Tricyclic Gyrase inhibitors

Patent metadata

Field	Value
Publication number	US-10865216-B2
Application number	US-201314427611-A
Country	US
Kind code	B2
Filing date	Sep 11, 2013
Priority date	Sep 12, 2012
Publication date	Dec 15, 2020
Grant date	Dec 15, 2020

Abstract

Related pharmaceutical compositions, uses and methods of making the compounds are also contemplated.

First claim

What is claimed is:

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;
h)

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 4

Assignees

• Merck Sharp & Dohme
• L Livermore Nat Security Llc

Inventors

• Bensen Daniel
• Borchardt Allen
• Chen Zhiyong
• Finn John M
• Lam Thanh To
• Lee Suk Joong
• Li Xiaoming
• Tari Leslie William
• Teng Min
• Trzoss Michael
• Zhang Junhu
• Jung Michael E
• Lightstone Felice C
• Wong Sergio E
• Nguyen Toan B

Classifications

• C07D515/22

  in which the condensed system contains four or more hetero rings · CPC title

• C07D498/22

  in which the condensed system contains four or more hetero rings · CPC title

• C07D487/22

  in which the condensed system contains four or more hetero rings · CPC title

• C07D487/16

  Peri-condensed systems · CPC title

• C07D519/00 Primary

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title