US2019077803A1PendingUtilityA1
Tetracycline compounds
Assignee: TETRAPHASE PHARMACEUTICALS INCPriority: May 8, 2009Filed: May 2, 2018Published: Mar 14, 2019
Est. expiryMay 8, 2029(~2.8 yrs left)· nominal 20-yr term from priority
Inventors:Chi-Li ChenRoger B. ClarkYonghong DengMinsheng HeLouis PlamondonCuixiang SunXiao-Yi XiaoMagnus P. Ronn
C07C 2603/74C07C 67/307C07D 207/08C07D 207/14A61P 31/12C07C 2601/08C07D 209/44C07D 209/52C07C 237/26C07D 211/58C07D 221/20C07C 2601/02C07D 295/15C07D 211/18C07D 207/06C07D 295/155C07D 401/04C07D 241/04C07D 211/34C07D 295/26C07D 295/108C07C 2602/08C07D 207/16C07C 275/24C07D 471/10C07D 413/06C07D 307/22C07D 211/14C07D 207/10C07C 2601/04C07D 223/04C07C 67/31C07C 2602/50C07D 205/04C07D 295/185C07C 311/19C07D 209/04C07C 2602/42C07C 311/06C07C 51/353C07C 2601/14C07D 209/14C07D 487/10C07D 295/135C07D 261/20C07C 2601/18C07D 295/13C07D 211/62C07C 67/08C07D 207/09C07C 2602/24C07C 67/317C07D 223/14C07D 213/74C07C 2603/46C07D 223/32C07D 211/46A61P 31/04C07C 67/313C07C 231/10
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Claims
Abstract
The present invention is directed to a compound represented by Structural Formula (I): or a pharmaceutically acceptable salt thereof. The variables for Structural Formula I are defined herein. Also described is a pharmaceutical composition comprising the compound of Structural Formula I and its therapeutic use.
Claims
exact text as granted — not AI-modified1 . A compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
X is selected from hydrogen, bromo, fluoro, chloro, C 1 -C 6 alkyl, —O—C 1 -C 6 alkyl, —S(O) m —C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, —O—C 3 -C 7 cycloalkyl, —S(O) m —C 3 -C 7 cycloalkyl, —CN, —N(R 4 )(R 5 ), and —NH—C(O)—(C 1 -C 6 alkylene)-N(R 4 )(R 5 ), wherein each alkyl, alkylene or cycloalkyl in the group represented by X is optionally substituted with fluoro;
Y is selected from fluoro, —C 1 -C 6 alkyl and —[C(R 1a )(R 1b )] m —N(R 2 )(R 2 )(R 3 );
Z is selected from hydrogen, fluoro,
bromo, —CN, —[C(R 1a )(R 1b )] n —N(R 2 )(R 3 ), —N(R 4 )(R 5 ), NO 2 , —NH—C(O)—(C 1 -C 4 alkylene)-N(R 4 )(R 5 ), C 1 -C 6 alkyl, —NH—C(O)—C 1 -C 6 alkyl, —NH—S(O) m —C 1 -C 6 alkyl, —NH—S(O) m —C 3 -C 10 carbocyclyl, —NH—S(O) m -(4-13 membered) heterocyclyl; each R 1a and R 1b is independently selected from hydrogen, C 1 -C 4 alkyl, and C 3 -C 10 carbocyclyl;
R 2 is selected from hydrogen, C 1 -C 12 alkyl, —C 0 -C 6 alkylene-C 3 -C 10 carbocyclyl, and —C 0 -C 6 alkylene-(4-13 membered) heterocyclyl;
R 3 is selected from hydrogen, C 1 -C 8 alkyl, —C 0 -C 6 alkylene-C 3 -C 10 carbocyclyl, —C 0 -C 6 alkylene-(4-13 membered) heterocyclyl, —C(O)—C 1 -C 6 alkyl, —C 0 -C 6 alkylene-C(O)N(R 4 )(R 5 ), —C(O)—C 1 -C 6 alkylene-N(R 4 )(R 5 ), —C 2 -C 6 alkylene-N(R 4 )(R 5 ), —S(O) m —C 1 -C 6 alkyl, —S(O) m —C 3 -C 10 carbocyclyl, and —S(O) m -(4-13 membered) heterocyclyl, wherein each alkyl, carbocyclyl, alkylene or heterocyclyl in the group represented by R 2 or R 3 is optionally and independently substituted with one or more substituents independently selected from fluoro, chloro, —OH, —O—C 1 -C 4 alkyl, C 1 -C 4 alkyl, fluoro-substituted-C 1 -C 4 alkyl, —N(R 4 )(R 5 ), C 3 -C 10 carbocyclyl or a (4-13 membered) heterocyclyl; or
R 2 and R 3 taken together with the nitrogen atom to which they are bound form a (4-7 membered) monocyclic heterocylic ring, or a (6-13 membered) bicyclic, spirocyclic or bridged heterocylic ring, wherein the (4-7 membered) monocyclic heterocylic ring, or the (6-13 membered) bicyclic, spirocyclic or bridged heterocyclic ring optionally comprises 1 to 4 additional heteroatoms independently selected from N, S and O; and wherein the (4-7 membered) monocyclic heterocylic ring, or the (6-13 membered) bicyclic, spirocyclic or bridged heterocyclic ring is optionally substituted with one or more substituents independently selected from C 3 -C 10 carbocyclyl, (4-13 membered) heterocyclyl, fluoro, chloro, —OH, —C 1 -C 4 fluoroalkyl, —C 1 -C 4 alkyl, —O—C 3 -C 10 carbocyclyl, —O-(4-13 membered) heterocyclyl, —C 0 -C 4 alkylene-O—C 1 -C 4 alkyl, —C 0 -C 4 alkylene-O—C 1 -C 4 fluoroalkyl, ═O, —C(O)—C 1 -C 4 alkyl, —C(O)N(R 4 )(R 5 ), —N(R 4 )—C(O)—C 1 -C 4 alkyl, and —C 0 -C 4 alkylene-N(R 4 )(R 5 ), and wherein each carbocyclyl or heterocyclyl substituent is optionally substituted with fluoro, chloro, —OH, C 1 -C 4 fluoroalkyl, C 1 -C 4 alkyl, —O—C 1 -C 4 alkyl, —O—C 1 -C 4 fluoroalkyl, —NH 2 , —NH(C 1 -C 4 alkyl), or —N(C 1 -C 4 alkyl) 2 ;
each of R 4 and R 5 is independently selected from hydrogen and C 1 -C 4 alkyl; or
R 4 and R 5 taken together with the nitrogen atom to which they are bound form a (4-7 membered) heterocylic ring optionally comprising one additional heteroatom selected from N, S and O, wherein the (4-7 membered) heterocylic ring is optionally substituted with fluoro, chloro, —OH, fluoro-substituted C 1 -C 4 alkyl, —C 1 -C 4 alkyl, or —C 1 -C 4 alkylene-O—C 1 -C 4 alkyl, and is optionally fused to phenyl;
each m is independently 0, 1 or 2; and
n is 1 or 2,
with the proviso that when Z is —NH—C(O)—C 1 -C 4 alkyl-N(R 4 )(R 5 ), X is other than fluoro.
2 . The compound of claim 1 , wherein:
Y is selected from fluoro,
methyl, —CH(R 1a )—N(R 2 )(R 3 ), —(CH 2 ) 2 —N(R 2 )(R 3 ), —NH(pyridyl), —NH(C 1 -C 8 alkyl), —NHC(O)—C 1 -C 3 alkylene-piperidine, —NHC(O)—C 1 -C 3 alkylene-pyrrolidine, and —NHS(O) 2 -phenyl, wherein each piperidine and each pyrrolidine in the group represented by Y is optionally substituted with one or more —C 1 -C 6 alkyl;
R 1a is selected from hydrogen and methyl;
R 2 is selected from hydrogen, C 1 -C 3 straight chained alkyl, C 1 -C 3 straight chained fluoroalkyl, cyclopropyl, and —CH 2 -cyclopropyl;
R 3 is selected from hydrogen, C 1 -C 8 alkyl, —CH 2 —CHF 2 , —C 2 -C 6 alkylene-O—C 1 -C 3 alkyl, —C 3 -C 10 cycloalkyl, —C 3 -C 10 cycloalkyl-substituted C 1 -C 3 alkyl, cyclopropyl-substituted cyclopropyl, —(CH 2 ) 2 -phenyl, and —S(O) 2 -phenyl, when R 2 is hydrogen or C 1 -C 2 alkyl, R 3 is additionally selected from benzyl; or
R 2 and R 3 taken together with the nitrogen atom to which they are bound form a ring selected from pyrrolidine, piperidine, piperazine or morpholine, wherein the ring is optionally substituted with one or more substituents independently selected from —OH, —C 1 -C 3 alkyl and —C 1 -C 3 alkylene-O—C 1 -C 3 alkyl, and wherein the ring is optionally fused to phenyl or spirofused to cyclopropyl.
3 . The compound of claim 1 , wherein:
Y is selected from fluoro, methyl, and —CH(R 1a )—N(R 2 )(R 3 ); R 1a is selected from hydrogen and methyl; R 2 is selected from hydrogen, C 1 -C 3 straight chained alkyl and —CH 2 -cyclopropyl; R 3 is selected from hydrogen, C 1 -C 8 alkyl, —CH 2 —CHF 2 , —C 1 -C 6 alkylene-O—C 1 -C 3 alkyl, C 3 -C 10 cycloalkyl, —(CH 2 ) 2 -phenyl and C 3 -C 10 cycloalkyl-substituted C 1 -C 3 alkyl, wherein each cycloalkyl in the group represented by R 3 is optionally substituted with —C 1 -C 3 alkyl or optionally benzofused and when R 2 is hydrogen or —C 1 -C 2 alkyl, R 3 is additionally selected from benzyl; or R 2 and R 3 taken together with the nitrogen atom to which they are bound form a ring selected from pyrrolidine and piperidine, wherein the ring is optionally substituted with one or more substituents independently selected from fluoro —C 1 -C 3 alkyl and —C 1 -C 3 alkylene-O—C 1 -C 3 alkyl, and wherein the ring is optionally fused to phenyl or spirofused to cyclopropyl.
4 . The compound of claim 1 , wherein at least one of X and Z is other than hydrogen.
5 . The compound of claim 4 , wherein both X and Z are other than hydrogen.
6 . The compound of claim 4 , wherein one of X and Z is hydrogen.
7 . The compound of claim 6 , wherein:
X is selected from hydrogen, fluoro, chloro, —CN, and —N(CH 3 ) 2 ; and Z is hydrogen, NH 2 or —CH 2 —NH—CH 2 —C(CH 3 ) 3 .
8 . The compound of claim 7 , wherein the compound is of Formula II:
or a pharmaceutically acceptable salt thereof.
9 . The compound of claim 8 , wherein X is fluoro, chloro or —N(CH 3 ) 2 .
10 . The compound of claim 9 , wherein:
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
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X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
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X is fluoro and —CH(R 1a )—NR 2 R 3 is
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X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
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X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is fluoro and —CH(R 1a )—NR 2 R 3 is
X is chloro and —CH(R 1a )—NR 2 R 3 is
X is chloro and —CH(R 1a )—NR 2 R 3 is
X is chloro and —CH(R 1a )—NR 2 R 3 is
X is chloro and —CH(R 1a )—NR 2 R 3 is
X is chloro and —CH(R 1a )—NR 2 R 3 is
X is chloro and —CH(R 1a )—NR 2 R 3 is
X is chloro and —CH(R 1a )—NR 2 R 3 is
X is chloro and —CH(R 1a )—NR 2 R 3 is
X is chloro and —CH(R 1a )—NR 2 R 3 is
X is chloro and —CH(R 1a )—NR 2 R 3 is
X is chloro and —CH(R 1a )—NR 2 R 3 is
X is —N(CH 3 ) 2 and —CH(R 1a )—NR 2 R 3 is
X is —N(CH 3 ) 2 and —CH(R 1a )—NR 2 R 3 is
X is —N(CH 3 ) 2 and —CH(R 1a )—NR 2 R 3 is
X is —N(CH 3 ) 2 and —CH(R 1a )—NR 2 R 3 is
X is —N(CH 3 ) 2 and —CH(R 1a )—NR 2 R 3 is
X is —N(CH 3 ) 2 and —CH(R 1a )—NR 2 R 3 is
X is —N(CH 3 ) 2 and —CH(R 1a )—NR 2 R 3 is
X is —N(CH 3 ) 2 and —CH(R 1a )—NR 2 R 3 is
or
X is —N(CH 3 ) 2 and —CH(R 1a )—NR 2 R 3 is
11 . The compound of claim 1 , wherein the compound is of Formula III:
or a pharmaceutically acceptable salt thereof.
12 . The compound of claim 11 , wherein the compound is of Formula IIIa:
or a pharmaceutically acceptable salt thereof.
13 . The compound of claim 12 , wherein:
—[C(R 1a )(R 1b )] n —N(R 2 )(R 3 ) is
14 . The compound of claim 11 , wherein the compound is of Formula IV:
or a pharmaceutically acceptable salt thereof.
15 . The compound of claim 14 , wherein the compound is of Formula IVa or IVb:
or a pharmaceutically acceptable salt thereof.
16 . The compound of claim 1 , wherein:
Y is —NHR 3 , and R 3 is pyridyl, C 1 -C 8 alkyl, —C(O)—C 1 -C 3 alkylene-piperidine, —C(O)—C 1 -C 3 alkylene-pyrrolidine, wherein each piperidine or pyrrolidine in the group represented by R 3 is optionally substituted with one or more C 1 -C 3 alkyl.
17 . The compound of claim 16 , wherein the compound is of Formula V:
or a pharmaceutically acceptable salt thereof.
18 . The compound of claim 17 , wherein R 3 is
19 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound of claim 1 .
20 . A method for treating an infection in a subject comprising administering to the subject an effective amount of the composition of claim 19 .
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