IP Library › Granted Patent US 10,865,216

Granted Patent B2

US 10,865,216 · App. 14/427,611 · Granted Dec 15, 2020

Tricyclic Gyrase inhibitors

Inventors: Daniel Bensen (Carlsbad, CA); Allen Borchardt (San Diego, CA); Zhiyong Chen (San Diego, CA); John M. Finn (Encinitas, CA); Thanh To Lam (San Diego, CA); Suk Joong Lee (San Diego, CA); Xiaoming Li (San Diego, CA); Leslie William Tari (San Diego, CA); Min Teng (San Diego, CA); Michael Trzoss (San Diego, CA); Junhu Zhang (San Diego, CA); Michael E. Jung (Los Angeles, CA); Felice C. Lightstone (Fremont, CA); Sergio E. Wong (San Jose, CA); Toan B. Nguyen (San Ramon, CA)

Assignees: MERCK SHARP & DOHME CORP.; LAWRENCE LIVERMORE NATIONAL SECURITY, LLC

C07D519/00 C07D487/04 C07D487/16 C07D487/22 C07D498/22 C07D515/22

View Patent ↗

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US 10,865,216
App. No.: 14/427,611
Granted: Dec 15, 2020
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

Abstract

Disclosed herein are compounds having the structure of Formula I and pharmaceutically suitable salts, esters, and prodrugs thereof that are useful as antibacterially effective tricyclic gyrase inhibitors. In addition, species of tricyclic gyrase inhibitors compounds are also disclosed herein. Related pharmaceutical compositions, uses and methods of making the compounds are also contemplated.

Claims (189)

1. A compound having the structure of Formula I

or pharmaceutically suitable salts thereof, wherein

L is:

a) O or S; or

b) NH, CH 2 , CHF, CF 2 , SCH 2 , OCH 2 , NHCH 2 , CH═CH, CH 2 CH 2 , SCH 2 CONH, OCH 2 CONH, NHCH 2 CONH, OCH 2 CH═CH, or SCH 2 CH═CH;

R 8 is:

a) H or an interacting substituent selected from the group consisting of H, F, Cl, Br, NH 2 , OH, 1-3C alkyl, amino-1-3C alkyl, aminocyclopropyl, OCH 3 , OCH 2 CH 3 , cyclopropyl, CH 2 cyclopropyl, CH 2 Cl, CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 , NHNH 2 , NHOH, NHNHCH 3 , NHOCH 3 , NHCD 3 , SCH 3 , NHCOH, CHCl 2 , and CHCH 2 ; or

b) a substituent having the following structure:

wherein R 8a is H or an interacting substituent selected from the group consisting of H, methyl, ethyl, and cyclopropyl;

wherein R 8b and R 8c are independently H or C1-C6 alkyl; wherein R 8d is

wherein Q is CH or N;

wherein R 8e is (CR 8g 2 ) n -basic amine, wherein each R 8g is independently H or C1-C3 alkyl;

wherein n is 0-2;

wherein R 8f is hydrogen or C1-C6 alkyl optionally substituted with OH or NH 2 ;

alternatively wherein R 8e and R 8f join to form a C3-C12 hydrocarbyl ring containing 0-3 heteroatoms selected from O, N and S;

wherein R 8j and R 8k are independently H or C1-C8 hydrocarbyl residue;

c) a substituent having the following structure:

R 9 is H;

R 2 is

a) a 6-membered aryl or heteroaryl ring containing 0-3 O, S, or N heteroatoms, optionally substituted with 0-3 noninterfering substituents, wherein the 6-membered aryl or heteroaryl ring of R 2 has a CH at each position immediately adjacent the position where R 2 attaches to L, if L is O or S;

b) a 6-membered aryl or heteroaryl ring containing 0-3 O, S, or N heteroatoms, optionally substituted with 0-3 noninterfering substituents, wherein the 6-membered aryl or heteroaryl ring of R 2 has a CF at each positions immediately adjacent the position where R 2 attaches to L, if L is O or S;

c) a 6-membered aryl or heteroaryl ring containing 0-3 O, S, or N heteroatoms, optionally substituted with 0-3 noninterfering substituents, wherein the 6-membered aryl or heteroaryl ring of R 2 has a CH or CF independently at each position immediately adjacent the position where R 2 attaches to L, if L is NH, CH 2 , CHF, or CF 2 ;

d) a 5-membered heteroaryl ring containing 1-4 O, S, or N heteroatoms, optionally substituted with 0-2 noninterfering substituents;

wherein the 5-membered heteroaryl ring of R 2 has O, S, N, NH, CH, CF, or

CCl, independently at each of the positions immediately adjacent the position where R 2 attaches to L, if L is O, S, NH, CH 2 , CHF, or CF 2 ;

e) a 6-membered or 5-membered non-aryl or non-heteroaryl ring containing 0-3 O, S, or N heteroatoms, optionally substituted with 0-3 noninterfering substituents;

wherein the 6-membered or 5-membered non-aryl or non-heteroaryl ring of R 2 has O, S, N, NH, CH, CF, or CH 2 , independently at each position immediately adjacent the position where R 2 attaches to L, if L is O, S, NH, CH 2 , CHF, or CF 2 ;

f) i) a 6-membered aryl or heteroaryl ring containing 0-3 O, S, or N heteroatoms, optionally substituted with 0-3 noninterfering substituents,

ii) a 5-membered heteroaryl ring containing 1-4 O, S, or N heteroatoms, optionally substituted with 0-2 noninterfering substituents, or

iii) a 6-membered or 5-membered non-aryl or non-heteroaryl ring containing 0-3 O, S, or N heteroatoms, optionally with 0-3 noninterfering substituents,

when L is selected from the group consisting of SCH 2 , OCH 2 , NHCH 2 , CH═CH, CH 2 CH 2 , SCH 2 CONH, OCH 2 CONH, NHCH 2 CONH, OCH 2 CH═CH, and SCH 2 CH═CH in any of f)i) to f)iii);

alternatively wherein 2 adjacent noninterfering substituents of R 2 in a)-f) form one or more fused rings with the 6-membered aryl or heteroaryl ring, the 5-membered heteroaryl ring, or the 6-membered or 5-membered non-aryl or non-heteroaryl ring;

g) a substituent having the following structure:

wherein R 2a contains an oxygen residue derived from an R 2 as in a)-f), wherein R 2 has an OH group, wherein the R 2 OH is replaced with an oxygen residue in R 2a , and wherein the oxygen residue is linked to P;

wherein R 2b , R 2c , R 2d , R 2f , and R 2g independently are each N or CR 2e wherein R 2e is H or C1-C4 alkyl optionally substituted with a noninterfering substituent; or

i) selected from the group consisting of

wherein the noninterfering substituents in a)-h) of R 2 are independently selected from the group consisting of OH, CO 2 H, CN, NH 2 , Br, Cl, F, SO 3 H, SO 2 NH 2 , SO 2 CH 3 , SOCH 3 , NHOH, NHOCH 3 , NO 2 , and C1-15 hydrocarbyl residue containing 0-5 O, S, or N heteroatoms optionally substituted with a substituent selected from the group consisting of OH, CN, ═O, NH 2 , NHOH, ═NOH, ═NNH 2 , ═NOCH 3 , Br, F, Cl, SO 3 H, and NO 2 ;

R 4 is

a) H;

b) an optionally substituted ORa; wherein Ra is a 5-6 membered aryl or heteroaryl containing 0-3 O, S, or N heteroatoms optionally substituted with 0-3 noninterfering substituents;

c) an optionally substituted secondary or tertiary amine attached to the C Ring through the secondary or tertiary amine N;

d) an optionally substituted 5-10 membered unsaturated cyclic or heterocyclic residue containing 0-3 N, O or S heteroatoms;

wherein the optional substituent is 0-3 noninterfering substituents;

wherein the R 4 substituent of a)-d) does not project greater than about 3 A below the plane of the A, B and C Rings toward the GyrB/ParE binding pocket floor in the bound conformation; and

wherein R 4 does not sterically interfere with R 2 or Z when the compound is in the bound conformation;

e) a substituent having the following structure:

wherein R 4a contains an oxygen residue derived from the R 4 as in b)-d) or g), wherein the R 4 has an OH group, wherein the R 4 OH is replaced with an oxygen residue in R 4a , and wherein the oxygen residue is linked to P;

wherein R 4′ —NH is derived from the R 4 as in b)-d) or g), wherein the R 4 contains a primary amine and wherein the NH in the primary amine links the R 4′ residue to the C═O;

wherein R 4b and R 4c are independently H or C1-C6 alkyl;

wherein R 4d is

wherein Q is CH or N;

wherein R 4e is (CR 4g 2 ) n -basic amine, wherein each R 4g is independently H or C1-C3 alkyl;

wherein n is 0-2;

wherein R 4f is hydrogen or C1-C6 alkyl optionally substituted with OH or NH 2 ;

alternatively wherein R 4e and R 4f join to form a ring;

wherein R 4j and R 4k are independently H or C1-C8 hydrocarbyl residue;

f) a substituent having the following structure

g) selected from the group consisting of:

wherein the noninterfering substituents for R 4 are independently selected from the group consisting of OH, CO 2 H, CN, NH 2 , Br, Cl, F, SO 3 H, NO 2 , and C1-15 hydrocarbyl residue containing 0-5 O, S, or N heteroatoms optionally substituted with OH, CN, ═O, NH 2 , ═NOH, ═NNH 2 , ═NOCH 3 , Br, F, Cl, SO 3 H, and NO 2 ;

X is CR X , wherein R X is H or an interacting substituent selected from the group consisting of CH 3 , Cl, Br, and F;

Y is CR Y , wherein R Y is H or an interacting substituent selected from the group consisting of CH 3 , CHF 2 , CF 3 , CN, CH 2 CH 3 , Cl, Br, and F;

Z is:

CR Z wherein R Z is H or an interacting substituent selected from the group consisting of CH 3 , CN, Cl, Br, and F;

provided that the compound of Formula I has at least one of the following moieties i)-iv):

i) L is NH, CH 2 , CHF, CF 2 , SCH 2 , OCH 2 , NHCH 2 , CH═CH, CH 2 CH 2 , SCH 2 CONH, OCH 2 CONH, NHCH 2 CONH, OCH 2 CH═CH, or SCH 2 CH═CH;

ii) R 8 is:

a) a substituent having the following structure:

wherein R 8a is H or an interacting substituent selected from the group consisting of H, methyl, ethyl, and cyclopropyl;

wherein R 8b and R 8c are independently H or C1-C6 alkyl;

wherein R 8d is

wherein Q is CH or N;

wherein R 8e is (CR 8g 2 ) n -basic amine, wherein each R 8g is independently H or C1-C3 alkyl;

wherein n is 0-2;

wherein R 8f is hydrogen or C1-C6 alkyl optionally substituted with OH or NH 2 ;

alternatively wherein R 8e and R 8f join to form a C3-C12 hydrocarbyl ring containing 0-3 heteroatoms selected from O, N and S;

wherein R 8j and R 8k are independently H or C1-C8 hydrocarbyl residue; or

b) a substituent having the following structure:

iii) R 2 is

a) a 6-membered aryl or heteroaryl ring containing 0-3 O, S, or N heteroatoms, optionally substituted with 0-3 noninterfering substituents,

wherein the 6-membered aryl or heteroaryl ring of R 2 has a CF at each position immediately adjacent to the position where R 2 attaches to L, if L is 0 or S;

b) a 6-membered aryl or heteroaryl ring containing 0-3 O, S, or N heteroatoms, optionally substituted with 0-3 noninterfering substituents,

wherein the 6-membered aryl or heteroaryl ring of R 2 has a CH or CF independently at each position immediately adjacent to the position where R 2 attaches to L, if L is NH, CH 2 , CHF, or CF 2 ;

c) a 5-membered heteroaryl ring containing 1-4 O, S, or N heteroatoms, optionally substituted with 0-2 noninterfering substituents;

wherein the 5-membered heteroaryl ring of R 2 has O, S, N, NH, CH, CF, or CCl, independently at each of the positions immediately adjacent to the position where R 2 attaches to L, if L is O, S, NH, CH 2 , CHF, or CF 2 ;

d) a 6-membered or 5-membered non-aryl or non-heteroaryl ring containing 0-3 O, S, or N heteroatoms, optionally substituted with 0-3 noninterfering substituents;

wherein the 6-membered or 5-membered non-aryl or non-heteroaryl ring of R 2 has O, S, N, NH, CH, CF, or CH 2 , independently at each position immediately adjacent to the position where R 2 attaches to L, if L is O, S, NH, CH 2 , CHF, or CF 2 ;

e) i) a 6-membered aryl or heteroaryl ring containing 0-3 O, S, or N heteroatoms, optionally substituted with 0-3 noninterfering substituents,

ii) a 5-membered heteroaryl ring containing 1-4 O, S, or N heteroatoms, optionally substituted with 0-2 noninterfering substituents, or

iii) a 6-membered or 5-membered non-aryl or non-heteroaryl ring containing 0-3 O, S, or N heteroatoms, optionally with 0-3 noninterfering substituents,

when L is selected from the group consisting of SCH 2 , OCH 2 , NHCH 2 , CH═CH, CH 2 CH 2 , SCH 2 CONH, OCH 2 CONH, NHCH 2 CONH, OCH 2 CH═CH, and SCH 2 CH═CH in any of e.i. to e.iii.;

alternatively wherein 2 adjacent noninterfering substituents of R 2 in a)-e) form one or more fused rings with the 6-membered aryl or heteroaryl ring, the 5-membered heteroaryl ring, or the 6-membered or 5-membered non-aryl or non-heteroaryl ring;

f) a substituent having the following structure:

wherein R 2a contains an oxygen residue derived from an R 2 as in a)-e), wherein R 2 has an OH group, wherein the R 2 OH is replaced with an oxygen residue in R 2a , and wherein the oxygen residue is linked to P;

wherein R 2b , R 2c , R 2d , R 2f and R 2g independently are each N or CR 2e wherein R 2e is H or C1-C4 alkyl optionally substituted with a noninterfering substituent; or

h) selected from the group consisting of

wherein the noninterfering substitutents for R 2 are the same as described above;

iv) R 4 is:

a) a substituent having the following structure:

wherein R 4a contains an oxygen residue derived from R 4 as in b)-d) or g), wherein the R 4 has an OH group, wherein the R 4 OH is replaced with an oxygen residue in R 4a , and wherein the oxygen residue is linked to P;

wherein R 4′ —NH is derived from R 4 as in b)-d) or g), wherein the R 4 contains a primary amine and wherein the NH in the primary amine links the R 4′ residue to the C═O;

wherein R 4b and R 4c are independently H or C1-C6 alkyl;

wherein R 4d is

wherein Q is CH or N;

wherein R 4e is (CR 4g 2 ) n -basic amine, wherein each R 4g are independently H or C1-C3 alkyl;

wherein n is 0-2;

wherein R 4f is hydrogen or C1-C6 alkyl optionally substituted with OH or NH 2 ;

alternatively wherein R 4e and R 4f join to form a ring;

wherein R 4j and R 4k are independently H or C1-C8 hydrocarbyl residue:,

b) a substituent having the following structure

c) selected from the group consisting of:

wherein the noninterfering substitutents for R 4 are the same as described above.

2. A compound having the formula:

3. A composition comprising an effective amount of compound of claim 1 and a pharmaceutically acceptable carrier.

4. A method of treating a bacterial infection comprising administering to a patient in need thereof an effective amount of compound of claim 1 .

5. The compound of claim 1 , wherein

L is O, S, NH, CH 2 , SCH 2 , or NHCH 2 ;

R 8 is H or an interacting substituent selected from the group consisting of Cl, F, Br, NH 2 , C 1-3 alkyl, amino C 1-3 alkyl, aminocyclopropyl, OCH 3 , cyclopropyl, and CH 2 cyclopropyl;

R 9 is H;

R 2 is

d) a 5-membered heteroaryl ring containing 1-4 O, S, or N heteroatoms, optionally substituted with 0-2 noninterfering substituents;

wherein the 5-membered heteroaryl ring of R 2 has O, S, N, NH, CH, CF, or CCl, independently at each of the positions immediately adjacent the position where

R 2 attaches to L, if L is O, S, NH, CH 2 , CHF, or CF 2 ;

e) a 6-membered or 5-membered non-aryl or non-heteroaryl ring containing 0-3 O, S, or N heteroatoms, optionally substituted with 0-3 noninterfering substituents;

wherein the 6-membered or 5-membered non-aryl or non-heteroaryl ring of R 2 has O, S, N, NH, CH, CF, or CH 2 , independently at each position immediately adjacent the position where R attaches to L, if L is O, S, NH, CH 2 , CHF, or CF 2 ;

wherein R 2b , R 2c , R 2d , R 2f , and R 2g independently is each N or CR 2e wherein the R 2e is C1-C4 alkyl optionally substituted with a noninterfering substituent; or

g) selected from the group consisting of

wherein the noninterfering substituents in a)-f) for R 2 are the same as in claim 1 ;

R 4 is

a) H;

b) an optionally substituted ORa; wherein Ra is a 5-6 membered aryl or heteroaryl containing 0-3 O, S, or N heteroatoms optionally substituted with 0-3 noninterfering substituents;

c) an optionally substituted secondary or tertiary amine attached to the C Ring through the secondary or tertiary amine N;

d) an optionally substituted 5-10 membered unsaturated cyclic or heterocyclic residue containing 0-3 N, O or S heteroatoms;

wherein the optional substituent is 0-3 noninterfering substituents; wherein the R 4 substituent of a)-d) does not project greater than about 3 A below the plane of the A, B and C Rings toward the GyrB/ParE binding pocket floor in the bound conformation; and

wherein R 4 does not sterically interfere with R 2 or Z when the compound is in the bound conformation;

wherein the noninterfering substituents in a)-d) for R 4 are the same as in claim 1 ;

e) selected from the group consisting of:

and the proviso is the same as in claim 1 .

6. The compound of claim 5 , wherein

the noninterfering substituents in R 2 and R 4 are independently selected from the group consisting of CO 2 H, CN, NH 2 , Br, Cl, F, SO 3 H, and C1-15 hydrocarbyl residue containing 0-5 O, S, or N heteroatoms optionally substituted with OH, CN, ═O, NH 2 ;