sub.1-4 alkyl, --(CH.sub.2).sub.0-4OR.sup.1,
--(CH.sub.2).sub.0-4CN, --(CH.sub.2).sub.0-4NR.sup.1R.sup.2,
--(CH.sub.2).sub.0-4-heterocyclyl, halogen, --C(O)NR.sup.1R.sup.2,
and --NR.sup.1C(O)R.sup.2; C.sub.6-10 aryl optionally substituted
with 0-2 substituents selected from the group consisting of
C.sub.1-4 alkyl, --(CH.sub.2).sub.0-4OR.sup.1,
--(CH.sub.2).sub.0-4CN, --(CH.sub.2).sub.0-4NR.sup.1R.sup.2,
--(CH.sub.2).sub.0-4-heterocyclyl, halogen, --C(O)NR.sup.1R.sup.2,
and --NR.sup.1C(O)R.sup.2; C.sub.3-7 carbocyclyl optionally
substituted with 0-2 substituents selected from the group
consisting of C.sub.1-4 alkyl, --(CH.sub.2).sub.0-4OR.sup.1,
--(CH.sub.2).sub.0-4CN, --(CH.sub.2).sub.0-4NR.sup.1R.sup.2,
--(CH.sub.2).sub.0-4-heterocyclyl, halogen, --C(O)NR.sup.1R.sup.2,
and --NR.sup.1C(O)R.sup.2; 5-10 membered heteroaryl optionally
substituted with 0-2 substituents selected from the group
consisting of C.sub.1-4 alkyl, --(CH.sub.2).sub.0-4OR.sup.1,
--(CH.sub.2).sub.0-4CN, --(CH.sub.2).sub.0-4NR.sup.1R.sup.2,
--(CH.sub.2).sub.0-4-heterocyclyl halogen, --C(O)NR.sup.1R.sup.2,
and --NR.sup.1C(O)R.sup.2; and 3-10 membered heterocyclyl
optionally substituted with 0-2 substituents selected from the
group consisting of C.sub.1-4 alkyl, --(CH.sub.2).sub.0-4OR.sup.1,
--(CH.sub.2).sub.0-4CN, --(CH.sub.2).sub.0-4NR.sup.1R.sup.2,
--(CH.sub.2).sub.0-4-heterocyclyl, halogen, --C(O)NR.sup.1R.sup.2,
and --NR.sup.1C(O)R.sup.2; [0068] R.sup.6 is selected from the
group consisting of H, halogen, optionally substituted --C.sub.1-6
alkyl, --OH, --C(O)OR, --P(O)(OR).sub.2, P(O)(OR)R.sup.1,
optionally substituted --O--C.sub.1-6 alkyl, --NR.sup.1R.sup.2,
--N(OR.sup.1)R.sup.2, optionally substituted --S--C.sub.1-6 alkyl,
--C(O)NR.sup.1R.sup.2, --S(O).sub.2NR.sup.1R.sup.2, CN, optionally
substituted --S(O)--C.sub.1-6 alkyl, optionally substituted
--S(O).sub.2--C.sub.1-6 alkyl, and a carboxylic acid isostere;
[0069] R is selected from --H, alkali metal, NH.sub.4.sup.+,
--C.sub.1-9alkyl, --CR.sup.10R.sup.10OC(O)C.sub.1-9alkyl,
--CR.sup.10R.sup.11OC(O)OC.sub.1-9alkyl,
--CR.sup.10R.sup.11OC(O)C.sub.6-10aryl,
--CR.sup.10R.sup.11OC(O)OC.sub.6-10aryl,
--CR.sup.10R.sup.11OC(O)NR.sup.10C.sub.1-9alkyl,
--CR.sup.10R.sup.11OC(O)NR.sup.10C.sub.6-10aryl, and
[0069] ##STR00006## [0070] R.sup.10 and R.sup.11 are independently
selected from the group consisting of --H, optionally substituted
C.sub.1-4alkyl, optionally substituted C.sub.3-7 carbocyclyl,
optionally substituted 5-10 membered heterocyclyl, optionally
substituted C.sub.6-10aryl, and optionally substituted 5-10
membered heteroaryl.
[0071] Some embodiments relate to a compound having the structure
of Formula (III) or (IV):
##STR00007## [0072] or a pharmaceutically acceptable salt thereof,
wherein: [0073] A is selected from the group consisting of
C.sub.3-10 carbocyclyl, C.sub.6-10aryl, 5-10 membered heteroaryl,
and 5-10 membered heterocyclyl; [0074] m is 0, 1 or 2; [0075]
Y.sup.7 is selected from the group consisting of CH.sub.2, O, S and
NH; [0076] n.sup.1 is 1, 2 or 3; [0077] each R.sup.7 is
independently selected from the group consisting of OH, optionally
substituted --O--C.sub.1-6 alkyl, --NR.sup.1R.sup.2, and
--N(OR.sup.1)R.sup.2; and [0078] Y.sup.4 is selected from the group
consisting of --O--, --S--, and --NR.sup.1--; [0079] Y.sup.5 is
selected from the group consisting of --OH, --SH, and --NHR.sup.1;
[0080] Y.sup.6 is selected from the group consisting of --OH,
optionally substituted --O--C.sub.1-6 alkyl, --NR.sup.1R.sup.2, and
--N(OR.sup.1)R.sup.2; [0081] each R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 are independently selected from --H, optionally substituted
C.sub.1-4alkyl, optionally substituted C.sub.3-7 carbocyclyl,
optionally substituted 4-10 membered heterocyclyl, optionally
substituted C.sub.6-10aryl, and optionally substituted 5-10
membered heteroaryl; [0082] R.sup.5 is present 1 to 5 times and
each R.sup.5 is independently selected from the group consisting of
H, OH, halogen, --CF.sub.3, optionally substituted C.sub.2-C.sub.6
alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally
substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted
C.sub.3-C.sub.7 carbocyclyl, optionally substituted 5-10 membered
heterocyclyl, optionally substituted C.sub.6-10aryl, optionally
substituted 5-10 membered heteroaryl, cyano, C.sub.1-C.sub.6
alkoxy(C.sub.1-C.sub.6)alkyl, aryloxy, sulfhydryl (mercapto), and
--(CH.sub.2).sub.p--Y.sup.3--(CH.sub.2).sub.qM'; [0083] p and q are
each independently 0 or 1; [0084] Y.sup.3 is selected from the
group consisting of --S--, --S(O)--, --S(O).sub.2--, --O--,
--CH.sub.2--, and --NR.sup.1--; [0085] M' is selected from the
group consisting of --C(O)NR.sup.1R.sup.2; --C(O)NR.sup.1OR.sup.2;
--NR.sup.1C(O)R.sup.2; --NR.sup.1C(O)NR.sup.2R.sup.3;
--NR.sup.1C(O)OR.sup.2; --NR.sup.1S(O).sub.2R.sup.2;
--NR.sup.1S(O).sub.2NR.sup.2R.sup.3; --C(.dbd.NR.sup.1)R.sup.2;
--C(.dbd.NR.sup.1)NR.sup.2R.sup.3;
--NR.sup.1CR.sup.2(.dbd.NR.sup.3);
--NR.sup.1C(.dbd.NR.sup.2)NR.sup.3R.sup.4; C.sub.1-4 alkyl
optionally substituted with 0-2 substituents selected from the
group consisting, --OR, --NR.sup.1R.sup.2, halogen,
--C(O)NR.sup.1R.sup.2, and --NR.sup.1C(O)R.sup.2; C.sub.6-10 aryl
optionally substituted with 0-2 substituents selected from the
group consisting of C.sub.1-4 alkyl, --OR.sup.1, --NR.sup.1R.sup.2,
halogen, --C(O)NR.sup.1R.sup.2, and --NR.sup.1C(O)R.sup.2;
C.sub.3-7 carbocyclyl optionally substituted with 0-2 substituents
selected from the group consisting of C.sub.1-4 alkyl, --OR.sup.1,
--NR.sup.1R.sup.2, halogen, --C(O)NR.sup.1R.sup.2, and
--NR.sup.1C(O)R.sup.2; 5-10 membered heteroaryl optionally
substituted with 0-2 substituents selected from the group
consisting of C.sub.1-4 alkyl, --OR.sup.1, --NR.sup.1R.sup.2,
halogen, --C(O)NR.sup.1R.sup.2, and --NR.sup.1C(O)R.sup.2; and 3-10
membered heterocyclyl optionally substituted with 0-2 substituents
selected from the group consisting of C.sub.1-4 alkyl, --OR.sup.1,
--NR.sup.1R.sup.2, halogen, --C(O)NR.sup.1R.sup.2, and
--NR.sup.1C(O)R.sup.2; [0086] R.sup.6 is selected from the group
consisting of H, halogen, optionally substituted --C.sub.1-6 alkyl,
--OH, --C(O)OR, optionally substituted --O--C.sub.1-6 alkyl,
--NR.sup.1R.sup.2, --N(OR.sup.1)R.sup.2, optionally substituted
--S--C.sub.1-6 alkyl, --C(O)NR.sup.1R.sup.2,
--S(O).sub.2NR.sup.1R.sup.2, CN, optionally substituted
--S(O)--C.sub.1-6 alkyl, optionally substituted
--S(O).sub.2--C.sub.1-6 alkyl, and a carboxylic acid isostere;
[0087] R is selected from --H, alkali metal, NH.sub.4.sup.+,
--C.sub.1-9alkyl, --CR.sup.10R.sup.11OC(O)C.sub.1-9alkyl,
--CR.sup.10R.sup.11OC(O)OC.sub.1-9alkyl,
--CR.sup.10R.sup.11OC(O)C.sub.6-10aryl,
--CR.sup.10R.sup.11OC(O)OC.sub.6-10aryl and
[0087] ##STR00008## [0088] R.sup.10 and R.sup.11 are independently
selected from the group consisting of --H, optionally substituted
C.sub.1-4alkyl, optionally substituted C.sub.3-7 carbocyclyl,
optionally substituted 5-10 membered heterocyclyl, optionally
substituted C.sub.6-10aryl, and optionally substituted 5-10
membered heteroaryl.
[0089] Some embodiments relate to a compound having the structure
selected from the group consisting of
##STR00009##
and pharmaceutically acceptable salts thereof.
[0090] Other embodiments disclosed herein include a pharmaceutical
composition comprising a therapeutically effective amount of a
compound disclosed herein and a pharmaceutically acceptable
excipient.
[0091] Other embodiments disclosed herein include a method of
treating or preventing a bacterial infection, comprising
administering to a subject in need thereof a compound disclosed
herein.
DETAILED DESCRIPTION
[0092] In some embodiments, compounds that contain a boronic acid
moiety are provided that act as antimicrobial agents and/or as
potentiators of antimicrobial agents Various embodiments of these
compounds include compounds having the structures of Formula (I) as
described above or pharmaceutically acceptable salts thereof.
[0093] In some embodiments, the compound described herein has the
structure of Formula (I') or a pharmaceutically acceptable salt
thereof. In some embodiments, the compound described herein has the
structure of Formula (II') or a pharmaceutically acceptable salt
thereof.
[0094] In some embodiments, the compound described herein has the
structure of Formula (I) or a pharmaceutically acceptable salt
thereof. In some embodiments, the compound described herein has the
structure of Formula (II) or a pharmaceutically acceptable salt
thereof.
[0095] In some embodiments, Q.sup.1 and Q.sup.2 are deuterium. In
some embodiments, Q.sup.1 is hydrogen and Q.sup.2 is deuterium. In
some embodiments, Q.sup.1 is --Y.sup.2--(CH.sub.2).sub.n-G and
Q.sup.2 is deuterium. In some embodiments, Q.sup.1 is
--Y.sup.2--(CH.sub.2).sub.n-G and Q.sup.2 is hydrogen.
[0096] In some embodiments, Q is --Y.sup.2--(CH.sub.2).sub.n-G. In
some embodiments, Q is H.
[0097] Some embodiments of compounds of Formula (I') or (I) include
compounds having the structure of Formula (I-1)
##STR00010## [0098] or a pharmaceutically acceptable salt thereof,
wherein: [0099] G is selected from the group consisting of
--C(O)R.sup.4, --C(O)(CH.sub.2).sub.0-3SR.sup.3, --C(O)OR.sup.3,
--C(O)NR.sup.1R.sup.2, --C(O)NR.sup.1OR.sup.3,
--NR.sup.1C(O)R.sup.4, --NR.sup.1C(O)NR.sup.1R.sup.2,
--NR.sup.1C(O)OR.sup.3, --NR.sup.1S(O).sub.2R.sup.3,
--NR.sup.1S(O).sub.2NR.sup.1R.sup.2, --C(.dbd.NR.sup.1)R.sup.4,
--C(.dbd.NR.sup.1)NR.sup.1R.sup.2, NR.sup.1CR.sup.4(.dbd.NR.sup.2),
--NR.sup.1C(.dbd.NR.sup.2)NR.sup.1R.sup.2, --S(O).sub.2R.sup.3,
optionally substituted C.sub.1-10 alkyl, optionally substituted
C.sub.2-10alkenyl, optionally substituted C.sub.2-10alkynyl,
optionally substituted C.sub.3-7 carbocyclyl, optionally
substituted 5-10 membered heterocyclyl, optionally substituted
C.sub.6-10aryl, optionally substituted 5-10 membered heteroaryl,
optionally substituted C.sub.3-7carbocyclyl-C.sub.1-6alkyl,
optionally substituted 5-10 membered heterocyclyl-C.sub.1-6alkyl,
optionally substituted C.sub.6-10aryl-C.sub.1-6alkyl, and
optionally substituted 5-10 membered heteroaryl-C.sub.1-6alkyl;
[0100] each R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are
independently selected from --H, optionally substituted
C.sub.1-4alkyl, optionally substituted C.sub.3-7 carbocyclyl,
optionally substituted 5-10 membered heterocyclyl, optionally
substituted C.sub.6-10aryl, and optionally substituted 5-10
membered heteroaryl; and [0101] R is selected from --H,
--C.sub.1-9alkyl, --CR.sup.10R.sup.11OC(O)C.sub.1-9alkyl,
--CR.sup.10R.sup.11OC(O)OC.sub.1-9alkyl, and
##STR00011##
[0102] Some embodiments of compounds of Formula (I-A), Formula (I)
or Formula (I-1) include compounds having the structure of Formula
(Ia):
##STR00012##
or a pharmaceutically acceptable salt thereof, wherein: n is 0 or
1; and J, L, and M are each independently selected from the group
consisting of CR.sup.5 and N.
[0103] Some embodiments of compounds of Formula (I'), Formula (I),
Formula (I-1), or Formula (Ia) or their pharmaceutically acceptable
salts have the following stereochemistry as shown in the structure
of formula (Ib)
##STR00013##
[0104] Some embodiments of compounds of Formula (I'), Formula (I),
Formula (I-1), or Formula (Ia) or their pharmaceutically acceptable
salts have the following stereochemistry as shown in the structure
of formula (Ic)
##STR00014##
[0105] Some embodiments of compounds of Formula (II') or Formula
(II) include compounds having the structure of Formula (IIa):
##STR00015## [0106] or a pharmaceutically acceptable salt thereof,
wherein: n is 0 or 1; and J, L, and M are each independently
selected from the group consisting of CR.sup.5 and N.
[0107] Some embodiments of compounds of Formula (II'), Formula (II)
or Formula (IIa) or their pharmaceutically acceptable salts include
compounds having the structure of Formula (IIb):
##STR00016##
[0108] Some embodiments of compounds of Formula (II'), Formula
(II), Formula (IIa), or Formula (IIb) or their pharmaceutically
acceptable salts include compounds having the structure of Formula
(IIc):
##STR00017##
[0109] In some embodiments of Formula (I'), (I), (I-1), (Ia), (Ib)
(Ic), (II'), (II), (IIa), (IIb), or (IIc), Y.sup.2 is selected from
the group consisting of --S--, --SO.sub.2--, --O--, or --NH--. In
some embodiments of Formula (I'), (I), (I-1), (Ia), (Ib) (Ic),
(II), (IIa), (IIb), or (IIc), Y.sup.2 is selected from the group
consisting of --S--, --SO.sub.2--, --O--, or --NR.sup.1--.
[0110] In some embodiments of Formula (I') or (I), Y.sup.4 is
--O--.
[0111] In some embodiments of Formula (Ia), (Ib) (Ic), (IIa),
(IIb), or (IIc), M is N. In some embodiments of Formula (Ia), (Ib)
(Ic), (IIa), (IIb), or (IIc), M is CR.sup.5. In some embodiments of
Formula (Ia), (Ib) (Ic), (IIa), (IIb), or (IIc), J and L are each
independently CR.sup.5. In some embodiments, J and L are CH. In
some embodiments of Formula (Ia), (Ib) (Ic), (IIa), (IIb), or
(IIc), J is N. In some embodiments of Formula (Ia), (Ib) (Ic),
(IIa), (IIb), or (IIc), L and M are each independently CR.sup.5. In
some embodiments of Formula (Ia), (Ib) (Ic), (IIa), (IIb), or
(IIc), L is N. In some embodiments of Formula (Ia), (Ib) (Ic),
(IIa), (IIb), or (IIc), J and M are each independently
CR.sup.5.
[0112] In some embodiments of Formula (I), R.sup.7 is --OH.
[0113] Some embodiments of the compounds of Formula (I') or Formula
(I) or their pharmaceutically acceptable salts can have the
structure of Formula (Id):
##STR00018##
[0114] In some embodiments of Formula (I'), (II'), (I), (II), (Ia),
(Ib) (Ic), (Id), (IIa), (IIb), or (IIc), Y.sup.2 is --O-- or --S--;
G is selected from the group consisting of C.sub.1-4alkyl, phenyl,
imidazole, pyrazole, triazole, tetrazole, thiazole, thiadiazole,
oxazole, oxadiazole, isoxazole, isothiazole, pyridine, pyrazine,
pyrimidine, pyridazine, and pyrazine, each optionally substituted
by 0-2 substituents selected from the group consisting of hydroxy,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
alkoxy(C.sub.1-C.sub.6)alkyl, aryloxy, halo(C.sub.1-C.sub.6)alkoxy,
amino, C-amido, and N-amido; and J, L and M are CR.sup.5.
[0115] In some embodiments of Formula (I'), (II'), (I), (II), (Ia),
(Ib), (Ic), (Id), (IIa), (IIb), or (IIc), G is C.sub.1-4alkyl. In
some embodiments, G is --CH.sub.3.
[0116] In some embodiments of Formula (I'), (II'), (I), (II), (Ia),
(Ib), (Ic), (Id), (IIa), (IIb), or (IIc), G is thiadiazole
optionally substituted with amino. In some embodiments, G is
##STR00019##
[0117] In some embodiments of Formula (I'), (II'), (I), (II), (Ia),
(Ib), (Ic), (Id), (IIa), (IIb), or (IIc), M is CR.sup.5; and each
R.sup.5 is independently selected from the group consisting of --H,
--C.sub.1-4alkyl, and halogen, --CF.sub.3, and
--(CH.sub.2).sub.p--Y.sup.3--(CH.sub.2).sub.qM'.
[0118] In some embodiments, R.sup.5 is CN, --C(O)OR.sup.1;
--C(O)NR.sup.1R.sup.2; --C(O)NR.sup.1OR.sup.2;
--NR.sup.1C(O)R.sup.2; --NR.sup.1C(O)NR.sup.2R.sup.3;
--NR.sup.1C(O)OR.sup.2; --NR.sup.1S(O).sub.2R.sup.2;
--NR.sup.1S(O).sub.2NR.sup.2R3; --C(.dbd.NR.sup.1)R.sup.2;
--C(.dbd.NR.sup.1)NR.sup.2R.sup.3;
--NR.sup.1CR.sup.2(.dbd.NR.sup.3);
--NR.sup.1C(.dbd.NR.sup.2)NR.sup.3R.sup.4;
--S(O)(CH.sub.2).sub.1-3R.sup.4, --S(O).sub.2NR.sup.1R.sup.2,
--S(O).sub.2NR.sup.1OR.sup.3, or
--NR.sup.1S(O).sub.2NR.sup.1OR.sup.3. In some embodiments, R.sup.5
is --(CH.sub.2).sub.p--Y.sup.3--(CH.sub.2).sub.qM'.
[0119] In some embodiments, p and q are each independently 0, 1, or
2. In some embodiments, p and q are each independently 0 or 1.
[0120] In some embodiments of Formula (I'), (II'), (I), (II), (Ia),
(Ib), (Ic), (Id), (IIa), (IIb), or (IIc), R.sup.5 is
--(CH.sub.2).sub.p--Y.sup.3--(CH.sub.2).sub.qM'; m is 0; p is 0;
Y.sup.3 is S or O; and M' is hydrogen; hydroxyl; C.sub.1-C.sub.4
alkyl optionally substituted with one or more substituents selected
from the group consisting of --O--C.sub.1-C.sub.6alkyl,
--S--C.sub.1-C.sub.6alkyl, amino, --C(O)-amino, --S(O).sub.2-amino,
hydroxy, cyano, azido, and halogen; C.sub.3-10 cycloalkyl
optionally substituted with one or more substituents selected from
the group consisting of C.sub.1-C.sub.6alkyl,
--O--C.sub.1-C.sub.6alkyl, --S--C.sub.1-C.sub.6alkyl, amino,
--C(O)-amino, --S(O).sub.2-amino, hydroxy, cyano, azido, and
halogen; C.sub.6-C.sub.10 aryl optionally substituted with one or
more substituents selected from the group consisting of
C.sub.1-C.sub.6alkyl, --O--C.sub.1-C.sub.6alkyl,
--S--C.sub.1-C.sub.6alkyl, amino, --C(O)-amino, --S(O).sub.2-amino,
hydroxy, cyano, azido, and halogen; 5 to 10 membered heteroaryl
optionally substituted with one or more substituents selected from
the group consisting of C.sub.1-C.sub.6alkyl,
--O--C.sub.1-C.sub.6alkyl, --S--C.sub.1-C.sub.6alkyl, amino,
--C(O)-amino, --S(O).sub.2-amino, hydroxy, cyano, azido, and
halogen; and 4 to 10 membered heterocyclyl optionally substituted
with one or more substituents selected from the group consisting of
C.sub.1-C.sub.6alkyl, --O--C.sub.1-C.sub.6alkyl,
--S--C.sub.1-C.sub.6alkyl, amino, --C(O)-amino, --S(O).sub.2-amino,
hydroxy, cyano, azido, and halogen.
[0121] In some embodiments, M' is selected from the group
consisting of halogen, cycano, --OH, --S(O).sub.2R.sup.1,
--S(O).sub.2NR.sup.1R.sup.2, --S(O).sub.2NR.sup.1OR.sup.3,
C.sub.1-4 alkyl optionally substituted with 0-2 substituents
selected from the group consisting of --OR.sup.1, --CN,
--NR.sup.1R.sup.2, -heterocyclyl, halogen, --C(O)NR.sup.1R.sup.2,
and --NR.sup.1C(O)R.sup.2; C.sub.2-4 alkenyl optionally substituted
with 0-2 substituents selected from the group consisting of
C.sub.1-4 alkyl, --(CH.sub.2).sub.0-4OR.sup.1,
--(CH.sub.2).sub.0-4CN, --(CH.sub.2).sub.0-4NR.sup.1R.sup.2,
--(CH.sub.2).sub.0-4-heterocyclyl, halogen, --C(O)NR.sup.1R.sup.2,
and --NR.sup.1C(O)R.sup.2; C.sub.2-4 alkynyl optionally substituted
with 0-2 substituents selected from the group consisting of
C.sub.1-4 alkyl, --(CH.sub.2).sub.0-4OR.sup.1,
--(CH.sub.2).sub.0-4CN, --(CH.sub.2).sub.0-4NR.sup.1R.sup.2,
--(CH.sub.2).sub.0-4-heterocyclyl, halogen, --C(O)NR.sup.1R.sup.2,
and --NR.sup.1C(O)R.sup.2; C.sub.6-10 aryl optionally substituted
with 0-2 substituents selected from the group consisting of
C.sub.1-4 alkyl, --(CH.sub.2).sub.0-4OR.sup.1,
--(CH.sub.2).sub.0-4CN, --(CH.sub.2).sub.0-4NR.sup.1R.sup.2,
--(CH.sub.2).sub.0-4-heterocyclyl, halogen, --C(O)NR.sup.1R.sup.2,
and --NR.sup.1C(O)R.sup.2; C.sub.3-7 carbocyclyl optionally
substituted with 0-2 substituents selected from the group
consisting of C.sub.1-4 alkyl, --(CH.sub.2).sub.0-4OR.sup.1,
--(CH.sub.2).sub.0-4CN, --(CH.sub.2).sub.0-4NR.sup.1R.sup.2,
--(CH.sub.2).sub.0-4-heterocyclyl, halogen, --C(O)NR.sup.1R.sup.2,
and --NR.sup.1C(O)R.sup.2; 5-10 membered heteroaryl optionally
substituted with 0-2 substituents selected from the group
consisting of C.sub.1-4 alkyl, --(CH.sub.2).sub.0-4OR.sup.1,
--(CH.sub.2).sub.0-4CN, --(CH.sub.2).sub.0-4NR.sup.1R.sup.2,
--(CH.sub.2).sub.0-4-heterocyclyl, halogen, --C(O)NR.sup.1R.sup.2,
and --NR.sup.1C(O)R.sup.2; and 3-10 membered heterocyclyl
optionally substituted with 0-2 substituents selected from the
group consisting of C.sub.1-4 alkyl, --(CH.sub.2).sub.0-4OR.sup.1,
--(CH.sub.2).sub.0-4CN, --(CH.sub.2).sub.0-4NR.sup.1R.sup.2,
--(CH.sub.2).sub.0-4-heterocyclyl, halogen, --C(O)NR.sup.1R.sup.2,
and --NR.sup.1C(O)R.sup.2.
[0122] In some embodiments of Formula (I'), (II'), (I), (II), (Ia),
(Ib), (Ic), (Id), (IIa), (IIb), or (IIc), R.sup.5 is halogen. In
some embodiments, R.sup.5 is F.
[0123] In some embodiments, R.sup.5 is --S--C.sub.1-C.sub.6alkyl,
--S--C.sub.1-C.sub.6 cycloalkyl, or --S-4 to 10 membered
heterocyclyl. In some embodiments, R.sup.5 is --S--CH.sub.3.
[0124] In some embodiments, R.sup.5 is --O--C.sub.1-C.sub.6alkyl,
--O--C.sub.1-C.sub.6 cycloalkyl, or --O-4 to 10 membered
heterocyclyl. In some embodiments, R.sup.5 is
##STR00020##
In some embodiments, R.sup.5 is --OCH.sub.3.
[0125] In some embodiments of Formula (I'), (II'), (I), (Ia), (Ib),
(Ic), (Id), (IIa), (IIb), or (IIc), n is 0 or 1; Y.sup.2 is --NH--;
G is selected from the group consisting of --C(O)R.sup.4,
--C(O)(CH.sub.2).sub.0-3SR.sup.3, --C(O)(CH.sub.2).sub.1-3R.sup.4,
--C(O)OR.sup.3, --C(O)NR.sup.1R.sup.2, --S(O).sub.2R.sup.3,
--C(.dbd.NR.sup.1)R.sup.4, and
--C(.dbd.NR.sup.1)NR.sup.1R.sup.2.
[0126] In some embodiments, G is selected from the group consisting
of --C(O)R.sup.4, --C(O)(CH.sub.2).sub.0-3SR.sup.3, --C(O)OR.sup.3,
--C(O)NR.sup.1R.sup.2, --S(O).sub.2R.sup.3,
--C(.dbd.NR.sup.1)R.sup.4, and --C(.dbd.NR.sup.1)NR.sup.1R.sup.2.
In some embodiments, G is --C(O)R.sup.4. In some embodiments, G is
--C(O)(CH.sub.2)R.sup.4.
[0127] In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Id),
(IIa), (IIb), or (IIc), G is --C(O)R.sup.4; wherein R.sup.4 is
optionally substituted C.sub.1-4alkyl or R.sup.4 is C.sub.1-4alkyl
substituted with C.sub.1-C.sub.4 alkylthio or R.sup.4 is
C.sub.1-4alkyl substituted with 5-10 membered heteroaryl optionally
substituted with halo, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, C.sub.1-C.sub.6 haloalkyl, and C.sub.1-C.sub.6 haloalkoxy
or R.sup.4 is optionally substituted 5-10 membered heteroaryl or
R.sup.4 is 5-10 membered heteroaryl substituted with amino. In some
embodiments, for the R.sup.4 in G, R.sup.4 is optionally
substituted C.sub.1-4alkyl. R.sup.4 is C.sub.1-4alkyl substituted
with C.sub.1-C.sub.4 alkylthio. In some embodiments, for the
R.sup.4 in G, R.sup.4 is --CH.sub.2SCH.sub.3. In some embodiments,
for the R.sup.4 in G, R.sup.4 is C.sub.1-4alkyl substituted with
5-10 membered heteroaryl optionally substituted with halo,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
haloalkyl, and C.sub.1-C.sub.6 haloalkoxy. In some embodiments, for
the R.sup.4 in G, R.sup.4 is
##STR00021##
In some embodiments, for the R.sup.4 in G, R.sup.4 is optionally
substituted 5-10 membered heteroaryl. In some embodiments, for the
R.sup.4 in G, R.sup.4 is 5-10 membered heteroaryl substituted with
amino. In some embodiments, R.sup.4
##STR00022##
[0128] In some embodiments, G is
##STR00023##
In some embodiments, G is
##STR00024##
In some embodiments, G is optionally substituted C.sub.6-10aryl. In
some embodiments, G is --S(O)(CH.sub.2).sub.1-3R.sup.3,
--S(O).sub.2NR.sup.1R.sup.2, --S(O).sub.2NR.sup.1OR.sup.3,
--NR.sup.1S(O).sub.2NR.sup.1OR.sup.3, --CN, --OR.sup.1, --SR.sup.1,
or --NR.sup.1R.sup.2.
[0129] In some embodiments of Formula (I'), (II'), (I), (Ia), (Ib),
(Ic), (Id), (IIa), (IIb), or (IIc), G is
--C(O)CH.sub.2SR.sup.3.
[0130] In some embodiments of Formula (I'), (II'), (I), (Ia), (Ib),
(Ic), (Id), (IIa), (IIb), or (IIc), when G is
--C(O)CH.sub.2SR.sup.3, R.sup.3 is C.sub.1-4alkyl. In some
embodiments, G is --C(O)(CH.sub.2)SCH.sub.3.
[0131] In some embodiments of Formula (I'), (II'), (I), (Ia), (Ib),
(Ic), (Id), (IIa), (IIb), or (IIc), when G is
--C(O)CH.sub.2SR.sup.3, R.sup.3 is 5-10 membered heterocyclyl.
[0132] In some embodiments of Formula (I'), (II'), (I), (Ia), (Ib),
(Ic), (Id), (IIa), (IIb), or (IIc), Y.sup.2 is --S(O).sub.2--.
[0133] In some embodiments of Formula (I'), (II'), (I), (Ia), (Ib),
(Ic), (Id), (IIa), (IIb), or (IIc), wherein Y.sup.2 is
--S(O).sub.2--, G is optionally substituted C.sub.6-10aryl.
[0134] In some embodiments of Formula (I'), (II'), (I), (Ia), (Ib),
(Ic), (Id), (IIa), (IIb), or (IIc), Y.sup.1 is CH or N. In some
embodiments, Y.sup.1 is CH. In some embodiments, Y.sup.1 is N.
[0135] Some embodiments include a compound selected from the group
consisting of:
##STR00025## ##STR00026##
or a pharmaceutically acceptable salt thereof.
[0136] Some embodiments of the compounds of Formula (III') or (III)
can have the structure of Formula (IIIa):
##STR00027## [0137] or its pharmaceutically acceptable salts
[0138] Some embodiments of the compounds of Formula (III') or (III)
can have the structure of Formula (IIIb):
##STR00028## [0139] or its pharmaceutically acceptable salts.
[0140] Some embodiments of the compounds of Formula (III') or (III)
can have the structure of Formula (IIIc):
##STR00029## [0141] or its pharmaceutically acceptable salts,
wherein: [0142] m is 0, 1, or 2; and [0143] J, L, and M are each
independently selected from the group consisting of CR.sup.5 and
N.
[0144] Some embodiments of the compounds of Formula (III'), (III),
or (IIIc) can have the structure of Formula (IIId):
##STR00030## [0145] or its pharmaceutically acceptable salts.
[0146] Some embodiments of the compounds of Formula (IV') or (IV)
can have the structure of Formula (IVa):
##STR00031## [0147] or its pharmaceutically acceptable salts,
wherein: [0148] m is 0, 1, or 2; and [0149] J, L, and M are each
independently selected from the group consisting of CR.sup.5 and
N.
[0150] Some embodiments of the compounds of Formula (IV'), (IV), or
(IVa) can have the structure of Formula (IVb):
##STR00032## [0151] or its pharmaceutically acceptable salts.
[0152] Some embodiments of the compounds of Formula (III'), (IV'),
(III) or (IV) can have the structure of Formula (III-1) or
(IV-1):
##STR00033## [0153] wherein J, L, and M are each independently
selected from the group consisting of CR.sup.5 and N.
[0154] In some embodiments, for the compounds of Formula (III') or
(IV'), n.sup.1 is 1 and Q.sup.1 and Q.sup.2 are deuterium. In some
embodiments, Q.sup.1 is hydrogen and Q.sup.2 is deuterium.
[0155] In some embodiments, for the compounds of Formula (III'),
(IV'), (III), (IV), (III-1), or (IV-1), Y.sup.7 is CH.sub.2, O, or
S. In some embodiments, Y.sup.7 is CH.sub.2. In some embodiments,
Y.sup.7 is O. In some embodiments, Y.sup.7 is S. In some
embodiments, Y.sup.7 is NH. In some embodiments, Y.sup.7 is O,
n.sup.1 is 1, and m is 1.
[0156] Some embodiments of the compounds of Formula (III'), (IV'),
(III), (IV), (III-1), (IV-1), or their pharmaceutically acceptable
salts can have the structure of Formula (III-2), or (IV-2):
##STR00034##
[0157] In some embodiments, M is CR.sup.5. In some embodiments, M
is N. In some embodiments, M is CH. In some embodiments, J is N,
and L and M are each independently CR.sup.5. In some embodiments, L
is N, and J and M are each independently CR.sup.5. In some
embodiments, M is N, and J and L are each independently
CR.sup.5.
[0158] In some embodiments, J and L are each independently
CR.sup.5. In some embodiments, J and L are CH. In some embodiments,
MJ and M are CH. In some embodiments, L and M are CH.
[0159] In some embodiments, R.sup.5 is selected from the group
consisting of C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.7 carbocyclyl,
C.sub.1-C.sub.6 heteroalkyl, 5-10 membered heterocyclyl,
C.sub.6-C.sub.10 aryl, 5-10 membered heteroaryl, cyano, hydroxy,
--OR.sup.3, --SR.sup.3, --S(O).sub.2M', --P(O)R.sup.1M', and
halogen. In some embodiments, R.sup.5 is halogen. In some
embodiments, R.sup.5 is F. In some embodiments, R.sup.5 is alkoxy.
In some embodiments, R.sup.5 is --OCH.sub.3. In some embodiments,
R.sup.5 is --OCH.sub.2CH.sub.3. In some embodiments, R.sup.5 is
--OH. In some embodiments, R.sup.5 is --SH. In some embodiments,
R.sup.5 is --SCH.sub.3. In some embodiments, R.sup.5 is
--S(O).sub.2M'. In some embodiments, R.sup.5 is
--S(O).sub.2CH.sub.3. In some embodiments, R.sup.5 is --SOM'. In
some embodiments, R.sup.5 is --S(O).sub.2CH.sub.3. In some
embodiments, R.sup.5 is cyano. In some embodiments, R.sup.5 is
--C.ident.CH. In some embodiments, R.sup.5 is --CHF.sub.2. In some
embodiments, R.sup.5 is --CF.sub.3. In some embodiments, R.sup.5 is
--C(O)NR.sup.1R.sup.2. In some embodiments, R.sup.5 is
--C(O)NH.sub.2. In some embodiments, R.sup.5 is
--C(.dbd.NR.sup.1)R.sup.2. In some embodiments, R.sup.5 is
--CH.dbd.N--OCH.sub.3. In some embodiments, R.sup.5 is
--COOR.sup.1. In some embodiments, R.sup.5 is --COOH. In some
embodiments, R.sup.5 is a C.sub.2-4 alkynyl, triazole, or diazole,
optionally substituted with 0-2 substituents selected from
--(CH.sub.2).sub.0-4OR.sup.1, --(CH.sub.2).sub.0-4CN,
--(CH.sub.2).sub.0-4NR.sup.1R.sup.2,
--(CH.sub.2).sub.0-4-heterocyclyl, halogen, --C(O)NR.sup.1R.sup.2,
and --NR.sup.1C(O)R.sup.2. In some embodiments, R.sup.5 is
##STR00035##
In some embodiments, R.sup.5 is
--(CH.sub.2).sub.p--Y.sup.3--(CH.sub.2).sub.qM'.
[0160] In some embodiments, Y.sup.3 is --S--, --O--, or --NH--. In
some embodiments, Y.sup.3 is --S--. In some embodiments, Y.sup.3 is
--O--. In some embodiments, Y.sup.3 is --NH--. In some embodiments,
Y.sup.3 is --S(O)-- or --S(O).sub.2--. In some embodiments, Y.sup.3
is --S(O)--. In some embodiments, Y.sup.3 is --S(O).sub.2--.
[0161] In some embodiments, M' is a 5-10 membered heteroaryl or
3-10 membered heterocyclyl, each optionally substituted with 0-2
substituents selected from the group consisting of C.sub.1-4 alkyl,
--(CH.sub.2).sub.0-4OR.sup.1, --(CH.sub.2).sub.0-4CN,
--(CH.sub.2).sub.0-4NR.sup.1R.sup.2,
--(CH.sub.2).sub.0-4-heterocyclyl, halogen, --C(O)NR.sup.1R.sup.2,
and --NR.sup.1C(O)R.sup.2. In some embodiments, M' is azetine,
thiadiazole, triazole, dioxolane, pyridine, morpholine, or
cyclopropyl, each optionally substituted with 0-2 substituents
selected from the group consisting of C.sub.1-4 alkyl,
--(CH.sub.2).sub.0-4OR.sup.1, --(CH.sub.2).sub.0-4CN,
--(CH.sub.2).sub.0-4NR.sup.1R.sup.2,
--(CH.sub.2).sub.0-4-heterocyclyl, halogen, --C(O)NR.sup.1R.sup.2,
and --NR.sup.1C(O)R.sup.2. In some embodiments, M' is
##STR00036##
each optionally substituted with 0-2 substituents selected from the
group consisting of C.sub.1-4 alkyl, --(CH.sub.2).sub.0-4OR.sup.1,
--(CH.sub.2).sub.0-4CN, --(CH.sub.2).sub.0-4NR.sup.1R.sup.2,
--(CH.sub.2).sub.0-4-heterocyclyl, halogen, --C(O)NR.sup.1R.sup.2,
and --NR.sup.1C(O)R.sup.2. In some embodiments, M' is
##STR00037##
In some embodiments, M' is cyano. In some embodiments, M' is --OH.
In some embodiments, M' is --S(O).sub.2R.sup.1 or
--S(O).sub.2NR.sup.1R.sup.2. In some embodiments, M' is
--S(O).sub.2CH.sub.3 or --S(O).sub.2NH.sub.2. In some embodiments,
M' is --C(O)NR.sup.1R.sup.2. In some embodiments, M' is
--C(O)NH.sub.2. In some embodiments, M' is C.sub.1-4 alkyl
optionally substituted with 0-2 substituents selected from the
group consisting of --OR.sup.1, --CN, --NR.sup.1R.sup.2,
-heterocyclyl halogen, --C(O)NR.sup.1R.sup.2, and
--NR.sup.1C(O)R.sup.2; C.sub.2-4 alkenyl optionally substituted
with 0-2 substituents selected from the group consisting of
C.sub.1-4 alkyl, --(CH.sub.2).sub.0-4OR.sup.1,
--(CH.sub.2).sub.0-4CN, --(CH.sub.2).sub.0-4NR.sup.1R.sup.2,
--(CH.sub.2).sub.0-4-heterocyclyl, halogen, --C(O)NR.sup.1R.sup.2,
and --NR.sup.1C(O)R.sup.2; or C.sub.2-4 alkynyl optionally
substituted with 0-2 substituents selected from the group
consisting of C.sub.1-4 alkyl, --(CH.sub.2).sub.0-4OR.sup.1,
--(CH.sub.2).sub.0-4CN, --(CH.sub.2).sub.0-4NR.sup.1R.sup.2,
--(CH.sub.2).sub.0-4-heterocyclyl, halogen, --C(O)NR.sup.1R.sup.2,
and --NR.sup.1C(O)R.sup.2. In some embodiments, M' is --C.ident.CH.
In some embodiments, M' is --C.ident.C--(CH.sub.2).sub.0-4OR.sup.1,
--C.ident.C--(CH.sub.2).sub.0-4NR.sup.1R.sup.2, or
--C.ident.C--(CH.sub.2).sub.0-4-heterocyclyl. In some embodiments,
M' is --C.ident.C--(CH.sub.2)--OCH.sub.3,
--C.ident.C--(CH.sub.2)--OH, --C.ident.C--(CH.sub.2)--NH.sub.2,
or
##STR00038##
In some embodiments, M' is --(CH.sub.2).sub.3NH.sub.2, CH.sub.2F,
CHF.sub.2, CF.sub.3, CH(CH.sub.2OH).sub.2, or
CH.sub.2N(CH.sub.3).sub.2. In some embodiments, M' is C.sub.1-4
alkyl.
[0162] In some embodiments, R.sup.5 is present twice. In some
embodiments,
[0163] L and M are each independently CR.sup.5; J is CH; and each
R.sup.5 is independently selected from the group consisting of OH,
halogen, CN, --C(O)OR.sup.1; --C(O)NR.sup.1R.sup.2;
--C(O)NR.sup.1OR.sup.2; --NR.sup.1C(O)R.sup.2;
--NR.sup.1C(O)NR.sup.2R.sup.3; --NR.sup.1C(O)OR.sup.2;
--NR.sup.1S(O).sub.2R.sup.2; --NR.sup.1S(O).sub.2NR.sup.2R.sup.3;
--C(.dbd.NR.sup.1)R.sup.2; --C(.dbd.NR.sup.1)NR.sup.2R.sup.3;
--NR.sup.1CR.sup.2 (.dbd.NR.sup.3);
--NR.sup.1C(.dbd.NR.sup.2)NR.sup.3R.sup.4;
--S(O)(CH.sub.2).sub.1-3R.sup.4, --S(O).sub.2NR.sup.1R.sup.2,
--S(O).sub.2NR.sup.1OR.sup.3, --NR.sup.1S(O).sub.2NR.sup.1OR.sup.3,
optionally substituted C.sub.2-C.sub.6 alkenyl, optionally
substituted C.sub.2-C.sub.6 alkynyl, optionally substituted
C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.7
carbocyclyl, optionally substituted 5-10 membered heterocyclyl,
optionally substituted C.sub.6-10aryl, optionally substituted 5-10
membered heteroaryl, cyano, C.sub.1-C.sub.6
alkoxy(C.sub.1-C.sub.6)alkyl, aryloxy, sulfhydryl (mercapto), and
--(CH.sub.2).sub.p--Y.sup.3--(CH.sub.2).sub.qM'. In some
embodiments, each R.sup.5 is independently halogen or --OM'. In
some embodiments, each R.sup.5 is independently F or --OCH.sub.3.
In some embodiments, each R.sup.5 is independently Cl or
--OCH.sub.3.
[0164] In some embodiments, R.sup.6 is --COOR or --P(O)(OR).sub.2.
In some embodiments, R.sup.1 is --COOH or --P(O)(OH).sub.2.
[0165] In some embodiments, R is H. In some embodiments, R is
alkali metal or NH.sub.4.sup.+. In some embodiments, R is Na.
[0166] Some specific embodiments of the compounds described herein
have the structure selected from the group consisting of
##STR00039##
and pharmaceutically acceptable salts thereof.
[0167] Some specific embodiments of the compounds described herein
have the structure selected from the group consisting of
##STR00040## ##STR00041## ##STR00042## ##STR00043## ##STR00044##
##STR00045## ##STR00046##
and pharmaceutically acceptable salts thereof.
[0168] In some embodiments, the pharmaceutically acceptable salt is
an alkaline metal salt or ammonium salt. In some embodiments, the
pharmaceutically acceptable salt is a sodium salt.
[0169] In some embodiments, the compound of formula (III) or (IV)
can have the structure selected from
##STR00047##
In some embodiments, the compound of formula (III'), (III), (IV)
and (IV') can have the structure selected from
##STR00048## ##STR00049## ##STR00050## ##STR00051## ##STR00052##
##STR00053## ##STR00054## ##STR00055##
[0170] Where the compounds disclosed herein have at least one
chiral center, they may exist as individual enantiomers and
diastereomers or as mixtures of such isomers, including racemates.
Separation of the individual isomers or selective synthesis of the
individual isomers is accomplished by application of various
methods which are well known to practitioners in the art. Unless
otherwise indicated, all such isomers and mixtures thereof are
included in the scope of the compounds disclosed herein.
Furthermore, compounds disclosed herein may exist in one or more
crystalline or amorphous forms. Unless otherwise indicated, all
such forms are included in the scope of the compounds disclosed
herein including any polymorphic forms. In addition, some of the
compounds disclosed herein may form solvates with water (i.e.,
hydrates) or common organic solvents. Unless otherwise indicated,
such solvates are included in the scope of the compounds disclosed
herein.
[0171] The skilled artisan will recognize that some structures
described herein may be resonance forms or tautomers of compounds
that may be fairly represented by other chemical structures, even
when kinetically; the artisan recognizes that such structures may
only represent a very small portion of a sample of such
compound(s). Such compounds are considered within the scope of the
structures depicted, though such resonance forms or tautomers are
not represented herein.
[0172] Isotopes may be present in the compounds described. Each
chemical element as represented in a compound structure may include
any isotope of said element. For example, in a compound structure a
hydrogen atom may be explicitly disclosed or understood to be
present in the compound. At any position of the compound that a
hydrogen atom may be present, the hydrogen atom can be any isotope
of hydrogen, including but not limited to hydrogen-1 (protium) and
hydrogen-2 (deuterium). Thus, reference herein to a compound
encompasses all potential isotopic forms unless the context clearly
dictates otherwise.
[0173] In some embodiments, due to the facile exchange of boron
esters, the compounds described herein may convert to or exist in
equilibrium with alternate forms. Accordingly, in some embodiments,
the compounds described herein may exist in combination with one or
more of these forms. For example, as shown below, the compounds
disclosed herein may exist in cyclic boronate monoesters as formula
I' or in acyclic form as boronic acids as formula II', or may exist
as a mixture of the two forms depending on the medium; the
compounds disclosed herein may exist in cyclic form as cyclic
boronate monoesters as formula III-1 or in acyclic form as boronic
acids as formula IV-1, or may exist as a mixture of the two forms
depending on the medium; the compounds disclosed herein may exist
in cyclic boronate monoesters as formula I or in acyclic form as
boronic acids as formula II, or may exist as a mixture of the two
forms depending on the medium. In another example, the compounds
disclosed herein may exist in cyclic form as cyclic boronate
monoesters as formula III' or in acyclic form as boronic acids as
formula IV', or may exist as a mixture of the two forms depending
on the medium; the compounds disclosed herein may exist in cyclic
form as cyclic boronate monoesters as formula III-1 or in acyclic
form as boronic acids as formula IV-1, or may exist as a mixture of
the two forms depending on the medium.
##STR00056##
[0174] In some embodiments, the compounds described herein may
exist in cyclic dimeric form as Formula (C) or trimeric form as
Formula (D), tetrameric form as Formula (E) as shown below, or
acylic dimeric, trimeric or tetrameric forms and the like. In some
embodiments, Q can be H or --Y.sup.2--(CH.sub.2).sub.n-G; Y' can be
CR.sup.1 or N; and X' can be --Y.sup.2--(CH.sub.2).sub.n-G in
Formula C, D and E.
##STR00057##
Definitions
[0175] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as is commonly understood by one
of ordinary skill in the art to which this disclosure belongs. All
patents, applications, published applications, and other
publications are incorporated by reference in their entirety. In
the event that there is a plurality of definitions for a term
herein, those in this section prevail unless stated otherwise.
[0176] A "prodrug" refers to an agent that is converted into the
parent drug in vivo. Prodrugs are often useful because, in some
situations, they may be easier to administer than the parent drug.
They may, for instance, be bioavailable by oral administration
whereas the parent is not. The prodrug may also have improved
solubility in pharmaceutical compositions over the parent drug. An
example, without limitation, of a prodrug would be a compound which
is administered as an ester (the "prodrug") to facilitate
transmittal across a cell membrane where water solubility is
detrimental to mobility but which then is metabolically hydrolyzed
to the carboxylic acid, the active entity, once inside the cell
where water-solubility is beneficial. A further example of a
prodrug might be a short peptide (polyaminoacid) bonded to an acid
group where the peptide is metabolized to reveal the active moiety.
Conventional procedures for the selection and preparation of
suitable prodrug derivatives are described, for example, in Design
of Prodrugs, (ed. H. Bundgaard, Elsevier, 1985), which is hereby
incorporated herein by reference in its entirety.
[0177] The term "pro-drug ester" refers to derivatives of the
compounds disclosed herein formed by the addition of any of several
ester-forming groups that are hydrolyzed under physiological
conditions. Examples of pro-drug ester groups include
pivoyloxymethyl, acetoxymethyl, phthalidyl, indanyl and
methoxymethyl, as well as other such groups known in the art,
including a (5-R-2-oxo-1,3-dioxolen-4-yl)methyl group. Other
examples of pro-drug ester groups can be found in, for example, T.
Higuchi and V. Stella, in "Pro-drugs as Novel Delivery Systems",
Vol. 14, A.C.S. Symposium Series, American Chemical Society (1975);
and "Bioreversible Carriers in Drug Design: Theory and
Application", edited by E. B. Roche, Pergamon Press: New York,
14-21 (1987) (providing examples of esters useful as prodrugs for
compounds containing carboxyl groups). Each of the above-mentioned
references is herein incorporated by reference in their
entirety.
[0178] "Metabolites" of the compounds disclosed herein include
active species that are produced upon introduction of the compounds
into the biological milieu.
[0179] "Solvate" refers to the compound formed by the interaction
of a solvent and a compound described herein, a metabolite, or salt
thereof. Suitable solvates are pharmaceutically acceptable solvates
including hydrates.
[0180] The term "pharmaceutically acceptable salt" refers to salts
that retain the biological effectiveness and properties of a
compound, which are not biologically or otherwise undesirable for
use in a pharmaceutical. In many cases, the compounds herein are
capable of forming acid and/or base salts by virtue of the presence
of amino and/or carboxyl groups or groups similar thereto.
Pharmaceutically acceptable acid addition salts can be formed with
inorganic acids and organic acids. Inorganic acids from which salts
can be derived include, for example, hydrochloric acid, hydrobromic
acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
Organic acids from which salts can be derived include, for example,
acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic
acid, maleic acid, malonic acid, succinic acid, fumaric acid,
tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic
acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic
acid, salicylic acid, and the like. Pharmaceutically acceptable
base addition salts can be formed with inorganic and organic bases.
Inorganic bases from which salts can be derived include, for
example, sodium, potassium, lithium, ammonium, calcium, magnesium,
iron, zinc, copper, manganese, aluminum, and the like; particularly
preferred are the ammonium, potassium, sodium, calcium and
magnesium salts. Organic bases from which salts can be derived
include, for example, primary, secondary, and tertiary amines,
substituted amines including naturally occurring substituted
amines, cyclic amines, basic ion exchange resins, and the like,
specifically such as isopropylamine, trimethylamine, diethylamine,
triethylamine, tripropylamine, and ethanolamine. Many such salts
are known in the art, as described in WO 87/05297, Johnston et al.,
published Sep. 11, 1987 (incorporated by reference herein in its
entirety). Some examples of pharmaceutically acceptable base
addition salts of the compounds disclosed herein have the structure
of Formula (IIIc-salt) or (IVa-salt):
##STR00058##
wherein Z can be an alkali metal or NH.sub.4.sup.+; and R can be an
alkali metal or NH.sub.4.sup.+. Some additional examples of
pharmaceutically acceptable base addition salts of the compounds
described herein have the structure of Formula (IIId-salt) or
(Ivb-salt):
##STR00059##
[0181] Some other examples of pharmaceutically acceptable base
addition salts of the compounds described herein have the structure
of Formula (I-salt) or (II-salt):
##STR00060##
[0182] As used herein, "C.sub.a to C.sub.b" or "C.sub.a-b" in which
"a" and "b" are integers refer to the number of carbon atoms in the
specified group. That is, the group can contain from "a" to "b",
inclusive, carbon atoms. Thus, for example, a "C.sub.1 to C.sub.4
alkyl" or "C.sub.1-4 alkyl" group refers to all alkyl groups having
from 1 to 4 carbons, that is, CH.sub.3--, CH.sub.3CH.sub.2--,
CH.sub.3CH.sub.2CH.sub.2--, (CH.sub.3).sub.2CH--,
CH.sub.3CH.sub.2CH.sub.2CH.sub.2--, CH.sub.3CH.sub.2CH(CH.sub.3)--
and (CH.sub.3).sub.3C--.
[0183] The term "halogen" or "halo," as used herein, means any one
of the radio-stable atoms of column 7 of the Periodic Table of the
Elements, e.g., fluorine, chlorine, bromine, or iodine, with
fluorine and chlorine being preferred.
[0184] As used herein, "alkyl" refers to a straight or branched
hydrocarbon chain that is fully saturated (i.e., contains no double
or triple bonds). The alkyl group may have 1 to 20 carbon atoms
(whenever it appears herein, a numerical range such as "1 to 20"
refers to each integer in the given range; e.g., "1 to 20 carbon
atoms" means that the alkyl group may consist of 1 carbon atom, 2
carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon
atoms, although the present definition also covers the occurrence
of the term "alkyl" where no numerical range is designated). The
alkyl group may also be a medium size alkyl having 1 to 9 carbon
atoms. The alkyl group could also be a lower alkyl having 1 to 4
carbon atoms. The alkyl group of the compounds may be designated as
"C.sub.1-4 alkyl" or similar designations. By way of example only,
"C.sub.1-4 alkyl" indicates that there are one to four carbon atoms
in the alkyl chain, i.e., the alkyl chain is selected from the
group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl,
iso-butyl, sec-butyl, and t-butyl. Typical alkyl groups include,
but are in no way limited to, methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, tertiary butyl, pentyl, hexyl, and the like.
[0185] As used herein, "alkoxy" refers to the formula --OR wherein
R is an alkyl as is defined above, such as "C.sub.1-9 alkoxy",
including but not limited to methoxy, ethoxy, n-propoxy,
1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, and
tert-butoxy, and the like.
[0186] As used herein, "alkylthio" refers to the formula --SR
wherein R is an alkyl as is defined above, such as "C.sub.1-9
alkylthio" and the like, including but not limited to
methylmercapto, ethylmercapto, n-propylmercapto,
1-methylethylmercapto (isopropylmercapto), n-butylmercapto,
iso-butylmercapto, sec-butylmercapto, tert-butylmercapto, and the
like.
[0187] As used herein, "alkenyl" refers to a straight or branched
hydrocarbon chain containing one or more double bonds. The alkenyl
group may have 2 to 20 carbon atoms, although the present
definition also covers the occurrence of the term "alkenyl" where
no numerical range is designated. The alkenyl group may also be a
medium size alkenyl having 2 to 9 carbon atoms. The alkenyl group
could also be a lower alkenyl having 2 to 4 carbon atoms. The
alkenyl group of the compounds may be designated as "C.sub.2-4
alkenyl" or similar designations. By way of example only,
"C.sub.2-4 alkenyl" indicates that there are two to four carbon
atoms in the alkenyl chain, i.e., the alkenyl chain is selected
from the group consisting of ethenyl, propen-1-yl, propen-2-yl,
propen-3-yl, buten-1-yl, buten-2-yl, buten-3-yl, buten-4-yl,
1-methyl-propen-1-yl, 2-methyl-propen-1-yl, 1-ethyl-ethen-1-yl,
2-methyl-propen-3-yl, buta-1,3-dienyl, buta-1,2,-dienyl, and
buta-1,2-dien-4-yl. Typical alkenyl groups include, but are in no
way limited to, ethenyl, propenyl, butenyl, pentenyl, and hexenyl,
and the like.
[0188] As used herein, "alkynyl" refers to a straight or branched
hydrocarbon chain containing one or more triple bonds. The alkynyl
group may have 2 to 20 carbon atoms, although the present
definition also covers the occurrence of the term "alkynyl" where
no numerical range is designated. The alkynyl group may also be a
medium size alkynyl having 2 to 9 carbon atoms. The alkynyl group
could also be a lower alkynyl having 2 to 4 carbon atoms. The
alkynyl group of the compounds may be designated as "C.sub.2-4
alkynyl" or similar designations. By way of example only,
"C.sub.2-4 alkynyl" indicates that there are two to four carbon
atoms in the alkynyl chain, i.e., the alkynyl chain is selected
from the group consisting of ethynyl, propyn-1-yl, propyn-2-yl,
butyn-1-yl, butyn-3-yl, butyn-4-yl, and 2-butynyl. Typical alkynyl
groups include, but are in no way limited to, ethynyl, propynyl,
butynyl, pentynyl, and hexynyl, and the like.
[0189] As used herein, "heteroalkyl" refers to a straight or
branched hydrocarbon chain containing one or more heteroatoms, that
is, an element other than carbon, including but not limited to,
nitrogen, oxygen and sulfur, in the chain backbone. The heteroalkyl
group may have 1 to 20 carbon atoms although the present definition
also covers the occurrence of the term "heteroalkyl" where no
numerical range is designated. The heteroalkyl group may also be a
medium size heteroalkyl having 1 to 9 carbon atoms. The heteroalkyl
group could also be a lower heteroalkyl having 1 to 4 carbon atoms.
The heteroalkyl group of the compounds may be designated as
"C.sub.1-4 heteroalkyl" or similar designations. The heteroalkyl
group may contain one or more heteroatoms. By way of example only,
"C.sub.1-4 heteroalkyl" indicates that there are one to four carbon
atoms in the heteroalkyl chain and additionally one or more
heteroatoms in the backbone of the chain.
[0190] The term "aromatic" refers to a ring or ring system having a
conjugated pi electron system and includes both carbocyclic
aromatic (e.g., phenyl) and heterocyclic aromatic groups (e.g.,
pyridine). The term includes monocyclic or fused-ring polycyclic
(i.e., rings which share adjacent pairs of atoms) groups provided
that the entire ring system is aromatic.
[0191] As used herein, "aryl" refers to an aromatic ring or ring
system (i.e., two or more fused rings that share two adjacent
carbon atoms) containing only carbon in the ring backbone. When the
aryl is a ring system, every ring in the system is aromatic. The
aryl group may have 6 to 18 carbon atoms, although the present
definition also covers the occurrence of the term "aryl" where no
numerical range is designated. In some embodiments, the aryl group
has 6 to 10 carbon atoms. The aryl group may be designated as
"C.sub.6-10 aryl," "C.sub.6 or C.sub.10 aryl," or similar
designations. Examples of aryl groups include, but are not limited
to, phenyl, naphthyl, azulenyl, and anthracenyl.
[0192] As used herein, "aryloxy" and "arylthio" refers to RO-- and
RS--, in which R is an aryl as is defined above, such as
"C.sub.6-10 aryloxy" or "C.sub.6-10 arylthio" and the like,
includingbut not limited to phenyloxy.
[0193] An "aralkyl" or "arylalkyl" is an aryl group connected, as a
substituent, via an alkylene group, such "C.sub.7-14 aralkyl" and
the like, including but not limited to benzyl, 2-phenylethyl,
3-phenylpropyl, and naphthylalkyl. In some cases, the alkylene
group is a lower alkylene group (i.e., a C.sub.1-4 alkylene
group).
[0194] As used herein, "heteroaryl" refers to an aromatic ring or
ring system (i.e., two or more fused rings that share two adjacent
atoms) that contain(s) one or more heteroatoms, that is, an element
other than carbon, including but not limited to, nitrogen, oxygen
and sulfur, in the ring backbone. When the heteroaryl is a ring
system, every ring in the system is aromatic. The heteroaryl group
may have 5-18 ring members (i.e., the number of atoms making up the
ring backbone, including carbon atoms and heteroatoms), although
the present definition also covers the occurrence of the term
"heteroaryl" where no numerical range is designated. In some
embodiments, the heteroaryl group has 5 to 10 ring members or 5 to
7 ring members. The heteroaryl group may be designated as "5-7
membered heteroaryl," "5-10 membered heteroaryl," or similar
designations. Examples of heteroaryl rings include, but are not
limited to, furyl, thienyl, phthalazinyl, pyrrolyl, oxazolyl,
thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl,
triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl,
pyrazinyl, triazinyl, quinolinyl, isoquinlinyl, benzimidazolyl,
benzoxazolyl, benzothiazolyl, indolyl, isoindolyl, and
benzothienyl.
[0195] A "heteroaralkyl" or "heteroarylalkyl" is heteroaryl group
connected, as a substituent, via an alkylene group. Examples
include but are not limited to 2-thienylmethyl, 3-thienylmethyl,
furylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl,
isoxazollylalkyl, and imidazolylalkyl. In some cases, the alkylene
group is a lower alkylene group (i.e., a C.sub.1-4 alkylene
group).
[0196] As used herein, "carbocyclyl" means a non-aromatic cyclic
ring or ring system containing only carbon atoms in the ring system
backbone. When the carbocyclyl is a ring system, two or more rings
may be joined together in a fused, bridged or spiro-connected
fashion. Carbocyclyls may have any degree of saturation provided
that at least one ring in a ring system is not aromatic. Thus,
carbocyclyls include cycloalkyls, cycloalkenyls, and cycloalkynyls.
The carbocyclyl group may have 3 to 20 carbon atoms, although the
present definition also covers the occurrence of the term
"carbocyclyl" where no numerical range is designated. The
carbocyclyl group may also be a medium size carbocyclyl having 3 to
10 carbon atoms. The carbocyclyl group could also be a carbocyclyl
having 3 to 6 carbon atoms. The carbocyclyl group may be designated
as "C.sub.3-6 carbocyclyl" or similar designations. Examples of
carbocyclyl rings include, but are not limited to, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl,
2,3-dihydro-indene, bicycle[2.2.2]octanyl, adamantyl, and
spiro[4.4]nonanyl.
[0197] A "(carbocyclyl)alkyl" is a carbocyclyl group connected, as
a substituent, via an alkylene group, such as "C.sub.4-10
(carbocyclyl)alkyl" and the like, including but not limited to,
cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl,
cyclopropylbutyl, cyclobutylethyl, cyclopropylisopropyl,
cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl,
cyclohexylethyl, cycloheptylmethyl, and the like. In some cases,
the alkylene group is a lower alkylene group.
[0198] As used herein, "cycloalkyl" means a fully saturated
carbocyclyl ring or ring system. Examples include cyclopropyl,
cyclobutyl, cyclopentyl, and cyclohexyl.
[0199] As used herein, "cycloalkenyl" means a carbocyclyl ring or
ring system having at least one double bond, wherein no ring in the
ring system is aromatic. An example is cyclohexenyl.
[0200] As used herein, "heterocyclyl" means a non-aromatic cyclic
ring or ring system containing at least one heteroatom in the ring
backbone. Heterocyclyls may be joined together in a fused, bridged
or spiro-connected fashion. Heterocyclyls may have any degree of
saturation provided that at least one ring in the ring system is
not aromatic. The heteroatom(s) may be present in either a
non-aromatic or aromatic ring in the ring system. The heterocyclyl
group may have 3 to 20 ring members (i.e., the number of atoms
making up the ring backbone, including carbon atoms and
heteroatoms), although the present definition also covers the
occurrence of the term "heterocyclyl" where no numerical range is
designated. The heterocyclyl group may also be a medium size
heterocyclyl having 3 to 10 ring members. The heterocyclyl group
could also be a heterocyclyl having 3 to 6 ring members. The
heterocyclyl group may be designated as "3-6 membered heterocyclyl"
or similar designations. In preferred six membered monocyclic
heterocyclyls, the heteroatom(s) are selected from one up to three
of O, N or S, and in preferred five membered monocyclic
heterocyclyls, the heteroatom(s) are selected from one or two
heteroatoms selected from O, N, or S. Examples of heterocyclyl
rings include, but are not limited to, azepinyl, acridinyl,
carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, imidazolidinyl,
morpholinyl, oxiranyl, oxepanyl, thiepanyl, piperidinyl,
piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidonyl,
pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl,
1,3-dioxinyl, 1,3-dioxanyl, 1,4-dioxinyl, 1,4-dioxanyl,
1,3-oxathianyl, 1,4-oxathiinyl, 1,4-oxathianyl, 2H-1,2-oxazinyl,
trioxanyl, hexahydro-1,3,5-triazinyl, 1,3-dioxolyl, 1,3-dioxolanyl,
1,3-dithiolyl, 1,3-dithiolanyl, isoxazolinyl, isoxazolidinyl,
oxazolinyl, oxazolidinyl, oxazolidinonyl, thiazolinyl,
thiazolidinyl, 1,3-oxathiolanyl, indolinyl, isoindolinyl,
tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl,
tetrahydrothiopyranyl, tetrahydro-1,4-thiazinyl, thiamorpholinyl,
dihydrobenzofuranyl, benzimidazolidinyl, and
tetrahydroquinoline.
[0201] A "(heterocyclyl)alkyl" is a heterocyclyl group connected,
as a substituent, via an alkylene group. Examples include, but are
not limited to, imidazolinylmethyl and indolinylethyl.
[0202] As used herein, "acyl" refers to --C(.dbd.O)R, wherein R is
hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-7 carbocyclyl, aryl, 5-10 membered heteroaryl, and 5-10
membered heterocyclyl, as defined herein. Non-limiting examples
include formyl, acetyl, propanoyl, benzoyl, and acryl.
[0203] An "O-carboxy" group refers to a "--OC(.dbd.O)R" group in
which R is selected from hydrogen, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 carbocyclyl, aryl, 5-10
membered heteroaryl, and 5-10 membered heterocyclyl, as defined
herein.
[0204] A "C-carboxy" group refers to a "--C(.dbd.O)OR" group in
which R is selected from hydrogen, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 carbocyclyl, aryl, 5-10
membered heteroaryl, and 5-10 membered heterocyclyl, as defined
herein. A non-limiting example includes carboxyl (i.e.,
--C(.dbd.O)OH).
[0205] A "cyano" group refers to a "--CN" group.
[0206] A "cyanato" group refers to an "--OCN" group.
[0207] An "isocyanato" group refers to a "--NCO" group.
[0208] A "thiocyanato" group refers to a "--SCN" group.
[0209] An "isothiocyanato" group refers to an "--NCS" group.
[0210] A "sulfinyl" group refers to an "--S(.dbd.O)R" group in
which R is selected from hydrogen, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 carbocyclyl, C.sub.6-10 aryl,
5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as
defined herein.
[0211] A "sulfonyl" group refers to an "--SO.sub.2R" group in which
R is selected from hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-7 carbocyclyl, C.sub.6-10 aryl, 5-10
membered heteroaryl, and 5-10 membered heterocyclyl, as defined
herein.
[0212] An "S-sulfonamido" group refers to a
"--SO.sub.2NR.sub.AR.sub.B" group in which R.sub.A and R.sub.B are
each independently selected from hydrogen, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 carbocyclyl,
C.sub.6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered
heterocyclyl, as defined herein.
[0213] An "N-sulfonamido" group refers to a
"--N(R.sub.A)SO.sub.2R.sub.B" group in which R.sub.A and R.sub.b
are each independently selected from hydrogen, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 carbocyclyl,
C.sub.6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered
heterocyclyl, as defined herein.
[0214] An "O-carbamyl" group refers to a
"--OC(.dbd.O)NR.sub.AR.sub.B" group in which R.sub.A and R.sub.B
are each independently selected from hydrogen, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 carbocyclyl,
C.sub.6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered
heterocyclyl, as defined herein.
[0215] An "N-carbamyl" group refers to an
"--N(R.sub.A)OC(.dbd.O)R.sub.B" group in which R.sub.A and R.sub.B
are each independently selected from hydrogen, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 carbocyclyl,
C.sub.6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered
heterocyclyl, as defined herein.
[0216] An "O-thiocarbamyl" group refers to a
"--OC(.dbd.S)NR.sub.AR.sub.B" group in which R.sub.A and R.sub.B
are each independently selected from hydrogen, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 carbocyclyl,
aC.sub.6-10 ryl, 5-10 membered heteroaryl, and 5-10 membered
heterocyclyl, as defined herein.
[0217] An "N-thiocarbamyl" group refers to an
"--N(R.sub.A)OC(.dbd.S)R.sub.B" group in which R.sub.A and R.sub.B
are each independently selected from hydrogen, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 carbocyclyl,
C.sub.6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered
heterocyclyl, as defined herein.
[0218] A "C-amido" group refers to a "--C(.dbd.O)NR.sub.AR.sub.B"
group in which R.sub.A and R.sub.B are each independently selected
from hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.3-7 carbocyclyl, C.sub.6-10 aryl, 5-10 membered
heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
[0219] An "N-amido" group refers to a
"--N(R.sub.A)C(.dbd.O)R.sub.B" group in which R.sub.A and R.sub.B
are each independently selected from hydrogen, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 carbocyclyl,
C.sub.6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered
heterocyclyl, as defined herein.
[0220] An "amino" group refers to a "--NR.sub.AR.sub.B" group in
which R.sub.A and R.sub.B are each independently selected from
hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-7 carbocyclyl, C.sub.6-10 aryl, 5-10 membered heteroaryl,
and 5-10 membered heterocyclyl, as defined herein.
[0221] An "aminoalkyl" group refers to an amino group connected via
an alkylene group.
[0222] An "alkoxyalkyl" group refers to an alkoxy group connected
via an alkylene group, such as a "C.sub.2-8 alkoxyalkyl" and the
like.
[0223] As used herein, a substituted group is derived from the
unsubstituted parent group in which there has been an exchange of
one or more hydrogen atoms for another atom or group. Unless
otherwise indicated, when a group is deemed to be "substituted," it
is meant that the group is substituted with one or more
substitutents independently selected from C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkenyl, C.sub.1-C.sub.6 alkynyl, C.sub.1-C.sub.6
heteroalkyl, C.sub.3-C.sub.7 carbocyclyl (optionally substituted
with halo, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 haloalkyl, and C.sub.1-C.sub.6 haloalkoxy),
C.sub.3-C.sub.7-carbocyclyl-C.sub.1-C.sub.6-alkyl (optionally
substituted with halo, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, C.sub.1-C.sub.6 haloalkyl, and C.sub.1-C.sub.6 haloalkoxy),
5-10 membered heterocyclyl (optionally substituted with halo,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
haloalkyl, and C.sub.1-C.sub.6 haloalkoxy), 5-10 membered
heterocyclyl-C.sub.1-C.sub.6-alkyl (optionally substituted with
halo, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 haloalkyl, and C.sub.1-C.sub.6 haloalkoxy), aryl
(optionally substituted with halo, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkyl, and
C.sub.1-C.sub.6 haloalkoxy), aryl(C.sub.1-C.sub.6)alkyl (optionally
substituted with halo, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, C.sub.1-C.sub.6 haloalkyl, and C.sub.1-C.sub.6 haloalkoxy),
5-10 membered heteroaryl (optionally substituted with halo,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
haloalkyl, and C.sub.1-C.sub.6 haloalkoxy), 5-10 membered
heteroaryl(C.sub.1-C.sub.6)alkyl (optionally substituted with halo,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
haloalkyl, and C.sub.1-C.sub.6 haloalkoxy), halo, cyano, hydroxy,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
alkoxy(C.sub.1-C.sub.6)alkyl (i.e., ether), aryloxy, sulfhydryl
(mercapto), halo(C.sub.1-C.sub.6)alkyl (e.g., --CF.sub.3),
halo(C.sub.1-C.sub.6)alkoxy (e.g., --OCF.sub.3), C.sub.1-C.sub.6
alkylthio, arylthio, amino, amino(C.sub.1-C.sub.6)alkyl, nitro,
O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido,
N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, acyl,
cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl,
sulfonyl, and oxo (.dbd.O). Wherever a group is described as
"optionally substituted" that group can be substituted with the
above substituents.
[0224] In some embodiments, substituted group(s) is (are)
substituted with one or more substituent(s) individually and
independently selected from C.sub.1-C.sub.4 alkyl, amino, hydroxy,
and halogen.
[0225] It is to be understood that certain radical naming
conventions can include either a mono-radical or a di-radical,
depending on the context. For example, where a substituent requires
two points of attachment to the rest of the molecule, it is
understood that the substituent is a di-radical. For example, a
substituent identified as alkyl that requires two points of
attachment includes di-radicals such as --CH.sub.2--,
--CH.sub.2CH.sub.2--, --CH.sub.2CH(CH.sub.3)CH.sub.2--, and the
like. Other radical naming conventions clearly indicate that the
radical is a di-radical such as "alkylene" or "alkenylene."
[0226] As used herein, "alkylene" means a branched, or straight
chain fully saturated di-radical chemical group containing only
carbon and hydrogen that is attached to the rest of the molecule
via two points of attachment (i.e., an alkanediyl). The alkylene
group may have 1 to 20 carbon atoms, although the present
definition also covers the occurrence of the term alkylene where no
numerical range is designated. The alkylene group may also be a
medium size alkylene having 1 to 9 carbon atoms. The alkylene group
could also be a lower alkylene having 1 to 4 carbon atoms. The
alkylene group may be designated as "C.sub.1-4 alkylene" or similar
designations. By way of example only, "C.sub.1-4 alkylene"
indicates that there are one to four carbon atoms in the alkylene
chain, i.e., the alkylene chain is selected from the group
consisting of methylene, ethylene, ethan-1,1-diyl, propylene,
propan-1,1-diyl, propan-2,2-diyl, 1-methyl-ethylene, butylene,
butan-1,1-diyl, butan-2,2-diyl, 2-methyl-propan-1,1-diyl,
1-methyl-propylene, 2-methyl-propylene, 1,1-dimethyl-ethylene,
1,2-dimethyl-ethylene, and 1-ethyl-ethylene.
[0227] As used herein, "alkenylene" means a straight or branched
chain di-radical chemical group containing only carbon and hydrogen
and containing at least one carbon-carbon double bond that is
attached to the rest of the molecule via two points of attachment.
The alkenylene group may have 2 to 20 carbon atoms, although the
present definition also covers the occurrence of the term
alkenylene where no numerical range is designated. The alkenylene
group may also be a medium size alkenylene having 2 to 9 carbon
atoms. The alkenylene group could also be a lower alkenylene having
2 to 4 carbon atoms. The alkenylene group may be designated as
"C.sub.2-4 alkenylene" or similar designations. By way of example
only, "C.sub.2-4 alkenylene" indicates that there are two to four
carbon atoms in the alkenylene chain, i.e., the alkenylene chain is
selected from the group consisting of ethenylene, ethen-1,1-diyl,
propenylene, propen-1,1-diyl, prop-2-en-1,1-diyl,
1-methyl-ethenylene, but-1-enylene, but-2-enylene,
but-1,3-dienylene, buten-1,1-diyl, but-1,3-dien-1,1-diyl,
but-2-en-1,1-diyl, but-3-en-1,1-diyl, 1-methyl-prop-2-en-1,1-diyl,
2-methyl-prop-2-en-1,1-diyl, 1-ethyl-ethenylene,
1,2-dimethyl-ethenylene, 1-methyl-propenylene,
2-methyl-propenylene, 3-methyl-propenylene,
2-methyl-propen-1,1-diyl, and 2,2-dimethyl-ethen-1,1-diyl.
[0228] When two R groups are said to form a ring (e.g., a
carbocyclyl, heterocyclyl, aryl, or heteroaryl ring) "together with
the atom to which they are attached," it is meant that the
collective unit of the atom and the two R groups are the recited
ring. The ring is not otherwise limited by the definition of each R
group when taken individually. For example, when the following
substructure is present:
##STR00061##
and R.sup.1 and R.sup.2 are defined as selected from the group
consisting of hydrogen and alkyl, or R.sup.1 and R.sup.2 together
with the nitrogen to which they are attached form a heteroaryl, it
is meant that R.sup.1 and R.sup.2 can be selected from hydrogen or
alkyl, or alternatively, the substructure has structure:
##STR00062##
where ring A is a heteroaryl ring containing the depicted
nitrogen.
[0229] Similarly, when two "adjacent" R groups are said to form a
ring "together with the atoms to which they are attached," it is
meant that the collective unit of the atoms, intervening bonds, and
the two R groups are the recited ring. For example, when the
following substructure is present:
##STR00063##
and R.sup.1 and R.sup.2 are defined as selected from the group
consisting of hydrogen and alkyl, or R.sup.1 and R.sup.2 together
with the atoms to which they are attached form an aryl or
carbocylyl, it is meant that R.sup.1 and R.sup.2 can be selected
from hydrogen or alkyl, or alternatively, the substructure has
structure:
##STR00064##
where A is an aryl ring or a carbocylyl containing the depicted
double bond.
[0230] Wherever a substituent is depicted as a di-radical (i.e.,
has two points of attachment to the rest of the molecule), it is to
be understood that the substituent can be attached in any
directional configuration unless otherwise indicated. Thus, for
example, a substituent depicted as -AE- or
##STR00065##
E includes the substituent being oriented such that the A is
attached at the leftmost attachment point of the molecule as well
as the case in which A is attached at the rightmost attachment
point of the molecule.
[0231] As used herein, "isosteres" of a chemical group are other
chemical groups that exhibit the same or similar properties. For
example, tetrazole is an isostere of carboxylic acid because it
mimics the properties of carboxylic acid even though they both have
very different molecular formulae. Tetrazole is one of many
possible isosteric replacements for carboxylic acid. Other
carboxylic acid isosteres contemplated include --SO.sub.3H,
--SO.sub.2HNR, --PO.sub.2(R).sub.2, --PO.sub.3(R).sub.2,
--CONHNHSO.sub.2R, --COHNSO.sub.2R, and --CONRCN, where R is
selected from hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-7 carbocyclyl, C.sub.6-10 aryl, 5-10
membered heteroaryl, and 3-10 membered heterocyclyl, as defined
herein. In addition, carboxylic acid isosteres can include 5-7
membered carbocycles or heterocycles containing any combination of
CH.sub.2, O, S, or N in any chemically stable oxidation state,
where any of the atoms of said ring structure are optionally
substituted in one or more positions. The following structures are
non-limiting examples of carbocyclic and heterocyclic isosteres
contemplated. The atoms of said ring structure may be optionally
substituted at one or more positions with R as defined above.
##STR00066##
[0232] It is also contemplated that when chemical substituents are
added to a carboxylic isostere, the compound retains the properties
of a carboxylic isostere. It is contemplated that when a carboxylic
isostere is optionally substituted with one or more moieties
selected from R as defined above, then the substitution and
substitution position is selected such that it does not eliminate
the carboxylic acid isosteric properties of the compound.
Similarly, it is also contemplated that the placement of one or
more R substituents upon a carbocyclic or heterocyclic carboxylic
acid isostere is not a substitution at one or more atom(s) that
maintain(s) or is/are integral to the carboxylic acid isosteric
properties of the compound, if such substituent(s) would destroy
the carboxylic acid isosteric properties of the compound.
[0233] Other carboxylic acid isosteres not specifically exemplified
in this specification are also contemplated.
[0234] The term "agent" or "test agent" includes any substance,
molecule, element, compound, entity, or a combination thereof. It
includes, but is not limited to, e.g., protein, polypeptide,
peptide or mimetic, small organic molecule, polysaccharide,
polynucleotide, and the like. It can be a natural product, a
synthetic compound, or a chemical compound, or a combination of two
or more substances. Unless otherwise specified, the terms "agent",
"substance", and "compound" are used interchangeably herein.
[0235] The term "analog" is used herein to refer to a molecule that
structurally resembles a reference molecule but which has been
modified in a targeted and controlled manner, by replacing a
specific substituent of the reference molecule with an alternate
substituent. Compared to the reference molecule, an analog would be
expected, by one skilled in the art, to exhibit the same, similar,
or improved utility. Synthesis and screening of analogs, to
identify variants of known compounds having improved
characteristics (such as higher binding affinity for a target
molecule) is an approach that is well known in pharmaceutical
chemistry.
[0236] The term "mammal" is used in its usual biological sense.
Thus, it specifically includes, but is not limited to, primates,
including simians (chimpanzees, apes, monkeys) and humans, cattle,
horses, sheep, goats, swine, rabbits, dogs, cats, rats and mice but
also includes many other species.
[0237] The term "microbial infection" refers to the invasion of the
host organism, whether the organism is a vertebrate, invertebrate,
fish, plant, bird, or mammal, by pathogenic microbes. This includes
the excessive growth of microbes that are normally present in or on
the body of a mammal or other organism. More generally, a microbial
infection can be any situation in which the presence of a microbial
population(s) is damaging to a host mammal. Thus, a mammal is
"suffering" from a microbial infection when excessive numbers of a
microbial population are present in or on a mammal's body, or when
the effects of the presence of a microbial population(s) is
damaging the cells or other tissue of a mammal. Specifically, this
description applies to a bacterial infection. Note that the
compounds of preferred embodiments are also useful in treating
microbial growth or contamination of cell cultures or other media,
or inanimate surfaces or objects, and nothing herein should limit
the preferred embodiments only to treatment of higher organisms,
except when explicitly so specified in the claims.
[0238] The term "pharmaceutically acceptable carrier" or
"pharmaceutically acceptable excipient" includes any and all
solvents, dispersion media, coatings, antibacterial and antifungal
agents, isotonic and absorption delaying agents and the like. The
use of such media and agents for pharmaceutically active substances
is well known in the art. Except insofar as any conventional media
or agent is incompatible with the active ingredient, its use in the
therapeutic compositions is contemplated. In addition, various
adjuvants such as are commonly used in the art may be included.
Considerations for the inclusion of various components in
pharmaceutical compositions are described, e.g., in Gilman et al.
(Eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of
Therapeutics, 8th Ed., Pergamon Press, which is incorporated herein
by reference in its entirety.
[0239] "Subject" as used herein, means a human or a non-human
mammal, e.g., a dog, a cat, a mouse, a rat, a cow, a sheep, a pig,
a goat, a non-human primate or a bird, e.g., a chicken, as well as
any other vertebrate or invertebrate.
[0240] An "effective amount" or a "therapeutically effective
amount" as used herein refers to an amount of a therapeutic agent
that is effective to relieve, to some extent, or to reduce the
likelihood of onset of, one or more of the symptoms of a disease or
condition, and includes curing a disease or condition. "Curing"
means that the symptoms of a disease or condition are eliminated;
however, certain long-term or permanent effects may exist even
after a cure is obtained (such as extensive tissue damage).
[0241] "Treat," "treatment," or "treating," as used herein refers
to administering a pharmaceutical composition for prophylactic
and/or therapeutic purposes. The term "prophylactic treatment"
refers to treating a subject who does not yet exhibit symptoms of a
disease or condition, but who is susceptible to, or otherwise at
risk of, a particular disease or condition, whereby the treatment
reduces the likelihood that the patient will develop the disease or
condition. The term "therapeutic treatment" refers to administering
treatment to a
Methods of Preparation
[0242] The compounds disclosed herein may be synthesized by methods
described below, or by modification of these methods. Ways of
modifying the methodology include, among others, temperature,
solvent, reagents etc., known to those skilled in the art. In
general, during any of the processes for preparation of the
compounds disclosed herein, it may be necessary and/or desirable to
protect sensitive or reactive groups on any of the molecules
concerned. This may be achieved by means of conventional protecting
groups, such as those described in Protective Groups in Organic
Chemistry (ed. J. F. W. McOmie, Plenum Press, 1973); and P. G. M.
Green, T. W. Wutts, Protecting Groups in Organic Synthesis (3rd
ed.) Wiley, New York (1999), which are both hereby incorporated
herein by reference in their entirety. The protecting groups may be
removed at a convenient subsequent stage using methods known from
the art. Synthetic chemistry transformations useful in synthesizing
applicable compounds are known in the art and include e.g. those
described in R. Larock, Comprehensive Organic Transformations, VCH
Publishers, 1989, or L. Paquette, ed., Encyclopedia of Reagents for
Organic Synthesis, John Wiley and Sons, 1995, which are both hereby
incorporated herein by reference in their entirety. The routes
shown and described herein are illustrative only and are not
intended, nor are they to be construed, to limit the scope of the
claims in any manner whatsoever. Those skilled in the art will be
able to recognize modifications of the disclosed syntheses and to
devise alternate routes based on the disclosures herein; all such
modifications and alternate routes are within the scope of the
claims.
[0243] In the following schemes, protecting groups for oxygen atoms
are selected for their compatibility with the requisite synthetic
steps as well as compatibility of the introduction and deprotection
steps with the overall synthetic schemes (P. G. M. Green, T. W.
Wutts, Protecting Groups in Organic Synthesis (3rd ed.) Wiley, New
York (1999)). Handling of protecting and/or sterodirecting groups
specific to boronic acid derivatives is described in a recent
review of chemistry of boronic acids: D. G. Hall (Ed.), Boronic
Acids. Preparation and Application in Organic Synthesis and
Medicine, Wiley VCH (2005) and in earlier reviews: Matteson, D. S.
(1988). Asymmetric synthesis with boronic esters. Accounts of
Chemical Research, 21(8), 294-300, and Matteson, D. S. (1989).
Tetrahedron, 45(7), 1859-1885), all of which are incorporated
herein by reference in their entirety. The latter review articles
also describe methodology for stereoselective insertion of
halomethine functionality next to the boronate which is employed in
the synthetic schemes below.
[0244] In addition to standard acid catalyzed deprotection, special
methods for removal of boronic acid protecting and/or
sterodirecting groups methods using fluorides (Yuen, A. K. L.,
& Hutton, C. A. (2005). Tetrahedron Letters, 46(46),
7899-7903--incorporated herein by reference in its entirety) or
periodate oxidation (Coutts, S. J., et al. (1994). Tetrahedron
Letters, 35(29), 5109-5112--incorporated herein by reference in its
entirety) can also be employed in preparations of the compounds
disclosed herein.
[0245] In strategies employing pinanediol or other diol-based
chiral auxiliaries for stereospecific introduction of new chiral
centers, the early stages of chemistry on boronic intermediates can
be performed on chiral boronate esters or alternatively nonchiral
borate/boronate intermediates can be used in early stages followed
by transesterification with chiral diols prior to the step where
stereoselection is required.
Synthesis of Compounds of Formula I', I, III' and III
[0246] The following example schemes are provided for the guidance
of the reader, and collectively represent an example method for
making the compounds encompassed herein. Furthermore, other methods
for preparing compounds described herein will be readily apparent
to the person of ordinary skill in the art in light of the
following reaction schemes and examples. Unless otherwise
indicated, all variables are as defined above.
[0247] Compounds of formula Ib where R is H can be prepared as
depicted in schemes 1-4 from key intermediates VI, VIII and XII,
which may be assembled by known reactions (Boronic Acids:
Preparations and Applications in Organic Synthesis, Medicine and
Materials, D. G. Hall, ed., Wiley-VCH, Weinheim, 2011, which is
incorporated herein by reference in its entirety).
##STR00067##
[0248] Compounds of formula Ib can be made starting from protected
aryl or heteroaryl intermediates of formula B' via a double
Matteson homologation sequence (J. Org. Chem., 2013, 78,
10009-10023, which is incorporated herein by reference in its
entirety). The compounds of formula B' may be attained from A' by
means of several earlier known methods (WO00458679, which is
incorporated herein by reference in its entirety) with conventional
protecting groups for R' and R'', such as those described in
Protective Groups in Organic Chemistry (ed. J. F. W. McOmie,
Plenum, 1973, which is incorporated herein by reference in its
entirety); and Protecting Groups in Organic Synthesis P. G. M.
Wutts, T. W. Green, Wiley, New York, 1999, which is incorporated
herein by reference in its entirety) from commercially available
salicylic acid derivatives. Aryl compounds of formula A' upon
boronation by well-known available methods (Chem. Rev. 2010, 110,
890-931, which is incorporated herein by reference in its entirety)
and boronate ester formation with desired chiral auxiliary give
precursor for Matteson homologation. Compounds of formula C' where
X.dbd.Cl and R' is Boc and R'' is t-Butyl or R' and R'' are
protected together as isopropylidine or any other groups protected
separately or together in cyclic form may be made from compounds of
formula B' via homologation upon chloromethylene insertion with
good stereocontrol by Matteson reaction conditions (WO00946098,
which is incorporated herein by reference in its entirety).
Compounds of formula C' where X is bromo may be made analogously to
the chloro compounds of Scheme 1, utilizing dibromomethane (J. Am.
Chem. Soc. 1990, 112, 3964-969, which is incorporated herein by
reference in its entirety). The halo derivatives of formula C'
where X is Cl or Br undergo stereospecific substitution to form
thioethers (WO 04064755, which is incorporated herein by reference
in its entirety), ethers (WO 12067664, which is incorporated herein
by reference in its entirety), amines (J. Organomet. Chem. 1979,
170, 259-64, which is incorporated herein by reference in its
entirety) or acetates (Tetrahedron 2005, 61, 4427-4536, which is
incorporated herein by reference in its entirety), to give
compounds of formula V. In an alternate approach, compounds of
formula C' where Y.sup.2 is S can be made via a thiol intermediate
by alkylation or arylation to introduce various G groups. Such
compounds may also be made via alkyl or thiomethylene boronate
esters by reaction with substituted benzyl halides (U.S. Pat. No.
6,586,615, which is incorporated herein by reference in its
entirety). The resulting products of formula V where Y.sup.2 is S
or O can be further homologated by a methylene insertion in a
second Matteson reaction to give compounds of formula VI.
Additionally, halo derivatives of formula C' where X is Cl or Br
undergo stereospecific substitution to form azides which can be
further elaborated to compounds of formula VI where
Y.sup.2.dbd.--NR2- by homologation, reduction, alkylation or amide
formation sequence (WO 01002424, which is incorporated herein by
reference in its entirety).
[0249] Simultaneous deprotection of pinane ester and salicylic acid
protective groups of compounds of formula VI can be achieved by
heating with dilute HCl, affording the desired compounds of
structure Ib. This transformation may also be achieved by treatment
with BCl.sub.3 or BBr.sub.3 (WO09064414), which is incorporated
herein by reference in its entirety. Alternatively, the
deprotection may be attained via transesterification with isobutyl
boronic acid in presence of dilute acid (WO09064413, which is
incorporated herein by reference in its entirety) or via other
known methods (J. Org. Chem. (2010), 75, 468-471, which is
incorporated herein by reference in its entirety).
[0250] Salicylic acid derivatives of formula A' where Y' is a
leaving group undergo coupling reaction with Reformatsky reagent of
acetate in Negishi conditions to give intermediates of formula VII
where X' is OR''' (Tetrahedron, 2014, 1508-1515, J. Org. Chem.,
2013, 78, 8250-8266, which is incorporated herein by reference in
its entirety) (Scheme 2). Such intermediates may be alkylated with
halomethylene boronate derivative (VIIA) to give compounds of
formula VIII in high stereoselectivity (J. Am. Chem. Soc., 2011,
133, 11936-11939, which is incorporated herein by reference in its
entirety). Intermediates of formula VII undergo methylenation to
give derivatives of IX (J. Org. Chem., 1986, 51, 2981-2988, which
is incorporated herein by reference in its entirety). Intermediates
of formula IX undergo asymmetric boronation in known conditions to
give compounds of formula VIII (J. Am. Chem. Soc., 2010, 132,
10630-10633, which is incorporated herein by reference in its
entirety). Such asymmetric boronation may also feasible where X' is
--NR.sup.1R.sup.2. Intermediates of formula VIII can be further
transformed to compound of formula Ib under the conditions
described in scheme 1.
##STR00068##
[0251] In an alternative sequence, compounds of formula Ib can be
made via boracarboxylation followed by asymmetric hydrogenation of
acetylene intermediate X as shown in scheme 3. Aryl or heteroaryl
derivatives formula A' can undergo Pd mediated coupling reaction to
give acetylene substituted compound with TMS-acetylene.
Boracarboxylation of alkynes with a diborane compound and carbon
dioxide in presence of an N-heterocyclic carbene copper (I) complex
as a catalyst gives .alpha.,.beta.-unsaturated .beta.-boralactone
derivatives regio- and stereoselectively via a
borylcupration/carboxylation (J. Am. Chem. Soc. 2012, 134,
14314-14317, which is incorporated herein by reference in its
entirety). Such resulting derivatives can be transformed to esters
of carboxylate and boronate to give intermediates of formula XI.
Asymmetric hydrogenation of intermediates of formula XI (Chem. Rev.
2003, 103, 3029-3070, which is incorporated herein by reference in
its entirety) may be utilized to give enatiomerically pure
compounds of XII. Such compounds may be further transformed to
compounds of formula Ib via VI by derivatization and hydrolysis as
described above in scheme 1.
##STR00069##
[0252] Compounds of formula Ib where Y.sup.1.dbd.CH,
Y.sup.2.dbd.--NHC(O)-- may be prepared from carboxylic acid of
formula XII (R'''.dbd.OH) as shown in scheme 4. Such compounds may
be converted to amides via Curtius rearrangement (Chem. Rev. 1988,
88, 297-368; Org. Lett., 2005, 4107-4110, which is incorporated
herein by reference in its entirety) followed by deprotection,
amide formation to give compounds of formula XIV. Compounds of
formula XIII may also be transformed to compounds of formula Ib
where Y.sup.2 is --NHC(O)--O-- by hydrolysis.
##STR00070##
[0253] Intermediates of formula XVII to attain compounds of formula
Ib may be prepared as shown in scheme 5. Such intermediates of
formula XVII can be synthesized from XIV where X' is a triflate or
bromo or iodo group by utilizing Reformatsky reagent of
bromomethylene acetate ester (J. Org. Chem., 2013, 78, 8250-8266;
Chem Lett., 1993, 845-848, which is incorporated herein by
reference in its entirety). Compounds where X' is substituted with
bromo or iodo groups can be attained from appropriately protected
commercial 2,5-hydroxy-benzoic acid derivatives (J. Med. Chem.,
2003, 46, 3437-3440, which is incorporated herein by reference in
its entirety). Intermediates of XIV can also be prepared via
carboxylation of derivatives of formula XV where Z' is a fluoro or
OR' or SR' by earlier described methods (WO12106995, which is
incorporated herein by reference in its entirety).
##STR00071##
[0254] In another exemplary synthetic scheme 6, the compound of
formula XX can be prepared from a salicylic acid derivative of
formula XVIII. The compounds of formula XVIII upon diallylation
under basic conditions followed by thermal Claisen rearrangement
(Org. React. 1975, 22, 1-252, which is incorporated herein by
reference in its entirety) and ester hydrolysis give compounds of
formula XIX. Such compounds upon protection and oxidation followed
by esterification result in phenylacetic acid compounds of formula
XX. Compounds of formula XX can be further transformed as shown
above in scheme 2. The compound of formula XVIII can also undergo
the steps listed above in Scheme 5 to form an
ortho-carboxylate-substituted compound of formula XIX.
##STR00072##
Synthesis of Prodrugs
[0255] Compounds of formula Ib where the R is a prodrug moiety may
be synthesized by a variety of known methods of different
carboxylic acid prodrugs (Prodrugs: Challenges and Rewards, V. J.
Stella, et al., ed., Springer, New York, 2007, which is
incorporated herein by reference in its entirety). These prodrugs
include but are not limited to substituted or non-substituted alkyl
esters, (acyloxy)alkyl (Synthesis 2012, 44, 207, which is
incorporated herein by reference in its entirety),
[(alkoxycarbonyl)oxy]methyl esters (WO10097675, which is
incorporated herein by reference in its entirety), or
(oxodioxolyl)methyl esters (J. Med. Chem. 1996, 39, 323-338, which
is incorporated herein by reference in its entirety). Such prodrugs
can be made from compounds of formula Ib where R.dbd.H by treatment
with acid or in neutral conditions (e.g., carbodiimide coupling) in
the presence of alcohols (ROH) or via base promoted esterification
with RX where X is a leaving group in the presence of an
appropriate base.
[0256] One exemplary but non-limiting general synthetic scheme for
preparing prodrugs is shown in Scheme 7 below. The boronic acid of
Formula Ib where R is hydrogen can react with a
chloro/bromo-substituted prodrug moiety to form a prodrug of
Formula Ib where R is a prodrug moiety. Examples of the prodrug
moiety R can be --C.sub.1-9alkyl,
--CR.sup.10R.sup.11OC(O)C.sub.1-9alkyl,
--CR.sup.10R.sup.11OC(O)OC.sub.1-9alkyl, and
##STR00073##
##STR00074##
[0257] Alternatively, boronate esters of formula XXI or
corresponding tetrafluoroborates (Chem. Rev. 2008, 108, 288-325,
which is incorporated herein by reference in its entirety) may be
also utilized for introduction of prodrugs and convert them to
final prodrugs (Scheme 8). Such carboxylic acids (XXI) can be made
from compounds of formula VI by selective deprotection of OR'. The
prodrug group may also be introduced earlier in the sequence in
compounds of formula V where R' is R. Such sequence where prodrug
is introduced in earlier intermediates is only feasible when the
ester is stable under the final deprotection conditions to remove
the phenol protective group and boronate ester group.
##STR00075##
[0258] Compounds of Formula IIIC may be prepared as shown in scheme
9. Compounds of formula IIIc where m is 0 and Y.sup.7 is
--CH.sub.2-- may be synthesized via intermediate A' by coupling of
vinyl boronate in Heck reaction conditions (J. Med. Chem., 2015,
58, 147-169, which is incorporated herein by reference in its
entirety) or by coupling of an acetylene derivative of protected
boronate via Sonagashira conditions (Tet., 2011, 67, 4306-4312,
which is incorporated herein by reference in its entirety). The
protection of such boronate substituted vinyl/acetylene
intermediates can be selected from pinacol or pinanediol or
dimethylaminonaphthalene (Org. Lett., 2008, 10, 377-380, which is
incorporated herein by reference in its entirety) or MIDA (J. Am.
Chem. Soc., 2009, 131, 6961-6963, which is incorporated herein by
reference in its entirety) groups. The resulting coupling products
can be hydrogenated under catalytic conditions to give intermediate
XXIII which can be further transformed to compounds of formula IIIc
as described earlier in scheme 1 or by other methods known in the
art. Alternatively, aryl intermediates of formula A' of desired
substitution can be converted to vinyl substituted intermediates
such as XXII which readily undergo Ir (Tetrahedron, 2004, 60,
10695-10700, which is incorporated herein by reference in its
entirety) or Cu (Tetrahedron Lett., 2015, 56, 2297-2302, which is
incorporated herein by reference in its entirety) mediated
borylation to form intermediates of formula XXIII. Compounds of
formula XXIII can also be made from acetylene substituted compounds
of formula X via borylation of corresponding lithiated acetylide
(Angew. Chem., Int. Ed., 2012, 51, 2947-2950, which is incorporated
herein by reference in its entirety) or in a Pd catalyzed reaction
(Org. Lett., 2016, 18, 432-435, which is incorporated herein by
reference in its entirety) followed by hydrogenation of resulting
products. Aryl intermediates of formula A' where Y'.dbd.H can be
utilized via Claisen rearrangement (Chem. Rev., 2004, 104,
2939-3002, which is incorporated herein by reference in its
entirety). Allyl ethers of A' intermediate where R'' is allyl
undergo Claisen rearrangement. Such rearrangement products can be
converted to haloethylene substitution via ozonolysis or periodate
reaction of terminal olefin to aldehydes followed by reduction and
conversion of resulting alcohols to halides. These primary or
secondary halides can be transformed to boronate esters of formula
XXIII under a variety of conditions including via reactions
catalyzed by Cu (Angew. Chem. Int. Ed., 2012, 51, 528-532; and Org.
Lett., 2012, 14, 890-893, which are incorporated herein by
reference in their entireties), Pd (J. Org. Chem., 2012, 77,
6629-6633, which is incorporated herein by reference in its
entirety), Fe (J. Am. Chem. Soc., 2014, 136, 9521-9523, which is
incorporated herein by reference in its entirety) Zn (Angew. Chem.
Int. Ed. 2014, 53, 1799-1803), Ni (J. Am. Chem. Soc., 2012, 134,
10693-10697, which is incorporated herein by reference in its
entirety). Compounds of formula IIIC where m=1 and Y is O, S or NR'
can be synthesized through intermediate XXIV where Y' is --OH, --SH
or --NHR, by alkylation of bromo/iodomethylene boronate ester of
pinacol or pinanediol (WO 09046098, which is incorporated herein by
reference in its entirety) (Scheme 9).
##STR00076##
[0259] A non-limiting example for makng compounds of formula IIIc
is shown in Scheme 10. Compounds of formula IIIc-1 where M is
R.sup.5 is --(CH.sub.2).sub.p--Y.sup.3--(CH.sub.2).sub.qM can be
made from intermediates of formula XXVI. Such compounds of XXVI can
be made from XXV where R.sup.5 is already introduced.
Alternatively, R.sup.5 can also be substituted at XXVI stage by
deprotection of --OR' or SR' or CR.sup.1R.sup.2OR.sup.1,
CR.sup.1R.sup.2SR.sup.1, CR.sup.1R.sup.2NHR' and reaction with
appropriate protected building blocks of R.sup.5 (scheme 10).
Compounds of formula IIIc wherein J and/or L is R.sup.5 is
--(CH.sub.2).sub.p--Y.sup.3--(CH.sub.2).sub.qM can also be made
from the appropriate intermediates XXV and XXVI using this
scheme.
##STR00077##
Administration and Pharmaceutical Compositions
[0260] The compounds are administered at a therapeutically
effective dosage. While human dosage levels have yet to be
optimized for the compounds described herein, generally, a daily
dose may be from about 0.25 mg/kg to about 120 mg/kg or more of
body weight, from about 0.5 mg/kg or less to about 70 mg/kg, from
about 1.0 mg/kg to about 50 mg/kg of body weight, or from about 1.5
mg/kg to about 10 mg/kg of body weight. Thus, for administration to
a 70 kg person, the dosage range would be from about 17 mg per day
to about 8000 mg per day, from about 35 mg per day or less to about
7000 mg per day or more, from about 70 mg per day to about 6000 mg
per day, from about 100 mg per day to about 5000 mg per day, or
from about 200 mg to about 3000 mg per day. The amount of active
compound administered will, of course, be dependent on the subject
and disease state being treated, the severity of the affliction,
the manner and schedule of administration and the judgment of the
prescribing physician.
[0261] Administration of the compounds disclosed herein or the
pharmaceutically acceptable salts thereof can be via any of the
accepted modes of administration for agents that serve similar
utilities including, but not limited to, orally, subcutaneously,
intravenously, intranasally, topically, transdermally,
intraperitoneally, intramuscularly, intrapulmonarilly, vaginally,
rectally, or intraocularly. Oral and parenteral administrations are
customary in treating the indications that are the subject of the
preferred embodiments.
[0262] The compounds useful as described above can be formulated
into pharmaceutical compositions for use in treatment of these
conditions. Standard pharmaceutical formulation techniques are
used, such as those disclosed in Remington's The Science and
Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins
(2005), incorporated by reference in its entirety. Accordingly,
some embodiments include pharmaceutical compositions comprising:
(a) a safe and therapeutically effective amount of a compound
described herein (including enantiomers, diastereoisomers,
tautomers, polymorphs, and solvates thereof), or pharmaceutically
acceptable salts thereof; and (b) a pharmaceutically acceptable
carrier, diluent, excipient or combination thereof.
[0263] In addition to the selected compound useful as described
above, come embodiments include compositions containing a
pharmaceutically-acceptable carrier. The term "pharmaceutically
acceptable carrier" or "pharmaceutically acceptable excipient"
includes any and all solvents, dispersion media, coatings,
antibacterial and antifungal agents, isotonic and absorption
delaying agents and the like. The use of such media and agents for
pharmaceutically active substances is well known in the art. Except
insofar as any conventional media or agent is incompatible with the
active ingredient, its use in the therapeutic compositions is
contemplated. In addition, various adjuvants such as are commonly
used in the art may be included. Considerations for the inclusion
of various components in pharmaceutical compositions are described,
e.g., in Gilman et al. (Eds.) (1990); Goodman and Gilman's: The
Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press,
which is incorporated herein by reference in its entirety.
[0264] Some examples of substances, which can serve as
pharmaceutically-acceptable carriers or components thereof, are
sugars, such as lactose, glucose and sucrose; starches, such as
corn starch and potato starch; cellulose and its derivatives, such
as sodium carboxymethyl cellulose, ethyl cellulose, and methyl
cellulose; powdered tragacanth; malt; gelatin; talc; solid
lubricants, such as stearic acid and magnesium stearate; calcium
sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame
oil, olive oil, corn oil and oil of theobroma; polyols such as
propylene glycol, glycerine, sorbitol, mannitol, and polyethylene
glycol; alginic acid; emulsifiers, such as the TWEENS; wetting
agents, such sodium lauryl sulfate; coloring agents; flavoring
agents; tableting agents, stabilizers; antioxidants; preservatives;
pyrogen-free water; isotonic saline; and phosphate buffer
solutions.
[0265] The choice of a pharmaceutically-acceptable carrier to be
used in conjunction with the subject compound is basically
determined by the way the compound is to be administered.
[0266] The compositions described herein are preferably provided in
unit dosage form. As used herein, a "unit dosage form" is a
composition containing an amount of a compound that is suitable for
administration to an animal, preferably mammal subject, in a single
dose, according to good medical practice. The preparation of a
single or unit dosage form however, does not imply that the dosage
form is administered once per day or once per course of therapy.
Such dosage forms are contemplated to be administered once, twice,
thrice or more per day and may be administered as infusion over a
period of time (e.g., from about 30 minutes to about 2-6 hours), or
administered as a continuous infusion, and may be given more than
once during a course of therapy, though a single administration is
not specifically excluded. The skilled artisan will recognize that
the formulation does not specifically contemplate the entire course
of therapy and such decisions are left for those skilled in the art
of treatment rather than formulation.
[0267] The compositions useful as described above may be in any of
a variety of suitable forms for a variety of routes for
administration, for example, for oral, nasal, rectal, topical
(including transdermal), ocular, intracerebral, intracranial,
intrathecal, intra-arterial, intravenous, intramuscular, or other
parental routes of administration. The skilled artisan will
appreciate that oral and nasal compositions comprise compositions
that are administered by inhalation, and made using available
methodologies. Depending upon the particular route of
administration desired, a variety of pharmaceutically-acceptable
carriers well-known in the art may be used.
Pharmaceutically-acceptable carriers include, for example, solid or
liquid fillers, diluents, hydrotropies, surface-active agents, and
encapsulating substances. Optional pharmaceutically-active
materials may be included, which do not substantially interfere
with the inhibitory activity of the compound. The amount of carrier
employed in conjunction with the compound is sufficient to provide
a practical quantity of material for administration per unit dose
of the compound. Techniques and compositions for making dosage
forms useful in the methods described herein are described in the
following references, all incorporated by reference herein: Modern
Pharmaceutics, 4th Ed., Chapters 9 and 10 (Banker & Rhodes,
editors, 2002); Lieberman et al., Pharmaceutical Dosage Forms:
Tablets (1989); and Ansel, Introduction to Pharmaceutical Dosage
Forms 8th Edition (2004).
[0268] Various oral dosage forms can be used, including such solid
forms as tablets, capsules, granules and bulk powders. Tablets can
be compressed, tablet triturates, enteric-coated, sugar-coated,
film-coated, or multiple-compressed, containing suitable binders,
lubricants, diluents, disintegrating agents, coloring agents,
flavoring agents, flow-inducing agents, and melting agents. Liquid
oral dosage forms include aqueous solutions, emulsions,
suspensions, solutions and/or suspensions reconstituted from
non-effervescent granules, and effervescent preparations
reconstituted from effervescent granules, containing suitable
solvents, preservatives, emulsifying agents, suspending agents,
diluents, sweeteners, melting agents, coloring agents and flavoring
agents.
[0269] The pharmaceutically-acceptable carrier suitable for the
preparation of unit dosage forms for peroral administration is
well-known in the art. Tablets typically comprise conventional
pharmaceutically-compatible adjuvants as inert diluents, such as
calcium carbonate, sodium carbonate, mannitol, lactose and
cellulose; binders such as starch, gelatin and sucrose;
disintegrants such as starch, alginic acid and croscarmelose;
lubricants such as magnesium stearate, stearic acid and talc.
Glidants such as silicon dioxide can be used to improve flow
characteristics of the powder mixture. Coloring agents, such as the
FD&C dyes, can be added for appearance. Sweeteners and
flavoring agents, such as aspartame, saccharin, menthol,
peppermint, and fruit flavors, are useful adjuvants for chewable
tablets. Capsules typically comprise one or more solid diluents
disclosed above. The selection of carrier components depends on
secondary considerations like taste, cost, and shelf stability,
which are not critical, and can be readily made by a person skilled
in the art.
[0270] Peroral compositions also include liquid solutions,
emulsions, suspensions, and the like. The
pharmaceutically-acceptable carriers suitable for preparation of
such compositions are well known in the art. Typical components of
carriers for syrups, elixirs, emulsions and suspensions include
ethanol, glycerol, propylene glycol, polyethylene glycol, liquid
sucrose, sorbitol and water. For a suspension, typical suspending
agents include methyl cellulose, sodium carboxymethyl cellulose,
AVICEL RC-591, tragacanth and sodium alginate; typical wetting
agents include lecithin and polysorbate 80; and typical
preservatives include methyl paraben and sodium benzoate. Peroral
liquid compositions may also contain one or more components such as
sweeteners, flavoring agents and colorants disclosed above.
[0271] Such compositions may also be coated by conventional
methods, typically with pH or time-dependent coatings, such that
the subject compound is released in the gastrointestinal tract in
the vicinity of the desired topical application, or at various
times to extend the desired action. Such dosage forms typically
include, but are not limited to, one or more of cellulose acetate
phthalate, polyvinylacetate phthalate, hydroxypropyl methyl
cellulose phthalate, ethyl cellulose, Eudragit coatings, waxes and
shellac.
[0272] Compositions described herein may optionally include other
drug actives.
[0273] Other compositions useful for attaining systemic delivery of
the subject compounds include sublingual, buccal and nasal dosage
forms. Such compositions typically comprise one or more of soluble
filler substances such as sucrose, sorbitol and mannitol; and
binders such as acacia, microcrystalline cellulose, carboxymethyl
cellulose and hydroxypropyl methyl cellulose. Glidants, lubricants,
sweeteners, colorants, antioxidants and flavoring agents disclosed
above may also be included.
[0274] A liquid composition, which is formulated for topical
ophthalmic use, is formulated such that it can be administered
topically to the eye. The comfort should be maximized as much as
possible, although sometimes formulation considerations (e.g. drug
stability) may necessitate less than optimal comfort. In the case
that comfort cannot be maximized, the liquid should be formulated
such that the liquid is tolerable to the patient for topical
ophthalmic use. Additionally, an ophthalmically acceptable liquid
should either be packaged for single use, or contain a preservative
to prevent contamination over multiple uses.
[0275] For ophthalmic application, solutions or medicaments are
often prepared using a physiological saline solution as a major
vehicle. Ophthalmic solutions should preferably be maintained at a
comfortable pH with an appropriate buffer system. The formulations
may also contain conventional, pharmaceutically acceptable
preservatives, stabilizers and surfactants.
[0276] Preservatives that may be used in the pharmaceutical
compositions disclosed herein include, but are not limited to,
benzalkonium chloride, PHMB, chlorobutanol, thimerosal,
phenylmercuric, acetate and phenylmercuric nitrate. A useful
surfactant is, for example, Tween 80. Likewise, various useful
vehicles may be used in the ophthalmic preparations disclosed
herein. These vehicles include, but are not limited to, polyvinyl
alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers,
carboxymethyl cellulose, hydroxyethyl cellulose and purified
water.
[0277] Tonicity adjustors may be added as needed or convenient.
They include, but are not limited to, salts, particularly sodium
chloride, potassium chloride, mannitol and glycerin, or any other
suitable ophthalmically acceptable tonicity adjustor.
[0278] Various buffers and means for adjusting pH may be used so
long as the resulting preparation is ophthalmically acceptable. For
many compositions, the pH will be between 4 and 9. Accordingly,
buffers include acetate buffers, citrate buffers, phosphate buffers
and borate buffers. Acids or bases may be used to adjust the pH of
these formulations as needed.
[0279] In a similar vein, an ophthalmically acceptable antioxidant
includes, but is not limited to, sodium metabisulfite, sodium
thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated
hydroxytoluene.
[0280] Other excipient components, which may be included in the
ophthalmic preparations, are chelating agents. A useful chelating
agent is edetate disodium, although other chelating agents may also
be used in place or in conjunction with it.
[0281] For topical use, creams, ointments, gels, solutions or
suspensions, etc., containing the compound disclosed herein are
employed. Topical formulations may generally be comprised of a
pharmaceutical carrier, co-solvent, emulsifier, penetration
enhancer, preservative system, and emollient.
[0282] For intravenous administration, the compounds and
compositions described herein may be dissolved or dispersed in a
pharmaceutically acceptable diluent, such as a saline or dextrose
solution. Suitable excipients may be included to achieve the
desired pH, including but not limited to NaOH, sodium carbonate,
sodium acetate, HCl, and citric acid. In various embodiments, the
pH of the final composition ranges from 2 to 8, or preferably from
4 to 7. Antioxidant excipients may include sodium bisulfite,
acetone sodium bisulfite, sodium formaldehyde, sulfoxylate,
thiourea, and EDTA. Other non-limiting examples of suitable
excipients found in the final intravenous composition may include
sodium or potassium phosphates, citric acid, tartaric acid,
gelatin, and carbohydrates such as dextrose, mannitol, and dextran.
Further acceptable excipients are described in Powell, et al.,
Compendium of Excipients for Parenteral Formulations, PDA J Pharm
Sci and Tech 1998, 52 238-311 and Nema et al., Excipients and Their
Role in Approved Injectable Products: Current Usage and Future
Directions, PDA J Pharm Sci and Tech 2011, 65 287-332, both of
which are incorporated herein by reference in their entirety.
Antimicrobial agents may also be included to achieve a
bacteriostatic or fungistatic solution, including but not limited
to phenylmercuric nitrate, thimerosal, benzethonium chloride,
benzalkonium chloride, phenol, cresol, and chlorobutanol.
[0283] The compositions for intravenous administration may be
provided to caregivers in the form of one more solids that are
reconstituted with a suitable diluent such as sterile water, saline
or dextrose in water shortly prior to administration. In other
embodiments, the compositions are provided in solution ready to
administer parenterally. In still other embodiments, the
compositions are provided in a solution that is further diluted
prior to administration. In embodiments that include administering
a combination of a compound described herein and another agent, the
combination may be provided to caregivers as a mixture, or the
caregivers may mix the two agents prior to administration, or the
two agents may be administered separately.
[0284] The actual dose of the active compounds described herein
depends on the specific compound, and on the condition to be
treated; the selection of the appropriate dose is well within the
knowledge of the skilled artisan.
Methods of Treatment
[0285] Some embodiments of the present invention include methods of
treating bacterial infections with the compounds and compositions
comprising the compounds described herein. Some methods include
administering a compound, composition, pharmaceutical composition
described herein to a subject in need thereof. In some embodiments,
a subject can be an animal, e.g., a mammal (including a human). In
some embodiments, the bacterial infection comprises a bacteria
described herein. As will be appreciated from the foregoing,
methods of treating a bacterial infection include methods for
preventing bacterial infection in a subject at risk thereof.
[0286] In some embodiments, the subject is a human.
[0287] Further embodiments include administering a combination of
compounds to a subject in need thereof. A combination can include a
compound, composition, pharmaceutical composition described herein
with an additional medicament.
[0288] Some embodiments include co-administering a compound,
composition, and/or pharmaceutical composition described herein,
with an additional medicament. By "co-administration," it is meant
that the two or more agents may be found in the patient's
bloodstream at the same time, regardless of when or how they are
actually administered. In one embodiment, the agents are
administered simultaneously. In one such embodiment, administration
in combination is accomplished by combining the agents in a single
dosage form. In another embodiment, the agents are administered
sequentially. In one embodiment the agents are administered through
the same route, such as orally. In another embodiment, the agents
are administered through different routes, such as one being
administered orally and another being administered i.v.
[0289] Examples of additional medicaments include an antibacterial
agent, antifungal agent, an antiviral agent, an anti-inflammatory
agent and an anti-allergic agent.
[0290] Preferred embodiments include combinations of a compound,
composition or pharmaceutical composition described herein with an
antibacterial agent such as a .beta.-lactam. Examples of such
.beta.-lactams include Amoxicillin, Ampicillin (e.g.,
Pivampicillin, Hetacillin, Bacampicillin, Metampicillin,
Talampicillin), Epicillin, Carbenicillin (Carindacillin),
Ticarcillin, Temocillin, Azlocillin, Piperacillin, Mezlocillin,
Mecillinam (Pivmecillinam), Sulbenicillin, Benzylpenicillin (G),
Clometocillin, Benzathine benzylpenicillin, Procaine
benzylpenicillin, Azidocillin, Penamecillin,
Phenoxymethylpenicillin (V), Propicillin, Benzathine
phenoxymethylpenicillin, Pheneticillin, Cloxacillin (e.g.,
Dicloxacillin, Flucloxacillin), Oxacillin, Methicillin, Nafcillin,
Faropenem, Biapenem, Doripenem, Ertapenem, Imipenem, Meropenem,
Panipenem, Cefazolin, Cefacetrile, Cefadroxil, Cefalexin,
Cefaloglycin, Cefalonium, Cefaloridine, Cefalotin, Cefapirin,
Cefatrizine, Cefazedone, Cefazaflur, Cefradine, Cefroxadine,
Ceftezole, Cefaclor, Cefamandole, Cefminox, Cefonicid, Ceforanide,
Cefotiam, Cefprozil, Cefbuperazone, Cefuroxime, Cefuzonam,
Cefoxitin, Cefotetan, Cefmetazole, Loracarbef, Cefixime,
Ceftazidime, Ceftriaxone, Cefeapene, Cefdaloxime, Cefdinir,
Cefditoren, Cefetamet, Cefmenoxime, Cefodizime, Cefoperazone,
Cefotaxime, Cefpimizole, Cefpiramide, Cefpodoxime, Cefsulodin,
Cefteram, Ceftibuten, Ceftiolene, Ceftizoxime, Flomoxef, Latamoxef,
Cefepime, Cefozopran, Cefpirome, Cefquinome, Ceftobiprole,
Ceftaroline, Ceftiofur, Cefquinome, Cefovecin, Aztreonam, Tigemonam
and Carumonam.
[0291] Preferred embodiments include .beta.-lactams such as
Ceftazidime, Biapenem, Doripenem, Ertapenem, Imipenem, Meropenem,
Tebipenem, Tebipenem pivoxil, Apapenem, and Panipenem.
[0292] Additional preferred embodiments include .beta.-lactams such
as Aztreonam, Tigemonam, and Carumonam.
[0293] Some embodiments include a combination of the compounds,
compositions and/or pharmaceutical compositions described herein
with an additional agent, wherein the additional agent comprises a
monobactam. Examples of monobactams include aztreonam, tigemonam,
nocardicin A, carumonam, and tabtoxin. In some such embodiments,
the compound, composition and/or pharmaceutical composition
comprises a class A, C, or D beta-lactamase inhibitor. Some
embodiments include co-administering the compound, composition or
pharmaceutical composition described herein with one or more
additional agents.
[0294] Some embodiments include a combination of the compounds,
compositions and/or pharmaceutical compositions described herein
with an additional agent, wherein the additional agent comprises a
class B beta lactamase inhibitor. An example of a class B beta
lactamase inhibitor includes ME1071 (Yoshikazu Ishii et al, "In
Vitro Potentiation of Carbapenems with ME1071, a Novel
Metallo-.beta.-Lactamase Inhibitor, against
Metallo-.beta.-lactamase Producing Pseudomonas aeruginosa Clinical
Isolates." Antimicrob. Agents Chemother. doi:10.1128/AAC.01397-09
(July 2010)). Some embodiments include co-administering the
compound, composition or pharmaceutical composition described
herein with one or more additional agents.
[0295] Some embodiments include a combination of the compounds,
compositions and/or pharmaceutical compositions described herein
with an additional agent, wherein the additional agent comprises
one or more agents that include a class A, B, C, or D beta
lactamase inhibitor. Some embodiments include co-administering the
compound, composition or pharmaceutical composition described
herein with the one or more additional agents.
Indications
[0296] The compounds and compositions comprising the compounds
described herein can be used to treat bacterial infections.
Bacterial infections that can be treated with the compounds,
compositions and methods described herein can comprise a wide
spectrum of bacteria. Example organisms include gram-positive
bacteria, gram-negative bacteria, aerobic and anaerobic bacteria,
such as Staphylococcus, Lactobacillus, Streptococcus, Sarcina,
Escherichia, Enterobacter, Klebsiella, Pseudomonas, Acinetobacter,
Mycobacterium, Proteus, Campylobacter, Citrobacter, Nisseria,
Baccillus, Bacteroides, Peptococcus, Clostridium, Salmonella,
Shigella, Serratia, Haemophilus, Brucella and other organisms.
[0297] More examples of bacterial infections include Pseudomonas
aeruginosa, Pseudomonas fluorescens, Pseudomonas acidovorans,
Pseudomonas alcaligenes, Pseudomonas putida, Stenotrophomonas
maltophilia, Burkholderia cepacia, Aeromonas hydrophilia,
Escherichia coli, Citrobacter freundii, Salmonella typhimurium,
Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis,
Shigella dysenteriae, Shigella flexneri, Shigella sonnei,
Enterobacter cloacae, Enterobacter aerogenes, Klebsiella
pneumoniae, Klebsiella oxytoca, Serratia marcescens, Francisella
tularensis, Morganella morganii, Proteus mirabilis, Proteus
vulgaris, Providencia alcalifaciens, Providencia rettgeri,
Providencia stuartii, Acinetobacter baumannii, Acinetobacter
calcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica,
Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia,
Bordetella pertussis, Bordetella parapertussis, Bordetella
bronchiseptica, Haemophilus influenzae, Haemophilus parainfluenzae,
Haemophilus haemolyticus, Haemophilus parahaemolyticus, Haemophilus
ducreyi, Pasteurella multocida, Pasteurella haemolytica,
Branhamella catarrhalis, Helicobacter pylori, Campylobacter fetus,
Campylobacter jejuni, Campylobacter coli, Borrelia burgdorferi,
Vibrio cholerae, Vibrio parahaemolyticus, Legionella pneumophila,
Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria
meningitidis, Kingella, Moraxella, Gardnerella vaginalis,
Bacteroides fragilis, Bacteroides distasonis, Bacteroides 3452A
homology group, Bacteroides vulgatus, Bacteroides ovalus,
Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides
eggerthii, Bacteroides splanchnicus, Clostridium difficile,
Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium
intracellulare, Mycobacterium leprae, Corynebacterium diphtheriae,
Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcus
agalactiae, Streptococcus pyogenes, Enterococcus faecalis,
Enterococcus faecium, Staphylococcus aureus, Staphylococcus
epidermidis, Staphylococcus saprophyticus, Staphylococcus
intermedius, Staphylococcus hyicus subsp. hyicus, Staphylococcus
haemolyticus, Staphylococcus hominis, or Staphylococcus
saccharolyticus.
[0298] To further illustrate this invention, the following examples
are included. The examples should not, of course, be construed as
specifically limiting the invention. Variations of these examples
within the scope of the claims are within the purview of one
skilled in the art and are considered to fall within the scope of
the invention as described, and claimed herein. The reader will
recognize that the skilled artisan, armed with the present
disclosure, and skill in the art is able to prepare and use the
invention without exhaustive examples. The following examples will
further describe the present invention, and are used for the
purposes of illustration only, and should not be considered as
limiting.
EXAMPLES
General Procedures
[0299] Materials used in preparing the cyclic boronic acid ester
derivatives described herein may be made by known methods or are
commercially available. It will be apparent to the skilled artisan
that methods for preparing precursors and functionality related to
the compounds claimed herein are generally described in the
literature including, for example, procedures described in U.S.
Pat. No. 7,271,186 and WO2009064414, each of which is incorporated
by reference in its entirety. In these reactions, it is also
possible to make use of variants which are themselves known to
those of ordinary skill in this art, but are not mentioned in
greater detail. The skilled artisan given the literature and this
disclosure is well equipped to prepare any of the compounds.
[0300] It is recognized that the skilled artisan in the art of
organic chemistry can readily carry out manipulations without
further direction, that is, it is well within the scope and
practice of the skilled artisan to carry out these manipulations.
These include reduction of carbonyl compounds to their
corresponding alcohols, oxidations, acylations, aromatic
substitutions, both electrophilic and nucleophilic,
etherifications, esterification and saponification and the like.
These manipulations are discussed in standard texts such as March
Advanced Organic Chemistry (Wiley), Carey and Sundberg, Advanced
Organic Chemistry (incorporated herein by reference in their
entirety) and the like.
[0301] The skilled artisan will readily appreciate that certain
reactions are best carried out when other functionality is masked
or protected in the molecule, thus avoiding any undesirable side
reactions and/or increasing the yield of the reaction. Often the
skilled artisan utilizes protecting groups to accomplish such
increased yields or to avoid the undesired reactions. These
reactions are found in the literature and are also well within the
scope of the skilled artisan. Examples of many of these
manipulations can be found for example in T. Greene and P. Wuts
Protecting Groups in Organic Synthesis, 4th Ed., John Wiley &
Sons (2007), incorporated herein by reference in its entirety.
[0302] The following example schemes are provided for the guidance
of the reader, and represent preferred methods for making the
compounds exemplified herein. These methods are not limiting, and
it will be apparent that other routes may be employed to prepare
these compounds. Such methods specifically include solid phase
based chemistries, including combinatorial chemistry. The skilled
artisan is thoroughly equipped to prepare these compounds by those
methods given the literature and this disclosure. The compound
numberings used in the synthetic schemes depicted below are meant
for those specific schemes only, and should not be construed as or
confused with same numberings in other sections of the
application.
[0303] Trademarks used herein are examples only and reflect
illustrative materials used at the time of the invention. The
skilled artisan will recognize that variations in lot,
manufacturing processes, and the like, are expected. Hence the
examples, and the trademarks used in them are non-limiting, and
they are not intended to be limiting, but are merely an
illustration of how a skilled artisan may choose to perform one or
more of the embodiments of the invention.
[0304] The following abbreviations have the indicated meanings:
[0305] DCM=dichloromethane [0306] DMF=N,N-dimethylformamide [0307]
ESBL=extended-spectrum .beta.-lactamase [0308] EtOAc=ethyl acetate
[0309]
HATU=2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate [0310] MeCN=acetonitrile [0311] NMR=nuclear
magnetic resonance [0312] TBDMSCl=tert-butyldimethylsilyl chloride
[0313] TBS=tert-butyldimethylsilyl [0314] TFA=trifluoroacetic acid
[0315] THF=tetrahydrofuran [0316] TLC=thin layer chromatography
[0317] The following example schemes are provided for the guidance
of the reader, and collectively represent an example method for
making the compounds provided herein. Furthermore, other methods
for preparing compounds described herein will be readily apparent
to the person of ordinary skill in the art in light of the
following reaction schemes and examples. Unless otherwise
indicated, all variables are as defined above.
Example 1
2-HYDROXY-4-(2-(THIOPHEN-2-YL)ACETAMIDO)-3,4-DIHYDRO-2H-BENZO[E][1,2]OXABO-
RININE-8-CARBOXYLIC ACID (1)
##STR00078## ##STR00079## ##STR00080##
[0318] Step 1: Synthesis of Compound 1B
[0319] To the solution of compound 1A (200 g, 1.314 mol) in THF
(500 mL) was added Boc.sub.2O (1146 g, 5.26 mol), DMAP (48 g, 0.394
mol) and .sup.tBuOH (1 L). The resulting solution was stirred at
60.degree. C. for 6 hours before it was concentrated in vacuo. The
residue was purified by flash column chromatography (ethyl
acetate/hexanes, v/v, 1/200.about.1/100) to give the title compound
1B (192.8 g, 47.6% yield) as colorless oil.
[0320] .sup.1H-NMR: (400 MHz, CDCl.sub.3) .delta. 7.73 (d, 1H),
7.35 (d, 1H), 7.15 (t, 1H), 2.25 (s, 3H), 1.60 (s, 9H), 1.58 (s,
9H).
Step 2: Synthesis of Compound 1C
[0321] To the solution of compound 1B (192.8 g, 625 mmol) and NBS
(122.4 g, 688 mmol) in CCl.sub.4 (1 L) was added BPO (15.1 g, 62.5
mmol). The resulting mixture was refluxed at 80.degree. C. for 15
hours. The solid was filtered off and the filtrate was concentrated
in vacuo. The residue was recrystallized with hexanes to afford the
title compound 1C (141 g, 58.2% yield) as white solid.
[0322] .sup.1H-NMR: (400 MHz, CDCl.sub.3) .delta. 7.87 (d, 1H),
7.55 (d, 1H), 7.26 (t, 1H), 4.49 (s, 2H), 1.59 (s, 9H), 1.55 (s,
9H).
Step 3: Synthesis of Compound 1D
[0323] To the suspension of CuI (480 mg, 2.51 mmol) in THF (100 mL)
was added vinylmagnesium bromide (12.6 mL, 1.0M in THF, 12.6 mmol)
dropwise at -50.degree. C. in 5 minutes. After 10 minutes, a
solution of compound 1C (3.24 g, 8.37 mmol) in THF (20 mL) was
added via syringe in 3 minutes. The resulting reaction mixture was
slowly warmed up to room temperature in 3 hours and stirred
overnight. The dark reaction mixture was quenched with saturated
NH.sub.4Cl and extracted with EtOAc twice. After drying over
Na.sub.2SO.sub.4, the organic solution was concentrated and
chromatographed (ethyl acetate/hexanes, v/v, 1/20.about.1/8) to
obtain the title compound 1D (1.81 g, 65% yield) as slightly yellow
oil.
[0324] .sup.1H-NMR: (300 MHz, CDCl.sub.3) .delta. 7.78 (dd, 1H),
7.38 (dd, 1H), 7.20 (t, 1H), 5.80-5.96 (m, 1H), 5.08 (d, 1H), 5.03
(s, 1H), 3.39 (d, 2H), 1.59 (s, 9H), 1.56 (s, 9H).
Step 4: Synthesis of Compound 1E
[0325] To a solution of 1D (2.0 g, 6.0 mmol) in CH.sub.2Cl.sub.2
(35 mL) and MeOH (5 mL) at -78.degree. C. was bubbled with O.sub.3
until light blue color appeared in the flask. Then Me.sub.2S (2.64
mL, 36 mmol) was added, and the solution was slowly warmed up to
room temperature where it was stirred for 16 h. The reaction
solution was concentrated in vacuo to dryness and used directly for
next step.
Step 5: Synthesis of Compound 1F
[0326] To a solution of crude 1E (about 6.0 mmol) in THF (80 mL),
t-BuOH (35 mL) and water (35 mL) at 0.degree. C. was added
2-methyl-2-butene (6.4 mL, 60 mmol), followed by NaClO.sub.2 (3.26
g, .about.80% purity, 36 mmol). After 30 min at 0.degree. C., then
reaction was quenched with NaHSO.sub.3 (5 g). The solution was
adjusted to pH=2 with 1N HCl, and extracted with EtOAc twice. The
combined organic layers were washed with brine and dried over
Na.sub.2SO.sub.4. After concentration, 1.2 g crude 1F was obtained
as light yellow oil, which was used directly for next step.
[0327] .sup.1H-NMR: (300 MHz, CDCl.sub.3) .delta. 7.83 (dd, 1H),
7.43 (dd, 1H), 7.22 (t, 1H), 3.66 (s, 2H), 1.57 (s, 9H), 1.53 (s,
9H).
Step 6: Synthesis of Compound 1G
[0328] To a solution of crude 1F (about 3.4 mmol) in MeCN (9 mL)
was added BnBr (0.81 mL, 6.8 mmol), followed by Et.sub.3N (0.71 mL,
5.1 mmol). The resulting solution was stirred at room temperature
for 6 hours. The reaction mixture was diluted with EtOAc and washed
with water and brine. The aqueous layers were extracted with EtOAc.
The combined organic layers were dried over Na.sub.2SO.sub.4. After
concentration, the residue was purified by column chromatography
(ethyl acetate/hexanes, v/v, 1/10.about.1/3) to obtain the title
compound 1G (0.82 g) as slightly yellow oil.
[0329] .sup.1H-NMR: (300 MHz, CDCl.sub.3) .delta. 7.82 (d, 1H),
7.43 (d, 1H), 7.25-7.36 (m, 5H), 7.21 (t, 1H), 5.12 (s, 2H), 3.70
(s, 2H), 1.56 (s, 9H), 1.52 (s, 9H).
Step 7: Synthesis of Compound 1H
[0330] To the solution of 1G (5.9 g, 13.3 mmol) in THF (50 mL) was
added LDA (freshly made from diisopropylamine (2.43 g, 17.3 mmol)
and n-BuLi (6.65 mL, 2.5 M in hexanes, 16.6 mmol) in 30 mL THF,
pre-cooled to -78.degree. C.) at -78.degree. C. via cannula. After
5 minutes, bromomethylboronic acid pinacol ester (4.1 g, 18.6 mmol)
was added via syringe. After 30 minutes at -78.degree. C.,
ZnCl.sub.2 (30 mL, 1M in Et.sub.2O, 30 mmol) was added slowly in 5
minutes. The resulting solution was slowly warmed up to room
temperature for 3 hours before it was quenched with saturated
NH.sub.4Cl. The reaction mixture was extracted with EtOAc twice and
dried over Na.sub.2SO.sub.4. After concentration, the residue was
purified by column chromatography (ethyl acetate/hexanes, v/v,
1/10.about.1/5) to obtain the title compound 1H (4.7 g) as slightly
yellow oil.
[0331] .sup.1H-NMR: (300 MHz, CDCl.sub.3) .delta. 7.80 (d, 1H),
7.42 (d, 1H), 7.20-7.36 (m, 5H), 7.20 (t, 1H), 4.92-5.19 (dd, 2H),
4.22 (dd, 1H), 1.58 (s, 9H), 1.55 (s, 9H), 1.24 (d, 2H), 1.15 (d,
12H).
Step 8: Synthesis of Compound 11
[0332] Compound 1H (4.7 g, 8.1 mmol) and (+)-pinanediol (1.65 g,
9.7 mmol) were stirred in THF (50 mL) at room temperature for 24
hours. The reaction mixture was concentrated and purified by column
chromatography (ethyl acetate/hexanes, v/v, 1/10.about.1/5) to
obtain the title compound 11 (2.8 g) as slightly yellow oil.
[0333] .sup.1H-NMR: (300 MHz, CDCl.sub.3) .delta. 7.80 (d, 1H),
7.42 (d, 1H), 7.18-7.36 (m, 5H), 7.18 (t, 1H), 4.92-5.21 (m, 2H),
4.24 (m, 1H), 4.18 (m, 1H), 2.17-2.32 (m, 1H), 2.00-2.16 (m, 1H),
1.92-2.00 (m, 1H), 1.65-1.86 (m, 2H), 1.60 (s, 9H), 1.51 (s, 9H),
1.22-1.31 (m, 5H), 1.12-1.16 (m, 3H), 0.77-0.84 (m, 3H).
Step 9: Synthesis of Compound 1J
[0334] Compound 11 (2.8 g, 4.4 mmol) and Pd/C (400 mg, 10%) were
stirred in EtOAc (50 mL) at room temperature under hydrogen (1 atm)
for 18 hours. The reaction mixture was filtered through Celite and
washed with EtOAc. After concentration, the mixture was purified by
column chromatography (ethyl acetate/hexanes, v/v, 1/2.about.1/1)
to obtain the title compound 1J (1.48 g) as white solid.
MS calcd for (C.sub.29H.sub.41BO.sub.9): 544 MS (ESI, negative)
found: (M-1): 543
Step 10: Synthesis of Compound 1K
[0335] Compound 1J (1.26 g, 2.3 mmol), DPPA (0.65 mL, 3.0 mmol) and
Et.sub.3N (0.48 mL, 3.5 mmol) were dissolved in dry toluene (12 mL)
at room temperature in nitrogen atmosphere. After 30 minutes, BnOH
(2.4 mL, 23 mmol) was added and the reaction mixture was heated to
80.degree. C. and stirred at this temperature for 16 hours. After
cooling down, the solution was concentrated and purified by column
chromatography (ethyl acetate/hexanes, v/v, 1/4.about.1/3) to
obtain the title compound 1K (0.88 g) as colorless oil.
MS calcd for (C.sub.36H.sub.48BNO.sub.9): 649 MS (ESI, positive)
found: (M+1): 650 MS (ESI, negative) found: (M-1): 648
Step 11: Synthesis of Compound 1L
[0336] To the solution of 1K (170 mg, 0.26 mmol) in 10 mL dioxane
was added Pd/C (80 mg, 10%) and HCl solution (0.13 mL, 4 N in
dioxane, 0.53 mmol). The resulting mixture was stirred at room
temperature under hydrogen (1 atm) atmosphere for 2 hours. The
reaction mixture was filtered through Celite and washed with
dioxane. The filtrate was directly used for next step.
MS calcd for (C.sub.28H.sub.42BNO.sub.7): 515 MS (ESI, positive)
found: (M+1): 516
Step 12: Synthesis of Compound 1M
[0337] To the solution of 2-thiopheneacetic acid (75 mg, 0.53 mmol)
in DMF (3 mL) was added HATU (209 mg, 0.55 mmol) at 0.degree. C.
After 20 minutes, the crude solution of 1L (0.26 mmol) in 10 mL
dioxane was added, followed by DIPEA (0.18 mL, 1.1 mmol). The
resulting mixture was warmed to room temperature and stirred for 1
hour until LC-MS monitoring indicating the completion of reaction.
The reaction mixture was concentrated to half volumn and diluted
with EtOAc/hexanes (4/1, v/v). After washed with 0.1N HCl, water
and brine, the organic layer was dried over Na.sub.2SO.sub.4. After
concentration, the residue was purified by column chromatography
(ethyl acetate/hexanes, v/v, 1/3.about.1/1) to obtain the title
compound 1M (85 mg) as slightly yellow solid.
MS calcd for (C.sub.34H.sub.46BNO.sub.8S): 639 MS (ESI, positive)
found: (M+1): 640 MS (ESI, negative) found: (M-1): 638
Step 13: Synthesis of Compound 1
[0338] To the mixture of 1M (85 mg, 0.13 mmol) and triethylsaline
(155 mg, 1.3 mmol) was added TFA (2 mL). The resulting solution was
stirred at room temperature for 1.5 hours before it was
concentrated to dryness. The residue was washed with hexanes twice
and purified by prep-HPLC (C18, acetonitrile and water as mobile
phases, 0.1% formic acid) to obtain the title compound T110 (16 mg)
as white solid.
MS calcd for (C.sub.15H.sub.14BNO.sub.5S): 331 MS (ESI, positive)
found: (M+1): 332 MS (ESI, negative) found: (M-1): 330
[0339] .sup.1H-NMR: (300 MHz, CDCl.sub.3) .delta. 7.82 (dd, 1H),
7.31 (dd, 1H), 7.24 (dd, 1H), 6.87 (d, 2H), 6.83 (t, 1H), 4.70 (m,
1H), 3.85 (s, 2H), 0.68-0.82 (m, 2H). NMR:
Example 2
4-(5-AMINO-1,3,4-THIADIAZOLE-2-CARBOXAMIDO)-2-HYDROXY-3,4-DIHYDRO-2H-BENZO-
[E][1,2]OXABORININE-8-CARBOXYLIC ACID (2)
##STR00081##
[0340] Step 1: Synthesis of Compound 1O
[0341] To the solution of 1K (200 mg, 0.31 mmol) in 10 mL dioxane
was added Pd/C (110 mg, 10%) and HCl solution (0.16 mL, 4 N in
dioxane, 0.62 mmol). The resulting mixture was stirred at room
temperature under hydrogen (1 atm) atmosphere for 2 hours. The
reaction mixture was filtered through Celite and washed with
dioxane.
[0342] To the solution of
5-(N-Boc-amino)-1,3,4-thiadiazole-2-carboxylic acid (114 mg, 0.46
mmol) in DMF (4 mL) was added HATU (190 mg, 0.5 mmol) at 0.degree.
C. After 20 minutes, the above solution in 10 mL dioxane was added,
followed by DIPEA (0.22 mL, 1.3 mmol). The resulting mixture was
warmed to room temperature and stirred for 1 hour until LC-MS
monitoring indicating the completion of reaction. The reaction
mixture was concentrated to half volumn and diluted with
EtOAc/hexanes (4/1, v/v). After washed with 0.1N HCl, water and
brine, the organic layer was dried over Na.sub.2SO.sub.4. After
concentration, the residue was purified by column chromatography
(ethyl acetate/hexanes, v/v, 1/3.about.1/1) to obtain the title
compound 10 (102 mg) as white solid.
MS calcd for (C.sub.36H.sub.51BN.sub.4O.sub.10S): 742 MS (ESI,
negative) found: (M-1): 741
Step 2: Synthesis of Compound 2
[0343] To the mixture of 10 (102 mg, 0.14 mmol) and triethylsaline
(1 mL) was added TFA (4 mL) and isobutylboronic acid (35 mg, 0.34
mmol). The resulting solution was stirred at room temperature 4
hours before it was concentrated to dryness. The residue was
purified by prep-HPLC (C18, acetonitrile and water as mobile
phases, 0.1% formic acid) to obtain the title compound T520 (8 mg)
as white solid.
MS calcd for (C.sub.12H.sub.11BN.sub.4O.sub.5S): 334 MS (ESI,
positive) found: (M+1): 335 MS (ESI, negative) found: (M-1):
333
[0344] .sup.1H-NMR: (300 MHz, CDCl.sub.3) .delta. 7.88 (dd, 1H),
7.48 (dd, 1H), 6.93 (t, 1H), 4.80 (m, 1H), 1.05-1.35 (m, 2H).
Example 3
2-HYDROXY-4-(2-(METHYLTHIO)ACETAMIDO)-3,4-DIHYDRO-2H-BENZO[E][1,2]OXABORIN-
INE-8-CARBOXYLIC ACID (3)
##STR00082##
[0345] Step 1: Synthesis of Compound 1N
[0346] To the solution of 1K (345 mg, 0.53 mmol) in 12 mL dioxane
was added Pd/C (2000 mg, 10%) and HCl solution (0.27 mL, 4 N in
dioxane, 1.1 mmol). The resulting mixture was stirred at room
temperature under hydrogen (1 atm) atmosphere for 2 hours. The
reaction mixture was filtered through Celite and washed with
dioxane.
[0347] To the solution of (methylthio)acetic acid (85 mg, 0.80
mmol) in DMF (5 mL) was added HATU (323 mg, 0.85 mmol) at 0.degree.
C. After 20 minutes, the above solution in 13 mL dioxane was added,
followed by DIPEA (0.35 mL, 2.1 mmol). The resulting mixture was
warmed to room temperature and stirred for 1 hour until LC-MS
monitoring indicating the completion of reaction. The reaction
mixture was concentrated to half volumn and diluted with
EtOAc/hexanes (4/1, v/v). After washed with 0.1N HCl, water and
brine, the organic layer was dried over Na.sub.2SO.sub.4. After
concentration, the residue was purified by column chromatography
(ethyl acetate/hexanes, v/v, 1/3.about.1/1) to obtain the title
compound 1N (150 mg) as white solid.
MS calcd for (C.sub.31H.sub.46BNO.sub.8S): 603 MS (ESI, positive)
found: (M+1): 604 MS (ESI, negative) found: (M-1): 602
Step 2: Synthesis of Compound 3
[0348] To the mixture of 1N (150 mg, 0.25 mmol) and triethylsaline
(150 mg) was added TFA (4 mL) and isobutylboronic acid (55 mg, 0.54
mmol). The resulting solution was stirred at room temperature 4
hours before it was concentrated to dryness. The residue was
purified by prep-HPLC (C18, acetonitrile and water as mobile
phases, 0.1% formic acid) to obtain the title compound 3 (16 mg) as
white solid.
MS calcd for (C.sub.12H.sub.14BNO.sub.5S): 295 MS (ESI, positive)
found: (M+1): 296 MS (ESI, negative) found: (M-1): 294
[0349] .sup.1H-NMR: (300 MHz, CDCl.sub.3) .delta. 7.92 (dd, 1H),
7.43 (dd, 1H), 6.94 (t, 1H), 4.80 (m, 1H), 3.34 (s, 2H), 2.12 (s,
3H), 0.80-1.00 (m, 2H).
Example 4
4-(BENZYLSULFONYL)-2-HYDROXY-3,4-DIHYDRO-2H-BENZO[E][1,4,2]OXAZABORININE-8-
-CARBOXYLIC ACID (4)
##STR00083##
[0350] Step 1: Synthesis of 4B
[0351] To a mixture of TFAA/TFA (20 mL/30 mL) was added compound 4A
(4.4 g, 24 mmol) at -4.degree. C., followed by acetone (8 mL)
dropwise over 30 mins. The solution was stirred at room temperature
overnight and 30 hours at 90.degree. C. The reaction mixture was
diluted with DCM, washed with water and saturated NaHCO.sub.3(aq),
dried over Na.sub.2SO.sub.4. After concentration, the mixture was
purified by silica gel chromatography to get the title compound 4B
(4.1 g, 76% yield).
[0352] .sup.1H NMR: (400 MHz, CDCl.sub.3) .delta. 8.22-8.28 (m,
2H), 7.23-7.27 (m, 1H), 1.82 (s, 6H).
Step 2: Synthesis of 4C
[0353] The mixture of compound 4B (4.1 g) and Pd/C (1 g, 10%) in
methanol (100 mL) was stirred under H.sub.2 (1 atm) for 12 h at
room temperature. After filtration, the filtrate was evaporated to
dryness, and purified by silica gel chromatography to afford the
title compound 4C (2.9 g, 81.7% yield).
[0354] .sup.1H NMR: (400 MHz, CDCl.sub.3) .delta. 7.33 (m, 1H),
6.88-6.95 (m, 2H), 3.83 (broad s, 2H), 1.74 (s, 6H).
Step 3: Synthesis of 4D
[0355] To a solution of compound 4C (2.8 g, 14.5 mmol) and
triethylamine (4.4 g, 43.5 mmol) in DCM (30 mL) was added
BnSO.sub.2Cl (2.77 g, 14.5 mmol). The mixture was stirred at room
temperature overnight before it was evaporated to dryness. The
residue was purified by silica gel chromatography to get the title
compound 4D (1 g, 20% yield).
[0356] .sup.1H NMR: (400 MHz, CDCl.sub.3) .delta. 7.70-7.72 (m,
2H), 7.31-7.37 (m, 3H), 7.23-7.26 (m, 2H), 7.06-7.09 (t, 1H), 6.58
(s, 1H), 4.39 (s, 2H), 1.69 (s, 6H).
Step 4: Synthesis of 4F
[0357] To a solution of compound 4D (1 g, 2.88 mmol) and
K.sub.2CO.sub.3 (1.19 g, 8.64 mmol) in DMF was added compound 4E
(1.18 g, 4.32 mmol) (WO2013/56163). The mixture was stirred at room
temperature overnight before it was evaporated to dryness. The
residue was purified by silica gel chromatography to get the title
compound 4F (0.5 g, 32% yield).
[0358] .sup.1H NMR: (400 MHz, CDCl.sub.3) .delta. 7.88-7.91 (m,
1H), 7.46-7.47 (m, 2H), 7.32-7.37 (m, 4H,), 6.98-7.00 (m, 1H), 4.40
(s, 2H), 4.22 (dd, 1H), 3.31 (s, 2H), 2.21-2.38 (m, 1H),
0.2.02-2.08 (m, 1H), 1.91-1.95 (m, 2H), 1.79-1.80 (s, 6H), 1.31 (s,
3H), 1.28 (s, 3H), 0.79 (s, 3H), 0.73 (d, 1H).
Step 5: Synthesis of 4
[0359] Compound 4F (500 mg) in HCl (6 mol/L, 2 mL) and 1,4-dioxane
(2 mL) was heated to reflux (oil bath: 110.degree. C.) for 3 hour
before it was concentrated to dryness. The residue purified by
prep-HPLC to afford 4 (82 mg) as white solid. The compound was
obtained as a mixture of cyclic and acyclic boronate.
[0360] .sup.1H NMR: (400 MHz, CD.sub.3OD) .delta. 7.42-7.43 (d, 1H,
J=4 Hz), 7.41-7.42 (d, 1H, J=4 Hz), 7.40-7.41 (d, 1H, J=4 Hz),
7.39-7.40 (m, 5H), 7.33-7.34 (m, 2H), 7.28-7.29 (m, 3H), 7.15-7.18
(m, 4H), 6.87-6.91 (m, 1H), 6.83-6.85 (m, 1H), 5.49 (s, 1H), 4.5
(s, 2H), 4.24 (s, 1H), 3.42 (s, 1H), 3.16 (s, 2H).
MS calcd for (C.sub.15H.sub.14BNO.sub.6S): 347.2 MS (ESI, positive)
found: (M+1): 348
Example 5
2-HYDROXY-3,4-DIHYDRO-1,2-BENZOXABORININE-8-CARBOXYLIC ACID
##STR00084##
[0361] Step 1: Synthesis of 5B
[0362] To the solution of [IrCl(cod)]2 (11.1 mg, 0.0165 mmol) and
dppe (13 mg, 0.033 mmol) in dichloromethane (1 mL) was added
pinacolborane (0.095 mL, 0.66 mmol) under N2 atmosphere. The
resulting solution was added into compound 5A (112 mg, 0.55 mmol)
(WO 2014107535) in dichloromethane (2 mL) and stirred at room
temperature for 18 hours. Crude NMR showed good conversion. The
reaction mixture was concentrated and purified by column
chromatography (silica gel, EtOAc/Hexanes, v/v, 1/4) to give the
titled compound 5B (150 mg) as colorless oil.
Step 2: Synthesis of 5
[0363] To the solution of compound 5B (.about.140 mg) in dioxane (5
mL) was added 6N aqueous HCl (5 mL). The resulting solution was
stirred at 100.degree. C. for 1.5 hours before it was cooled down.
The reaction mixture was concentrated and purified by C18
reverse-phase prep-HPLC (acetonitrile and water as mobile phases,
0.1% formic acid) to give titled compound 5 (39 mg) as white
solid.
MS calcd for (C.sub.9H.sub.9BO.sub.4): 192 MS (ESI, negative)
found: (2M-1): 383
[0364] .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 7.68 (dd, 1H),
7.33 (dd, 1H), 6.79 (t, 1H), 2.69 (t, 2H), 1.09 (t, 2H).
Example 6
DISODIUM;
4,4-DIHYDROXY-5-OXA-8-AZA-4-BORANUIDABICYCLO[4.4.0]DECA-1(6),7,9-
-TRIENE-7-CARBOXYLATE
##STR00085##
[0365] Step 1: Synthesis of 6B
[0366] To a solution of known compound 6A (7 g, 21.73 mmol, 1.0 eq,
Tetrahedron, 2011, 67, 8757) in THF:MeOH:H.sub.2O (2:2:1, 100 mL)
was added LiOH (1.37 g, 32.6 mmol, 1.5 eq) at room temperature. The
mixture was stirred at rt for 1.5 hours. The solvent was removed
under reduced pressure. The residue was redissolved in water,
adjusted pH to 1 with 1N HCl, and extracted with ethyl acetate. The
organics were dried over Na.sub.2SO4, and concentrated to yield
residue, which was purified by column chromatography
(DCM:MeOH=10:1) to give compound 6B (4.85 g, 72%). H NMR
(CD.sub.3OD, 300 MHz): .delta. 8.21 (d, J=4.8 Hz, 1H), 7.88 (d,
J=4.8 Hz, 1H), 7.55-7.36 (m, 5H), 5.15 (s, 2H).
Step 2: Synthesis of 6C
[0367] To a solution of compound 6B (4.8 g, 15.58 mmol, 1.0 eq) in
.sup.tBuOH (150 mL) was added DMAP (195 mg, 1.596 mmol, 0.1 eq) and
Boc.sub.2O (10.2 g, 46.74 mmol, 3 eq). The mixture was stirred
overnight at 60.degree. C. The solvent was removed under reduced
pressure, and the resulting residue was purified by column
chromatography (ethyl acetate:hexanes=1:3) to give compound 6C (4.9
g, 86%). H NMR (CDCl.sub.3, 300 MHz): .delta. 8.23 (d, J=4.8 Hz,
1H), 7.63 (d, J=5.1 Hz, 1H), 7.55-7.38 (m, 5H), 5.13 (s, 2H),
1.58-1.57 (m, 9H).
Step 3: Synthesis of 6D
[0368] To a solution of compound 6C (4.9 g, 13.45 mmol, 1.0 eq) in
isopropyl alcohol (250 mL) was added PdCl.sub.2 (dppf) (878 mg,
1.08 mmol, 0.08 eq), potassium vinyltrifluroborate (4.5 g, 33.59
mmol, 2.5 eq), and triethylamine (2.04 g, 20.17 mmol, 1.5 eq). The
mixture was purged with N.sub.2 and stirred at 86.degree. C. for 3
hours. The solvent was removed under reduced pressure, and the
resulting residue was purified by column chromatography (ethyl
acetate:hexanes=1:3) to give compound 6D (3.77 g, 90%). H NMR
(CDCl.sub.3, 300 MHz): .delta. 8.38 (d, 1H), 7.52-7.28 (m, 6H),
6.95 (dd, 1H), 5.95 (dd, 1H), 5.56 (dd, 1H), 5.01 (s, 2H), 1.6-1.58
(m, 9H).
Step 3: Synthesis of 6E
[0369] To a solution of PinBH (1.86 g, 14.54 mmol, 1.2 eq),
[IrCl(COD)].sub.2 (163 mg, 0.263 mmol, 0.02 eq) and dppe (191 mg,
0.479 mmol, 0.04 eq) in DCM (100 mL) was added compound 6D (3.77 g,
12.11 mmol, 1.0 eq) in DCM (50 mL). The mixture was purged with
N.sub.2 and stirred overnight at room temperature. After addition
of MeOH (10 mL), the solvent was removed under reduced pressure,
and the resulting residue was purified by column chromatography
(ethyl acetate:hexanes=1:3) to give compound 6E (2.58 g, 48%). H
NMR (CDCl.sub.3, 300 MHz): .delta. 8.36 (d, 1H), 7.51-7.29 (m, 6H),
5.03 (s, 2H), 2.80 (t, 2H), 1.59 (s, 9H). 1.29-1.18 (m, 14H).
Step 4: Synthesis of 6F
[0370] To a solution of compound 6E (2.58 g, 5.87 mmol, 1.0 eq) in
MeOH (100 mL) was added Pd/C. The mixture was stirred overnioght at
room temperature. The mixture was filtered through celite and
concentrated under reduced pressure. The resulting residue was
purified by column chromatography (DCM:MeOH=10:1) to give impure
compound 6F (.about.1.5 g).
MS calcd for (C.sub.12H.sub.16BNO.sub.4): 249 MS (ESI, positive)
found: (M+1): 250
Step 5: Synthesis of 6
[0371] Step 1: A solution of compound 6F (1.5 g, 6 mmol, 1.0 eq) in
TFA (12 mL) and TES (3 mL) was stirred at rt for 1.5 h. The mixture
was concentrated, and purified by C18 reverse-phase prep-HPLC
(acetonitrile and water as mobile phases, 0.1% formic acid). After
lyophilization, the obtained white solid was dissolved in
MeCN/H.sub.2O, and adjusted to pH about 7.9 using 0.1N aqueous
NaOH. After stirred at room temperature overnight, the solution was
concentrated, and re-purified by C.sub.18 reverse-phase prep-HPLC
(acetonitrile and water as mobile phases, neutral) to give the
desired 6 sodium salt as white solid.
MS calcd for (C.sub.8H.sub.8BNO.sub.4): 193 MS (ESI, positive)
found: (M+1) 194; (M+1+H.sub.2O) 212.
[0372] .sup.1H NMR (300 MHz, D.sub.2O): .delta. 7.59 (d, 1H), 7.08
(d, 1H), 2.55 (t, 2H), 0.48 (t, 2H).
Example 7
DISODIUM;4,4-DIHYDROXY-8-METHOXY-5-OXA-4-BORANUIDABICYCLO[4.4.0]DECA-1(6),-
7,9-TRIENE-7-CARBOXYLATE
##STR00086##
[0373] Step 1: Synthesis of 7B
[0374] To a solution of 2, 6-dimethoxybenzoic acid (7A) (50 g,
0.275 mol) in CHCl.sub.3 (1 L) at 0.degree. C. was added dropwise
bromine (14.4 mL, 0.263 mol). The reaction mixture was stirred at
25.degree. C. for 30 hours, before it was concentrated to dryness.
The residue was purified by column chromatography (ethyl
acetate/hexanes) to afford compound 7B (32.5 g, 48%) as white
solid.
Step 2: Synthesis of 7C
[0375] To the solution of compound 7B (32.5 g, 0.132 mol) in THF
(200 mL) was added Boc.sub.2O (114.7 g, 0.526 mol), DMAP (4.8 g,
0.04 mol) and tBuOH (400 mL). The resulting solution was stirred at
60.degree. C. for 6 hours before it was concentrated in vacuo. The
residue was quickly passed through a silica gel column (ethyl
acetate/hexanes) to give the corresponding t-butyl ester. To the
solution of this ester and Boc.sub.2O (17 g, 0.078 mol) in DCM (300
mL) was added DMAP (475 mg, 3.89 mmol). The resulting reaction
mixture was stirred at room temperature for 1 hour before it was
concentrated to dryness. The residue was purified by column
chromatography (ethyl acetate/hexanes) to afford compound 7C (52.1
g, 98%) as white solid.
Step 3: Synthesis of 7D
[0376] To a mixture of Zn powder (20 g, 0.302 mol) and compound 7E
(100 mg, 0.37 mmol) in anhydrous THF (100 mL) was added DIBAL-H
(2.45 mL, 6.05 mmol, 1.5 M in toluene) at room temperature. The
mixture was stirred at room temperature for 5 min, then more
compound 7E (33 g, 0.121 mol) in anhydrous THF (100 mL) was added
dropwise into the mixture over 20 min. The reaction mixture was
warmed up to 50.degree. C. and stirred at this temperature for 1
hour before it was settled down at room temperature. The top layer
of clear solution was transferred into a mixture of compound 7C (20
g, 50 mmol) and Pd(t-Bu3P)2 (917 mg, 1.79 mmol) in THF (300 mL) at
room temperature under N.sub.2. After stirring at room temperature
for 1 hour, the reaction mixture was concentrated, and purified by
column chromatography (ethyl acetate/hexanes) to afford compound 7D
(21 g, 81%) as light yellow solid.
Step 4: Synthesis of 7F
[0377] To a solution of dichloromethane (4.2 mL, 0.066 mol) in
anhydrous THF (200 mL), was added dropwise n-butyllithium (2.5 M in
hexane, 18.5 mL, 0.046 mol) along the wall of the flask over 1 h at
-100.degree. C. (cooled with liquid nitrogen and methanol), while
keeping the internal temperature below -90.degree. C. After the
addition, the mixture was stirred at -100.degree. C. for 30 min
before slow addition of the solution of compound 7D (17 g, 0.033
mol) in anhydrous THF (60 mL) over 1 h at -100.degree. C. The
reaction mixture was slowly warmed up to room temperature over a
period of 6 hours and stirred overnight. The solvent was evaporated
and the residue was purified by column chromatography (ethyl
acetate/hexanes) to afford compound 7F (16.5 g, 88%) as light
yellow solid.
Step 5: Synthesis of 7G
[0378] To a solution of compound 7F (3.0 g, 5.3 mmol, 1.0 eq) (WO
2014107536) in anhydrous THF (60 mL) was added a solution of
LiBHEt.sub.3 in THF (1 M, 13.27 mL, 13.3 mmol, 2.5 eq) over 20 min
at -78.degree. C. The mixture was stirred at rt overnight. The
solvent was removed under reduced pressure. The crude was purified
by column chromatography (PE/EA=50:1 to 9:1) to give compound 7G
(2.2 g, 78%). H NMR (CDCl.sub.3, 400 MHz): .delta. 7.24 (d, J=8.8
Hz, 1H), 6.74 (d, J=8.4 Hz, 1H), 4.28-4.23 (m, 1H), 3.79 (s, 3H),
2.60 (m, 2H), 2.39-2.25 (m, 2H), 2.20-2.12 (m, 1H), 2.04-2.01 (m,
1H), 1.95-1.88 (m, 1H), 1.85-1.75 (m, 1H), 1.57 (s, 9H), 1.53 (s,
9H), 1.35 (s, 3H), 1.27 (s, 3H), 1.11-1.02 (m, J=7.6 Hz, 2H), 0.83
(s, 3H).
Step 6: Synthesis of 7
[0379] To a mixture of compound 7G (2.0 g, 3.77 mmol, 1.0 eq),
i-BuB(OH).sub.2 (499 mg, 3.77 mmol, 1.3 eq) in hexane (20 mL) and
methanol (20 mL) was added 1 mL of hydrochloric acid at 0.degree.
C. The reaction mixture was stirred at rt overnight. The methanol
layer was concentrated to give crude product (1.7 g).
[0380] The crude product (1.7 g) was then dissolved in
dichloromethane (7 mL) and TFA (7 mL) was added slowly at 0.degree.
C. The reaction was stirred at rt for 1 h. The mixture was
concentrated and the residue was diluted with methanol (3 mL) and
water (3 mL). The mixture was then adjusted to pH 12 with 0.1N
aqueous solution of NaOH and stirred at rt overnight. The solid was
filtered, washed with acetonitrile-water and dried to afford 7 (650
mg, 71%) as a white solid.
MS calcd for (C.sub.10H.sub.11BO.sub.5): 222 MS (ESI, positive)
found: (M+1) 223
[0381] H NMR (CD.sub.3OD, 400 MHz): .delta. 6.71 (d, J=8.0 Hz, 1H),
6.18 (d, J=8.4 Hz, 1H), 3.70 (s, 3H), 2.55 (t, J=6.8 Hz, 2H), 0.43
(t, J=7.2 Hz, 2H).
Example 8
DISODIUM;
8-FLUORO-4,4-DIHYDROXY-5-OXA-4-BORANUIDABICYCLO[4.4.0]DECA-1(6),-
7,9-TRIENE-7-CARBOXYLATE
##STR00087##
[0382] Step 1: Synthesis of 8B
[0383] The synthesis of the compound 8A can be found in WO
2014107536, which is incorporated herein by reference in its
entirety. To a solution of compound 8A (3.0 g, 5.4 mmol, 1.0 eq) in
anhydrous THF (80 mL) was added a solution of LiBHEt.sub.3 in THF
(1 M, 13.6 mL, 13.6 mmol, 2.5 eq) over 20 min at -78.degree. C. The
reaction was stirred at rt overnight and the solvent was removed
under reduced pressure. The residue was purified by column
chromatography (PE/EA=10:1) to give compound 8B (2.0 g, 71%).
.sup.1H NMR (CDCl.sub.3, 400 MHz): .delta. 7.32-7.26 (m, 1H), 6.92
(t, J=8.8 Hz, 1H), 4.25 (dd, J=8.8 Hz, 1.6 Hz, 1H), 2.65 (dd, J=8.4
Hz, 2H), 2.31-2.28 (m, 1H), 2.19-2.15 (m, 1H), 2.02 (t, J=5.6 Hz,
1H), 1.90-1.88 (m, 1H), 1.83-1.78 (m, 1H), 1.59 (s, 9H), 1.54 (s,
9H), 1.35 (s, 3H), 1.28 (s, 3H), 1.11 (dd, J=8.4 Hz, 2H), 1.03 (d,
J=10.4 Hz, 1H), 0.83 (s, 3H).
Step 2: Synthesis of 8
[0384] A solution of compound 8B (2.0 g, 3.86 mmol, 1.0 eq) in 90%
TFA (12 mL) and TES (4 mL) was stirred at rt for 1 h. The mixture
was concentrated to give the crude product (1.5 g) which was used
directly in next step without purification.
[0385] To a solution of the crude product (1.5 g) in dioxane (5 mL)
and hydrochloric acid (5 mL) was added i-BuB(OH).sub.2 (590 mg,
5.79 mmol, 1.5 eq). The mixture was stirred at rt for 1 h. The
solvent was removed under reduced pressure. The mixture was then
adjusted to pH 12 with 0.1 N aqueous solution of NaOH and was
stirred at rt for 48 h. The mixture was then purified by prep-HPLC
to give 8 (370 mg, 41%) as white solid.
MS calcd for (C.sub.9H.sub.8BFO.sub.4): 210 MS (ESI, positive)
found: (M+1) 211
[0386] .sup.1H NMR (D.sub.20, 400 MHz): .delta. 6.93 (m, 1H), 6.40
(m, J=8.8 Hz, 1H), 2.60 (t, J=6.4 Hz, 2H), 0.40 (t, J=7.2 Hz,
2H).
Example 9
Disodium;(3S)-4,4-dihydroxy-3-methyl-5-oxa-4-boranuidabicyclo[4.4.0]deca-1-
(6),7,9-triene-7-carboxylate
##STR00088##
[0387] Step 1: Synthesis of 9B
[0388] To a solution of compound 9A (US2014/194381) (1.1 g, 2.06
mmol, 1.0 eq) in anhydrous THF (10 mL) was added dropwise a
solution of methyl magnesium bromide in THF (3 M, 1.03 mL, 3.1
mmol, 1.5 eq) over 5 min at -78.degree. C. The reaction mixture was
slowly warmed up to room temperature in 18 h before it was quenched
with saturated aq NH.sub.4Cl. The organic layer was concentrated
and the residue was purified by column chromatography (PE/EA=10:1)
to give compound 9B (0.9 g, 81%).
Step 2: Synthesis of 9
[0389] To a solution of compound 9B (0.5 g) in dioxane (2 mL) and
concentrated HCl (2 mL) was added i-BuB(OH).sub.2 (184 mg, 1.83
mmol, 2 eq) at room temperature. The mixture was stirred at rt for
3 h. The reaction mixture was concentrated in vacuo, and the
residue was dissolved in H.sub.2O/MeCN. The resulting solution was
adjusted to pH=12 and purified by prep-HPLC (C18, neutral) to give
9 (18 mg, 9%) as white solid.
MS calcd for (C.sub.10H.sub.11BO.sub.4): 206 MS (ESI, positive)
found: (M+1): 207
[0390] .sup.1H NMR (CD.sub.3OD, 400 MHz): .delta. 7.643-7.659 (d,
J=6.4, 1 H), 7.158-7.303 (dd, J=7.6, 1 H), 6.710-6.883 (m, 1H),
2.598-2.758 (m, 2H), 1.255-1.295 (m, 3H), 0.796-0.885 (m, 1H).
Example 10
Disodium;(3R)-4,4-dihydroxy-3-methyl-5-oxa-4-boranuidabicyclo[4.4.0]deca-1-
(6),7,9-triene-7-carboxylate
##STR00089##
[0391] Step 1: Synthesis of 10B
[0392] To a solution of compound 10A (prepared as 9A using
(-)-Pinanediol) (2 g, 3.74 mmol, 1.0 eq) in anhydrous THF (20 mL)
was added dropwise a solution of methyl magnesium bromide in THF (3
M, 1.87 mL, 5.61 mmol, 1.5 eq) over 10 min at -78.degree. C. The
reacion mixture was slowly warmed up to room temperature in 18
hours before it was quenched with saturated NH.sub.4Cl. The organic
layer was concentrated and the residue was purified by column
chromatography (PE/EA=10:1) to give compound 10B (1.3 g, 66%).
Step 2: Synthesis of 10
[0393] To a solution of compound 10B (1.3 g) in dioxane (6 mL) and
hydrochloric acid (6 mL) was added i-BuB(OH).sub.2 (516 mg, 5.05
mmol, 2 eq) at room temperature. The mixture was stirred at rt for
3 hours. The reaction mixture was concentrated in vacuo, and the
residue was dissolved in H.sub.2O/MeCN. The resulting solution was
adjusted to pH=12 and purified by prep-HPLC (C18, neutral
conditions) to give 10 (295 mg, 51%) as white solid.
MS calcd for (C.sub.10H.sub.11BO.sub.4): 206 MS (ESI, positive)
found: (M+1): 207
[0394] .sup.1H NMR (CD.sub.3OD, 400 MHz): .delta. 7.564 (s, 1H),
7.064-7.078 (d, J=5.6, 1 H), 6.606-6.644 (d, J=15.2, 1 H),
2.807-2.854 (m, 1H), 2.397-2.450 (m, 1H), 0.789-0.875 (m, 4H).
Example 11
Disodium;(3
S)-4,4-dihydroxy-8-methoxy-3-methyl-5-oxa-4-boranuidabicyclo[4.4.0]deca-1-
(6),7,9-triene-7-carboxylate
##STR00090##
[0395] Step 1: Synthesis of 11A
[0396] To a solution of compound 7F (1.1 g, 1.95 mmol, 1.0 eq) in
anhydrous THF (10 mL) was added dropwise a solution of methyl
magnesium bromide in THF (3 M, 0.98 mL, 2.93 mmol, 1.5 eq) over 5
min at -78.degree. C. The reaction mixture was slowly warmed up to
room temperature in 18 hours before it was quenched with saturated
NH.sub.4Cl. The organic layer was concentrated and the residue was
purified by column chromatography (PE/EA=10:1) to give compound 11A
(0.9 g, 81%).
Step 2: Synthesis of 11
[0397] To a solution of compound 11A (0.45 g) in dioxane (3 mL) and
hydrochloric acid (3 mL) was added i-BuB(OH).sub.2 (169 mg, 1.65
mmol, 2 eq) at room temperature. The mixture was stirred at rt for
3 hours. The reaction mixture was concentrated in vacuo, and the
residue was dissolved in H.sub.2O/MeCN. The resulting solution was
adjusted to pH=12 and purified by prep-HPLC (C18, neutral) to give
11 (75 mg, 38%) as white solid.
[0398] ESI-MS: [M+H].sup.+: 237
[0399] H NMR (CD.sub.3OD, 400 MHz): .delta. 6.747-6.767 (d, J=8, 1
H), 6.226-6.247 (dd, J=8.4, 1 H), 3.676-3.711 (m, 3H), 2.618-2.653
(m, 1H), 2.285-2.340 (m, 1H), 0.805-0.822 (m, 3H), 0.722-0.725 (m,
1H).
Example 12
Disodium;(3R)-4,4-dihydroxy-3-(2-hydroxyethyl)-8-methoxy-5-oxa-4-boranuida-
bicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylate
##STR00091##
[0400] Step 1: Synthesis of 12A
[0401] To a solution of compound 7F (5 g, 8.85 mmol, 1.0 eq) in
anhydrous THF (50 mL) was added allylmagnesium bromide (11.5 mL, 1
M in THF, 11.5 mmol, 1.3 eq) dropwise over 10 minutes at
-78.degree. C. The reaction mixture was slowly warmed up to room
temperature in 18 hours before it was quenched with saturated
NH.sub.4Cl. The organic layer was concentrated and the residue was
purified by column chromatography (PE/EA=10:1) to give compound 12A
(4.5 g, 89%).
Step 2: Synthesis of 12B
[0402] To a solution of compound 12A (730 mg, 1.28 mmol, 1.0 eq) in
DCM (30 mL) was bubbled with O.sub.3 at -78.degree. C. until the
solution turned to slightly blue. The nitrogen was bubbled in to
remove the color. The colorless solution was added dimethylsulfide
(3 mL) and slowly warmed up to room temperature in 6 hours. The
solvent was removed under reduced pressure and the residue was
purified by column chromatography (PE/EA=3:1) to give compound 12B
(400 mg, 55%).
Step 3: Synthesis of 12C
[0403] To a solution of compound 12B (400 mg, 0.69 mmol, 1.0 eq) in
anhydrous THF (50 mL) was added NaBH.sub.4 (31 mg, 0.83 mmol, 1.2
eq) at 0.degree. C. The mixture was stirred at room temperature for
1 hour before it was concentrated under reduced pressure. The
residue was purified by column chromatography (PE/EA=1:1) to give
compound 12C (180 mg, 45%).
Step 4: Synthesis of 12
[0404] To a solution of compound 12C (180 mg) in dioxane (3 mL) and
hydrochloric acid (3 mL) was added i-BuB(OH).sub.2 (64 mg, 0.63
mmol, 2 eq). The mixture was stirred at rt for 3 hours. The
reaction mixture was concentrated in vacuo, and the residue was
dissolved in H.sub.2O/MeCN. The resulting solution was adjusted to
pH=12 and purified by prep-HPLC (C18, neutral) to give 12 (9 mg,
10%) as white solid.
[0405] ESI-MS: [M+H].sup.+: 267
[0406] .sup.1H NMR (CD.sub.3OD, 400 MHz): .delta. 6.735-6.754 (d,
J=7.6, 1 H), 6.214-6.235 (dd, J=8.4, 1 H), 3.701 (s, 3H),
3.607-3.685 (m, 2H), 2.518-2.553 (m, 1H), 2.485-2.496 (m, 1H),
1.758-1.823 (m, 1H), 1.458-1.495 (m, 1H), 1.005-1.012 (m, 1H).
Example 13
Disodium;4,4-dihydroxy-8-(triazol-1-yl)-5-oxa-4-boranuidabicyclo[4.4.0]dec-
a-(6),7,9-triene-7-carboxylate
##STR00092## ##STR00093##
[0407] Step 1: Synthesis of 13B
[0408] To a solution of 13A (142.2 g, 497 mmol, 1.0 eq) in dry THF
(350 mL) was added LDA (freshly made, 544 mmol, 1.1 eq) at
-78.degree. C. The mixture was slowly warmed up to room temperature
for 12 hours under nitrogen atmosphere. The mixture was
concentrated and the residue was partitioned in EA and water. The
aqueous layer was adjusted to PH=6 with 1N HCl. The organic layer
was washed with brine, dried over Na.sub.2SO.sub.4 and then
concentrated under reduced pressure to give 13B (142.6 g, 98%).
Step 2: Synthesis of 13C
[0409] To a solution of 13B (45 g, 156 mmol, 1.0 eq) in
EtOH/H.sub.2O (200 mL, 7/3, v/v) was added NaN.sub.3 (20.5 g, 3.15
mol, 2.0 eq), CuI (3 g, 157 mmol, 0.1 eq),
N1,N2-dimethylethane-1,2-diamine (2.1 g, 23.8 mmol, 0.15 eq) and
Sodium L-ascorbate (1.55 g, 7.82 mmol, 0.08 eq). The mixture was
stirred at 80.degree. C. for 2 hours under nitrogen atmosphere. The
mixture was cooled to room temperature and quenched with 0.2 N HCl.
The resulting mixture was extracted with EA (2.times.) and the
organic layer was washed with water, brine. The solvent was removed
in vacuo and the residue was purified by column chromatography on
silica gel (PE:EA=100:1 to 30:1) to give 13C (25.8 g, 66%).
Step 3: Synthesis of 13D
[0410] To a solution of 13C (23 g, 92.4 mmol, 1.0 eq) in dry THF
(250 mL) was added Boc.sub.2O (26.2 g, 120.1 mmol, 1.3 eq), DMAP
(1.13 g, 9.24 mmol, 0.1 eq) and TEA (10.3 g, 101.6 mmol, 1.1 eq).
The mixture was stirred at room temperature for 12 hours. The
reaction was monitored by TLC. The mixture was concentrated and the
residue was purified by column chromatography on silica gel
(PE:EA=1:0-100:1) to give 13D (32.2 g, 86%).
Step 4: Synthesis of 13E
[0411] To a solution of 13D (20.1 g, 57.6 mmol, 1.0 eq) in
CCl.sub.4 (300 mL) was added NBS (11.3 g, 63.4 mmol, 1.1 eq) and
BPO (2.8 g, 11.5 mmol, 0.2 eq). The mixture was stirred at
100.degree. C. for 12 hours under nitrogen atmosphere. The reaction
was monitored by TLC. The mixture was concentrated and the residue
was purified by column chromatography on silica gel (PE:EA=300:1 to
20:1) to give 13E (18 g, 79%).
Step 5: Synthesis of 13F
[0412] To a solution of 13E (18.3 g, 42.7 mmol, 1.0 eq) in dioxane
(550 mL) was added diboron reagent (18.4 g, 51.2 mmol, 1.2 eq),
KOAc (8.4 g, 85.5 mmol, 2.0 eq) and PdCl.sub.2 (dppf) (1.7 g, 2.1
mmol, 0.05 eq). The mixture was stirred at 70.degree. C. for 12
hours under nitrogen atmosphere. The reaction was monitored by TLC.
The resulting mixture was filtered and the filtrate was
concentrated under reduced pressure. The residue was purified by
column chromatography on silica gel (PE:EA=20:1 to 10:1) to give
13F (8 g, 36%).
[0413] ESI-MS: [M+H].sup.+: 528
Step 6: Synthesis of 13G
[0414] To a solution of 13F (6 g, 11.39 mmol, 1.0 eq) in dry THF
(120 mL) was added CH.sub.2ICl (4.02 g, 22.77 mmol, 2.0 eq),
followed by slow addition of n-BuLi (7.75 ml, 19.35 mmol, 1.7 eq)
at -78.degree. C. in 20 minutes under nitrogen atmosphere. The
mixture was slowly warmed up to 0.degree. C. in 12 hours. The
reaction was monitored by TLC. The mixture was concentrated and the
residue was purified by column chromatography on silica gel
(PE:EA=200:1 to 10:1) to give 13G (3.67 g, 60%).
Step 7: Synthesis of 13H
[0415] A mixture of 13G (500 mg, 0.92 mmol, 1.0 eq), TMS-acetylene
(2.27 g, 23.1 mmol, 25.0 eq), CuI (529 mg, 2.77 mmol, 3.0 eq) and
DIPEA (1.08 g, 8.36 mmol, 9.0 eq) in THF (5 mL) was stirred at
80.degree. C. for 12 hours under nitrogen atmosphere. The reaction
was monitored by TLC. The resulting mixture was filtered and the
filtrate was concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel (PE:EA=100:1 to
5:1) to give 13H (410 mg, 70%).
Step 8: Synthesis of 13I
[0416] To a solution of 13H (360 mg, 0.56 mmol, 1.0 eq) in THF (12
mL) was added TBAF (2.8 mL, 1M in THF, 2.8 mmol, 5.0 eq) under
nitrogen atmosphere. After 2 hours at 50.degree. C. reaction
mixture was cooled down and concentrated. The residue was purified
by column chromatography on silica gel (PE:EA=50:1 to 2:1) to give
13I (260 mg, 81%).
Step 9: Synthesis of 13
[0417] To the solution of 13I (50 mg, 0.08 mmol, 1.0 eq) in dioxane
(1 mL) was added i-BuB(OH).sub.2 (23 mg, 0.22 mmol, 2.5 eq) and
concentrated HCl (1 mL). The reaction mixture was stirred at rt for
1 hour. The reaction mixture was concentrated in vacuo, and the
residue was dissolved in H.sub.2O/MeCN. The resulting solution was
adjusted to pH=12 and purified by prep-HPLC (C18, neutral) to give
13 (10.4 mg, 46%) as white solid.
[0418] ESI-MS: [M+H].sup.+: 260
[0419] .sup.1H NMR (400 MHz, D.sub.2O): .delta. 8.14 (s, 1H), 7.88
(s, 1H), 7.17 (d, J=8.8 Hz, 1H), 6.80 (d, J=7.6 Hz, 1H), 2.78-2.74
(m, 2H), 0.54 (d, J=7.2 Hz, 2H).
Example 14
Disodium;8-[4-(2-aminoethyl)triazol-1-yl]-4,4-dihydroxy-5-oxa-4-boranuidab-
icyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylate
##STR00094##
[0420] Step 1: Synthesis of 14A
[0421] To a solution of compound 13G (220 mg, 0.37 mmol, 1.0 eq) in
THF (5 mL) was added tert-butyl but-3-yn-1-ylcarbamate (375 mg,
2.22 mmol, 6.0 eq), CuI (141 mg, 0.74 mmol, 2.0 eq) and DIPEA (287
mg, 2.22 mmol, 6.0 eq). The mixture was stirred at 60.degree. C.
for 12 hours under nitrogen atmosphere. The reaction was monitored
by TLC. The mixture was filtered and concentrated. The residue was
purified by column chromatography on silica gel (PE/EA=10:1 to 2:1)
to give compound 14A (195 mg, 70%).
Step 2: Synthesis of 14
[0422] To the solution of 14A (250 mg, 0.35 mmol, 1.0 eq) in
dioxane (3 mL) was added i-BuB(OH).sub.2 (90 mg, 0.88 mmol, 2.5 eq)
and concentrated HCl (3 mL). The reaction mixture was stirred at rt
for 1 hour. The reaction mixture was concentrated in vacuo, and the
residue was dissolved in H.sub.2O/MeCN. The resulting solution was
adjusted to pH=12 and purified by prep-HPLC (C18, neutral) to give
14 (10.4 mg, 46%) as white solid.
[0423] ESI-MS: [M+H].sup.+: 303
[0424] .sup.1H NMR (400 MHz, D.sub.2O): .delta. 8.03 (s, 1H), 7.14
(d, J=7.6 Hz, 1H), 6.76 (d, J=7.6 Hz, 1H), 3.41-3.37 (m, 2H),
3.19-3.13 (m, 2H), 2.73 (d, J=6.0 Hz, 2H), 0.47 (d, J=5.2 Hz,
2H).
Example 15
Disodium;4,4-dihydroxy-8-(1H-pyrazol-5-yl)-5-oxa-4-boranuidabicyclo[4.4.0]-
deca-1(6),7,9-triene-7-carboxylate
##STR00095## ##STR00096##
[0425] Step 1: Synthesis of 15B
[0426] To the solution of compound 15A (298 g, 1.93 mol, 1.0 eq)
and DIA (98 g, 0.97 mol, 0.5 eq) in DCM (3.5 L) was added NBS (362
g, 2.03 mol, 1.05 eq) in small portions at -78.degree. C. The
mixture was slowly warmed to room temperature and stirred for 16 h
as TLC monitoring showed the completion of reaction. The raction
mixture was evaporated to dryness, and the residue was stirred in 1
N HCl (2 L) 0.5 hour. The precipitate was filtrated to give
compound 15B (370 g, 83%) as light yellow solid.
Step 2: Synthesis of 15C
[0427] A solution of compound 15B (370 g, 1.59 mol, 1.0 eq) in
t-BuOH/THF (800 mL/1600 mL) was stirred at 55.degree. C. for 10
minutes before Boc.sub.2O (1750 g, 8.03 mol, 5.05 eq) and DMAP
(155.2 g, 1.27 mol, 0.8 eq) were added in small portions. The
mixture was stirred at 55.degree. C. until compound 15B was fully
consumed. The mixture was cooled to room temperature and more
Boc.sub.2O (693 g, 3.18 mol, 2 eq) and DMAP (155.2 g, 1.27 mol, 0.8
eq) were added. After 18 hours, the reaction mixture was
concentrated to dryness in vacuo, purified by column chromatography
to give compound 15C (700 g, 90%).
Step 3: Synthesis of 15D
[0428] The mixture of compound 15C (230 g, 0.47 mol, 1.0 eq),
potassium vinyltrifluoroborate (126 g, 0.94 mol, 2.0 eq), TEA (143
g, 1.42 mol, 3.0 eq) and PdCl.sub.2 (dppf).sub.2 (20 g, 23.5 mmol,
0.05 eq) in dioxane (3.0 L) was stirred at 90.degree. C. for 72
hours under N.sub.2 atmosphere. Completion of the reaction was
monitored by NMR. The mixture was concentrated and purified by
column chromatography (eluted with PE) to give compound 15D (94 g,
46%).
Step 4: Synthesis of 15E
[0429] The mixture of compound 15D (94 g, 215.6 mmol, 1.0 eq),
Bis(pinacolato)diboron (82 g, 323.4 mmol, 1.5 eq), Cu.sub.2O (1.54
g, 10.8 mmol, 0.05 eq), K.sub.2HPO.sub.3 (56.3 g, 323.4 mmol, 1.5
eq) and PPh.sub.3 (2.82 g, 10.8 mmol, 0.05) in MeOH (1.2 L) was
stirred at 50.degree. C. for 16 hours. The reaction was monitored
by HNMR. The reaction mixture was filtered, and the filtrated was
concentrated in vacuo. The residue was purified by flash
chromatography to give compound 15E (88.5 g, 73%).
[0430] ESI-MS: [M+H].sup.+: 565
Step 5: Synthesis of 15F
[0431] The mixture of compound 15E (88.5 g, 157 mmol, 1.0 eq) and
(+)-pinanediol (69.5 g, 0.409 mol, 2.61 eq) in THF (500 mL) was
stirred at room temperature for 72 hours. The reaction mixture was
concentrated in vacuo and the residue was purified by flash
chromatography to give compound 15F (90 g, 100%).
[0432] ESI-MS: [M+H].sup.+: 617
Step 6: Synthesis of 15G
[0433] A solution of compound 15F (100.6 g, 0.163 mol, 1.0 eq) in
THF (500 mL) was added pyrrolidine (11.6 g, 14 mL, 0.163 mmol, 1.0
eq) at room temperature. The reaction mixture was stirred at
35.degree. C. for 3 hours before it was concentrated in vacuo. The
residue was purified by flash chromatography to give compound 15G
(90 g, 98%). ESI-MS: [M+H].sup.+: 517
Step 7: Synthesis of 15H
[0434] To a solution of compound 15G (8.2 g, 15.9 mol, 1.0 eq) in
DCM (50 mL) was added TEA (2.1 g, 20.8 mmol, 1.3 eq), followed by
Tf.sub.2O (4.7 g, 16.7 mmol, 1.05 eq) dropwise at -78.degree. C.
The mixture was warmed to room temperature and stirred for 16
hours, LC-MS indicating the completion of reaction. The reaction
solution was concentrated in vacuo, and the residue was stirred in
200 mL PE at room temperature for 0.5 hour. Then the solid was
filtered off, and the PE layer was concentrated to give crude
compound 15H (7.43 g, 72%) as yellow oil.
[0435] ESI-MS: [M+H].sup.+: 649
Step 8: Synthesis of 15I
[0436] The mixture of 3-pyrazoleboronic acid (155 mg, 1.39 mmol,
1.5 eq), CuCl.sub.2 (9 mg, 0.091 mmol, 0.1 eq) and ZnCl.sub.2 (126
mg, 0.926 mmol, 1.0 eq) in DMF (5 mL) was degassed and stirred at
room temperature for 20 minutes. Then Cs.sub.2CO.sub.3 (603 mg,
1.85 mmol, 2.0 eq) and compound 15H (600 mg, 0.926 mmol, 1.0 eq)
were added in sequence. The mixture was stirred for another 20
minutes before PdCl.sub.2 (dppf).sub.2 (38 mg, 0.047 mmol, 0.05 eq)
was added. The reaction mixture was degassed again and stirred at
85.degree. C. for 20 hours. The reaction was monitored by LC-MS.
After filtration through a short celite pad, the filtrate was
concentrated and purified by flash chromatography (PE:EA=20:1 to
1:1) to give compound 15I (136 mg, 26%).
[0437] ESI-MS: [M+H].sup.+: 567
Step 9: Synthesis of 15
[0438] To the solution of compound 15I (50 mg, 0.088 mmol, 1.0 eq)
in dioxane (1 mL) was added i-BuB(OH).sub.2 (23 mg, 0.226 mmol, 2.5
eq), followed by concentrated HCl (1 mL). The reaction mixture was
stirred at room temperature for 16 hours. The reaction was
monitored by LC-MS. The reaction mixture was concentrated in vacuo,
and the residue was dissolved in H.sub.2O/MeOH. The resulting
solution was adjusted to pH=12 and purified by prep-HPLC (C18,
neutral) to give 15 (9.0 mg, 35%) as white solid.
[0439] LC-MS: [M+1]=259
[0440] .sup.1H NMR (400 MHz, D.sub.2O): .delta. 7.67 (s, 1H), 7.11
(d, J=7.6 Hz, 1H), 6.99 (d, J=6.4 Hz, 1H), 6.59 (s, 1H), 2.76-2.72
(m, 2H), 0.71 (m, 2H).
Example 16
Disodium;4,4-dihydroxy-8-(1H-triazol-5-yl)-5-oxa-4-boranuidabicyclo[4.4.0]-
deca-1(6),7,9-triene-7-carboxylate
##STR00097##
[0441] Step 1: Synthesis of 16A
[0442] The solution of compound 15H (1 g, 1.54 mmol, 1.0 eq),
ethynyltrimethylsilane (300 mg, 3.085 mmol, 2.0 eq), CuI (14.7 mg,
0.077 mmol, 0.05 eq), Pd(dppf)Cl.sub.2 (63 mg, 0.077 mmol, 0.05 eq)
and TEA (467 mg, 4.6 mmol, 3.0 eq) in dioxane (15 mL) was refluxed
for 5 hours under nitrogen atmosphere. The reaction was monitored
by TLC. The reaction mixture was concentrated and the residue was
purified by flash chromatography to give compound 16A (600 mg, 70%)
as yellow oil.
Step 2: Synthesis of 16B
[0443] To the solution of compound 16A (240 mg, 0.40 mmol, 1.0 eq)
in THF (2 mL) was added TBAF (0.80 mL, 1M in THF, 0.80 mmol, 2.0
eq). The resulting solution was stirred at 35.degree. C. for 16
hours. The reaction mixture was diluted with EA and washed with
water and brine. The organic layer was concentrated to give crude
compound 16B (180 mg, 85%) which was used directly for the next
step.
Step 3: Synthesis of 16C
[0444] The mixture of compound 16B (180 mg, 0.34 mmol, 1.0 eq),
TMS-N.sub.3 (1.18 g, 10.2 mmol, 30 eq) and CuI (195 mg, 1.02 mmol,
3.0 eq) in dioxane (2 mL) was stirred at 80.degree. C. for 16 hours
under nitrogen atmosphere. The reaction was monitored by LC-MS.
After cooled to room temperature, the reaction mixture was
filtrated through silica gel pad and washed with EA. The filtrate
was concentrated to give crude compound 16C (200 mg, 91%) which was
used directly for the next step.
Step 4: Synthesis of 16D
[0445] To the solution of compound 16C (200 mg, 0.31 mmol, 1.0 eq)
in THF (2 mL) was added TBAF (0.62 mL, 1 M in THF, 0.62 mmol, 2.0
eq). The resulting solution was stirred at 35.degree. C. for 16
hours. The reaction mixture was monitored by LC-MS. The reaction
mixture was diluted with EA and washed with water and brine. The
organic layer was concentrated to give crude compound 16D (150 mg,
85%) which was used directly for next step.
Step 5: Synthesis of 16
[0446] To the solution of 16D (150 mg, 0.26 mmol, 1.0 eq) in
dioxane (3 mL) was added i-BuB(OH).sub.2 (54 mg, 0.53 mmol, 2.0 eq)
and concentrated HCl (3 mL). The reaction mixture was stirred at rt
for 16 hours. The reaction mixture was concentrated in vacuo, and
the residue was dissolved in H.sub.2O/MeOH. The resulting solution
was adjusted to pH=12 and purified by prep-HPLC (C18, neutral) to
give 16 (33 mg, 48%) as white solid.
[0447] ESI-MS: [M+H].sup.+: 260
[0448] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 8.01-7.99 (m,
1H), 7.02-6.98 (m, 2H), 2.72-2.65 (m, 2H), 1.31-1.25 (m, 2H).
Example 17
Disodium;8-[1-(2-aminoethyl)triazol-4-yl]-4,4-dihydroxy-5-oxa-4-boranuidab-
icyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylate
##STR00098##
[0449] Step 1: Synthesis of 17A
[0450] A mixture of compound 16B (180 mg, 0.34 mmol, 1.0 eq),
N-Boc-2-azido-ethylamine (127 mg, 0.68 mmol, 2.0 eq) and CuI (65
mg, 0.34 mmol, 1.0 eq) in dioxane (2 mL) was stirred at 80.degree.
C. for 4 hours under nitrogen atmosphere. The reaction was
monitored by LC-MS. After cooled to room temperature, the reaction
mixture was filtrated through silica gel pad and washed with EA.
The filtrate was concentrated to give crude compound 17A (200 mg,
82%) which was used directly for the next step.
[0451] ESI-MS: [M+H].sup.+: 711
Step 2: Synthesis of 17
[0452] To the solution of 17A (200 mg, 0.28 mmol, 1.0 eq) in
dioxane (3 mL) was added i-BuB(OH).sub.2 (62 mg, 0.56 mmol, 2.0 eq)
and concentrated HCl (3 mL). The reaction mixture was stirred at rt
for 16 hours. The reaction mixture was concentrated in vacuo, and
the residue was dissolved in H.sub.2O/MeOH. The resulting solution
was adjusted to pH=12 and purified by prep-HPLC (C18, neutral) to
give 17 (31 mg, 36%) as white solid.
[0453] ESI-MS: [M+H].sup.+: 303
[0454] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 8.12 (s, 1H),
7.13 (d, J=8.0 Hz, 1H), 6.94 (d, J=8.0 Hz, 1H), 4.50-4.46 (m, 2H),
3.40 (d, J=1.2 Hz, 1H), 3.21-3.19 (m, 1H), 2.71-2.67 (m, 2H), 0.63
(d, J=6.4 Hz, 2H).
Example 18
Disodium;8-ethynyl-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),-
7,9-triene-7-carboxylate
##STR00099##
[0456] To the solution of 16B (140 mg, 0.27 mmol, 1.0 eq) in
dioxane (3 mL) was added i-BuB(OH).sub.2 (58 mg, 0.54 mmol, 2.0 eq)
and concentrated HCl (3 mL). The reaction mixture was stirred at rt
for 16 hours. The reaction mixture was concentrated in vacuo, and
the residue was dissolved in H.sub.2O/MeOH. The resulting solution
was adjusted to pH=12 and purified by prep-HPLC (C18, neutral) to
give 18 (8 mg, 13%) as white solid.
[0457] ESI-MS: [M+H].sup.+: 217
[0458] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 6.99 (d, J=7.6
Hz, 1H), 6.87 (d, J=7.6 Hz, 1H), 2.68-2.64 (m, 2H), 2.51 (s, 1H),
0.47-0.42 (m, 2H).
Example 19
Disodium;8-(azetidin-3-ylsulfanylmethyl)-4,4-dihydroxy-5-oxa-4-boranuidabi-
cyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylate
##STR00100##
[0459] Step 1: Synthesis of 19A
[0460] To a solution of 15H (7.0 g, 10.8 mmol, 1.0 eq) in dioxane
(100 mL) was added CH.sub.2CHBF.sub.3K (7.74 g, 12.96 mmol, 1.2
eq), PdCl.sub.2 (dppf) (790 mg, 1.08 mmol, 0.1 eq) and TEA (3.72 g,
32.4 mmol, 3.0 eq). The mixture was flushed with nitrogen and
stirred at 100.degree. C. for 12 hours. The resulting mixture was
cooled down to room temperature and filtered. The filtrated was
concentrated and the residue was purified by column chromatography
on silica gel (PE/EA=10:1) to give 19A (4 g, 62%) as yellow
oil.
Step 2: Synthesis of 19B
[0461] A solution of 19A (3 g, 5.7 mmol, 1.0 eq) in dichloromethane
(30 mL) was bubbled with O.sub.3 at -78.degree. C. until the color
of the solution turned to light blue. Nitrogen gas was then bubbled
and Me.sub.2S (5 mL) was added. The solution was slowly warmed up
to room temperature over 8 h and was concentrated under reduced
pressure. The residue was purified by column chromatography on
silica gel (PE/EA=10:1) to give 19B (1.7 g, 45%) as yellow
solid.
Step 3: Synthesis of 19C
[0462] To a solution of 19B (1.7 g, 3.21 mmol, 1.0 eq) in THF (15
mL) was added NaBH(OAc).sub.3 (1.7 g, 8 mmol, 2.5 eq) at 0.degree.
C. The mixture slowly warmed up to room temperature in 2 hours
before it was concentrated in vacuo. The residue was purified by
column chromatography on silica gel (PE/EA=5:1) to give 19C (1.2 g,
86%) as yellow solid.
Step 4: Synthesis of 19D
[0463] To a solution of 19C (1.2 g, 2.26 mmol, 1.0 eq) in DCM (20
mL) was added CBr4 (1.1 g, 3.39 mmol, 1.5 eq) and PPh.sub.3 (8.9
mg, 3.39 mmol, 1.5 eq). The mixture was stirred at room temperature
for 2 hours and was concentrated in vacuo. The residue was purified
by column chromatography on silica gel (PE/EA=5:1) to give 19D (450
mg, 48%) as yellow solid.
Step 5: Synthesis of 19E
[0464] To a solution of 19D (150 mg, 0.25 mmol, 1.0 eq) in DCM (5
mL) was added 1-Boc-3-mercapto-azetidine (52 mg, 0.27 mmol, 1.1 eq)
and TEA (50.6 mg, 0.5 mmol, 2.0 eq). The mixture was stirred at
room temperature for 1 hour. The reaction mixture was concentrated
in vacuo and the residue was purified by prep-TLC (PE/EA=4:1) to
give 19E (120 mg, 83%) as yellow solid.
Step 6: Synthesis of 19
[0465] To the solution of 19E (120 mg, 0.17 mmol, 1.0 eq) in
dioxane (2 mL) was added i-BuB(OH).sub.2 (35 mg, 0.34 mmol, 2.0 eq)
and concentrated HCl (2 mL). The reaction mixture was stirred at rt
for 2 hours. The reaction mixture was concentrated in vacuo, and
the residue was dissolved in H.sub.2O/MeCN. The resulting solution
was adjusted to pH=12 and purified by prep-HPLC (C18, neutral) to
give 19 (11 mg, 21%) as white solid.
[0466] ESI-MS: [M+H].sup.+: 294
[0467] .sup.1H NMR (400 MHz, CD.sub.3OD/D.sub.2O): .delta. 6.78 (d,
J=7.6 Hz, 1H), 6.57 (d, J=7.2 Hz, 1H), 3.92 (s, 2H), 3.80 (s, 2H),
3.69-3.67 (m, 1H), 3.60-3.58 (m, 2H), 2.52-2.50 (m, 2H), 0.4-0.38
(m, 2H).
Example 20
Disodium;4,4-dihydroxy-8-(1,3,4-thiadiazol-2-ylsulfanylmethyl)-5-oxa-4-bor-
anuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylate
##STR00101##
[0468] Step 1: Synthesis of 20A
[0469] To a solution of 19D (180 mg, 0.3 mmol, 1.0 eq) in DCM (2
mL) was added 2-mercapitothiadiazole (44 mg, 0.36 mmol, 1.2 eq) and
TEA (61 mg, 0.6 mmol, 2.0 eq). The mixture was stirred at room
temperature for 1 h before it was concentrated in vacuo. The
residue was purified by prep-TLC (PE/EA=2:1) to give 20A (150 mg,
78%) as yellow solid.
Step 2: Synthesis of 20
[0470] To the solution of 20A (150 mg, 0.24 mmol, 1.0 eq) in
dioxane (2 mL) was added i-BuB(OH).sub.2 (50 mg, 0.48 mmol, 2.0 eq)
and concentrated HCl (2 mL). The reaction mixture was stirred at rt
for 1 hour. The reaction mixture was concentrated in vacuo, and the
residue was dissolved in H.sub.2O/MeCN. The resulting solution was
adjusted to pH=12 and purified by prep-HPLC (C18, neutral) to give
20 (60 mg, 58%) as white solid.
[0471] ESI-MS: [M+H].sup.+: 323
[0472] .sup.1H NMR (400 MHz, CD.sub.3OD/D.sub.2O): .delta. 9.30 (s,
1H), 6.75 (d, J=4.4 Hz, 1H), 6.59 (d, J=7.6 Hz, 1H), 4.51 (s, 2H),
2.57 (s, 2H), 0.43 (s, 2H).
Example 21
Disodium;8-(3-aminopropylsulfanylmethyl)-4,4-dihydroxy-5-oxa-4--
boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylate
##STR00102##
[0473] Step 1: Synthesis of 21A
[0474] To a solution of 19D (120 mg, 0.2 mmol, 1.0 eq) in DCM (3
mL) was added 3-aminopropane-1-thiol (31 mg, 0.24 mmol, 1.2 eq) and
TEA (42 mg, 0.4 mmol, 2.0 eq). The reaction mixture was stirred at
room temperature for 2 hours before it was concentrated in vacuo.
The residue was purified by prep-TLC (PE/EA=4:1) to give 21A (100
mg, 76%) as light yellow oil.
Step 2: Synthesis of 21
[0475] To a solution of 21A (100 mg, 0.16 mmol, 1.0 eq) in dioxane
(2 mL) was added i-BuB(OH).sub.2 (33 mg, 0.32 mmol, 2.0 eq) and
concentrated HCl (2 mL). The mixture was stirred at room
temperature for 2 hours. The reaction mixture was concentrated in
vacuo, and the residue was dissolved in H.sub.2O/MeCN. The
resulting solution was adjusted to pH=12 and purified by prep-HPLC
(C18, neutral) to give 21 (26 mg, 32%) as white solid.
[0476] ESI-MS: [M+H].sup.+: 296
[0477] .sup.1H NMR (400 MHz, CD.sub.3OD/D.sub.2O): .delta. 6.89 (m,
1H), 6.75-6.68 (m, 1H), 3.96 (s, 2H), 2.86-2.80 (m, 2H), 2.67-2.62
(m, 2H), 2.59-2.55 (m, 2H), 1.88 (s, 2H), 1.33-1.26 (m, 2H).
Example 22
Disodium;8-[(5-amino-1,3,4-thiadiazol-2-yl)sulfanylmethyl]-4,4-dihydroxy-5-
-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylate
##STR00103##
[0478] Step 1: Synthesis of 22A
[0479] To a solution of 19D (160 mg, 0.37 mmol, 1.0 eq) in DCM (20
mL) was added 2-amino-5-mercaptothiadiazole (45 mg, 0.52 mmol, 2.0
eq), TEA (61 mg, 0.52 mmol, 2.0 eq) and DMF (5 mL). The mixture was
stirred at room temperature for 1 hour. The mixture was then
partitioned in H.sub.2O and DCM. The organic layer was washed with
water and brine, dried over Na.sub.2SO.sub.4. After concentration
under reduced pressure, crude 22A (240 mg) was obtained as yellow
oil.
Step 2: Synthesis of 22
[0480] To a solution of 22A (240 mg, 0.37 mmol, 1.0 eq) in dioxane
(5 mL) was added i-BuB(OH).sub.2 (77 mg, 0.74 mmol, 2.0 eq) and
conc.HCl (5 mL). The mixture was stirred at room temperature for 2
hours. The reaction mixture was concentrated in vacuo, and the
residue was dissolved in H.sub.2O/MeCN. The resulting solution was
adjusted to pH=12 and purified by prep-HPLC (C18, neutral) to give
22 (70 mg, 30%) as white solid.
[0481] ESI-MS: [M+H].sup.+: 338
[0482] .sup.1H NMR (400 MHz, CD.sub.3OD/D.sub.2O): .delta. 7.00 (d,
J=7.6 Hz, 1H), 6.57 (d, J=8.0 Hz, 1H), 4.79 (s, 2H), 2.67-2.62 (m,
2H), 1.29-1.25 (m, 2H).
Example 23
Disodium;8-[[1-(2-aminoethyl)triazol-4-yl]methoxy]-4,4-dihydroxy-5-oxa-4-b-
oranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylate
##STR00104##
[0483] Step 1: Synthesis of 23A
[0484] The mixture of 19D (1.2 g, 2.33 mmol, 1.0 eq) and
K.sub.2CO.sub.3 (0.963 g, 6.98 mmol, 3.0 eq) in acetone (10 mL) was
stirred at room temperature for 10 minutes, followed by the
addition of propargylbromide (0.83 g, 6.98 mmol, 3.0 eq). The
resulting mixture was stirred at 60.degree. C. for 40 hours. The
reaction was monitored by LC-MS. After filtration through a short
celite pad, the filtrate was concentrated under reduced pressure
and the residue was purified by flash chromatography on silica
(PE/EA=50:1 to 5:1) to give 23A (0.78 g, 60%).
Step 2: Synthesis of 23B
[0485] To a solution of 23A (100 mg, 0.181 mmol, 1.0 eq) in dioxane
(2 mL) was added 2-azido-N-Bocethylamine (40 mg, 0.215 mmol, 1.2
eq) and CuI (70 mg, 0.362 mmol, 2.0 eq). The mixture was stirred at
60.degree. C. for 3 hours under nitrogen atmosphere in a sealed
tube. The reaction was monitored by LC-MS. After filtration and
concentration, the crude residue was purified by prep-TLC
(PE/EA=1:1) to give 23B (125 mg, 93%).
Step 3: Synthesis of 23
[0486] To a solution of 23B (100 mg, 0.18 mmol, 1.0 eq) in dioxane
(3 mL) was added i-BuB(OH).sub.2 (37 mg, 0.36 mmol, 2.0 eq) and
concentrated HCl (3 mL). The reaction mixture was stirred at room
temperature for 16 hours. The reaction mixture was concentrated in
vacuo, and the residue was dissolved in H.sub.2O/MeOH. The
resulting solution was adjusted to pH=12 and purified by prep-HPLC
(C18, neutral) to give 23 (14.2 mg, 32%).
[0487] ESI-MS: [M+H].sup.+: 333
[0488] .sup.1H NMR (400 MHz, D.sub.2O): .delta. 8.06 (s, 1H), 7.08
(d, J=8.8 Hz, 1H), 6.65 (d, J=6.8 Hz, 1H), 5.29-5.22 (m, 2H),
4.74-4.62 (m, 2H), 3.80-3.25 (m, 2H), 2.69-2.64 (m, 2H), 0.93-0.73
(m, 2H).
Example 24
Disodium;4,4-dihydroxy-8-(1H-triazol-4-ylmethoxy)-5-oxa-4-boranuidabicyclo-
[4.4.0]deca-1(6),7,9-triene-7-carboxylate
##STR00105##
[0489] Step 1: Synthesis of 24A
[0490] To a solution of 23A (154 mg, 0.278 mmol, 1.0 eq) in dioxane
(1.5 mL) were added TMSN.sub.3 (560 mg, 4.86 mmol, 25.0 eq) and CuI
(360 mg, 1.89 mmol, 10.0 eq). The reaction mixture was stirred at
80.degree. C. for 48 h. The reaction was monitored by LC-MS. After
filtration and concentration in vacuo to remove the excessive
TMSN.sub.3, the crude product 24A (175 mg, 94%) was obtained, which
was used directly for the next step.
Step 2: Synthesis of 24
[0491] To a solution of 24A (170 mg, 0.285 mmol, 1.0 eq) in dioxane
(1.0 mL) was added i-BuB(OH).sub.2 (73 mg, 0.713 mmol, 2.5 eq) and
concentrated HCl (1.0 mL). The reaction mixture was stirred at room
temperature for 16 hours. The reaction was monitored by LC-MS. The
reaction mixture was concentrated in vacuo, and the residue was
dissolved in H.sub.2O/MeOH. The resulting solution was adjusted to
pH=9 and purified by prep-HPLC (C18, neutral) to give 24 (13.8 mg,
22%).
[0492] ESI-MS: [M+H].sup.+: 290
[0493] .sup.1H NMR (400 MHz, D.sub.2O): .delta. 7.89 (s, 1H), 6.89
(d, J=7.6 Hz, 1H), 6.38 (d, J=8.4 Hz, 1H), 5.21 (s, 2H), 2.58-2.55
(m, 2H), 0.41 (t, J=6.8 Hz, 2H).
Example 25
2-Hydroxy-7-prop-2-ynoxy-3,4-dihydro-1,2-benzoxaborinine-8-carboxylic
acid
##STR00106##
[0494] Step 1: Synthesis 25
[0495] To a solution of 23A (100 mg, 0.18 mmol, 1.0 eq) in dioxane
(3 mL) was added i-BuB(OH).sub.2 (37 mg, 0.36 mmol, 2.0 eq) and
concentrated HCl (3 mL). The reaction mixture was stirred at rt for
16 hours. The reaction was monitored by LC-MS. The reaction mixture
was concentrated in vacuo, and the residue was purified by
prep-HPLC (C18, 0.1% HCOOH as buffer) to give 25 (14.2 mg,
32%).
[0496] ESI-MS: [M+H].sup.+: 247
[0497] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 7.19 (d, J=8.0
Hz, 1H), 6.70 (d, J=8.0 Hz, 1H), 4.80 (s, 2H), 2.99 (s, 1H), 2.69
(t, J=7.2 Hz, 2H), 1.06 (t, J=8.0 Hz, 2H).
Example 26
7-(1,3-Dioxolan-2-ylmethoxy)-2-hydroxy-3,4-dihydro-1,2-benzoxaborinine-8-c-
arboxylic acid
##STR00107##
[0498] Step 1: Synthesis of 26A
[0499] A mixture of compound 15G (800 mg, 1.55 mmol, 1.0 eq),
2-(bromomethyl)-1,3-dioxolane (780 mg, 4.65 mmol, 3.0 eq) and
Cs.sub.2CO.sub.3 (2.5 g, 7.75 mmol, 5.0 eq) in anhydrous DMF (40
mL) was stirred at room temperature overnight. The mixture was
filtered and concentrated in vacuo. The residue was purified by
column chromatography (PE/EA=10:1) to give compound 26A (140 mg,
16.4%).
Step 2: Synthesis of 26
[0500] To a solution of compound 26A (140 mg) in dioxane (4 mL) and
hydrochloric acid (1 mL) was added i-BuB(OH).sub.2 (50 mg, 0.46
mmol, 2 eq). The mixture was stirred at room temperature for 1 hour
and was directly purified by prep-HPLC to give 26 (14 mg, 9%) as
white solid.
[0501] ESI-MS: [M+H].sup.+: 295
[0502] H NMR (D.sub.2O, 400 MHz): .delta.7.235-7.241 (m, 1H),
6.594-6.615 (d, J=8.4, 1H), 5.252 (m, 1H), 4.764-4.863 (m, 2H),
4.148-4.165 (m, 2H), 3.936-3.941 (m, 2H), 2.668-2.701 (m, 2H),
1.040-1.078 (m, 2H).
Example 27
Disodium;4,4-dihydroxy-8-(2-morpholinoethoxy)-5-oxa-4-boranuidabicyclo[4.4-
.0]deca-1(6),7,9-triene-7-carboxylate
##STR00108##
[0503] Step 1: Synthesis of 27A
[0504] A solution compound 15G (600 mg, 1.163 mmol, 1.0 eq),
4-(2-chloroethyl)morpholine hydrochloride (649 mg, 3.489 mmol, 3.0
eq) and Cs.sub.2CO.sub.3 (1.9 g, 5.8 mmol, 5.0 eq) in anhydrous DMF
(12 mL) was stirred at room temperature overnight. The solvent was
removed under reduced pressure and the residue was purified by
column chromatography (PE/EA=10:1) to give compound 27A (120 mg,
16.4%) as yellow oil.
Step 2: Synthesis of 27
[0505] To a solution of compound 27A (120 mg) in dioxane (2 mL) and
hydrochloric acid (2 mL) was added i-BuB(OH).sub.2 (38.4 mg, 0.38
mmol, 2 eq). The mixture was stirred at room temperature for 1 hour
before it was concentrated under reduced pressure. The residue was
dissolved in H.sub.2O/MeOH. The resulting solution was adjusted to
pH=12 and purified by prep-HPLC (C18, neutral) to give 27 (54 mg,
9%) as white solid.
[0506] ESI-MS: [M+H].sup.+: 322
[0507] .sup.1H NMR (D.sub.2O, 400 MHz): .delta.6.907-6.929 (d,
J=8.8, 1H), 6.336-6.357 (d, J=8.4, 1H), 4.151-4.175 (m, 2H),
3.790-3.813 (m, 4H), 2.924-2.949 (m, 2H), 2.790-2.798 (m, 4H),
2.573-2.607 (m, 2H), 0.391-0.425 (m, 2H).
Example 28
Disodium;4,4-dihydroxy-8-(4-pyridylmethoxy)-5-oxa-4-boranuidabicyclo[4.4.0-
]deca-1(6),7,9-triene-7-carboxylate
##STR00109##
[0508] Step 1: Synthesis of 28A
[0509] The mixture of 15G (350 mg, 0.678 mmol, 1.0 eq) and
K.sub.2CO.sub.3 (562 mg, 4.07 mmol, 6.0 eq) in DMF (5 mL) was
stirred at room temperature for 10 minutes, followed by the
addition of 4-(bromomethyl)pyridine hydrobromide (515 mg, 2.04
mmol, 3.0 eq). The resulting mixture was stirred at room
temperature for 16 hours. The reaction was monitored by LC-MS.
After filtration through a short celite pad, the filtrate was
concentrated under reduced pressure and the residue was purified by
flash chromatography on silica (PE/EA=10:1-0:1) to give compound
28A (100 mg, 24%).
Step 2: Synthesis of 28
[0510] To a solution of 28A (60 mg, 0.099 mmol, 1.0 eq) in dioxane
(2 mL) was added i-BuB(OH).sub.2 (25 mg, 0.247 mmol, 2.5 eq) and
concentrated HCl (2 mL). The mixture was stirred at rt for 3 hours.
The reaction mixture was concentrated in vacuo, and the residue was
dissolved in H.sub.2O/MeOH. The resulting solution was adjusted to
pH=8 and purified by prep-HPLC (C18, neutral) to give 28 (5 mg,
20%) as white solid.
[0511] ESI-MS: [M+H].sup.+: 300
[0512] .sup.1H NMR (400 MHz, D.sub.2O): .delta. 8.47 (s, 2H), 7.49
(s, 2H), 6.84 (s, 1H), 6.28 (d, J=8.0 Hz, 1H), 5.17 (s, 2H), 2.57
(s, 2H), 0.41 (s, 2H).
Example 29
Disodium;8-(2,2-difluoroethoxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4-
.0]deca-1(6),7,9-triene-7-carboxylate
##STR00110##
[0513] Step 1: Synthesis 29A
[0514] A mixture of compound 15G (500 mg, 0.968 mmol, 1.0 eq),
1,1-difluoro-2-iodoethane (278.8 mg, 1.452 mmol, 1.5 eq) and
Cs.sub.2CO.sub.3 (946 mg, 2.90 mmol, 3.0 eq) in DMF (5 mL) was
stirred at room temperature for 2 hours. The reaction was monitored
by LC-MS. After filtration through a short celite pad, the filtrate
was concentrated under reduced pressure and the residue was
purified by prep-TLC (PE/EA=10:1) to give compound 29A (160 mg,
28%).
Step 2: Synthesis 29
[0515] To a solution of 29A (150 mg, 0.259 mmol, 1.0 eq) in dioxane
(1 mL) was added i-BuB(OH).sub.2 (52.4 mg, 0.518 mmol, 2.0 eq) and
concentrated HCl (1 mL). The reaction mixture was stirred at room
temperature for 24 hours. The reaction mixture was concentrated in
vacuo, and the residue was dissolved in H.sub.2O/MeCN. The
resulting solution was adjusted to pH=12 and purified by prep-HPLC
(C18, neutral) to give 29 (55 mg, 72%).
[0516] ESI-MS: [M+H].sup.+: 273
[0517] .sup.1H NMR (400 MHz, CD.sub.3OD/DMSO): .delta. 6.89 (d,
J=8.0 Hz, 1H), 6.38-6.30 (m, 1H), 6.17-6.15 (m, 1H), 4.24-4.17 (m,
2H), 3.32-3.29 (m, 2H), 0.53-0.49 (m, 2H).
Example 30
Disodium;4,4-dihydroxy-8-(4-hydroxybut-2-ynoxy)-5-oxa-4-boranuidabicyclo[4-
.4.0]deca-1(6),7,9-triene-7-carboxylate
##STR00111##
[0518] Step 1: Synthesis of 30B
[0519] A mixture of Compound 15G (500 mg, 0.969 mmol, 1.0 eq),
compound 30A (J. Med. Chem., 1994, 37, 3739-48) (238 mg, 1.45 mmol,
1.5 eq) and Cs.sub.2CO.sub.3 (948 mg, 2.91 mmol, 3.0 eq) in DMF (8
mL) was stirred at 50.degree. C. for 12 hours. The reaction was
monitored by LC-MS. After filtration through a short celite pad,
the filtrate was concentrated under reduced pressure and the
residue was purified by prep-TLC (PE/EA=5:1) to give compound 30B
(58 mg, 10%).
Step 2: Synthesis of 30
[0520] To a solution of compound 30B (58 mg, 0.099 mmol, 1.0 eq) in
dioxane (1 mL) was added i-BuB(OH).sub.2 (20 mg, 0.198 mmol, 2.0
eq) and concentrated HCl (1 mL). The reaction mixture was stirred
at rt for 30 minutes. The reaction mixture was concentrated in
vacuo, and the residue was dissolved in H.sub.2O/MeCN. The
resulting solution was adjusted to pH=12 and purified by prep-HPLC
(C18, neutral) to give compound 30 (24 mg, 81%).
[0521] ESI-MS: [M+H].sup.+: 277
[0522] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 6.72 (d, J=8.0
Hz, 1H), 6.29 (d, J=8.4 Hz, 1H), 4.64-4.60 (m, 2H), 4.22-4.16 (m,
2H), 3.71-3.67 (m, 1H), 3.62-3.56 (m, 1H), 2.53 (s, 1H), 0.42 (s,
2H).
Example 31
Disodium;4,4-dihydroxy-8-(4-methoxybut-2-ynoxy)-5-oxa-4-boranuidabicyclo[4-
.4.0]deca-1(6),7,9-triene-7-carboxylate
##STR00112##
[0523] Step 1: Synthesis of 31B
[0524] To a solution of compound 31A (10 g, 0.116 mol, 1.0 eq) in
DMSO (200 mL) was added KOH (6.6 g, 0.116 mol, 1.0 eq). The mixture
was stirred at room temperature for 30 min before MeI (16.5 g,
0.116 mol, 1.0 eq) was added dropwise. After 30 minutes at room
temperature, the reaction mixture was poured into water and
extracted with DCM (2.times.). The organic layer was concentrated
in vacuo and the residue was purified by flash chromatography on
silica (PE/EA=5:1) to give compound 31B (2.3 g, 20%).
Step 2: Synthesis of 31C
[0525] To a solution of compound 31B (1.0 g, 10 mmol, 1.0 eq) in
THF (10 mL) was added TEA (1.0 g, 10 mmol, 1.0 eq) at 0.degree. C.,
followed by dropwise addition of MsCl (1.15 g, 10 mmol, 1.0 eq).
The mixture was stirred at room temperature for 30 minutes before
it was concentrated to dryness. The residue was dissolved in EA and
washed with water and brine. The organic phase was dried over
Na.sub.2SO.sub.4 before it was concentrated in vacuo to give crude
compound 31C (1.8 g, 100%).
Step 3: Synthesis of 31D
[0526] The mixture of compound 15G (1.0 g, 1.94 mmol, 1.0 eq),
compound 31C (690 mg, 3.87 mmol, 2.0 eq) and Cs.sub.2CO.sub.3 (1.9
g, 5.81 mmol, 3.0 eq) in DMF (15 mL) was stirred at 50.degree. C.
for 12 hours under nitrogen atmosphere. The reaction was monitored
by LC-MS. The mixture was filtered, concentrated under reduced
pressure, and the residue was purified by flash chromatography on
silica (PE/EA=5:1) to give compound 31D (600 mg, 52%).
Step 4: Synthesis of 31
[0527] To a solution of compound 31D (300 mg, 0.50 mmol, 1.0 eq) in
dioxane (2 mL) was added i-BuB(OH).sub.2 (101 mg, 1.00 mmol, 2.0
eq) and concentrated HCl (2 mL). The reaction mixture was stirred
at rt for 1 hour. The reaction mixture was concentrated in vacuo,
and the residue was dissolved in H.sub.2O/MeCN. The resulting
solution was adjusted to pH=12 and purified by prep-HPLC (C18,
neutral) to give compound 31 (52 mg, 33%).
[0528] ESI-MS: [M+H].sup.+: 291
[0529] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 6.82 (d, J=8.4
Hz, 1H), 6.38 (d, J=8.0 Hz, 1H), 4.76 (s, 2H), 4.14-4.09 (m, 2H),
3.37-3.35 (m, 3H), 2.62-2.56 (m, 2H), 0.54-0.50 (m, 2H).
Example 32
Disodium;8-(4-aminobut-2-noxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.-
0]deca-1(6),7,9-triene-7-carboxylate
##STR00113##
[0530] Step 1: Synthesis of 32B
[0531] The mixture of compound 15G (600 mg, 1.16 mmol, 1.0 eq), 32A
(Bioorg. Med. Chem. Lett., 2010, 20, 3165-68) (450 mg, 1.71 mmol,
1.5 eq) and Cs.sub.2CO.sub.3 (1.1 g, 3.38 mmol, 3.0 eq) in DMF (10
mL) was stirred at 50.degree. C. for 12 hours under nitrogen
atmosphere. The reaction was monitored by LC-MS. The mixture was
filtered and concentrated under reduced pressure. The residue was
purified by flash chromatography on silica (PE/EA=4:1) to give
compound 32B (340 mg, 43%).
Step 6: Synthesis of 32
[0532] To a solution of compound 32B (300 mg, 0.44 mmol, 1.0 eq) in
dioxane (3 mL) was added i-BuB(OH).sub.2 (89 mg, 0.88 mmol, 2.0 eq)
and concentrated HCl (2 mL). The reaction mixture was stirred at rt
for 1 hour. The reaction mixture was concentrated in vacuo, and the
residue was dissolved in H.sub.2O/MeCN. The resulting solution was
adjusted to pH=12 and purified by prep-HPLC (C18, neutral) to give
compound 32 (31 mg, 24%).
[0533] ESI-MS: [M+H].sup.+: 276
[0534] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 6.96 (d, J=7.6
Hz, 1H), 6.45 (d, J=8.8 Hz, 1H), 5.57 (s, 4H), 3.65-3.41 (m, 2H),
2.62-2.57 (m, 2H), 0.81-0.76 (m, 2H).
Example 33
(2-Hydroxy-7-methoxy-3,4-dihydro-1,2-benzoxaborinin-8-yl)phosphonic
acid
##STR00114##
[0535] Step 1: Synthesis of 33B
[0536] To the solution of 33A (9.8 g, 79 mmol, 1.0 eq) in DCM (100
mL) was added NBS (14.8 g, 82.9 mmol, 1.05 eq) in DCM (150 mL)
dropwise at 0.degree. C. The reaction mixture was stirred at room
temperature for 2 hours under nitrogen atmosphere before it was
concentrated in vacuo to dryness. The residue was purified by flash
chromatography on silica (PE/EA=20:1 to 5:1) to give 33B (10.2 g,
64%).
Step 2: Synthesis of 33C
[0537] To a solution of 33B (9.2 g, 45.5 mmol, 1.0 eq) in DCM (100
mL) was added diethyl phosphorochloridate (8.64 g, 50.1 mmol, 1.1
eq) and Et.sub.3N (6.9 g, 68.3 mmol, 1.5 eq) dropwise. The mixture
was stirred at room temperature for 16 hours before it was
concentrated to dryness. The residue was purified by column
chromatography (PE/EA=10:1 to 5:1) to give 33C (13.9 g, 90%).
Step 3: Synthesis of 33D
[0538] To a solution of 33C (13.9 g, 0.04 mol, 1.0 eq) in anhydrous
THF (150 mL) was added LDA (36 mL, 2M in THF, 0.072 mol, 1.8 eq)
dropwise at -78.degree. C. The reaction mixture was slowly warmed
to room temperature in 2 hours before it was quenched with
saturated aqueous NH.sub.4Cl. The mixture was extracted with EA and
dried over Na.sub.2SO.sub.4. The crude product was purified by
column chromatography (PE/EA=20:1 to 5:1) to give 33D (8.8 g,
63%).
Step 4: Synthesis of 33E
[0539] A mixture of 33D (3.0 g, 8.88 mmol, 1.0 eq),
CH.sub.2CHBF.sub.3K (2.38 g, 17.75 mmol, 2.0 eq), PdCl.sub.2 (dppf)
(579 mg, 0.71 mmol, 0.08 eq) and DIPEA (3.4 g, 26.6 mmol, 3.0 eq)
in dioxane (30 mL) was stirred at 100.degree. C. for 16 hours under
nitrogen atmosphere. The reaction was monitored by TLC. The mixture
was filtered, evaporated to dryness, and purified by column
chromatography (PE/EA=20:1 to 10:1) to give compound 33E (1.4 g,
55%).
Step 5: Synthesis of 33F
[0540] To the solution of 33E (1.4 g, 4.89 mmol, 1.0 eq) in DCM (15
mL) was added Boc.sub.2O (1.6 g, 7.34 mmol, 1.5 eq), TEA (1.49 g,
14.7 mmol, 3.0 eq) and DMAP (60 mg, 0.49 mmol, 0.1 eq). The mixture
was stirred at room temperature for 16 hours before it was
evaporated to dryness. The residue was purified by column
chromatography (PE/EA=5:1 to 2:1) to give 33F (1.9 g, 100%).
Step 6: Synthesis of 33G
[0541] To a mixture of 33F (300 mg, 0.78 mmol, 1.0 eq) in DCM (3
mL) was added 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (199 mg, 1.55
mmol, 2.0 eq), [IrCl(COD)].sub.2 (10.4 mg, 0.016 mmol, 0.02 eq) and
dppe (12.4 mg, 0.03 mmol, 0.04 eq). The mixture was stirred at room
temperature for 16 hours before it was evaporated to dryness. The
residue was purified by column chromatography (PE/EA=5:1 to 1:1) to
give 33G (350 mg, 88%).
[0542] ESI-MS: [M+H].sup.+: 515
Step 7: Synthesis of 33
[0543] To a solution of 33G (200 mg, 0.39 mmol, 1.0 eq) in DCM (5
mL) was added TMSBr (298 mg, 1.95 mmol, 8.0 eq). The mixture was
stirred at room temperature for 16 hours before it was
concentrated. The residue was purified by pre-HPLC (C18) to give 33
(39.5 mg, 39%) as white solid.
[0544] ESI-MS: [M+H].sup.+: 259
[0545] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 7.19 (d, J=8.4
Hz, 1H), 6.43-6.38 (m, 1H), 3.82 (d, J=12.4 Hz, 3H), 2.61-2.56 (m,
2H), 1.06-1.01 (m, 2H).
Example 34
6-Fluoro-2-hydroxy-7-methoxy-3,4-dihydro-1,2-benzoxaborinine-8-carboxylic
acid
##STR00115##
[0546] Step 1: Synthesis of 34B
[0547] To a solution of 34A (500 mg, 3.52 mmol, 1.0 eq) in THF (5
mL) was added Boc.sub.2O (921 mg, 4.23 mmol, 1.2 eq) and DMAP (22
mg, 0.17 mmol, 0.05 eq). The mixture was stirred at room
temperature for 2 hours before it was concentrated in vacuo. The
residue was purified by column chromatography (PE/EA=20:1 to 5:1)
to give 34B (767 mg, 90%).
Step 2: Synthesis of 34C
[0548] To a solution of 34B (5.0 g, 20.7 mmol, 1.0 eq) in anhydrous
THF (50 mL) was added LDA (26 mL, 2M in THF, 52 mmol, 2.5 eq,
freshly made) dropwise -78 OC. The reaction mixture was slowly
warmed to room temperature in 2 hours before it was quenched with
saturated aqueous NH.sub.4Cl. The mixture was extracted with EA and
dried over Na.sub.2SO.sub.4. The crude product was purified by
column chromatography (PE/EA=20:1 to 5:1) to give 34C (3.6 g,
75%).
Step 3: Synthesis of 34D
[0549] To a solution of 34C (3.6 g, 14.9 mmol, 1.0 eq) in DCM (40
mL) was added NBS (2.9 g, 16.4 mmol, 1.1 eq) and DIA (300 mg, 2.98
mmol, 0.2 eq). The reaction mixture was stirred at room temperature
for 0.5 hour. The reaction was monitored by TLC. The mixture was
evaporated to dryness, and the residue was purified by column
chromatography (PE/EA=20:1 to 5:1) to give 34D (1.9 g, 40%).
Step 4: Synthesis of 34E
[0550] To a solution of 34D (1.9 g, 5.9 mmol, 1.0 eq) in THF (20
mL) was added Boc.sub.2O (1.5 g, 7.08 mmol, 1.2 eq) and DMAP (36
mg, 0.295 mmol, 0.05 eq). The mixture was stirred at room
temperature for 2 hours before it was concentrated in vacuo. The
residue was purified by column chromatography (PE/EA=20:1 to 5:1)
to give 34E (2.5 g, 100%).
Step 5: Synthesis of 34G
[0551] To a solution of 34E (2.47 g, 5.9 mmol, 1.0 eq) and
Pd(t-Bu.sub.3P).sub.2 (300 mg, 0.59 mmol, 0.1 eq) in THF (30 mL)
was added 34F (WO 0946098) (freshly made, about 8.8 mmol in THF,
1.5 eq) dropwise over 10 min under N.sub.2. The mixture was stirred
at room temperature overnight before it was concentrated in vacuo.
The residue was purified by column chromatography (PE/EA=10:1) to
give 34G (660 mg, 23%).
[0552] ESI-MS: [M+H].sup.+: 535
Step 6: Synthesis of 34H
[0553] To a solution of 34G (300 mg, 0.56 mmol, 1.0 eq) and
CH.sub.2ICl (198 mg, 1.12 mmol, 2.0 eq) in THF (3 mL) was added
n-BuLi (0.4 mL, 2.5 M in hexanes, 0.96 mmol, 1.7 eq) dropwise in 10
minutes at -78.degree. C. The mixture was slowly warmed up to room
temperature overnight. The mixture was concentrated in vacuo and
the residue was purified by prep-TLC (PE/EA=5:1) to give 34H (220
mg, 71%).
[0554] ESI-MS: [M+H].sup.+: 549
Step 7: Synthesis of 34
[0555] To a solution of 34H (220 mg, 0.40 mmol, 1.0 eq) in dioxane
(3 mL) was added i-BuB(OH).sub.2 (82 mg, 0.80 mmol, 2.0 eq) and
concentrated HCl (2 mL). The reaction mixture was stirred at room
temperature for 3 hours. The reaction mixture was concentrated in
vacuo, and the residue was dissolved in H.sub.2O/MeCN. The
resulting solution was adjusted to pH=10-12 with 1N NaOH and
purified by prep-HPLC (C18, neutral) to give 34 (18 mg, 19%).
[0556] ESI-MS: [M+H].sup.+: 241
[0557] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 7.06 (s, 1H),
3.80 (s, 3H), 2.72-2.68 (m, 2H), 1.10-1.05 (m, 2H).
Example 35
6,7-Difluoro-2-hydroxy-3,4-dihydro-1,2-benzoxaborinine-8-carboxylic
acid
##STR00116##
[0558] Step 1: Synthesis of 35B
[0559] To a solution of 35A (400 mg, 3.1 mmol, 1.0 eq) in THF (5
mL) was added Boc.sub.2O (811 mg, 3.7 mmol, 1.2 eq) and DMAP (20
mg, 0.16 mmol, 0.05 eq). The mixture was stirred at rt for 2 hours
before it was concentrated in vacuo. The residue was purified by
column chromatography (PE/EA=10:1) to give 35B (470 mg, 66%).
Step 2: Synthesis of 35C
[0560] To a solution of 35B (470 mg, 2.04 mmol, 1.0 eq) in
anhydrous THF (20 mL) was added LDA (1.5 mL, 2M in THF, 3.06 mmol,
1.5 eq) dropwise at -78.degree. C. The mixture was slowly warmed up
to room temperature in 6 hours before it was quenched with
saturated aqueous NH.sub.4Cl solution. The mixture was extracted
with EA and dried over Na.sub.2SO.sub.4. The organic layer was
concentrated, and the residue was purified by column chromatography
(PE/EA=20:1) to give 35C (317 mg, 67%).
Step 3: Synthesis of 35D
[0561] To a solution of 35C (317 mg, 1.38 mmol, 1.0 eq) in DCM (100
mL) was added DIA (27.9 mg, 0.276 mmol, 0.2 eq) and NBS (259 mg,
82.9 mmol, 1.05 eq). The mixture was stirred at room temperature
for 16 hours before it was filtered and concentrated under vacuum
to give crude 35D (436 mg, 100%).
Step 4: Synthesis of 35E
[0562] To a solution of 35D (436 mg, 1.41 mmol, 1.0 eq) in DCM (2
mL) was added Boc.sub.2O (323 mg, 1.48 mmol, 1.05 eq) and DMAP (9
mg, 0.07 mmol, 0.05 eq). The mixture was stirred at room
temperature for 1 hours before it was evaporated to dryness. The
residue was purified by column chromatography (PE/EA=200:1 to
100:1) to give 35E (475 mg, 82%).
Step 5: Synthesis of 35F
[0563] A mixture of 35E (475 mg, 1.16 mmol, 1.0 eq),
CH.sub.2CHBF.sub.3K (310 mg, 2.32 mmol, 2.0 eq), PdCl.sub.2 (dppf)
(76 mg, 0.09 mmol, 0.08 eq) and DIPEA (448 mg, 3.47 mmol, 3.0 eq)
in dioxane (5 mL) was stirred at 80.degree. C. for 16 hours under
nitrogen atmosphere. The reaction was monitored by TLC. The mixture
was filtered and the filtrate was purified by column chromatography
(PE/EA=100:1 to 30:1) to give 35F (240 mg, 58%).
Step 6: Synthesis of 35G
[0564] To a solution of 35F (240 mg, 0.67 mmol, 1.0 eq) in DCM (2
mL) was added 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (172 mg, 1.34
mmol, 2.0 eq), [IrCl(COD)].sub.2 (9 mg, 0.013 mmol, 0.02 eq) and
dppe (11 mg, 0.027 mmol, 0.04 eq). The mixture was stirred at room
temperature for 16 hours under nitrogen atmosphere. The reaction
was monitored by TLC. The mixture was concentrated and purified by
prep-TLC (PE/EA=20:1) to give 35G (107 mg, 33%).
[0565] ESI-MS: [M+H].sup.+: 485
Step 7: Synthesis of 35
[0566] To a solution of 35G (100 mg, 0.207 mmol, 1.0 eq) in DCM (2
mL) at 0.degree. C. was added 90% TFA (0.5 mL). The mixture was
stirred at room temperature for 5 hours before it was concentrated
in vacuo. The residue was purified by pre-HPLC (C18) to give 35
(12.9 mg, 27%) as white solid.
[0567] ESI-MS: [M+CH.sub.3CN+H].sup.+=270
[0568] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 7.27-7.16 (m,
1H), 2.70-2.56 (m, 2H), 1.07-0.95 (m, 2H).
Example 36
Disodium;4,4-dihydroxy-8-methylsulfanyl-5-oxa-4-boranuidabicyclo[4.4.0]dec-
a-(6),7,9-triene-7-carboxylate
##STR00117##
[0569] Step 1: Synthesis of 36B
[0570] A mixture of 36A (WO 15179308) (3.0 g, 7.7 mmol, 1.0 eq) and
MeSNa (1.08 g, 15.4 mmol, 2.0 eq) in DMF (20 mL) was stirred at
room temperature for 16 hours under nitrogen atmosphere. The
reaction was monitored by TLC. The reaction mixture was
concentrated in vacuo and purified by column chromatography (EA/PE,
1:5) to obtain 36B (1.41 g, 44%).
Step 2: Synthesis of 36C
[0571] To a mixture of 36B (1 g, 2.39 mmol, 1.0 eq),
CH.sub.2CHBF.sub.3K (801 mg, 5.98 mmol, 2.5 eq) and
Cs.sub.2CO.sub.3 (2.34 g, 7.18 mmol, 3.0 eq) in THF/H.sub.2O (9
mL/1 mL) was added PdCl.sub.2 (dppf) (300 mg, 0.367 mmol, 0.15 eq).
The reaction mixture was stirred at room temperature for 16 hours
under nitrogen atmosphere. The reaction was monitored by TLC. The
mixture was filtered and washed with EA. The filtrate was
concentrated and purified by column chromatography (PE/EA=20:1) to
give 36C (600 mg, 68%).
Step 3: Synthesis of 36D
[0572] To a solution of 36C (700 mg, 1.91 mmol, 1.0 eq) in DCM (7
mL) was added 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (489 mg, 3.82
mmol, 2.0 eq), [IrCl(COD)].sub.2 (38.5 mg, 0.057 mmol, 0.03 eq) and
dppe (46 mg, 0.114 mmol, 0.06 eq). The mixture was stirred at room
temperature for 20 hours under nitrogen atmosphere before it was
concentrated in vacuo. The residue was purified by column
chromatography (PE/EA=20:1 to 5:1) to give 36D (130 mg, 14%).
[0573] ESI-MS: [M+H].sup.+:495
Step 4: Synthesis of 36E
[0574] A solution of 36D (120 mg, 0.243 mmol, 1.0 eq) in 90% THF (1
mL) and DCM (1 mL) was stirred at room temperature for 2 hours. The
reaction mixture was concentrated and the residue was dissolved in
MeCN/water. The resulting solution was adjusted to pH=10 with 1N
NaOH and purified by prep-HPLC (C18, neutral) to give 36E (28 mg,
44%) as white solid.
[0575] ESI-MS: [M-H2O+H].sup.+: 221
[0576] .sup.1H NMR (400 MHz, CD.sub.3OD/D.sub.2O): .delta. 7.06 (d,
J=8.4 Hz, 1H), 6.60 (d, J=8.0 Hz, 1H), 2.65-2.61 (m, 2H), 2.32 (s,
3H), 0.71-0.67 (m, 2H).
Example 37
Disodium;9-fluoro-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7-
,9-triene-7-carboxylate
##STR00118##
[0577] Step 1: Synthesis of 37B
[0578] A mixture of 37A (5.1 g, 33 mmol, 1.0 eq) and NBS (6.4 g, 36
mmol, 1.1 eq) in AcOH (25 mL) was stirred at 80.degree. C. for 24
hours. The reaction was monitored by TLC. The mixture was
concentrated in vacuo and the residue was purified by column
chromatography (PE/EA=2:1 to 1:1) to give 37B (6.5 g, 85%).
[0579] ESI-MS: [M-H].sup.-: 233, 235
Step 2: Synthesis of 37C
[0580] A mixture of 37B (6.1 g, 26 mmol, 1.0 eq), Boc.sub.2O (28 g,
130 mmol, 5.0 eq) and DMAP (3.2 g, 26 mmol, 1.0 eq) in t-BuOH/THF
(60 mL/40 mL) was stirred at 60.degree. C. for 16 hours. The
mixture was concentrated in vacuo and the residue was purified by
column chromatography (PE/EA=10:1 to 5:1) to give 37C (1.5 g,
15%).
Step 3: Synthesis of 37D
[0581] A mixture of 37C (1.6 g, 4.75 mmol, 1.0 eq),
CH.sub.2CHBF.sub.3K (1.27 g, 9.5 mmol, 2.0 eq), DIPEA (1.84 g, 14.2
mmol, 3.0 eq) and PdCl.sub.2 (dppf) (310 mg, 0.38 mmol, 0.08 eq) in
dioxane (20 mL) was stirred at 85.degree. C. for 16 hours under
nitrogen atmosphere. The mixture was filtered and washed with EA.
The filtrate was concentrated and purified by column chromatography
(PE/EA=20:1) to give 37D (900 mg, 65%).
Step 4: Synthesis of 37E
[0582] To a solution of 37D (347 mg, 1.03 mmol, 1.0 eq) in DCM (4
mL) was added 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (263 mg, 2.05
mmol, 2.0 eq), [IrCl(COD)].sub.2 (21 mg, 0.031 mmol, 0.03 eq) and
dppe (25 mg, 0.062 mmol, 0.06 eq). The mixture was stirred at room
temperature for 5 hours before it was concentrated. The residue was
purified by column chromatography (PE/EA=10:1 to 5:1) to give 37E
(120 mg, 25%).
[0583] ESI-MS: [M+H].sup.+: 467
Step 5: Synthesis of 37
[0584] A solution of 37E (100 mg, 0.215 mmol, 1.0 eq) in 90% THF
(2.5 mL) and DCM (2.5 mL) was stirred at room temperature for 2
hours. The mixture was concentrated and purified by prep-HPLC
(C18). The obtained solid was dissolved in MeCN/H.sub.2O and was
adjusted to pH=9 with 0.1 N NaOH. After lyophilization, the Na salt
of 37 (70 mg, 100%) was obtained as white solid.
[0585] ESI-MS: [M+MeCN+H].sup.+: 252
[0586] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 6.98 (d, J=6.4
Hz, 1H), 6.61 (d, J=6.4 Hz, 1H), 2.65-2.60 (m, 2H), 0.48-0.44 (m,
2H).
Example 38
Disodium;8,8-dihydroxy-7-oxa-2-aza-8-boranuidabicyclo[4.4.0]deca-1,3,5-tri-
ene-5-carboxylate
##STR00119## ##STR00120##
[0587] Step 1: Synthesis of 38B
[0588] A solution of compound 38A (5.0 g, 38.6 mmol, 1.0 eq),
(Boc.sub.2)O (9.17 g, 42.4 mmol, 1.1 eq) and DMAP (0.472 g, 3.86
mmol, 0.1 eq) in anhydrous DCM (100 mL) was stirred at room
temperature for 0.5 hour. The solvent was removed under reduced
pressure and the residue was purified by column chromatography
(PE/EA=5:1) to give compound 38B (8.0 g, 90%).
[0589] ESI-MS: [M+H].sup.+: 230
Step 2: Synthesis of 38C
[0590] To a solution of compound 38B (4.0 g, 17.4 mmol, 1.0 eq) in
anhydrous THF (50 ml) was slowly added LDA (10.5 mL, 2 M in THF,
20.9 mmol, 1.2 eq) over 10 minutes at -78.degree. C. The mixture
was warmed up and stirred at room temperature for 2 hours before it
was quenched by saturated NH.sub.4Cl solution. The organic layer
was concentrated under reduced pressure and the residue was
purified by column chromatography (PE/EA=51) to give compound 38C
(0.9 g, 23%).
[0591] ESI-MS: [M+H].sup.+: 230
Step 3: Synthesis of 38D
[0592] A solution of compound 38C (0.8 g, 3.5 mmol, 1.0 eq),
potassium vinyltrifluoroborate (0.61 g, 4.53 mmol, 1.3 eq), TEA
(1.06 g, 10.5 mmol, 3.0 eq) and PdCl.sub.2 (dppf) (0.256 g, 0.35
mmol, 0.1 eq) in dioxane (10 ml) was stirred at 80.degree. C. for
10 hours under N.sub.2. After cooled down, the mixture was filtered
and the filtrate was concentrated under reduced pressure. The
residue was purified by column chromatography (PE/EA=10:1) to give
compound 38D (0.58 g, 67%).
[0593] ESI-MS: [M+H].sup.+: 222
Step 4: Synthesis of 38E
[0594] A solution of compound 38D (0.53 g, 2.4 mmol, 1.0 eq),
(Boc.sub.2)O (0.68 g, 3.1 mmol, 1.3 eq) and DMAP (0.147 g, 1.2
mmol, 0.5 eq) in anhydrous DCM (6 mL) was stirred at room
temperature for 1 hour. The solution was concentrated under reduced
pressure and the residue was purified by column chromatography
(PE/EA=10:1) to give compound 38E (0.76 g, 98%).
[0595] ESI-MS: [M+H].sup.+: 322
Step 5: Synthesis of 38F
[0596] A solution of compound 38E (0.3 g, 0.94 mmol, 1.0 eq),
Bin.sub.2Pin.sub.2 (0.275 g, 1.08 mmol, 1.15 eq), Cu.sub.2O (11 mg,
0.076 mmol, 0.08 eq), K.sub.2HPO.sub.4 (0.197 g, 1.13 mmol, 1.2 eq)
and PPh.sub.3 (0.028 g, 0.104 mmol, 0.11 eq) in MeOH (3 mL) was
stirred at 85.degree. C. for 4 hours under N.sub.2. The mixture was
filtered and the filtrate was concentrated in vacuo to give crude
compound 38F (400 mg, 94%).
[0597] ESI-MS: [M+H].sup.+: 450
Step 6: Synthesis of 38
[0598] A solution of crude compound 38F (0.4 g, 0.9 mmol, 1.0 eq)
in 90% aq TFA (3 mL) and Et.sub.3SiH (3 mL) was stirred overnight
at 30.degree. C. The solvent was removed in vacuo, and the residue
was dissolved in H.sub.2O/MeCN. The resulting solution was adjusted
to pH=12 with 1N NaOH and purified by prep-HPLC (C18, neutral) to
give 38 (37 mg, 30%) as white solid.
[0599] ESI-MS: [M+H].sup.+: 194
[0600] .sup.1H NMR (CD.sub.3OD, 400 MHz): .delta. 7.475-7.473 (d,
1H), 7.001 (d, 1H), 2.535-2.435 (t, J=20, 2H), 0.289-0.253 (t,
J=7.2, 2H)
Example 39
2-Hydroxy-7-methylsulfonyl-3,4-dihydro-1,2-benzoxaborinine-8-carboxylic
acid
##STR00121##
[0601] Step 1: Synthesis of 39A
[0602] To a solution of 36B (1.4 g, 3.35 mmol, 1.0 eq) in DCM (40
mL) was added m-CPBA (1.73 g, 10 mmol, 3.0 eq) slowly at 0.degree.
C. The mixture was slowly warmed up to room temperature in 3 hours.
The reaction was monitored by TLC. The mixture was quenched with
aqueous Na2S2O3 and washed with water. The organic layer was dried
over Na.sub.2SO.sub.4 and then concentrated in vacuo to give crude
39A (1.31 g, 87%).
Step 2: Synthesis of 39B
[0603] A mixture of 39A (1.3 g, 2.88 mmol, 1.0 eq),
CH.sub.2CHBF.sub.3K (0.77 g, 5.76 mmol, 2.0 eq), PdCl.sub.2 (dppf)
(169 mg, 0.23 mmol, 0.08 eq) and DIPEA (1.83 g, 14.2 mmol, 3.0 eq)
in dioxane (20 mL) was stirred at 85.degree. C. for 16 hours under
nitrogen atmosphere. The reaction was monitored by TLC. The mixture
was filtered and concentrated in vacuo. The residue was purified by
column chromatography to give 39B (870 mg, 76%).
[0604] ESI-MS: [M+H].sup.+: 399
Step 3: Synthesis of 39C
[0605] To a solution of 39B (770 mg, 1.93 mmol, 1.0 eq) in DCM (7
mL) was added 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (495 mg, 3.87
mmol, 2.0 eq), [IrCl(COD)].sub.2 (26 mg, 0.039 mmol, 0.02 eq) and
dppe (31 mg, 0.077 mmol, 0.04 eq). The mixture was stirred at room
temperature for 20 hours under nitrogen atmosphere. The reaction
was monitored by TLC. The mixture was concentrated in vacuo, the
residue was purified by prep-TLC to give 39C (120 mg, 12%).
[0606] ESI-MS: [M+H].sup.+: 527
Step 4: Synthesis of 39
[0607] The solution of 39C (110 mg, 0.21 mmol, 1.0 eq) in 90% THF
(1 mL) and DCM (4 mL) was stirred at room temperature for 2 hours.
The reaction mixture was concentrated and the residue was dissolved
in MeCN/water. The resulting solution was purified by prep-HPLC to
give 39 (17 mg, 30%).
[0608] ESI-MS: [M-H2O+H].sup.+: 253
[0609] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 7.55 (d, J=7.6
Hz, 1H), 7.42-7.39 (m, 1H), 3.19 (s, 3H), 2.91-2.86 (m, 2H),
1.11-1.06 (m, 2H).
Example 40
Disodium;4,4-dihydroxy-8-methylsulfinyl-5-oxa-4-boranuidabicyclo[4.4.0]dec-
a-1(6),7,9-triene-7-carboxylate
##STR00122##
[0610] Step 1: Synthesis of 40A
[0611] To the solution of compound 36B (2.0 g, 4.79 mmol, 1.0 eq)
in anhydrous DCM (10 mL) was added m-CPBA (0.827 g, 4.79 mmol, 1.0
eq) in DCM (2 mL) at -78.degree. C. The reaction mixture was
stirred at -78.degree. C. for 2 hours before it was quenched with
aqueous Na.sub.2S.sub.2O.sub.3. The reaction mixture was
partitioned in DCM and H.sub.2O. After dried over Na.sub.2SO.sub.4
the organic layer was concentrated in vacuo. The residue was
purified by column chromatography (PE/EA=5:1) to give compound 40A
(2.02 g, 97%).
Step 2: Synthesis of 40B
[0612] A solution of compound 40A (2.02 g, 4.66 mmol, 1.0 eq),
potassium vinyltrifluoroborate (1.56 g, 11.5 mmol, 2.5 eq),
Cs.sub.2CO.sub.3 (4.46 g, 13.7 mmol, 3.0 eq) and PdCl.sub.2 (dppf)
(1.03 g, 1.4 mmol, 0.3 eq) in THF/H.sub.2O (30 ml, 9/1, v/v) was
stirred at 85.degree. C. overnight under N.sub.2. The mixture was
filtered and solvent was removed under reduced pressure. The
residue was purified by column chromatography (PE/EA=5:1) to give
compound 40B (1.56 g, 88%).
[0613] ESI-MS: [M+H].sup.+: 383
Step 3: Synthesis of 40C
[0614] To a solution of 40B (500 mg, 1.31 mmol, 1.0 eq) in
anhydrous DCM (7 mL) was added
4,4,5,5-tetramethyl-1,3,2-dioxaborolane (336 mg, 2.62 mmol, 2.0
eq), [IrCl(COD)].sub.2 (27 mg, 0.04 mmol, 0.03 eq) and dppe (32 mg,
0.08 mmol, 0.06 eq). The mixture was stirred at room temperature
for 20 hours under nitrogen atmosphere. The reaction was monitored
by TLC. The mixture was concentrated in vacuo, the residue was
purified by column chromatography (PE/EA=5:1) to give compound 40C
(0.59 g, 89%).
[0615] ESI-MS: [M+H].sup.+: 511
Step 4: Synthesis of 40
[0616] A solution of compound 40C (300 mg, 0.59 mmol, 1.0 eq) in
90% TFA (2 mL) and DCM (2 mL) was stirred at room temperature for 3
h. The reaction mixture was concentrated and the residue was
dissolved in MeCN/water. The resulting solution was adjusted to
pH=10 with 1N NaOH and purified by prep-HPLC (C18, neutral) to give
40 (50 mg, 33%) as white solid.
[0617] ESI-MS: [M+H].sup.+: 255
[0618] .sup.1H NMR (CD3OD, 400 MHz): .delta. 7.439-7.420 (m, 1H),
7.382-7.364 (m, 1H), 2.840 (s, 3H), 2.743-2.704 (t, J=8 Hz, 2H),
1.036-10.17 (t, J=7.6 Hz, 2H)
Example 41
6-Chloro-2-hydroxy-7-methoxy-3,4-dihydro-1,2-benzoxaborinine-8-carboxylic
acid
##STR00123##
[0619] Step 1: Synthesis of 41B
[0620] To a solution of compound 41A (10.0 g, 40 mmol, 1.0 eq) in
AcOH (100 mL) was added SO.sub.2Cl.sub.2 (11.0 g, 0.08 mol, 2.0 eq)
dropwise over 5 min at room temperature. The reaction mixture was
stirred at 40.degree. C. overnight before it was concentrated in
vacuo. The residue was purified by column chromatography
(PE/EA=3:1) to give compound 41B (8.5 g, 80%).
Step 2: Synthesis of 41C
[0621] To a solution of compound 41B (8.5 g, 35.6 mmol, 1.0 eq) in
t-BuOH/THF (200 mL, 1/1, v/v) was added (Boc).sub.2O (31 g, 142
mmol, 4.0 eq) and DMAP (427 mg, 3.5 mmol, 0.1 eq) over 20 minutes.
The mixture was stirred at 65.degree. C. overnight before it was
concentrated in vacuo. The residue was purified by column
chromatography (PE/EA=10:1) to give compound 41C (13 g, 75%).
Step 3: Synthesis of 41E
[0622] To a solution of compound 41C (13 g, 30 mmol, 1.0 eq) and
Pd(PBu.sub.3).sub.2 (1.5 g, 2.98 mmol, 0.1 eq) in anhydrous THF
(400 mL) was added a solution of 41D (WO 15179308) (freshly made,
about 40 mmol in THF, 1.3 eq) dropwise over 10 min under N.sub.2.
The mixture was stirred at room temperature overnight before it was
concentrated in vacuo. The residue was purified by column
chromatography (PE/EA=10:1) to give compound 41E (8.8 g, 60%).
[0623] ESI-MS: [M+H].sup.+: 551
Step 4: Synthesis of 41F
[0624] To a solution of compound 41E (500 mg, 0.91 mmol, 1.0 eq)
and CH.sub.2ICl (319 mg, 1.82 mmol, 2.0 eq) in anhydrous THF (15
mL) was slowly added n-BuLi (0.54 mL, 2.5 M in hexanes, 1.36 mmol,
1.5 eq) over 10 minutes at -78.degree. C. The mixture was slowly
warmed up to room temperature overnight. The reaction solution was
concentrated in vacuo and the residue was purified by column
chromatography (PE/EA=10:1) to give compound 41F (0.46 g, 80%).
[0625] ESI-MS: [M+H].sup.+: 565
Step 5: Synthesis of 41
[0626] To a solution of compound 41F (0.46 g, 0.816 mmol, 1.0 eq)
in dioxane (4 mL) and concentrated HCl (4 mL) was added
i-BuB(OH).sub.2 (166 mg, 1.63 mmol, 2.0 eq). The mixture was
stirred at room temperature for 1 hours. The reaction mixture was
concentrated under reduced pressure and the mixture was purified by
prep-HPLC (C18) to give 41 (21 mg, 15%) as white solid.
[0627] ESI-MS: [M+H].sup.+: 257
[0628] .sup.1H NMR (CD.sub.3OD, 400 MHz): .delta. 7.260 (s, 1H),
3.858 (s, 3H), 2.723-2.684 (t, J=8.0, J=7.6, 2 H), 1.080-1.041 (t,
J=7.6, J=8.0, 2 H)
Example 42
Disodium;4,4,8-trihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-tri-
ene-7-carboxylate
##STR00124##
[0630] To the mixture of compound 15G (500 mg, 0.97 mmol, 1.0 eq),
i-BuB(OH).sub.2 (148 mg, 1.45 mmol, 1.5 eq) in hexane (9 mL) and
methanol (9 mL) was added about 10 drops of concentrated HCl at
0.degree. C. The reaction mixture was stirred at room temperature
overnight. The methanol layer was separated and washed with hexanes
(2.times.). The methanol layer was then concentrated and the
residue was added 90% aqueous TFA (6 mL) and TES (2 mL). The
mixture was stirred at room temperature for 1 hours before it was
concentrated under reduced pressure. The residue was dissolved in
MeCN/water and adjusted to pH=12 with 0.1 N NaOH. The resulting
solution was purified by prep-HPLC (C18, neutral) to give 42 (6 mg,
10%) as yellow solid.
[0631] ESI-MS: [2M-H].sup.-: 415
[0632] .sup.1H NMR (CD.sub.3OD, 400 MHz): .delta. 6.950 (d, 1H),
6.169-6.148 (d, J=8.4, 1 H), 2.573-2.535 (t, J=8.0, J=7.2, 2 H),
0.896-0.878 (t, 2H)
Example 43
Disodium;8-(2-fluoroethoxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]d-
eca-1(6),7,9-triene-7-carboxylate
##STR00125##
[0633] Step 1: Synthesis of 43A
[0634] The mixture of compound 15G (500 mg, 0.97 mmol, 1.0 eq),
1-fluoro-2-iodoethane (340 mg, 1.94 mmol, 2.0 eq) and
Cs.sub.2CO.sub.3 (947 mg, 2.9 mmol, 3.0 eq) in anhydrous DMF (15
mL) was stirred at room temperature overnight. The solvent was
removed under reduced pressure and the residue was purified by
column chromatography (PE/EA=10:1) to give compound 43A (300 mg,
70%).
[0635] ESI-MS: [M+H].sup.+: 563
Step 2: Synthesis of 43
[0636] To a solution of compound 43A (200 mg, 0.36 mmol, 1.0 eq) in
dioxane (3 mL) and concentrated HCl (3 mL) was added
i-BuB(OH).sub.2 (73 mg, 0.71 mmol, 2.0 eq). The mixture was stirred
at rt for 1 hour. The reaction mixture was concentrated in vacuo,
and the residue was dissolved in H.sub.2O/MeCN. The resulting
solution was adjusted to pH=12 with 1N NaOH and purified by
prep-HPLC (C18, neutral) to give 43 (62 mg, 50%) as white
solid.
[0637] ESI-MS: [M+H].sup.+: 255
[0638] .sup.1H NMR (CD.sub.3OD, 400 MHz): .delta. 6.787-6.766 (d,
J=8.4, 1 H), 6.255-6.235 (d, J=8.0, 1 H), 4.736-4.715 (t, J=4.0,
J=4.4, 1 H), 4.616-4.596 (t, 1H), 4.197-4.176 (t, 1H), 4.126-4.104
(t, 1H), 2.591-2.556 (t, 2H), 0.507-0.473 (t, J=6.8, 2 H)
Example 44
2-hydroxy-7-[2-hydroxy-1-(hydroxymethyl)ethoxy]-3,4-dihydro-1,2-benzoxabor-
inine-8-carboxylic acid
##STR00126##
[0639] Step 1: Synthesis of 44A
[0640] To a solution of compound 15G (800 mg, 1.55 mmol, 1.0 eq)
and 3-iodooxetane (485 mg, 2.63 mmol, 1.7 eq) in anhydrous DMF (15
mL) was added Cs.sub.2CO.sub.3. The mixture was stirred at
50.degree. C. overnight before it was concentrated under reduced
pressure. The residue was purified by column chromatography
(PE/EA=20:1 to 5:1) to give compound 44A (200 mg, 30%).
[0641] ESI-MS: [M+H].sup.+: 573
Step 2: Synthesis of 44
[0642] The solution of compound 44A (200 mg) in 90% aqueous TFA (6
mL) and TES (2 mL) was stirred at 35.degree. C. overnight before it
was concentrated under reduced pressure. The mixture was purified
by prep-HPLC to give 44 (26 mg, 20%) as white solid.
[0643] ESI-MS: [M-H2O+H].sup.+: 265
[0644] .sup.1H NMR (CD.sub.3OD, 400 MHz): .delta. 7.293-7.273 (d,
J=8.0, 1H), 6.694-6.674 (d, J=8.0, 1H), 4.387-4.330 (t, J=10, 2 H),
3.764-3.734 (t, J=6.4, J=5.6, 2 H), 3.687-3.675 (d, J=5.2, 1 H),
2.731 (s, 2H), 1.040 (s, 2H)
Example 45
Disodium;8-(cyclopropylmethoxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4-
.0]deca-1(6),7,9-triene-7-carboxylate
##STR00127##
[0645] Step 1: Synthesis of 45A
[0646] To a solution of compound 15G (0.5 g, 0.97 mmol, 1.0 eq) and
Cs.sub.2CO.sub.3 (0.947 g, 2.9 mmol, 3.0 eq) in anhydrous DMF (8
ml) was added (bromomethyl)cyclopropane (196 mg, 1.45 mmol, 1.5 eq)
dropwise over 5 minutes. After 2.5 hours at room temperature, the
reaction mixture was concentrated under reduced pressure and the
residue was purified by prep-TLC (PE/EA=10:1) to give compound 45A
(180 mg, 33%).
[0647] ESI-MS: [MH].sup.+: 571
Step 2: Synthesis of 45
[0648] To a solution of compound 45A (180 mg) in dioxane (2 mL) and
concentrated HCl (0.2 mL) was added i-BuB(OH).sub.2 (65 mg, 0.64
mmol, 2 eq). The mixture was stirred at room temperature for 18
hours. The reaction mixture was concentrated in vacuo, and the
residue was dissolved in H.sub.2O/MeCN. The resulting solution was
adjusted to pH=12 with 1N NaOH and purified by prep-HPLC (C18,
neutral) to give 45 (31 mg, 38%) as white solid.
[0649] ESI-MS: [M+H].sup.+: 263
[0650] .sup.1H NMR (CD.sub.3OD, 400 MHz): .delta. 6.696-6.675 (d,
J=8.4, 1 H), 6.180-6.159 (d, J=8.4, 1 H), 3.774-3.757 (d, J=6.8,
2H), 2.576-2.542 (t, J=6.8, 2H), 1.318-1.228 (t, J=18, 1 H),
0.507-0.485 (d, J=8.8, 2 H), 0.402-0.368 (t, J=6.8, 2 H),
0.311-0.299 (d, J=4.8, 2 H).
Example 46
7-(2-Amino-2-oxo-ethoxy)-2-hydroxy-3,4-dihydro-1,2-benzoxaborinine-8-carbo-
xylic acid
##STR00128##
[0651] Step 1: Synthesis of 46A
[0652] To a solution of compound 15G (0.5 g, 0.97 mmol, 1.0 eq) and
Cs.sub.2CO.sub.3 (0.947 g, 2.9 mmol, 3.0 eq) in anhydrous DMF (8
mL) was added of chloroacetonitrile (147 mg, 1.94 mmol, 2.0 eq)
over 5 minutes. The mixture was stirred at room temperature for 1.5
hours before it was concentrated under reduced pressure. The
residue was purified by column chromatography (PE/EA=5:1) to give
compound 46A (0.30 g, 55.7%).
[0653] ESI-MS: [M+H].sup.+: 556
Step 2: Synthesis of 46
[0654] To a solution of compound 46A (0.30 g) in dioxane (3 mL) and
concentrated HCl (0.3 mL) was added i-BuB(OH).sub.2 (112 mg, 1.1
mmol, 2 eq). The mixture was stirred at room temperature for 18
hours. The reaction mixture was concentrated in vacuo, and the
residue was dissolved in H.sub.2O/MeCN. The resulting solution was
adjusted to pH=12 with 1N NaOH and purified by prep-HPLC (C18,
neutral) to give 46 (41 mg, 28%) as white solid.
[0655] ESI-MS: [M-H2O+H].sup.+: 266
[0656] .sup.1H NMR (CD.sub.3OD, 400 MHz): .delta. 6.749-6.728 (d,
J=8.4, 1 H), 6.148-6.127 (d, J=8.4, 1 H), 4.463 (s, 2H),
3.703-3.678 (t, J=9.6, 1 H), 3.593-3.570 (t, J=9.2, 1 H),
2.537-2.503 (t, J=6.8, 2 H), 0.419-0.392 (t, J=9.4, 2H).
Example 47
7-(Cyanomethoxy)-2-hydroxy-3,4-dihydro-1,2-benzoxaborinine-8-carboxylic
acid
##STR00129##
[0658] To a solution of compound 46A (0.32 g, 0.58 mmol, 1.0 eq)
and i-BuB(OH).sub.2 (0.836 g, 0.83 mmol, 1.5 eq) in MeOH/n-hexane
(2.5 mL/2.5 mL) was added concentrated HCl (5 drops) dropwise. The
reaction mixture was stirred at 30.degree. C. for 3 hours. The
methanol layer was separated and washed with hexanes (2.times.).
The methanol layer was then concentrated and the residue was added
DCM (2 mL) and then TFA (2.5 mL). The reaction solution was stirred
at room temperature for 2.5 hours before it was concentrated under
reduced pressure. The residue was purified by prep-HPLC (C18) to
give 46 (11 mg, 8%) as white solid.
[0659] ESI-MS: [M+H].sup.+: 248
[0660] .sup.1H NMR (CD.sub.3OD, 400 MHz): .delta. 7.239-7.219 (d,
J=0.8, 1 H), 6.700 (d, 1H), 4.974 (s, 2H), 2.736-2.398 (t, J=6.4, 2
H), 1.094-1.053 (t, J=8.0, 2 H),
Example 48
Disodium;8-[2-(dimethylamino)ethoxy]-4,4-dihydroxy-5-oxa-4-boranuidabicycl-
o[4.4.0]deca-1(6),7,9-triene-7-carboxylate
##STR00130##
[0661] Step 1: Synthesis of 48A
[0662] A solution of compound 15G (0.8 g, 1.55 mmol, 1.0 eq),
N,N-dimethyl-2-chloroethylamine HCl salt (0.67 g, 4.65 mmol, 3.0
eq) and Cs.sub.2CO.sub.3 (2.53 g, 7.75 mmol, 5.0 eq) in anhydrous
DMF (15 mL) was stirred at 50.degree. C. for 18 hours. The reaction
mixture was concentrated under reduced pressure and the residue was
partitioned in EA and 0.2 N HCl. The organic phase was concentrated
to give crude 48A which was directly used for next step.
[0663] ESI-MS: [M+H].sup.+: 588
Step 2: Synthesis of 48
[0664] To a solution of crude compound 48A (0.8 g, 1.36 mmol, 1.0
eq) in dioxane (6 mL) and concentrated (6 mL) was added
i-BuB(OH).sub.2 (0.275 g, 2.72 mmol, 2.0 eq). The mixture was
stirred at room temperature for 18 hours. The reaction mixture was
concentrated in vacuo, and the residue was dissolved in
H.sub.2O/MeCN. The resulting solution was adjusted to pH=12 with 1N
NaOH and purified by prep-HPLC (C18, neutral) to give 48 (61 mg,
16%) as white solid.
[0665] ESI-MS: [M+H].sup.+: 280
[0666] .sup.1H NMR (CD3OD, 400 MHz): .delta. 6.788-6.766 (d, J=8.8,
1 H), 6.276-6.255 (d, J=8.4, 1 H), 4.193-40165 (t, J=11.2, 2H),
2.953 (t, 2H), 2.585-2.550 (t, J=14, 2 H), 2.513 (s, 6H),
0.478-0.445 (t, J=13.2, 2 H).
Example 49
Disodium;4,4-dihydroxy-8-(hydroxymethyl)-5-oxa-4-boranuidabicyclo[4.4.0]de-
ca-1(6),7,9-triene-7-carboxylate
##STR00131##
[0668] To a solution of 19C (150 mg, 0.28 mmol, 1.0 eq) in dioxane
(2 mL) 32 was added i-BuB(OH).sub.2 (58 mg, 0.57 mmol, 2.0 eq) and
conc.HCl (2 mL). The reaction mixture was stirred at rt for 3
hours. The reaction mixture was concentrated in vacuo, and the
residue was dissolved in H.sub.2O/MeCN. The resulting solution was
adjusted to pH=12 and purified by prep-HPLC (C18, neutral) to give
49 (28 mg, 40%) as white solid.
[0669] ESI-MS: [M+H].sup.+: 223
[0670] .sup.1H NMR (400 MHz, CD.sub.3OD/H.sub.2O): .delta.
7.15-7.12 (m, 1H), 6.76 (d, J=6.8 Hz, 1H), 4.77 (s, 2H), 3.30 (s,
1H), 2.66-2.60 (m, 2H), 1.30-1.26 (m, 2H).
Example 50
Disodium;8-(difluoromethyl)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]d-
eca-1(6),7,9-triene-7-carboxylate
##STR00132##
[0671] Step 1: Synthesis of 50A
[0672] To the solution of 19B (280 mg, 0.53 mmol, 1.0 eq) in DCM (8
mL) was added DAST (427 mg, 2.65 mmol, 5.0 eq) slowly at 0.degree.
C. The reaction mixture was stirred at room temperature for 16
hours. The mixture was diluted with DCM and washed with water.
After concentration, the residue was purified by prep-TLC to give
50A (83 mg, 20%).
[0673] ESI-MS: [M+H].sup.+: 421
Step 2: Synthesis of 50
[0674] To the solution of 50A (60 mg, 0.143 mmol, 1.0 eq) in DCM
(0.5 mL) was added TFA (0.2 mL). The resulting solution was stirred
at room temperature for 1 hour before it was concentrated. The
residue was dissolved in H.sub.2O/MeCN. The resulting solution was
adjusted to pH=12 and purified by prep-HPLC (C18, neutral) to give
50 (18 mg, 60%).
[0675] ESI-MS: [2M-H].sup.-: 483
[0676] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 7.65 (dt, 1H),
7.21 (d, J=7.6 Hz, 1H), 7.05 (d, J=8.0 Hz, 1H), 2.72-2.66 (t, 2H),
0.96-0.91 (t, 2H).
Example 51
Disodium;4,4-dihydroxy-8-(methanesulfonamido)-5-oxa-4-boranuidabicyclo[4.4-
.0]deca-1(6),7,9-triene-7-carboxylate
##STR00133##
[0677] Step 1: Synthesis of 51A
[0678] A mixture of 13G (700 mg, 1.29 mmol, 1.0 eq) and Pd/C (150
mg, 10%) in MeOH (7 mL) was stirred under 1 atm hydrogen atmosphere
at room temperature for 3 hours. The mixture was filtered and the
filtrate was concentrated in vacuo. The residue was purified by
flash chromatography on silica (PE/EA) to give 51A (320 mg,
48%).
[0679] ESI-MS: [M+H].sup.+: 516
Step 2: Synthesis of 51B
[0680] To a mixture of 51A (200 mg, 0.388 mmol, 1.0 eq) in
Pyridine/DCM (3 mL/1 mL) was added MsCl (106 mg, 0.931 mmol, 2.4
eq) dropwise at 0.degree. C. The mixture was stirred at room
temperature for 3 hours before it was concentrated in vacuo. The
residue was purified by prep-TLC to give 51B (110 mg, 48%).
[0681] ESI-MS: [M+H].sup.+:594
Step 3: Synthesis of 51
[0682] To a solution of 51B (100 mg, 0.169 mmol, 1.0 eq) in dioxane
(2 mL) was added i-BuB(OH).sub.2 (34.2 mg, 0.338 mmol, 2.0 eq) and
concentrated HCl (2 mL). The reaction mixture was stirred at room
temperature for 1 hour. The reaction mixture was concentrated in
vacuo, and the residue was dissolved in H.sub.2O/MeCN. The
resulting solution was adjusted to pH=12 and purified by prep-HPLC
(C18, neutral) to give 51 (22 mg, 46%) as white solid.
[0683] ESI-MS: [2M-H].sup.-: 569
[0684] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 6.80 (d, J=8.0
Hz, 1H), 6.68 (d, J=8.0 Hz, 1H), 2.84 (s, 3H), 2.62-2.58 (m, 2H),
0.48-0.43 (m, 2H).
Example 52
Disodium;4,4-dihydroxy-8-(sulfamoylamino)-5-oxa-4-boranuidabicyclo[4.4.0]d-
eca-1(6),7,9-triene-7-carboxylate
##STR00134##
[0685] Step 1: Synthesis of 52A
[0686] To a mixture of 51A (130 mg, 0.252 mmol, 1.0 eq) in pyridine
(3 mL) was added ClSO.sub.2NHBoc (81.3 mg, 0.378 mmol, 1.5 eq) at
0.degree. C., The mixture was stirred at room temperature for 1
hour before it was concentrated in vacuo. The residue was purified
by prep-TLC to give 52A (100 mg, 57%).
[0687] ESI-MS: [M+H].sup.+: 695
Step 2: Synthesis of 52
[0688] To a solution of 52A (80 mg, 0.115 mmol, 1.0 eq) in dioxane
(2 mL) was added i-BuB(OH).sub.2 (23.3 mg, 0.23 mmol, 2.0 eq) and
concentrated HCl (1 mL). The reaction mixture was stirred at rt for
1 hour. The reaction mixture was concentrated in vacuo, and the
residue was dissolved in H.sub.2O/MeCN. The resulting solution was
adjusted to pH=12 and purified by prep-HPLC (C18, neutral) to give
52 (10 mg, 30%).
[0689] ESI-MS: [2M-H].sup.-: 571
[0690] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 6.75 (d, J=7.6
Hz, 1H), 2.59-2.55 (m, 2H), 2.04-2.03 (m, 2H), 0.48-0.44 (m,
2H).
Example 53
Trisodium;4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-trien-
e-7,8-dicarboxylate
##STR00135##
[0691] Step 1: Synthesis of 53A
[0692] A solution of compound 19B (330 mg, 0.624 mmol, 1.0 eq),
NaClO.sub.2 (113 mg, 1.25 mmol, 2 eq) and NH.sub.2SO.sub.3H (122
mg, 1.25 mmol, 2 eq) in dioxane/H.sub.2O (9 mL/3 mL) was stirred at
0.degree. C. for 2 hours. The reaction solution was concentrated
under reduced pressure and the residue was purified by column
chromatography (PE/EA=1:1) to give compound 53A (200 mg, 63%).
[0693] ESI-MS: [M+H].sup.+:545
Step 2: Synthesis of 53
[0694] To a solution of compound 53A (200 mg) and i-BuB(OH).sub.2
(75 mg, 0.73 mmol, 2 eq) in dioxane (3 mL) was added concentrated
HCl (3 mL) at room temperature. The reaction mixture was stirred at
rt for 1 hour. The reaction mixture was concentrated in vacuo, and
the residue was dissolved in H.sub.2O/MeCN. The resulting solution
was adjusted to pH=12 and purified by prep-HPLC (C18, neutral) to
give 53 (11 mg, 10%) as white solid.
[0695] ESI-MS: [M+H].sup.+: 237
[0696] .sup.1H NMR (CD.sub.3OD, 400 MHz): .delta. 7.021-7.003 (d,
J=7.2, 1 H), 6.810-6.791 (d, J=7.6, 1 H), 2.647-2.614 (t, J=6.6, 2
H), 0.524-0.491 (t, J=7.0, 2 H)
Example 54
Disodium;8-cyano-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,-
9-triene-7-carboxylate
##STR00136##
[0697] Step 1: Synthesis of 54A
[0698] To a solution of compound 19B (1.0 g, 1.89 mmol, 1.0 eq) in
ethanol (15 mL) was added hydroxylamine (160 mg, 2.84 mmol, 1.5
eq). The mixture was stirred at room temperature for 2 hours before
it was concentrated under reduced pressure. The crude product 54A
(1.01 g) was used directly for next step.
[0699] ESI-MS: [M+H].sup.+: 544
Step 2: Synthesis of 54B
[0700] To a solution of compound 54A (1.01 g, 1.86 mmol, 1.0 eq)
and PPh.sub.3 (1.07 g, 4.1 mmol, 2.2 eq) in DCM (20 mL) was added
I.sub.2 (1.04 g, 4.1 mmol, 2.2 eq) at room temperature. The mixture
was stirred at 40.degree. C. overnight before it was concentrated
under reduced pressure. The residue was purified by column
chromatography (PE/EA=30:1 to 7:1) to give compound 54B (55 mg,
7%).
[0701] ESI-MS: [M+H].sup.+: 526
Step 3: Synthesis of 54
[0702] To a solution of the compound 54B (55 mg) in dioxane (2 mL)
and concentrated HCl (2 mL) was added i-BuB(OH).sub.2 (22 mg, 0.21
mmol, 2.0 eq). The reaction mixture was stirred at rt for 1 hour.
The reaction mixture was concentrated in vacuo, and the residue was
dissolved in H.sub.2O/MeCN. The resulting solution was adjusted to
pH=12 and purified by prep-HPLC (C18, neutral) to give 54 (7 mg,
20%) as white solid.
[0703] ESI-MS: [M+H].sup.+: 218
[0704] .sup.1H NMR (CD.sub.3OD, 400 MHz): .delta. 7.281-7.263 (d,
J=7.2, 1H), 6.992-6.975 (d, J=6.8, 1H), 2.724-2.706 (t, 2H),
2.220-2.183 (t, 2H), 2.015-1.998 (t, 2H), 0.897-0.863 (t, 2H),
0.510-0.486 (t, 2H).
Example 55
Disodium;4,4-dihydroxy-8-(methoxyiminomethyl)-5-oxa-4-boranuidabicyclo[4.4-
.0]deca-1(6),7,9-triene-7-carboxylate
##STR00137##
[0705] Step 1: Synthesis of 55A
[0706] To the solution of compound 19B (300 mg, 0.57 mmol, 1.0 eq)
in ethanol (10 mL) was added methoxyamine hydrochloride salt. After
2 hours at room temperature, the reaction mixture was concentrated
under reduced pressure. The crude intermediate 55A (300 mg) was
used directly for next step without purification.
[0707] ESI-MS: [M+H].sup.+: 558
Step 2: Synthesis of 55
[0708] To a solution of the crude 55A (300 mg) in dioxane (5 mL)
and concentrated HCl (1 mL) was added i-BuB(OH).sub.2 (82 mg, 0.81
mmol, 1.5 eq). The reaction mixture was stirred at rt for 1 hour.
The reaction mixture was concentrated in vacuo, and the residue was
dissolved in H.sub.2O/MeCN. The resulting solution was adjusted to
pH=12 and purified by prep-HPLC (C18, neutral) to give 55 (15 mg,
20%) as white solid.
[0709] ESI-MS: [M+H].sup.+: 250
Example 56
Disodium;8-(difluoromethoxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]-
deca-1(6),7,9-triene-7-carboxylate
##STR00138##
[0710] Step 1: Synthesis of 56B
[0711] A solution of compound 56A (prepared from 15C using
procedure as in step 6 of Example 15) (6.00 g, 15.4 mmol, 1.0 eq)
and potassium carbonate (2.13 g, 15.4 mmol, 1.0 eq) in anhydrous
DMF (15 mL) was cooled to -78.degree. C. and bubbled with
bromodifluoromethane (.about.6 g, .about.3 eq). The reaction
mixture was warmed up and then heated up to 80.degree. C. After 2.5
hours, the mixture was cooled down and partitioned in ethyl acetate
and 0.1 N aqueous HCl. The organic layer was washed with water
(2.times.10 mL) and dried over Na.sub.2SO.sub.4. The solvent was
removed under reduced pressure, and the residue was purified by
column chromatography (hexanes/EtOAc=15:1) to give compound 56B
(2.2 g, 32%) as slight yellow oil.
[0712] H NMR (CDCl.sub.3, 300 MHz): .delta.7.60 (d, 1H), 7.01 (d,
1H), 6.49 (t, 1H), 1.56 (s, 18H).
Step 2: Synthesis of 56C
[0713] The mixture of compound 56B (600 mg, 1.37 mmol, 1.0 eq),
potassium vinyltrifluoroborate (457 mg, 3.43 mmol, 2.5 eq),
PdCl.sub.2 (dppf) (57 mg, 0.07 mmol, 0.05 eq) and triethylamine
(0.27 mL, 2.06 mmol, 1.5 eq) in 2-propanol (25 mL) was degassed and
filled with N.sub.2 (3.times.), then was heated to reflux. After
refluxing for 18 hours, the mixture was cooled down and filtered.
The solution was concentrated under reduced pressure, and the
residue was purified by column chromatography (hexanes/EtOAc=6:1)
to give compound 56C (478 mg, 90%) as slight yellow solid. HNMR
(CDCl.sub.3, 300 MHz): .delta.7.55 (d, 1H), 7.15 (d, 1H), 6.72 (dd,
1H), 6.50 (t, 1H), 5.75 (d, 1H), 5.39 (d, 1H), 1.56 (s, 18H).
Step 3: Synthesis of 56D
[0714] The catalyst [IrCl(cod)].sub.2 (16 mg, 0.025 mmol, 0.02 eq)
and ligand dppe (20 mg, 0.049 mmol, 0.04 eq) were dissolved in
dichloromethane (4 mL) under N.sub.2 atmosphere and stirred at room
temperature. After 5 minutes, pinBH (0.23 mL, 1.49 mmol, 1.2 eq)
and the solution of compound 56C (478 mg, 1.24 mmol, 1.0 eq) were
added under N.sub.2 atmosphere. After stirring at room temperature
for 18 hours, the reaction mixture was concentrated under reduced
pressure, and the residue was purified by column chromatography
(hexanes/EtOAc=10:1) to give compound 56D (315 mg, 49%) as slight
yellow solid.
[0715] ESI-MS: [M+H].sup.+: 515
Step 4: Synthesis of 56
[0716] To the mixture of compound 56D (315 mg, 0.612 mmol, 1.0 eq)
and triethylsilane (712 mg, 6.12 mmol, 10 eq) was added TFA (5 mL)
at room temperature. After 3 hours, the mixture was concentrated
and re-dissolved in MeCN/H.sub.2O (5 mL, 1/1, v/v) and adjusted to
PH=9 with 1 N NaOH solution. The solution was stirred at room
temperature for 20 hours and then purified by prep-HPLC (C18,
neutral) to give 56 Na salt (43 mg) as white solid.
[0717] H NMR (D.sub.2O, 300 MHz): .delta.6.83 (d, J=8.4 Hz, 1H),
6.50 (t, J=74.7 Hz, 1H), 6.36 (d, J=8.4 Hz, 1H), 2.47 (t, J=7.5 Hz,
2H), 0.37 (t, J=7.2 Hz, 2H).
[0718] ESI-MS: [2M-H].sup.-: 515
Example 57
Disodium;8-ethoxy-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-(6),7,-
9-triene-7-carboxylate
##STR00139##
[0719] Step 1: Synthesis of 57A
[0720] To the solution of compound 56A (1.0 g, 2.6 mmol, 1.0 eq)
and potassium carbonate (524 mg, 3.8 mmol, 1.5 eq) in anhydrous DMF
(15 mL) was added iodoethane (2.1 mL, 26 mmol, 10 eq). After 18
hours at room temperature, the reaction mixture was partitioned in
ethyl acetate and 0.1 N aqueous HCl. The organic layer was washed
with water (2.times.) and dried over Na.sub.2SO.sub.4. The solvent
was removed under reduced pressure, and the residue was purified by
column chromatography (hexanes/EtOAc=20:1 to 5/1) to give compound
57A (1.06 g, 98%) as slight yellow oil.
[0721] .sup.1H NMR (CDCl.sub.3, 300 MHz): .delta.7.48 (d, J=9.0 Hz,
1H), 6.68 (d, J=9.0 Hz, 1H), 4.03 (q, J=7.2 Hz, 2H), 1.56 (s, 18H),
1.38 (t, J=7.2 Hz, 3H).
Step 2: Synthesis of 57B
[0722] To the mixture of Zn powder (830 mg, 12.7 mmol, 5.0 eq) and
7E (55 mg, 0.2 mmol) in anhydrous THF (2.0 mL) was added DIBAL-H
(0.26 mL, 0.26 mmol, 1.0 M in hexanes, 0.05 eq) at room
temperature. The mixture was stirred at 30.degree. C. for 5 min,
then more (+)-pinanediolborate methylenebromide (1.38 g, 5.0 mmol,
2.0 eq) in anhydrous THF (3.0 mL) was added drop-wise into the
mixture over 10 minutes. The reaction mixture was stirred at
50.degree. C. for 2 hours before it was cooled to room temperature
and settled down. The top clear solution was transferred into a
mixture of compound 57A (1.06 g, 2.5 mmol, 1.0 eq) and
Pd(t-Bu.sub.3P).sub.2 (64 mg, 0.13 mmol, 0.05 eq) in THF (10 mL)
under N.sub.2 atmosphere. The mixture was stirred at room
temperature for 2.5 hours before it was concentrated in vacuo. The
obtained residue was purified by column chromatography
(hexanes/EtOAc=10:1 to 5/1) to give compound 57B (1.25 g, 97%) as
slight yellow oil.
[0723] ESI-MS: [M+H].sup.+: 531
Step 3: Synthesis of 57C
[0724] To the solution of compound 57B (320 mg, 0.61 mmol, 1.0 eq)
and chloroiodomethane (0.09 mL, 1.2 mmol, 2.0 eq) in THF (2.0 mL)
was added n-BuLi (0.36 mL, 2.5 M in hexanes, 0.9 mmol, 1.5 eq)
slowly at -78.degree. C. under N.sub.2 atmosphere. The resulting
solution was slowly warmed up to room temperature in 18 hours
before it was concentrated under reduced pressure. The obtained
residue was purified by column chromatography (hexanes/EtOAc=10:1)
to give compound 57C (250 mg, 76%) as slight yellow oil.
[0725] ESI-MS: [M+H].sup.+: 545
Step 4: Synthesis of 57
[0726] To the mixture of compound 57C (75 mg, 0.14 mmol, 1.0 eq)
and i-BuB(OH).sub.2 (42 mg, 0.42 mmol, 3.0 eq) in hexanes (3.0 mL)
and MeOH (3.0 mL) was added concentrated HCl (2 drops) at room
temperature. After 20 hours, the two layers were separated and the
MeOH layer was washed with hexanes (2.times.). The MeOH layer was
concentrated and was added triethylsilane (162 mg, 1.4 mmol, 10 eq)
and TFA (3 mL) at room temperature. After 3 hours, the reaction
mixture was concentrated and re-dissolved in MeCN/H.sub.2O (5 mL,
1/1, v/v) and adjusted to PH=10 with 1 N NaOH solution. The
solution was stirred at room temperature for 20 hours and then
purified by prep-HPLC (C18, neutral) to give 57 Na salt (31 mg) as
white solid.
[0727] .sup.1H NMR (D.sub.2O, 300 MHz): .delta.6.67 (d, J=8.1 Hz,
1H), 6.15 (d, J=8.4 Hz, 1H), 3.98 (q, 2H), 2.55 (t, 2H), 1.31 (t,
3H), 0.42 (t, 2H).
[0728] ESI-MS: [M-H.sub.2O+H].sup.+: 219
Example 58
8-Fluoro-2-hydroxy-3,5-dihydro-1,4,2-benzodioxaborepine-9-carboxylic
acid
##STR00140##
[0729] Step 1: Synthesis of 58B
[0730] The mixture of compound 58A (prepared from of 36A (WO
15179308) via hydrolysis as in synthesis of 36D and acetonide
formation as in 7J) (4.4 g, 16 mmol, 1.0 eq), potassium
vinyltrifluoroborate (3.2 g, 24 mol, 1.5 eq), TEA (4.86 g, 48 mol,
3.0 eq) and PdCl.sub.2 (dppf) (653 mg, 0.8 mmol, 0.05 eq) in
dioxane (30 mL) was stirred at 100.degree. C. for 12 hours under
N.sub.2 atmosphere. The mixture was concentrated and purified by
column chromatography (hexanes/EtOAc=5:1 to 1/1) to give compound
58B (1.6 g, 45% yield) as yellow solid.
Step 2: Synthesis of 58C
[0731] To a solution of compound 58B (1.6 g, 7.2 mmol, 1.0 eq) in
DCM (30 mL) was bubbled with O.sub.3 at -78.degree. C. until the
solution turned to slightly blue. The nitrogen was bubbled in to
remove the color. The colorless solution was added dimethylsulfide
(3 mL) and slowly warmed up to room temperature in 6 hours. The
solvent was removed under reduced pressure and the residue was
purified by column chromatography (PE/EA=3:1) to give compound 58C
(1.0 g, 62%) as yellow oil.
Step 3: Synthesis of 58D
[0732] To a solution of compound 58C (1.0 g, 4.46 mmol, 1.0 eq) in
anhydrous THF (20 mL) was added NaBH.sub.4 (254 mg, 6.7 mmol, 1.5
eq) at 0.degree. C. The mixture was stirred at room temperature for
1 hour before it was quenched with water. The reaction mixture was
concentrated under reduced pressure, and the residue was purified
by column chromatography (PE/EA=1:1) to give compound 58D (650 mg,
64%) as yellow solid.
[0733] .sup.1H NMR (CDCl.sub.3, 400 MHz): .delta.7.62 (dd, 1H),
6.85 (dd, 1H), 4.66 (s, 2H), 1.76 (s, 6H).
Step 4: Synthesis of 58E
[0734] To the solution of compound 58D (192 mg, 0.85 mmol, 1.0 eq)
in anhydrous THF (4 mL) was added a suspension of NaH (51 mg, 60%
in mineral oil, 1.28 mmol, 1.5 eq) in THF (2 mL) dropwise at
0.degree. C. under nitrogen atmosphere. After 10 minutes, a
solution of (+)-pinanediolborate methylenebromide (464 mg, 1.7
mmol, 2.0 eq) in THF (4 mL) was added into above solution and the
reaction mixture was slowly heated up to 50.degree. C. After 3
hours, the reaction was quenched with saturated aqueous NH.sub.4Cl
and extracted with ethyl acetate. The organic layer was dried over
Na.sub.2SO.sub.4. The solvent was removed under reduced pressure,
and the residue was purified by column chromatography
(hexanes/EtOAc=20:1 to 5/1) to give compound 58E (102 mg, 29%) as
colorless oil.
[0735] ESI-MS: [M+H].sup.+: 419
Step 2: Synthesis of 58
[0736] The mixture of compound 58E (85 mg, 0.20 mmol, 1.0 eq) in
dioxane (0.5 mL) and 3N NaOH (0.5 mL) was stirred at room
temperature for 2 hours, LCMS indicating the disappearance of
starting material. To this mixture was then added 5N HCl (0.7 mL)
and i-BuB(OH).sub.2 (61 mg, 0.6 mmol, 3.0 eq). After overnight at
room temperature, the reaction mixture was concentrated in vacuo
and the residue was purified by prep-HPLC (C18, acetonitrile and
water as mobile phases, 0.1% HCOOH) to give 58 (8.7 mg) as white
solid.
[0737] .sup.1H NMR (CD.sub.3OD, 300 MHz): .delta.7.53 (dd, 1H),
6.64 (dd, 1H), 4.48 (s, 2H), 3.30 (s, 2H).
[0738] ESI-MS: [3M-2H.sub.2O--H].sup.-: 641
Example 59
Disodium;4,4-dihydroxy-5-oxa-9-aza-4-boranuidabicyclo[4.4.0]deca-1(6),7,9--
triene-7-carboxylate
##STR00141##
[0739] Step 1: Synthesis of 59B
[0740] To the solution of compound 59A (J. Med. Chem., 2008, 51,
5330-41) (2.9 g, 13.3 mmol, 1.0 eq) in TFAA (6 mL) and TFA (12 mL)
was added acetone (5 mL) dropwise at room temperature. After 1
hour, the reaction mixture was added DMF (15 mL) to give a clear
brown solution, followed by more acetone (5 mL). After stirred at
room temperature for 18 hours, the mixture was concentrated in
vacuo and the residue was partitioned in EtOAc/hexanes (3/1, v/v)
and saturated NaHCO.sub.3. The organic layer was washed with water
(2.times.) and dried over Na.sub.2SO.sub.4. The solvent was removed
under reduced pressure, and the residue was purified by column
chromatography (hexanes/EtOAc=3:1 to 0/1) to give compound 59B (2.1
g, 61%) as yellow solid.
[0741] .sup.1H NMR (CDCl.sub.3, 300 MHz): .delta.8.99 (s, 1H), 8.80
(s, 1H), 1.83 (s, 6H).
Step 2: Synthesis of 59C
[0742] The mixture of compound 59B (820 mg, 3.18 mmol, 1.0 eq),
potassium vinyltrifluoroborate (554 mg, 4.13 mmol, 1.3 eq),
PdCl.sub.2 (dppf) (130 mg, 0.16 mmol, 0.05 eq) and triethylamine
(0.89 mL, 6.4 mmol, 2 eq) in 2-propanol (30 mL) was degassed and
filled with N.sub.2 (3.times.), then was heated to reflux. After
refluxing for 20 hours, the mixture was cooled down and filtered.
The solution was concentrated under reduced pressure, and the
residue was purified by column chromatography (hexanes/EtOAc=3/1 to
1/1) to give compound 59C (517 mg, 79%) as slight yellow solid.
[0743] .sup.1H NMR (CDCl.sub.3, 300 MHz): .delta.8.97 (s, 1H), 8.74
(s, 1H), 6.76 (dd, 1H), 5.95 (d, J=18.0 Hz, 1H), 5.50 (d, J=11.4
Hz, 1H), 1.78 (s, 6H).
Step 3: Synthesis of 59D
[0744] The catalyst [IrCl(cod)].sub.2 (24 mg, 0.036 mmol, 0.03 eq)
and ligand dppe (29 mg, 0.073 mmol, 0.06 eq) were dissolved in
dichloromethane (4 mL) under N.sub.2 atmosphere and stirred at room
temperature. After 5 minutes, pinBH (0.21 mL, 1.44 mmol, 1.2 eq)
and compound 59C (246 mg, 1.2 mmol, 1.0 eq) were added, and the
solution was flushed with N.sub.2 again. After stirring at room
temperature for 18 hours, the reaction mixture was concentrated
under reduced pressure, and the residue was purified by column
chromatography (hexanes/EtOAc=3/1 to 1/1) to give compound 59D (82
mg, 21%) as slight yellow solid.
[0745] ESI-MS: [M+H].sup.+: 334
Step 4: Synthesis of 59
[0746] The mixture of compound 59D (82 mg, 0.24 mmol, 1.0 eq) in
dioxane (0.5 mL) and 3N NaOH (0.5 mL) was stirred at room
temperature for 2 hours, LCMS indicating the disappearance of
starting material. The reaction mixture was concentrated in vacuo
and the residue was purified by prep-HPLC (C18, acetonitrile and
water as mobile phases, neutral) to give 59 Na salt (8.0 mg) as
off-white solid.
[0747] .sup.1H NMR (D.sub.2O, 300 MHz): .delta.8.05 (s, 1H), 7.86
(s, 1H), 2.59 (t, J=7.2 Hz, 2H), 0.41 (t, J=7.2 Hz, 2H).
[0748] ESI-MS: [M+H].sup.+: 194
Example 60
Disodium;3,3-dideuterio-4,4-dihydroxy-8-methoxy-5-oxa-4-boranuidabicyclo[4-
.4.0]deca-1(10),6,8-triene-7-carboxylate
##STR00142##
[0749] Step 1: Synthesis of 60B
[0750] To the solution of PPh.sub.3CD.sub.3I (896 mg, 2.2 mmol, 1.1
eq) in THF (15 mL) was added n-BuLi (0.84 mL, 2.5 M in hexanes, 2.1
mmol, 1.05 eq) dropwise in 5 minutes at -78.degree. C. After 1
hour, compound 60A (473 mg, 2.0 mmol, 1.0 eq) in THF (8 mL) was
slowly added into above reaction mixture. The reaction mixture was
slowly warmed up to room temperature and stirred for 1 hour. The
mixture was quenched with saturated NH.sub.4Cl and extracted with
EtOAc (2.times.). The organic layer was concentrated in vacuo and
the residue was purified by column chromatography
(hexanes/EtOAc=3:1 to 1/1) to give compound 60B (170 mg, 36%) as
white solid.
[0751] .sup.1H NMR (CDCl.sub.3, 300 MHz): .delta.7.65 (d, J=9.0 Hz,
1H), 6.80 (s, 1H), 6.64 (d, J=9.0 Hz, 1H), 3.97 (s, 3H), 1.73 (s,
6H).
Step 2: Synthesis of 60C
[0752] The mixture of compound 60B (155 mg, 0.66 mmol, 1.0 eq),
bis(pinacolato)diboron (192 mg, 0.76 mmol, 1.15 eq) and PPh.sub.3
(19 mg, 0.07 mmol, 0.11 eq) in methanol (2 mL) was added
K.sub.2HP.sub.4 (137 mg, 0.79 mmol, 1.2 eq), and then Cu.sub.2O
(7.5 mg, 0.05 mmol, 0.08 eq). The resulting mixture was flushed
with nitrogen and stirred at 40.degree. C. for 6 hours before it
was partitioned in EtOAc and 0.1 M K.sub.2HP.sub.4. The organic
layer was washed with 0.1 M K.sub.2HP.sub.4 and dried over
Na.sub.2SO.sub.4. The solution was concentrated under reduced
pressure, and the residue was purified by column chromatography
(hexanes/EtOAc=3/1 to 1/1) to give compound 60D (191 mg, 80%) as
white crystal.
[0753] ESI-MS: [M+H].sup.+: 365
Step 3: Synthesis of 60
[0754] The mixture of compound 60D (65 mg, 0.18 mmol, 1.0 eq) in
dioxane (0.4 mL) and 3N NaOH (0.4 mL) was stirred at room
temperature for 2 hours, LCMS indicating the disappearance of
starting material. The reaction mixture was concentrated in vacuo
and the residue was purified by prep-HPLC (C18, acetonitrile and
water as mobile phases, 0.1% HCOOH). The obtained solid was
dissolved in MeCN/H.sub.2O and was adjusted to PH=8 with 0.1 N
NaOH. Sodium salt of 60 was obtained as white solid (11 mg) after
lyophilization.
[0755] .sup.1H NMR (D.sub.2O, 300 MHz): .delta.6.78 (d, J=8.4 Hz,
1H), 6.22 (d, J=8.4 Hz, 1H), 3.59 (s, 3H), 2.43 (s, 2H).
[0756] ESI-MS: [M-H2O+H].sup.+: 207
Example 61
Disodium;
8-carbamoyl-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(-
6),7,9-triene-7-carboxylate
##STR00143##
[0757] Step 1: Synthesis of 61A
[0758] To a solution of compound 19B (300 mg, 0.57 mmol, 1.0 eq) in
ethanol (8.0 mL) was added hydroxyamine HCl salt (60 mg, 0.85 mmol,
1.5 eq). The mixture was stirred at room temperature for 2 hours
before it was concentrated under reduced pressure. The residue was
purified by prep-TLC to give compound 61A (200 mg, 65%).
[0759] ESI-MS: [M+H].sup.+: 544
Step 2: Synthesis of 61
[0760] To a solution of compound 61A (200 mg, 0.37 mmol, 1.0 eq) in
dioxane (2 mL) was added i-BuB(OH).sub.2 (75 mg, 0.74 mmol, 2.0 eq)
and concentrated HCl (2 mL). The reaction mixture was stirred at
room temperature for 3 hours. The reaction mixture was concentrated
in vacuo, and the residue was dissolved in H.sub.2O/MeCN. The
resulting solution was adjusted to pH=10 with 1N NaOH and purified
by prep-HPLC (C18, neutral) to give 61 Na salt (11 mg, 12%) as
white solid.
[0761] ESI-MS: [M+H].sup.+: 236
[0762] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 6.94 (d, J=7.6
Hz, 1H), 6.84 (d, J=7.6 Hz, 1H), 2.68-2.64 (m, 2H), 0.53-0.48 (m,
2H).
Example 62
Disodium;8-[4-(azetidin-1-yl)but-2-ynoxy]-4,4-dihydroxy-5-oxa-4-boranuidab-
icyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylate
##STR00144##
[0763] Step 1: Synthesis of 62A
[0764] To a solution of compound 15G (1.0 g, 1.9 mmol, 1.0 eq) in
DMF (15 mL) was added 1,4-dichlorobut-2-yne (490 mg, 4.0 mmol, 2.0
eq), K.sub.2CO.sub.3 (800 mg, 5.8 mmol, 3.0 eq) and NaI (290 mg,
1.9 mmol, 1.0 eq). The mixture was stirred at 80.degree. C. for 3
hours before it was concentrated under reduced pressure. The
residue was purified by column chromatography (hexanes/EtOAc=10/1
to 5/1) to give compound 62A (900 mg, 77%).
[0765] ESI-MS: [M+H].sup.+: 603
Step 2: Synthesis of 62B
[0766] To a solution of compound 62A (500 mg, 0.83 mmol, 1.0 eq) in
DMF (10 mL) was added azetidine (95 mg, 1.66 mmol, 2.0 eq) and
K.sub.2CO.sub.3 (458 mg, 3.3 mmol, 4.0 eq). The mixture was stirred
at 50.degree. C. for 2 before it was concentrated under reduced
pressure. The residue was purified by column chromatography
(hexanes/EtOAc=10/1 to 3/1) to give compound 62B (220 mg, 43%).
[0767] ESI-MS: [M+H].sup.+: 524
Step 3: Synthesis of 62
[0768] The mixture of compound 62B (200 mg, 0.38 mmol, 1.0 eq), TES
(0.5 mL) and i-BuB(OH).sub.2 (5 mg, 49 mmol, 2.0 eq) in 90% aqueous
TFA (1 mL) was stirred at room temperature for half hour before it
was concentrated in vacuo. The residue was dissolved in water/MeCN
and adjusted to PH=12 with 1N NaOH. The solution was purified by
prep-HPLC (C18, neutral) to give 62 sodium salt (56 mg, 51%) as
white solid.
[0769] ESI-MS: [M+H].sup.+: 316
[0770] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 6.69 (d, J=8.4
Hz, 1H), 6.34 (d, J=8.4 Hz, 1H), 4.68 (s, 2H), 3.31-3.29 (m, 4H),
3.27-3.25 (m, 2H), 2.58-2.53 (m, 2H), 2.07-2.02 (m, 2H), 0.44-0.42
(m, 2H).
Example 63
Disodium;4,4-dihydroxy-8-methoxy-5-oxa-9-aza-4-boranuidabicyclo[4.4.0]deca-
-1(6),7,9-triene-7-carboxylate
##STR00145## ##STR00146##
[0771] Step 1: Synthesis of 63B
[0772] To a solution of compound 63A (10 g, 68 mmol, 1.0 eq) in dry
THF (50 mL) was added freshly made LDA (121.6 mmol, in 60 mL THF,
1.8 eq) at -78.degree. C. The mixture was stirred at -78.degree. C.
for half hour before bubbled with dry CO.sub.2 gas. The resulting
mixture was slowly warmed up to room temperature and quenched with
1N HCl. The mixture was extracted with EA, and the organic layer
was dried over Na.sub.2SO.sub.4. After concentration under reduced
pressure, compound 63B (12.8 g, 97%) was obtained as off-white
solid without further purification.
Step 2: Synthesis of 63C
[0773] To a solution of compound 63B (1.0 g, 5.2 mmol, 1.0 eq) in
dry THF (6.0 mL) was added tert-butyl 2,2,2-trichloroacetimidate
(1.6 ml, 8.9 mmol, 1.7 eq) and BF.sub.3-Et.sub.2O (0.034 ml, 0.26
mmol, 0.05 eq) at 0.degree. C. The reaction solution was stirred at
room temperature for 2 hours under nitrogen atmosphere before it
was quenched with saturated aqueous NaHCO.sub.3. The mixture was
extracted with EA and the organic layer was dried over
Na.sub.2SO.sub.4. After concentration under reduced pressure,
compound 63C (1.44 g, 99%) was obtained as light yellow oil, which
was used for next step without further purification.
Step 3: Synthesis of 63D
[0774] To a solution of compound 63C (12.2 g, 49.5 mmol, 1.0 eq) in
DMF (20 mL) was added BnOH (5.14 ml, 49.5 mmol, 1.0 eq) at
0.degree. C., followed by NaH (2.6 g, 64.4 mmol, 1.3 q). The
mixture was stirred at 0.degree. C. for half hour under nitrogen
atmosphere before it was quenched with water. The mixture was
extracted with PE/EA (1:1) and dried over Na.sub.2SO.sub.4. After
concentration under reduced pressure, compound 63D (7.1 g, 50%) was
obtained as yellow oil, which was used for next step without
further purification.
Step 4: Synthesis of 63E
[0775] The suspension of compound 63D (4.2 g, 1.47 mmol, 1.0 eq)
and Pd/C (200 mg, 10%) in dry THF/MeOH (20 mL/10 mL) was stirred at
room temperature for 4 hours under 1 atm hydrogen atmosphere. The
reaction mixture was filtered and the filtrate was concentrated and
purified by column chromatography (PE/EA=5:1 to 1:1) to give
compound 63E (3.3 g, 98%).
Step 5: Synthesis of 63F
[0776] To a solution of compound 63E (1.5 g, 6.22 mmol, 1.0 eq) in
CHCl.sub.3 (5 mL) at 0.degree. C. was added NBS (1.22 g, 6.85 mmol,
1.1 eq). The mixture was stirred at room temperature for 2 hours
before it was concentrated. The residue was triturated with PE/EA
(20:1). After filtration, the filtrate was concentrated to give
compound 63F (1.98 g, 98%), which was directly used for next step
without further purification.
Step 6: Synthesis of 63G
[0777] To a solution of compound 63F (1.2 g, 2.93 mmol, 1.0 eq) in
DMF (10 mL) was added Cs.sub.2CO.sub.3 (607 mg, 4.4 mmol, 1.5 eq)
and BnBr (0.52 mL, 4.4 mmol, 1.5 eq). The mixture was stirred at
room temperature for 2 hours before it was concentrated. The
residue was purified by column chromatography (hexanes/EtOAc=20/1
to 5/1) to give compound 63G (1.0 g, 64%).
Step 7: Synthesis of 63H
[0778] To a solution of compound 63G (2.37 g, 5.97 mmol, 1.0 eq) in
MeOH (20 mL) was added MeONa (645 mg, 11.9 mmol, 2.0 eq). The
mixture was stirred at room temperature for 16 hours before it was
concentrated. The residue was purified by column chromatography
(hexanes/EtOAc=10/1) to give compound 63H (926 mg, 39%).
Step 8: Synthesis of 63I
[0779] To a solution of compound 63H (926 mg, 2.36 mmol, 1.0 eq) in
dioxane/H.sub.2O (12 mL/1.5 mL) was added potassium
vinyltrifluoroborate (631 mg, 4.71 mmol, 2.0 eq), Cs.sub.2CO.sub.3
(2.3 g, 7.07 mmol, 3.0 eq) and PdCl.sub.2 (dppf) (154 mg, 0.18
mmol, 0.08 eq). The mixture was stirred at 100.degree. C. for 3
hours under hydrogen atmosphere. The resulting mixture was filtered
and the filtrate was concentrated in vacuo. The residue was
purified by column chromatography (hexanes/EtOAc=4/1 to 2/1) to
give compound 631 (408 mg, 50%).
Step 9: Synthesis of 63J
[0780] To a solution of compound 631 (100 mg, 0.3 mmol, 1.0 eq) in
dichloromethane (10 mL) was added
4,4,5,5-tetramethyl-1,3,2-dioxaborolane (75 mg, 0.6 mmol, 2.0 eq),
[IrCl(COD)].sub.2 (6 mg, 0.01 mmol, 0.03 eq) and dppe (7 mg, 0.02
mmol, 0.06 eq). The mixture was stirred at 30.degree. C. for 12
hours under hydrogen atmosphere. The resulting mixture was
concentrated under reduced pressure to give crude compound 63J (120
mg) which was used directly for the next step without further
purification.
[0781] ESI-MS: [M+H].sup.+: 470
Step 10: Synthesis of 63K
[0782] The solution of crude compound 63J (210 mg, 0.45 mmol, 1.0
eq) and (+)-pinanediol (114 mg, 0.67 mmol, 1.5 eq) in THF (5 mL)
was stirred at room temperature for 12 hours. The resulting mixture
was concentrated and the residue was purified by prep-TLC
(hexanes/EtOAc=4/1) to give compound 63K (80 mg, 28%).
[0783] ESI-MS: [M+H].sup.+: 522
Step 11: Synthesis of 63L
[0784] The suspension of compound 63K (75 mg, 0.14 mmol, 1.0 eq)
and Pd/C (20 mg, 10%) in EtOAc (2 mL) was stirred at room
temperature for 12 hours under 1 atm hydrogen atmosphere. The
mixture was filtered and concentrated to give compound 63L (35 mg,
56%).
[0785] ESI-MS: [M+H].sup.+: 432
Step 12: Synthesis of 63
[0786] To the mixture of compound 63L (35 mg, 0.08 mmol, 1.0 eq)
and TES (1 mL) in TFA (90% aqueous, 3 mL) was added i-BuB(OH).sub.2
(17 mg, 0.16 mmol, 2 eq). The mixture was stirred at room
temperature for 1 hour before it was concentrated to dryness. The
residue was dissolved in H.sub.2O/MeCN and was adjusted to PH=12
with 1N NaOH. The resulting solution was purified by prep-HPLC
(C18, neutral) to give 63 Na salt (8 mg, 44%) as white solid.
[0787] ESI-MS: [M+H].sup.+: 242
[0788] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 7.47 (s, 1H),
3.81 (s, 3H), 2.62-2.50 (m, 2H), 0.53-0.45 (m, 2H).
Example 64
2-Hydroxy-7-[(1,3,4-thiadiazol-2-ylamino)methyl]-3,4-dihydro-1,2-benzoxabo-
rinine-8-carboxylic acid
##STR00147##
[0789] Step 1: Synthesis of 64A
[0790] The mixture of compound 19B (500 mg, 0.95 mmol, 1.0 eq), 4A
molecular sieves (250 mg), AcOH (0.3 mL) and
1,3,4-thiadiazol-2-amine (240 mg, 2.4 mmol, 2.5 eq) in DCE (10 mL)
was stirred at room temperature for 1 hour before NaBH(OAc).sub.3
(403 mg, 1.9 mmol, 2 eq) was added. The mixture was stirred at
70.degree. C. for 12 hours before it was filtered and concentrated
under reduced pressure. The residue was purified by column
chromatography (hexanes/EtOAc=4/1 to 2/1) to give compound 64A (150
mg, 26%).
[0791] ESI-MS: [M+H].sup.+: 614
Step 2: Synthesis of 64
[0792] To a solution of compound 64A (110 mg, 0.18 mmol, 1.0 eq)
and TES (1 mL) in TFA (90% aqueous, 3 mL) was added i-BuB(OH).sub.2
(38 mg, 0.37 mmol, 2 eq). The mixture was stirred at room
temperature for 2 hours before it was concentrated to dryness. The
residue was purified by prep-HPLC (C18, 0.1% HCOOH) to give 64 (13
mg, 24%) as white solid.
[0793] ESI-MS: [M+H].sup.+: 306
[0794] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 8.62 (d, J=14 Hz,
1H), 7.29-7.24 (m, 1H), 6.92-6.85 (m, 1H), 4.84-4.72 (m, 2H),
3.31-3.25 (m, 2H), 0.74-0.70 (m, 2H).
Example 65. Potentiation of Aztreonam
[0795] The potency and spectrum of .beta.-lactamase inhibitors
(BLIs) was determined by assessing their aztreonam potentiation
activity in a dose titration potentiation assay using strains of
various bacteria that are resistant to aztreonam due to expression
of various .beta.-lactamases. Aztreonam is a monobactam antibiotic
and is hydrolyzed by the majority of beta-lactamases that belong to
class A or C (but not class B or D). The potentiation effect was
observed as the ability of BLI compounds to inhibit growth in the
presence of sub-inhibitory concentration of aztreonam. MICs of test
strains varied from 64 .mu.g/mL to >128 .mu.g/mL. Aztreonam was
present in the test medium at 4 .mu.g/mL. Compounds were tested at
concentrations up to 40 .mu.g/mL. In this assay, potency of
compounds was reported as the minimum concentration of BLI required
to inhibit growth of bacteria in the presence of 4 .mu.g/mL of
aztreonam (MPC.sub.@4). Table 1B summarizes the BLI potency of
aztreonam potentiation (MPC.sub.@4) for various strains
overexpressing class A (ESBL and KPC), and class C beta-lactamases.
Aztreonam MIC for each strain is also shown.
TABLE-US-00001 TABLE 1 Activity of BLIs to potentiate aztreonam
against strains expressing class A and class C enzymes. Aztreonam
MIC (.mu.g/mL) >128 >128 64 128 AZT AZT >128 AZT AZT
>128 >128 MPC4 MPC4 AZT MPC4 MPC4 AZT 64 AZT CTX- CTX- MPC4
SHV- TEM- MPC4 AZT MPC4 M-14 M-15 SHV-5 12 10 KPC-2 MPC4 CMY-6
Compound KP1005 KP1009 ec308 KP1010 ec302 KP1004 ECL1002 EC1010 1 X
X X X X X Y X 2 X X X X X X X X 3 X X X X X X X X 4 Z Z Z Z Z Z Z Z
5 Z Y Z Y Z X Z Y 6 X X Y X X X X X 7 X X X X X X X X 8 X X X X X X
X X 9 Z Z Y Y Z X Y Y 10 Z Z Z Y Z Y Z Z 11 Y Y Y Y Y Y Y X 12 Z Y
Y Y Z Y Y Y 13 X X X X X X X X 14 Y Y Y X Y X Z Y 15 Y X X X X X X
X 16 X X Y X X X X X 17 Z Z Z Y Z X Z Y 18 Y X X X X X X X 19 Y X X
X Y X Y X 20 Y X X X X X X X 21 Y Y Y X Y X Y X 22 Z Y Y X X X Y X
23 Y X Y X X X X X 24 X X X X X X X X 25 Y X X X X X X X 26 Y Y Y X
Y X X X 27 Z Y Y X Y X X X 28 Z Y Y X X X Y X 29 Y Y X X Y X X X 30
Y X X X X X X X 31 Y Y X X Y X X X 32 Y X Y X X X X X 33 Z Z Z Z Z
Z Z Y 34 X X X X X X X X 35 X X X X X X X X 36 Y Y X X X X X X 37 Y
Y Y X Y X Y X 38 Z Z Z Z Z Y Z Y 39 X X X X X X X X 40 X X X X X X
X X 41 Y X X X X X X X 42 Z Z Y X Y Y Z Z 43 X X X X X X X X 44 Y Y
Y X Y X Y X 45 Z Z Y X Y X Y X 46 X X X X X X X X 47 X X X X X X X
X 48 Z Y Y X Y X Y X 49 X X X X X X X X 50 X X X X X X X X 51 Y Y X
X X Y Z Y 52 Z Y Y X Y X X X 53 Y Y Y X Y X X X 54 Z Z Z Z Z Z Z Y
55 Y X X X X X X X 56 X X X X X X X X 57 Y X X X X X X X 58 Z Z Z Y
Z X X X 59 Y Y Y X X X Z Y 60 X X X X X X X X 62 X X X X X X X X 64
Y X X X X X X X Tazobactam Y Y Y X X Z Z Y Clavulanic X X X X X Z Z
Z Acid X = MPC.sub.@4 .ltoreq.5 .mu.g/mL Y = 5 .mu.g/mL <
MPC.sub.@4 .ltoreq. 20 .mu.g/mL Z = MPC.sub.@4 >20 .mu.g/mL
Example 66. Potentiation of Tigemonam
[0796] Selected .beta.-lactamase inhibitors were also tested for
their ability to potentiate the monobactam tigemonam. The
potentiation effect was observed as the ability of BLI compounds to
inhibit growth in the presence of sub-inhibitory concentration of
tigemonam. MICs of test strains varied from 16 .mu.g/mL to >64
.mu.g/mL. Tigemonam was present in the test medium at 4 .mu.g/mL.
Compounds were tested at concentrations up to 40 .mu.g/mL. In this
assay potency of compounds was reported as the minimum
concentration of BLI required to inhibit growth of bacteria in the
presence of 4 .mu.g/mL of aztreonam (MPC.sub.@4). Table 2
summarizes the BLI potency of tigemonam potentiation (MPC.sub.@4)
for various strains overexpressing class A (ESBL) and class C
beta-lactamases. Tigemonam MIC for each strain is also shown.
TABLE-US-00002 TABLE 2 Activity of BLIs to potentiate tigemonam
against strains expressing class A and class C enzymes. Tigemonam
MIC (.mu.g/mL) >64 >64 >64 TIG TIG >64 >64 TIG 16
MPC.sub.4 MPC.sub.4 TIG TIG MPC.sub.4 32 TIG CTX-M- CTX-M-
MPC.sub.4 MPC.sub.4 TEM- TIG MPC4 14 15 SHV-5 SHV-12 10 MPC4 CMY-6
Compound KP1005 KP1009 ec308 KP1010 ec302 ECL1002 EC1010 1 X X X X
Y X X 2 X X X X X X X 3 X X X X Y X X 4 Z Z Z Z Z Y X 5 Z Z Z Y Y X
X 6 Y X X X Y X X 7 X X X X Y X X 8 X X X X X X X 9 Z Z Z Y Z X X
10 Z Z Z Z Z Y X 11 Z Y Y X Z X X 12 Z Z Z Y Z X X 13 X X X X X X X
14 Z Y Y Y Z X X 15 Z Y Y X Y X X 16 Y Y Y X Y X X 17 Z Z Z Y Z Y X
18 Z Z Z X X X X 19 Z Y Y X Z X X 20 Y Y Y X Y X X 21 Z Y Z Y Z X X
22 Z Y Y X Y X X 23 Z Y Y X Y X X 24 Z X X X X X X 25 Z X X X X X X
26 Z Y Y X Z X X 27 Z Z Z Y Z X X 28 Z Z X X Y X X 29 Y Z Y Y Z X X
30 Y Y Y X Y X X 31 Y Y X X Y X X 32 Y Y Y X Z X X 33 Z Z Z Z Z X X
34 Z X X X X X X 35 Y X X X X X X 36 Y Y Y X Z X X 37 Z Z Z Y Z X X
38 Z Z Z Z Z Y X 39 Y X X X Y X X 40 X X X X X X X 41 Y X X X Y X X
42 Z Z Z Y Z Y X 43 X X X X Y X X 44 Z Z Z Y Z X X 45 Z Z Z X Z X X
46 Z X X X Y X X 47 X X X X X X X 48 Z Z Z Y Z X X 49 X X X X Y X X
50 X X X X X X X 51 Z Z Y X Y X X 52 Z Z Z X Z X X 53 Z Z Z Y Z X X
54 Z Z Z Z Z Y X 55 Z Y X X Y X X 56 X X X X X X X 57 Y Y Y X Y X X
58 Z Z Z Z Z X X 59 Z Y Z Y Y Y X 60 X X X X X X X 62 Y Y Y X Y X X
64 Y Y Y X X X X Tazobactam Y Y X X X Y X Clavulanic X X X X X Z Z
Acid X = MPC.sub.@4 .ltoreq.5 .mu.g/mL Y = 5 .mu.g/mL <
MPC.sub.@4 .ltoreq. 20 .mu.g/mL Z = MPC.sub.@4 >20 .mu.g/mL
Example 67. Potentiation of Biapenem
[0797] .beta.-lactamase inhibitors were also tested for their
ability to potentiate the carbapenem biapenem against strains
producing class A (KPC) and class D (OXA-48) carbapenemases. The
potentiation effect was observed as the ability of BLI compounds to
inhibit growth in the presence of a sub-inhibitory concentration of
biapenem. Biapenem MIC of test strains were 16-32 .mu.g/mL.
Biapenem was present in the test medium at 1 .mu.g/mL. Compounds
were tested at concentrations up to 40 .mu.g/mL. In this assay
potency of compounds was reported as the minimum concentration of
BLI required to inhibit growth of bacteria in the presence of 1
.mu.g/mL of biapenem (MPC.sub.@1). Table 3 summarizes the BLI
potency of biapenem potentiation (MPC.sub.@1) for two strains
overexpressing class A (KPC) and class D (OXA-48) carbapenemases.
Biapenem MIC for each strain is also shown.
TABLE-US-00003 TABLE 3 Activity of BLIs to potentiate biapenem
against strains expressing class A (KPC) or class D (OXA-48)
carbapenemases. Biapenem MIC (.mu.g/mL) 32 16 BPM MPC.sub.1 BPM
MPC.sub.1 KP1004 OXA-48 Compound KPC-2 KP1086 1 X Y 2 X X 3 X X 4 X
Z 5 X X 6 X X 7 X X 8 X X 9 X X 10 X Y 11 X Y 12 X Y 13 X X 14 X X
15 X X 16 X Y 17 X X 18 X X 19 X X 20 X X 21 X X 22 X Y 23 X X 24 X
X 25 X X 26 X X 27 X Y 28 X X 29 X X 30 X Y 31 X X 32 X X 33 X X 34
X X 35 X X 36 X X 37 X X 38 X Y 39 X X 40 X X 41 X X 42 X X 43 X X
44 X X 45 X X 46 X Y 47 X X 48 X X 49 X X 50 X X 51 X X 52 X X 53 X
X 54 X Z 55 X X 56 X X 57 X X 58 X X 59 X X 60 X X 62 X X 64 X Y
Tazobactam Z Y Clavulanic Acid Y Z X = MPC.sub.@1 .ltoreq. 5
.mu.g/mL Y = 5 .mu.g/mL < MPC.sub.@1 .ltoreq. 20 .mu.g/mL Z =
MPC.sub.@1 > 20 .mu.g/mL
Example 68. Potentiation of Meropenem
[0798] .beta.-lactamase inhibitors were also tested for their
ability to potentiate the carbapenem meropenem against strains of
Acinetobacter baumannii producing class D (OXA-23 and OXA-72)
carbapenemases. The potentiation effect was observed as the ability
of BLI compounds to inhibit growth in the presence of a
sub-inhibitory concentration of meropenem. Meropenem MIC of test
strains were 32 to >64 .mu.g/mL. Meropenem was present in the
test medium at 8 .mu.g/mL. Compounds were tested at concentrations
up to 20 .mu.g/mL. In this assay potency of compounds was reported
as the minimum concentration of BLI required to inhibit growth of
bacteria in the presence of 8 .mu.g/mL of meropenem (MPC.sub.@8).
Table 4 summarizes the BLI potency of meropenem potentiation
(MPC.sub.@8) for two strains overexpressing OXA-72 and OXA-23
carbapenemases. Meropenem MIC for each strain is also shown.
TABLE-US-00004 TABLE 4 Activity of BLIs to potentiate meropenem
against strains expressing class D carbapenemases from
Acinetobacter baumannii Meropenem MIC (.mu.g/mL) >64 32 MPM
MPC.sub.8 MPM MPC.sub.8 AB1053 AB1054 Compound OXA-72 OXA-23 1 ND
ND 2 ND ND 3 Y Z 4 ND ND 5 Z Y 6 X X 7 X X 8 X X 9 Z Z 10 Z Z 11 X
Y 12 Y Y 13 X X 14 X X 15 X X 16 X Y 17 X X 18 X X 19 X X 20 Y Y 21
X X 22 Z Y 23 X X 24 X X 25 X X 26 X Y 27 Y Y 28 X X 29 X Y 30 X X
31 X X 32 X X 33 Y Y 34 X X 35 X X 36 Y X 37 Z Z 38 Z Z 39 X X 40 Z
Z 41 X X 42 Z Z 43 X X 44 X Y 45 X X 46 X Y 47 X X 48 X Y 49 Y Y 50
Y Y 51 Z Z 52 Z Z 53 X X 54 Z Z 55 Z Z 56 X X 57 X X 58 Z Z 59 Y Z
60 X X 62 X X 64 Y Y Tazobactam ND ND Clavulanic Acid ND ND ND =
Not determined. X = MPC.sub.@1 .ltoreq. 5 .mu.g/mL Y = 5 .mu.g/mL
< MPC.sub.@1 .ltoreq. 20 .mu.g/mL Z = MPC.sub.@1 > 20
.mu.g/mL
Example 69. Inhibitory Activity
[0799] K.sub.i values of inhibition of purified class A, C and D
enzymes were determined spectrophotometrically using nitrocefin as
reporter substrate. Purified enzymes were mixed with various
concentrations of inhibitors in reaction buffer and incubated for
10 min at room temperature. Nitrocefin was added and substrate
cleavage profiles were recorded at 490 nm every 10 sec for 10 min.
The results of these experiments are presented in Table 5. These
experiments confirmed that the described compounds are inhibitors
with a broad-spectrum of activity towards various
.beta.-lactamases.
TABLE-US-00005 TABLE 5 Activity of BLIs (Ki, uM) to inhibit
cleavage of nitrocefin by purified class A, C and D enzymes Ki Ki
Ki Ki Ki Ki (CTX- (SHV- (TEM- (KPC- Ki Ki (Pa- (OXA- (OXA- M-14,
12, 10, 2, (P99, AmpC, 48, 23, NCF), NCF), NCF), NCF), NCF), NCF),
NCF), NCF), Compound uM uM uM uM uM uM uM uM 1 X X X X X ND X ND 2
X X X X X ND X ND 3 X X X X X X X X 4 X X X X X ND X ND 5 X X X X X
ND X Y 6 X X X X X X X X 7 X X X X X X X X 8 X ND X X X X X X 9 X Y
Y X X X X Y 10 X Y Y X Y X X Z 11 X ND X X X X X X 12 X ND X X X Y
X Y 13 X ND X X X X X X 14 X ND X X Y Z X X 15 X X X X X X X X 16 X
ND X X X X X X 17 X Y Y X Y Y X X 18 X X X X X X X X 19 X ND X X X
X X X 20 X ND X X X X X X 21 X ND X X X X X X 22 X ND X X X X X X
23 X X X X X X X X 24 X X X X X X X X 25 X X X X X X X X 26 ND ND X
X X X X X 27 X ND X X X Y X X 28 X ND X X X X X X 29 X ND X X X X X
X 30 ND ND X X X X X X 31 ND ND X X X X X X 32 ND ND X X X X X X 33
X ND Z Z Y Z X X 34 X ND X X X X X X 35 X ND X X X X X X 36 ND ND X
X X X X X 37 ND ND X X X X X X 38 ND ND Y Y Z Z X Z 39 X ND X X X X
X X 40 ND ND X X X X X ND 41 X ND X X X X X X 42 X ND X X Y Y X Y
43 X ND X X X X X X 44 ND ND X X X X X X 45 X ND X X X X X X 46 X
ND X X X X X X 47 ND ND X X X X X X 48 X ND X X Y Y X X 49 X ND X X
X X X X 50 X ND X X X X X X 51 X ND X X X X X X 52 X ND X X X X X Y
53 X ND X X X X X X 54 ND ND Z Z Y Z X Y 55 X ND X X X X X X 56 X X
X X X X X X 57 X ND X X X X X X 58 X ND Y X X X X Y 59 X ND X X Z Y
X Z 60 X ND X X X X X X 62 X ND X X X X X X 64 X ND X X X X X X
Tazobactam X X X Z Z Y Y ND Clavulanic X X X Z Z ND Z ND Acid X =
K.sub.i .ltoreq.0.1 .mu.M Y = 0.1 .mu.M < K.sub.i .ltoreq. 1
.mu.M Z = K.sub.i >1 .mu.M ND = not determined
Example 70
MexAB-OprM Dependent Efflux of BLIs
[0800] Efflux of BLIs from Pseudomonas aeruginosa by the MexAB-OprM
efflux pump was also evaluated. The plasmid expressing the gene
encoding KPC-2 was introduced into two strains of P. aeruginosa,
PAM1032 and PAM1154 that overexpressed or lacked MexAB-OprM,
respectively. Due to expression of KPC-2 both strains became
resistant to biapenem. Biapenem is not affected by efflux in P.
aeruginosa and both strains had the same biapenem MIC of 32
.mu.g/ml. Potency of BLIs to potentiate biapenem in these strains
was determined. Potency was defined as the ability of BLI to
decrease MIC of biapenem 64-fold, from 32 .mu.g/ml to 0.5 .mu.g/ml,
or MPC.sub.64. The ratio of MPC.sub.64 values for each BLI in
PAM1032/KPC-2 (efflux proficient) and PAM1154/KPC-2 (efflux
deficient) was determined to generate the Efflux Index (EI).
TABLE-US-00006 TABLE 6 MexAB-OprM Dependent Efflux of BLIs from P.
aeruginosa PAM1032/ PAM1154/ KPC-2 KPC-2 Biapenem Biapenem Compound
MPC64 MPC64 EI 1 40 2.5 16 2 20 1.25 16 3 20 2.5 8 4 >80 5
>16 5 20 0.3 64 6 5 0.3 16 7 2.5 0.6 4 8 5 0.6 8
[0801] Although the invention has been described with reference to
embodiments and examples, it should be understood that numerous and
various modifications can be made without departing from the spirit
of the invention. Accordingly, the invention is limited only by the
following claims.
* * * * *