Beta-tetrazolyl-propionic acids as metallo-beta-lactamase inhibitors

Patent metadata

Field	Value
Publication number	US-9839642-B2
Application number	US-201515309533-A
Country	US
Kind code	B2
Filing date	May 4, 2015
Priority date	May 9, 2014
Publication date	Dec 12, 2017
Grant date	Dec 12, 2017

Abstract

The present invention relates to compounds of formula I that are metallo-β-lactamase inhibitors, the synthesis of such compounds, and the use of such compounds for use with β-lactam antibiotics for overcoming resistance.

First claim

What is claimed:

1. A compound of formula Ia or Ib

or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is:
a) —C 2-8 alkyl,
b) —C 1-4 alkyl substituted with 1, 2, or 3 halo substituents or 1 substituent selected from —C 3-6 cycloalkyl, —CN, —C(═O)NH 2 , —OH, —C 1-3 alkoxy, phenyl, and HetY,
c) —C 2-6 alkenyl,
d) —C 3-6 cycloalkyl, or
e) HetY,

R 2 is hydrogen, C 1-4 alkyl, or C 1-4 alkoxy;
HetY is a 4- to 6-membered saturated monocyclic ring with 1 heteroatom ring atom selected from N and O;
W is AryA; HetA; —(CH 2 ) 1-2 -AryA; —CH(CH 3 )-phenyl; or cyclohexyl substituted with —COOH or —NH 2 ;
AryA is an aromatic ring system selected from:
a) 5- to 6-membered monocyclic aromatic ring with 0, 1, 2 or 3 heteroatom ring atoms independently selected from N and S, optionally substituted with 1 or 2 substituents R; or
b) 9- to 11-membered bicyclic aromatic ring system with 1, 2 or 3 heteroatom ring atoms selected from N, O, and S, optionally substituted with 1 substituent R′ selected from Br, C 1-6 alkyl, —NH 2 , and —NHCH 2 CH 2 OH;

HetA is a piperidinyl ring optionally substituted with 1 substituent selected from —C(═O)CH 3 ;
each R is independently
halo;
—CF 3 ;
C 1-6 alkyl optionally substituted with —NR x R y or 1 or 2 —OH;
C 3-6 cycloalkenyl optionally substituted with —NR x R y ;
—(CH 2 ) 0-1 NHR z ;
—CN;
—C(NH 2 )═NOH;
—C(═O)NR x R y ;
—C(═O)NHR z ;
—C(═O)OH;
—NR x R y ;
—N + (CH 3 ) 3 ;
—NHCH 2 CH 2 CH(CF 3 )NH 2 ;
—NHCH 2 C(═O)N(CH 3 ) 2 ;
—NHCH 2 CH 2 SO 2 NH 2 ;
—NHC(═NH)NH 2 ;
—OH;
—OR z ;
—OCH 2 CH(NH 2 )CH 2 OH;
—SCH 3 ;
—SO 2 R w ;
AryB;
—NH(CH 2 ) 0-2 -AryB;
—O-AryB;
—(CH 2 ) 0-2 -HetB;
—CH 2 O(CH 2 ) 0-2 -HetB;
—C(═O)-HetB;
—NH(CH 2 ) 0-2 -HetB; or
—O-HetB;

AryB is
a) a 5- to 6-membered monocyclic aromatic ring with 0, 1, or 2 heteroatom ring atoms independently selected from N and S, optionally substituted with 1, 2 or 3 substituents independently selected from
F;
—CH 3 ;
—CH 2 NH 2 ;
—CH 2 N(CH 3 ) 2 ;
—CH 2 CH 2 NH 2 ,
—CH 2 C(CH 3 ) 2 NH 2 ;
—CH 2 OH;
—C(CH 3 ) 2 OH;
—C(═O)NR x R y ;
—NR x R y ;
—NHC(═O)CH 3 ;
—NHSO 2 CH 3 ;
—N(CH 3 )SO 2 CH 3 ;
—OH;
—OCH 3 ;
—SO 2 CH 3 ;
—SO 2 NH 2 ;
—(CH 2 ) 0-1 -AryC;
—C 0 -C 2 alkyl-HetC; and
—O-HetC;

b) triazolyl;
c) tetrazolyl;
d) 1,3-dimethylpyrimidine-2,4(1H,3H)-dione; or
e) a 9- to 10-membered bicyclic aromatic ring with 0, 1, 2 or 3 heteroatom ring atoms independently selected from N or O, optionally substituted with Br, —CH 3 , —CN, —NH 2 , or oxo;

HetB is
a) a 4- to 6-membered saturated or monosaturated monocyclic ring with 1 or 2 heteroatom ring atoms independently selected from N and O, optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo; —CF 3 ; C 1-6 alkyl, C 1-6 aminoalkyl; C 1-6 hydroxyalkyl; —CH(═NH);
—C(═NH)NH 2 ; —C(═O)CH 3 ; —C(═O)NHCH 3 ; —C(═O)NHSO 2 CH 3 ; —NH 2 ;
—NHSO 2 CH 3 , —OH; oxo; —SO 2 CH 3 ; AryC; or HetC; or

b) a 8- to 10-membered bicyclic saturated ring system with 1, 2 or 3 ring atoms independently selected from N or O, optionally substituted with 1 or 2 substituents independently selected from —CH 3 and oxo; wherein the rings in the bicyclic ring system are fused or spirocyclic;

AryC is phenyl, pyridinyl, or tetrazolyl;
HetC is a 4- to 6-membered saturated monocyclic ring with 1 or 2 heteroatom ring atoms independently selected from N and O, optionally substituted with 1 or 2 substituents selected from —CH 3 , —OH and oxo;
each R x and R y is independently hydrogen or C 1-6 alkyl;
each R z is independently —(CH 2 ) 0-1 -C 3-6 cycloalkyl optionally substituted with —NH 2 ;
C 1-6 aminoalkyl; or C 1-6 hydroxyalkyl; and
R w is selected from C 1-8 alkyl and C 3-6 cycloalkyl.

2. The compound of claim 1 , which has the formula Ic or Id

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH 2 CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 , —CH(CH 3 )CH 2 CH 3 , —C(CH 3 ) 3 , —CH 2 CH 2 CH 2 CH 2 CH 3 , —CH(CH 3 )CH 2 CH 2 CH 3 , —CH 2 CH 2 CH 2 CH(CH 3 ) 2 , —CH 2 CH 2 CH 2 CH 2 CH 2 CH(CH 3 ) 2 , —CH 2 CH 2 F, —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CH 2 CH 2 CF 3 , —CH 2 -cyclopropyl, —CH 2 -cyclopentyl, —CH 2 CH 2 -cyclohexyl, —CH 2 CH 2 CH 2 CH 2 CN, —CH 2 CH 2 CH 2 CH 2 C(═O)NH 2 , —CH 2 CH 2 CH 2 CH 2 OH, —CH 2 CH 2 CH 2 OCH 3 , —CH 2 -phenyl, —CH 2 CH 2 CH 2 CH 2 -phenyl, CH 2 —CH(CH 3 )-phenyl, —CH 2 CH 2 CH 2 -piperidinyl, —CH 2 -oxetanyl, —CH 2 CH═CH 2 , —CH 2 CH 2 CH═C(CH 3 ) 2 , cyclopentyl, tetrahydrofuranyl, or tetrahydropyranyl.

4. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein W is

5. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein W is

wherein
R A and R B are independently Br; F; Cl; —CF 3 ; —CH 3 ; —CH 2 NH 2 ; —CH 2 CH 2 NH 2 ; —CN; —CH 2 OH; —CONH 2 ; —CONCH 3 ; —CON(CH 3 ) 2 ; —CONH-cyclopropyl; —CONHCH 2 -cyclopropyl; —CONHCH 2 CH 2 NH 2 ; —CONHCH 2 CH 2 OH; —COOH; —NH 2 ; —NHCH 3 ; —NHCH 2 CH 2 OH; —NHC(═NH)NH 2 ; —OH; —OCH 2 CH 2 NH 2 ; —NH-cyclopentyl-NH 2 ;—SO 2 CH 3 ; —SO 2 -cyclopropyl; AryB; HetB; —CO-piperazinyl; —CH 2 -tetrahydropyranyl;—CH 2 -piperidinyl optionally substituted with —NH 2 ; —NH-pyrrolidinyl; —NHCH 2 -piperidinyl with —OH; —NH-tetrahydroisoquinolinyl; —O-phenyl substituted with —CONH 2 , —CH 2 OH, —CH 2 NH 2 , —CH 2 C(CH 3 ) 2 NH 2 , —CH(CH 3 )NH 2 , —CH 2 CH 2 NH 2 , piperidinyl, pyrrolidinyl, or piperazinyl; —O-tetrahydroisoquinolinyl; —O-tetrahydroquinolinyl; or —O-pyridinyl optionally substituted with piperazinyl;
AryB is
1) phenyl substituted with —CH 2 NH 2 , —CH 2 N(CH 3 ) 2 , —CH 2 OH, —CONH 2 , —CONHCH 3 , —NHSO 2 CH 3 , —SO 2 CH 3 , —SO 2 NH 2 , AryC, HetC, —CH 2 -HetC, or tetrazolyl;
2) pyridinyl optionally substituted with —C(CH 3 ) 2 OH, —NH 2 , —N(CH 3 ) 2 , —NH 2 or F;
3) piperazinyl optionally substituted with —CH 3 , —CH 2 -piperidinyl, —O-piperidinyl, or morpholinyl;
4) pyrimidinyl substituted with —NH 2 , —N(CH 3 ) 2 , —NHCH 2 CH 2 OH, —NHCOCH 3 , —NCH 3 SO 2 CH 3 , or HetC;
5) pyrazinyl substituted with two —CH 3 ;
6) pyrazolyl optionally substituted with 1 to 3 substitutents selected from —CH 3 , phenyl, and —CH 2 -pyridinyl;
7) dimethylpyrimidinedione;
8) tetrazolyl;
9) thiazolyl substituted with —CH 2 OH;
10) 1,2,3,4-tetrahydroquinoline;
11) imidazopyridinone;
12) indazolyl;
13) isoindolinone;
14) isoindolinyl;
15) isoquinolinyl optionally substituted with —CN;
16) methylbenzotriazolyl;
17) benzooxazinone;
18) triazolopyridinyl; or
19) 1,2,3,4-tetrahydronaphthalen-2-amine;

HetB is
1) azetidinyl substituted with —NH 2 ; —CH 2 NH 2 ; —CH 2 CH 2 NH 2 ; —C(CH 3 ) 2 NH 2 ; —CH 2 CH 2 OH; —SO 2 CH 3 ; morpholinyl; piperazinyl; (CH 2 OH) 2 ; —CH 2 NH 2 and —CH 3 ; or —OH and —CF 3 ;
2) pyrrolidinyl optionally substituted with —CH 2 NH 2 , —CH 2 OH, —CONHCH 3 , —NH 2 , —OH, or AryC;
3) piperidinyl optionally substituted with —CH 3 , —CH 2 NH 2 , —C(CH 3 ) 2 NH 2 , —CH 2 OH, —CONHCH 3 , —CH 2 NHSO

Assignees

• Merck Sharp & Dohme

Inventors

• Tang Haifeng
• Yang Shu-Wei
• Mandal Mihir
• Su Jing
• Li Guoqing
• Pan Weidong
• Tang Haiqun
• Dejesus Reynalda
• Pan Jianping
• Hagmann William
• Ding Fa-Xiang
• Xiao Li
• Pasternak Alexander
• Huang Yuhua
• Dong Shuzhi
• Yang Dexi

Classifications

• A61K31/43

  Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula [IMAGE cpc-sch-A61K-0952.gif], e.g. penicillins, penems · CPC title

• C07D403/12

  linked by a chain containing hetero atoms as chain links · CPC title

• A61K31/44

  Non condensed pyridines; Hydrogenated derivatives thereof · CPC title

• C07D401/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title