US2013274475A1PendingUtilityA1
Beta-lactamase inhibitors
Est. expiryJan 18, 2028(~1.5 yrs left)· nominal 20-yr term from priority
A61P 9/00A61P 31/00A61P 31/04A61P 43/00C07D 471/08A61K 2300/00C07D 211/78C07D 211/58C07D 487/08C07B 2200/13C07D 211/60C07D 519/00A61K 31/46A61K 31/407A61K 31/437A61K 31/198
40
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Claims
Abstract
Substituted bicyclic beta-lactams of Formula I: are β-lactamase inhibitors, wherein a, X, R 1 and R 2 are defined herein. The compounds and pharmaceutically acceptable salts thereof are useful in the treatment of bacterial infections in combination with β-lactam antibiotics. In particular, the compounds can be employed with a β-lactam antibiotics (e.g., imipenem, piperacillin, or ceftazidime) against microorganisms resistant to β-lactam antibiotics due to the presence of the β-lactamases.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
the bond identified as “a” is a single bond or a double bond;
when bond a is a single bond, X is:
(1) CH 2 ,
(2) CH 2 CH 2 ,
(3) CH 2 CH 2 CH 2 ,
(4) CH═CH,
(5) CH 2 —CH═CH, or
(6) CH═CH—CH 2 ;
when bond a is a double bond, X is:
(1) CH,
(2) CH—CH 2 , or
(3) CH—CH═CH;
R 1 is:
(1) C(O)N(R 3 )R 4 ,
(2) C(O)OR 3 , or
(3) C(O)OR 5 ;
R 2 is SO 3 M, OSO 3 M, SO 2 NH 2 , PO 3 M, OPO 3 M, CH 2 CO 2 M, CF 2 CO 2 M, or CF 3 ;
M is H or a pharmaceutically acceptable cation;
R 3 is:
(1) C 1-8 alkyl substituted with a total of from 1 to 4 substituents selected from the group consisting of (i) zero to 2 N(R A )R B , (ii) zero to 2 R C , and (iii) zero to 1 of AryA, HetA, or HetB,
(2) CycA,
(3) HetA,
(4) AryA,
(5) HetB, or
(6) AryB;
R 4 is H or C 1-8 alkyl optionally substituted with N(R A )R B ;
or alternatively, when R 1 is C(O)N(R 3 )R 4 , R 3 and R 4 together with the N atom to which they are both attached form a 4- to 9-membered, saturated monocyclic ring optionally containing 1 heteroatom in addition to the nitrogen attached to R 3 and R 4 selected from N, O, and S, where the S is optionally oxidized to S(O) or S(O) 2 ; wherein the monocyclic ring is optionally fused to, bridged with, or spiro to a 4- to 7-membered, saturated heterocyclic ring containing from 1 to 3 heteroatoms independently selected from N, O and S, where the S is optionally oxidized to S(O) or S(O) 2 , to form a bicyclic ring system, wherein the monocyclic ring or the bicyclic ring system so formed is optionally substituted with 1 or 2 substituents each of which is independently: (1) C 1-6 alkyl, (2) C 1-6 fluoroalkyl, (3) (CH 2 ) 1-2 G wherein G is OH, O—C 1-6 alkyl, O—C 1-6 fluoroalkyl, N(R A )R B , C(O)N(R A )R B , C(O)R A , CO 2 R A , or SO 2 R A , (4) O—C 1-6 alkyl, (5) O—C 1-6 fluoroalkyl, (6) OH, (7) oxo, (8) halogen, (9) N(R A )R B , (10) C(O)N(R A )R B , (11) C(O)R A , (12) C(O)—C 1-6 fluoroalkyl, (13) C(O)OR A , or (14) S(O) 2 R A ;
R 5 is C 1-8 alkyl substituted with 1 or 2 substituents each of which is independently N(R A )C(O)-AryA;
CycA is C 4-9 cycloalkyl which is optionally substituted with a total of from 1 to 4 substituents selected from zero to 2 (CH 2 ) n N(R A )R B and zero to 2 (CH 2 ) n R C ;
HetA is a 4- to 9-membered saturated or mono-unsaturated heterocyclic ring containing from 1 to 3 heteroatoms independently selected from N, O and S, wherein any ring S is optionally oxidized to S(O) or S(O) 2 and either 1 or 2 ring carbons are optionally oxidized to C(O); wherein the ring is optionally fused with a C 3-7 cycloalkyl; and wherein the optionally fused, saturated or mono-unsaturated heterocyclic ring is optionally substituted with a total of from 1 to 4 substituents selected from zero to 2 (CH 2 ) n N(R A )R B and zero to 2 (CH 2 ) n R C ;
AryA is phenyl which is optionally substituted with a total of from 1 to 4 substituents selected from zero to 2 (CH 2 ) n N(R A )R B and zero to 2 (CH 2 ) n R C ;
HetB is a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms selected from 1 to 3 N atoms, zero or 1 O atom, and zero or 1 S atom; wherein the heteroaromatic ring is optionally fused with a 5- to 7-membered, saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from N, O and S, wherein any ring S is optionally oxidized to S(O) or S(O) 2 and either 1 or 2 non-fused ring carbons are optionally oxidized to C(O); and wherein the optionally fused heteroaromatic ring is optionally substituted with a total of from 1 to 4 substituents selected from zero to 2 (CH 2 ) n N(R A )R B and zero to 2 (CH 2 ) n R C ;
AryB is a bicyclic ring system which is phenyl fused with a 5- to 7-membered saturated heterocyclic ring containing from 1 to 3 heteroatoms independently selected from N, O and S, wherein any ring S is optionally oxidized to S(O) or S(O) 2 , and wherein the bicyclic ring system is optionally substituted with a total of from 1 to 4 substituents selected from zero to 2 (CH 2 ) n N(R A )R B and zero to 2 (CH 2 ) n R C ;
each n is independently an integer which is 0, 1, 2, or 3;
each R A is independently H or C 1-8 alkyl;
each R B is independently H or C 1-8 alkyl;
each R C is independently C 1-6 alkyl, OH, O—C 1-8 alkyl, OC(O)—C 1-8 alkyl, C(═NH)NH 2 , NH—C(═NH)NH 2 , halogen, CN, C(O)R A , C(O)OR A , C(O)N(R A )R B , SO 2 R A , SO 2 N(R A )R B , pyridyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl;
and provided that:
(A) when R 1 is C(O)OR 3 and R 3 is AryA, then AryA is not (i) unsubstituted phenyl, (ii) phenyl substituted with NH 2 , (iii) phenyl substituted with OH, (iii) phenyl substituted with O—C 1-6 alkyl, (iv) phenyl substituted with one or more halogens, or (v) phenyl substituted with C 1-6 alkyl;
(B) when R 1 is C(O)OR 3 and R 3 is C 1-6 alkyl substituted with HetB, then HetB is not pyridyl;
(C) when R 1 is C(O)OR 3 and R 3 is CH 2 -AryA or CH 2 CH 2 -AryA, then AryA is not (i) unsubstituted phenyl, (ii) phenyl substituted with NH 2 , OH, O—C 1-6 alkyl, or C 1-6 alkyl, or (iii) phenyl substituted with one or more halogens;
(D) when R 1 is C(O)N(R 3 )R 4 , R 3 is AryA, CH 2 -AryA or CH 2 CH 2 -AryA, and R 4 is H or C 1-6 alkyl, then AryA is not unsubstituted phenyl, phenyl substituted with N(CH 3 ) 2 , or phenyl substituted with C(O)NH 2 ;
(E) when R 1 is C(O)N(R 3 )R 4 , R 3 is C 1-6 alkyl substituted with HetB, and R 4 is H or C 1-6 alkyl, then HetB is not pyridyl; and
(F) when R 1 is C(O)OR 3 and R 3 is C 1-6 alkyl substituted with R C , then R C is not C(O)NH 2 .
2 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein bond a is a single bond and X is —CH 2 — or —CH 2 CH 2 —.
3 . The compound according to claim 1 or claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 2 is OSO 3 M.
4 . The compound according to claim 6 , or a pharmaceutically acceptable salt thereof, wherein R 2 is OSO 3 H.
5 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is C(O)N(R 3 )R 4 .
6 . The compound according to claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 3 is HetA, CH 2 -HetA, CH 2 CH 2 -HetA, CH(CH 3 )-HetA, or CH(CH 2 OH)-HetA.
7 . The compound according to claim 6 , or a pharmaceutically acceptable salt thereof, wherein HetA is an optionally fused, saturated heterocyclic ring selected from the group consisting of azetidinyl, pyrrolidinyl, oxopyrrolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, 1,1-dioxidotetrahydrothiopyranyl, azepanyl, oxazepanyl, azocanyl, and azabicyclo[3.1.0]cyclohexyl, wherein the heterocyclic is optionally substituted with 1 or 2 (CH 2 ) n N(R A )R B and optionally substituted with 1 or 2 (CH 2 ) n R C .
8 . The compound according to claim 6 , or a pharmaceutically acceptable salt thereof, which is a compound selected from the group consisting of:
wherein T is H, C 1-3 alkyl, pyrrolidin-3-yl, piperidin-4-yl, (CH 2 ) 2-3 —O—C 1-3 alkyl, (CH 2 ) 2-3 OH, (CH 2 ) 2-3 F, (CH 2 ) 2-3 -piperidinyl, (CH 2 ) 2-3 -pyrrolidinyl; and T′ is H, Cl, Br, F, C 1-3 alkyl, O—C 1-3 alkyl, OH, NH 2 , N(H)—C 1-3 alkyl, or N(—C 1-3 alkyl) 2 .
9 . The compound according to claim 8 , or a pharmaceutically acceptable salt thereof, wherein T is H, CH 3 , pyrrolidin-3-yl, piperidin-4-yl, (CH 2 ) 2-3 OCH 3 , (CH 2 ) 2-3 OH, (CH 2 ) 2-3 F, (CH 2 ) 2-3 -piperidinyl, (CH 2 ) 2-3 -pyrrolidinyl; and T′ is H, F, O—C 1-3 alkyl, OH, NH 2 , N(H)CH 3 , N(CH 3 ) 2 .
10 . The compound according to claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 3 is HetB.
11 . The compound according to claim 12 , or a pharmaceutically acceptable salt thereof, wherein HetB is a heteroaromatic selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, thiazolyl, piperidothiazolyl, pyrrolidothiazolyl, piperidopyridyl, and pyrrolidopyridyl, wherein the heteroaromatic ring is optionally substituted with 1 or 2 (CH 2 ) n N(R A )R B and optionally substituted with 1 or 2 (CH 2 ) n R C groups.
12 . The compound according to claim 10 , or a pharmaceutically acceptable salt thereof, which is a compound selected from the group consisting of:
wherein V, V′, V″, Y, Y′ and Z are each independently selected from the group consisting of H, CH 3 , pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, CH 2 -pyrrolidinyl, CH 2 -piperidinyl, CH 2 -piperazinyl, CH 2 -morpholinyl, CH 2 -thiomorpholinyl, NH 2 , N(H)CH 3 , N(CH 3 ) 2 , CH 2 NH 2 , CH 2 N(H)CH 3 and CH 2 N(CH 3 ) 2 ; with the proviso that:
(i) at least one of V, V′ and V″ is H; and
(ii) at least one of Y and Y′ is H.
13 . The compound according to claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 3 is AryA.
14 . The compound according to claim 13 , or a pharmaceutically acceptable salt thereof, wherein AryA is phenyl which is optionally substituted with 1 or 2 substituents each of which is independently C 1-3 alkyl, CH 2 NH 2 , CH 2 N(H)—C 1-3 alkyl, CH 2 N(—C 1-3 alkyl) 2 , O—C 1-3 alkyl, Cl, Br, F, NH 2 , N(H)—C 1-3 alkyl, N(—C 1-3 alkyl) 2 , C(O)NH 2 , C(O)N(H)—C 1-3 alkyl, C(O)N(—C 1-3 alkyl) 2 , C(O)—C 1-3 alkyl, C(O)O—C 1-3 alkyl, OC(O)—C 1-3 alkyl, S(O) 2 —C 1-3 alkyl, S(O) 2 NH 2 , S( 0 ) 2 N(H)—C 1-3 alkyl, S(O) 2 N(—C 1-3 alkyl) 2 , pyrrolidinyl, piperidinyl, morpholinyl, CH 2 -pyrrolidinyl, CH 2 -piperidinyl, or CH 2 -morpholinyl.
15 . The compound according to claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 together with the N atom to which they are both attached form a heterocyclyl selected from the group consisting of:
wherein the ring is optionally substituted with 1 or 2 substitutents each of which is independently C 1-3 alkyl, CF 3 , CH 2 OH, CH 2 O—C 1-3 alkyl, CH 2 OCF 3 , CH 2 NH 2 , CH 2 N(H)—C 1-3 alkyl, CH 2 N(—C 1-3 alkyl) 2 , O—C 1-3 alkyl, OCF 3 , oxo, Cl, Br, F, NH 2 , N(H)—C 1-3 alkyl, N(—C 1-3 alkyl) 2 , C(O)NH 2 , C(O)N(H)—C 1-3 alkyl, C(O)N(—C 1-3 alkyl) 2 , C(O)—C 1-3 alkyl, C(O)O—C 1-3 alkyl, or S(O) 2 —C 1-3 alkyl.
16 . The compound according to claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 3 is AryB.
17 . The compound according to claim 16 , or a pharmaceutically acceptable salt thereof, wherein AryB is a bicyclic ring selected from the group consisting of 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 2,3-dihydro-1H-isoindolyl and 2,3-dihydro-1H-indolyl, wherein the bicyclic ring is optionally substituted with 1 or 2 substituents each of which is independently C 1-3 alkyl, CH 2 NH 2 , CH 2 N(H)—C 1-3 alkyl, CH 2 N(—C 1-3 alkyl) 2 , O—C 1-3 alkyl, Cl, Br, F, NH 2 , N(H)—C 1-3 alkyl, N(—C 1-3 alkyl) 2 , C(O)NH 2 , C(O)N(H)—C 1-3 alkyl, C(O)N(—C 1-3 alkyl) 2 , C(O)—C 1-3 alkyl, C(O)O—C 1-3 alkyl, OC(O)—C 1-3 alkyl, S(O) 2 —C 1-3 alkyl, S(O) 2 NH 2 , S(O) 2 N(H)—C 1-3 alkyl, S(O) 2 N(—C 1-3 alkyl) 2 , pyrrolidinyl, piperidinyl, morpholinyl, CH 2 -pyrrolidinyl, CH 2 -piperidinyl, or CH 2 -morpholinyl.
18 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is C(O)OR 3 .
19 . The compound according to claim 18 , or a pharmaceutically acceptable salt thereof, wherein R 3 is HetA, CH 2 -HetA, CH 2 CH 2 -HetA, or AryA.
20 . The compound according to claim 19 , or a pharmaceutically acceptable salt thereof, wherein:
HetA is a heterocyclic ring selected from the group consisting of azetidinyl, pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, azepanyl, oxazepanyl, oxazolidinyl, isoxazolidinyl, morpholinyl, and tetrahydropyranyl, wherein the heterocyclic ring is optionally substituted with 1 or 2 substituents each of which is independently C 1-3 alkyl, CH 2 NH 2 , CH 2 N(H)—C 1-3 alkyl, CH 2 N(—C 1-3 alkyl) 2 , O—C 1-3 alkyl, Cl, Br, F, NH 2 , N(H)—C 1-3 alkyl, N(—C 1-3 alkyl) 2 , C(O)NH 2 , C(O)N(H)—C 1-3 alkyl, C(O)N(—C 1-3 alkyl) 2 , C(O)—C 1-3 alkyl, C(O)O—C 1-3 alkyl, OC(O)—C 1-3 alkyl, S(O) 2 —C 1-3 alkyl, S(O) 2 NH 2 , S(O) 2 N(H)—C 1-3 alkyl, or S(O) 2 N(—C 1-3 alkyl) 2 ; and AryA is phenyl which is optionally substituted with 1 or 2 substituents each of which is independently C 1-3 alkyl, CH 2 NH 2 , CH 2 N(H)—C 1-3 alkyl, CH 2 N(—C 1-3 alkyl) 2 , O—C 1-3 alkyl, Cl, Br, F, NH 2 , N(H)—C 1-3 alkyl, N(—C 1-3 alkyl) 2 , C(O)NH 2 , C(O)N(H)—C 1-3 alkyl, C(O)N(—C 1-3 alkyl) 2 , C(O)—C 1-3 alkyl, C(O)O—C 1-3 alkyl, OC(O)—C 1-3 alkyl, S(O) 2 —C 1-3 alkyl, S(O) 2 NH 2 , S( 0 ) 2 N(H)—C 1-3 alkyl, S(O) 2 N(—C 1-3 alkyl) 2 , pyrrolidinyl, piperidinyl, morpholinyl, CH 2 -pyrrolidinyl, CH 2 -piperidinyl, or CH 2 -morpholinyl.
21 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is C(O)OR 5 .
22 . A compound according to claim 1 , which is a compound selected from the group consisting of:
(2S,5R)-7-oxo-N-piperidin-4-yl-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)—N-[(4S)-azepan-4-yl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)—N-[(4R)-azepan-4-yl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide; (2S,5R)-7-oxo-N-[(3R)-pyrrolidin-3-yl]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide; (2S,5R)-7-oxo-N-[(3S)-pyrrolidin-3-yl]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide; (2S,5R)—N-azocan-5-yl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)-7-oxo-N-pyridin-4-yl-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)—N-(2-methoxypyridin-4-yl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)—N-[2-(dimethylamino)pyridin-4-yl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)—N-[4-(aminomethyl)phenyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)-7-oxo-2-[(piperidin-4-ylamino)carbonyl]-1,6-diazabicyclo[3.2.1]octane-6-sulfonic acid; (4R,6S)-2-oxo-N-piperidin-4-yl-3-(sulfooxy)-1,3-diazabicyclo[2.2.1]-heptane-6-carboxamide; (4R,6S)-2-oxo-N-[(4S)-azepan-4-yl]-3-(sulfooxy)-1,3-diazabicyclo[2.2.1]-heptane-6-carboxamide; (4R,6S)-2-oxo-N-pyridin-4-yl-3-(sulfooxy)-1,3-diazabicyclo[2.2.1]heptane-6-carboxamide; and pharmaceutically acceptable salts thereof.
23 . A compound according to claim 1 , which is a compound selected from the group consisting of:
(2S,5R)-7-oxo-N-[(3R)-pyrrolidin-3-yl]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)—N-[(3R,4S)-3-fluoropiperidin-4-yl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)-7-oxo-6-(sulfooxy)-N-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)-7-oxo-N-(5-piperidin-4-ylpyridin-2-yl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; piperidin-4-ylmethyl(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate; Diastereomer 1 of (2S,5R)-7-oxo-N-[(3)-piperidin-3-yl]-6-(sulfooxy)-1,6-diaza-bicyclo[3.2.1]octane-2-carboxamide; Diastereomer 2 of (2S,5R)-7-oxo-N-[(3)-piperidin-3-yl]-6-(sulfooxy)-1,6-diaza-bicyclo[3.2.1]octane-2-carboxamide; (2S,5R)-7-oxo-N-azetidin-3-yl-6-(sulfooxy)-1,6-diaza-bicyclo[3.2.1]octane-2-carboxamide; (2S,5R)-7-oxo-N-[(3R)-pyrrolidin-3-yl]-6-(sulfooxy)-1,6-diaza-bicyclo[3.2.1]octane-2-carboxamide; (2S,5R)-7-oxo-N-[(4R)-azepan-4-yl]-6-(sulfooxy)-1,6-diaza-bicyclo[3.2.1]octane-2-carboxamide; (2S,5R)-7-oxo-N-[1-methylpiperidin-4-yl]-6-(sulfooxy)-1,6-diaza-bicyclo[3.2.1]octane-2-carboxamide; (2S,5R)-7-oxo-N-[(3S,4S)-3-fluoropiperidin-4-yl]-6-(sulfooxy)-1,6-diaza-bicyclo[3.2.1]octane-2-carboxamide or its 3R,4R diastereomer or a mixture thereof; (2S,5R)-7-oxo-N-[(3S,4R)-3-fluoropiperidin-4-yl]-6-(sulfooxy)-1,6-diaza-bicyclo[3.2.1]octane-2-carboxamide; (2S,5R)-7-oxo-N-[1,1-dioxidotetrahydro-2H-thiopyran-4-yl]-6-(sulfooxy)-1,6-diaza-bicyclo[3.2.1]octane-2-carboxamide; (2S,5R)—N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)—N-[(3R,4R)-4-aminopyrrolidin-3-yl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)—N-[(3R,4R)-4-hydroxypyrrolidin-3-yl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)—N-[(3R,4S)-4-hydroxypyrrolidin-3-yl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)—N-[(3R,4S)-4-fluoropyrrolidin-3-yl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)—N-[(3S,4R)-4-fluoropyrrolidin-3-yl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)-7-oxo-N-[(3S)-1-piperidin-4-yl-2-oxopyrrolidin-3-yl]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)-7-oxo-N-[(3R)-1-piperidin-4-yl-2-oxopyrrolidin-3-yl]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)—N-[(3S,4R)-3-fluoroazepan-4-yl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)—N-[(3R,4S)-3-fluoroazepan-4-yl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)—N-[(3-fluoroazetidin-3-yl)methyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)-7-oxo-N-(pyrrolidin-2-ylmethyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)-7-oxo-N-(piperidin-2-ylmethyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)-7-oxo-N-(piperidin-4-ylmethyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)—N-(2-hydroxy-1-piperidin-4-ylethyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)—N-[(2S)-1,4-oxazepan-2-ylmethyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)—N-[(2R)-1,4-oxazepan-2-ylmethyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)-7-oxo-N-(2-piperidin-4-ylethyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)-7-oxo-N-(2-piperidin-1-ylethyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)-7-oxo-N-(2-piperazin-1-ylethyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)—N-3-azabicyclo[3.1.0]hex-6-yl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)—N-methyl-7-oxo-N-piperidin-4-yl-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)-2-{[2-(aminomethyl)piperidin-1-yl]carbonyl}-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octan-7-one; (2S,5R)-2-[(4-aminopiperidin-1-yl)carbonyl]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octan-7-one; (2S,5R)-2-(piperazin-1-ylcarbonyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octan-7-one; (2S,5R)-2-(2,7-diazaspiro[3.5]non-2-ylcarbonyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octan-7-one; (2S,5R)-2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-ylcarbonyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octan-7-one; (2S,5R)-2-{[(3R)-3-aminopyrrolidin-1-yl]carbonyl}-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octan-7-one; (2S,5R)-2-{[(3S)-3-aminopyrrolidin-1-yl]carbonyl}-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octan-7-one; (2S,5R)-2-{[3-(dimethylamino)pyrrolidin-1-yl]-carb-onyl}-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octan-7-one; (2S,5R)—N-[4-(aminomethyl)phenyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)—N-[3-(aminomethyl)phenyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)—N-[2-(aminomethyl)phenyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)—N-{4-[(methylamino)methyl]phenyl}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)—N-{3-[(methylamino)methyl]phenyl}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)—N-{4-[(dimethylamino)methyl]phenyl}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)—N-{4-[(pyrrolidinyl)methyl]phenyl}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)-7-oxo-6-(sulfooxy)-N-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1,6-diazabicyclo-[3.2.1]octane-2-carboxamide; (2S,5R)—N-(2,3-dihydro-1H-isoindol-5-yl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)—N-(2,3-dihydro-1H-indol-5-yl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; 4-({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo-[3.2.1]oct-2-yl]carbonyl}amino)benzoic acid; (2S,5R)—N-[4-(aminocarbonyl)phenyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)—N-[4-(aminosulfonyl)phenyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)—N-[3-(aminocarbonyl)phenyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)-7-oxo-N-pyridin-3-yl-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)-7-oxo-N-pyridin-2-yl-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)—N-(2,6-dipyrrolidin-1-ylpyridin-4-yl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)—N-(6-aminopyridin-2-yl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)—N-[4-(dimethylamino)pyridin-2-yl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)—N-[4-(aminomethyl)pyridin-2-yl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)—N-[5-(aminomethyl)pyridin-2-yl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)—N-(4-piperidin-4-ylpyridin-2-yl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)—N-(6-piperidin-4-ylpyridin-2-yl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)—N-(5-piperazin-1-ylpyridin-2-yl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)—N-(5-morpholin-4-ylpyridin-2-yl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)—N-(5-pyrrolidin-1-yl-pyridin-2-yl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)-7-oxo-N-pyrazin-2-yl-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)-7-oxo-N-pyrimidin-4-yl-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)-7-oxo-N-(2-piperazin-1-ylpyrimidin-4-yl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)—N-(1-methyl-1H-imidazol-2-yl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)—N-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)-7-oxo-6-(sulfooxy)-N-1,3-thiazol-2-yl-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)-7-oxo-6-(sulfooxy)-N-(4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)—N-(6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (4S)-azepan-4-yl(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate; (4R)-azepan-4-yl(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate; piperidin-4-yl(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate; (3R)-pyrrolidin-3-yl(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate; (3S)-pyrrolidin-3-yl(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate; azetidin-3-yl(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate; (3 S,4R)-3-fluoropiperidin-4-yl(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate; (3R,4S)-3-fluoropiperidin-4-yl(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate; (3R,4R)-3-fluoropiperidin-4-yl(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate; (3S,4S)-3-fluoropiperidin-4-yl(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate; (3S,4S)-4-fluoropiperidin-3-yl(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate; (3S,4R)-4-fluoropiperidin-3-yl(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate; (3R,4S)-4-fluoropyrrolidin-3-yl(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate; (3S,4R)-4-fluoropyrrolidin-3-yl(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate; (3R,4R)-4-fluoropyrrolidin-3-yl(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate; (3S,4S)-4-fluoropyrrolidin-3-yl(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate; (4S)-isoxazolidin-4-yl(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate; (4R)-isoxazolidin-4-yl(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate; pyrazolidin-4-yl(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate; 2-aminoethyl(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate; 2-piperidin-1-ylethyl(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate; 2-piperidin-4-ylethyl(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate; (4-methylpiperidin-4-yl)methyl(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate; 1,4-oxazepan-2-ylmethyl(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate; 4-(aminomethyl)phenyl(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate; 2-{[3,4-bis(acetyloxy)benzoyl]amino}ethyl(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate; 2-{[3,4-bis(acetyloxy)benzoyl]amino}-1-{{[3,4-bis(acetyloxy)benzoyl]amino}methyl)ethyl(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate; and pharmaceutically acceptable salts thereof.
24 . A compound according to claim 1 , which is a compound selected from the group consisting of:
(2S,5R)-7-oxo-N-piperidin-4-yl-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)—N-[4-(aminomethyl)phenyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)-7-oxo-N-[(3R)-pyrrolidin-3-yl]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)-7-oxo-6-(sulfooxy)-N-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S,5R)-7-oxo-N-(5-piperidin-4-ylpyridin-2-yl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; piperidin-4-ylmethyl(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate; and pharmaceutically acceptable salts thereof.
25 . A compound according to claim 24 , which is (2S,5R)-7-oxo-N-piperidin-4-yl-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide or a pharmaceutically acceptable salt thereof.
26 . A compound according to claim 24 , which is (2S,5R)-7-oxo-N-[(3R)-pyrrolidin-3-yl]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide or a pharmaceutically acceptable salt thereof.
27 . A compound according to claim 1 , which is which is (2S,5R)-7-oxo-N-piperidin-4-yl-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide in the form of a crystalline monohydrate.
28 . A pharmaceutical composition which comprises a compound according to any one of claims 1 to 27 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
29 . A pharmaceutical composition according to claim 28 , which further comprises a beta-lactam antibiotic.
30 . A method for treating a bacterial infection which comprises administering to a subject in need of such treatment (i) a therapeutically effective amount of a compound according to any one of claims 1 to 27 , or a pharmaceutically acceptable salt thereof, optionally in combination with a beta-lactam antibiotic or (ii) a pharmaceutical composition according to any claim 27 or claim 28 .
31 . Use of a compound of a compound according to any one of claims 1 to 27 , or a pharmaceutically acceptable salt thereof, optionally in combination with a beta lactam antibiotic, in the manufacture of a medicament for treating a bacterial infection.
32 . A process for preparing a compound of Formula P-II:
which comprises:
(A) contacting a ketosulfoxonium glide of Formula P-I:
with an iridum, rhodium, or ruthenium catalyst to obtain Compound P-II;
wherein:
P G is an amine protective group selected from the group consisting of carbamates and benzylamines;
R U is CH 3 or phenyl;
R V is CH 3 or phenyl;
R 4 is H or C 1-4 alkyl;
T′ is H, Cl, Br, F, C 1-3 alkyl, O—C 1-3 alkyl, OH, NH 2 , N(H)—C 1-3 alkyl, or N(—C 1-3 alkyl) 2 ;
p is zero, 1 or 2; q is zero, 1, or 2; and p+q=zero, 1, 2, or 3.
33 . The process according to claim 32 , wherein P G is Cbz and Compound P-II is Compound P-IIa:
and wherein the process further comprises:
(B) treating Compound P-IIa with a reducing agent to obtain a compound of Formula P-III:
and
(C) contacting Compound P-III with a sulfonyl halide of formula R̂—SO 2 W in the presence of a tertiary amine base to obtain a compound of Formula P-IV:
wherein:
W is halogen; and
R̂ is:
(1) phenyl optionally substituted with from 1 to 3 substituents each of which is independently C 1-4 alkyl, C 1-4 haloalkyl, O—C 1-4 alkyl, O—C 1-4 haloalkyl, Cl, Br, F, or NO 2 ;
(2) C 1-4 alkyl; or
(3) C 1-4 haloalkyl.
34 . The process according to claim 33 , which further comprises:
(D) contacting Compound P-IV with N-Boc-O-benzylhydroxylamine in the presence of a base to obtain a compound of Formula P-V:
and
(E) treating Compound P-V with an acid to obtain a compound of Formula P-VI:
35 . The process according to claim 34 , which further comprises:
(F) contacting Compound P-VI with phosgene, diphosgene or triphosgene in the presence of a tertiary amine, and then adding an aqueous solution of acid to obtain a compound of Formula P-VII:
and
(G) contacting Compound P-VII with a source of hydrogen in the presence of a hydrogenolysis catalyst and in the presence of a Boc-producing agent to obtain a compound of Formula P-VIII:
36 . A process according to claim 32 , wherein the compound of Formula P-II is Compound p-2:
which comprises:
(A) contacting ketosulfoxonium ylide p-1:
with a catalyst selected from the group consisting of iridium cyclooctadiene chloride dimer, RuCl 2 (PPh 3 ), Ru(DMSO) 4 Cl 2 , and Rh 2 (TFA) 4 , to obtain Compound p-2.
37 . The process according to claim 36 , which further comprises:
(B) treating Compound p-2 with a reducing agent selected from the group consisting of Li borohydride, Na borohydride and K borohydride, to obtain Compound p-3:
and
(C) contacting Compound p-3 with a sulfonyl halide of formula R̂—SO 2 W in the presence of a tri-C 1-4 alkylamine base to obtain a compound of Formula p-4:
wherein W is chlorine; and
R̂ is methyl, chloromethyl, phenyl, 4-bromophenyl, 4-trifluoromethylphenyl, or 4-methylphenyl.
38 . The process according to claim 37 , which further comprises:
(D) contacting Compound p-4 with N-Boc-O-benzylhydroxylamine in the presence of a a base selected from the group consisting of Li t-butoxide, Na t-butoxide, K t-butoxide and K amyloxide to obtain Compound p-5:
and
(E) treating Compound p-5 with an acid selected from the group consisting of methanesulfonic acid, chloromethanesulfonic acid, p-toluenesulfonic acid and benzenesulfonic acid to obtain a compound of Formula p-6:
39 . The process according to claim 38 , which further comprises:
(F) contacting Compound p-6 with triphosgene in the presence of a tri-C 1-4 alkylamine base, and then adding an aqueous solution of phosphoric acid to obtain Compound p-7:
and
(G) contacting Compound p-7 with hydrogen in the presence of a Pd catalyst and a Boc-producing agent selected from the group consisting of di-t-butylcarbonate and Boc-ON to obtain Compound p-8:
40 . A compound selected from the group consisting of:
wherein:
P G is an amine protective group selected from the group consisting of carbamates and benzylamines;
R U is CH 3 or phenyl;
R V is CH 3 or phenyl;
R 4 is H or C 1-4 alkyl;
T′ is H, Cl, Br, F, C 1-3 alkyl, O—C 1-3 alkyl, OH, NH 2 , N(H)—C 1-3 alkyl, or N(—C 1-3 alkyl) 2 ;
p is zero, 1 or 2; q is zero, 1, or 2; p+q=zero, 1, 2, or 3; and
R̂ is:
(1) phenyl optionally substituted with from 1 to 3 substituents each of which is independently C 1-4 alkyl, C 1-4 haloalkyl, O—C 1-4 alkyl, O—C 1-4 haloalkyl, Cl, Br, F, or NO 2 ;
(2) C 1-4 alkyl; or
(3) C 1-4 haloalkyl.
41 . A compound according to claim 40 , which is selected from the group consisting of:
wherein R̂ is methyl, chloromethyl, phenyl, 4-bromophenyl, 4-trifluoromethylphenyl, or 4-methylphenyl.Join the waitlist — get patent alerts
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