Substituted tricyclic heterocyclic compounds as metallo-beta-lactamase inhibitors

Abstract

The present invention relates to substituted tricyclic heterocyclic compounds of formula (I), their pharma- ceutically acceptable salts, and pharmaceutical compositions, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , X1, X2, X3, X4, X5, and "n" are as defined herein. The present invention also relates to compositions comprising a metallo-beta-lactamase (MBL) inhibitor compound of the present invention or a pharma- ceutically acceptable salt thereof, and a pharma- ceutical acceptable carrier, optionally in combination with a beta-lactam antibiotic and / or a beta-lactamase inhibitor. The present invention further relates to a method for treating a bacterial infection, comprising administering to a patient a therapeutically effective amount of a compound of the present invention in combination with a therapeutically effective amount of one or more beta-lactam antibiotics, and optionally in combination with one or more beta-lactamase inhibitor compounds. The compounds of the present invention are useful in the methods described herein for reducing or overcoming antibiotic resistance. [Formula 1] TIFF2024520130000093.tif4159 Formula I

Description

[Technical field]

[0001] The present invention relates to substituted tricyclic heterocyclic compounds of formula (I) and pharma- ceutically acceptable salts thereof.

[0002] [ka] Formula I

[0003] In particular, the present invention relates to substituted tricyclic heterocyclic compounds of formula (I) and pharma- ceutically acceptable salts thereof, which are useful as inhibitors of metallo-beta-lactamase (MBL) enzymes and are useful in reducing or eliminating antibiotic-resistant bacteria. More particularly, the present invention also relates to processes for preparing the compounds of formula (I). The present invention further relates to pharmaceutical compositions comprising the compounds of formula (I) or pharma- ceutically acceptable salts thereof. [Background technology]

[0004] Multidrug-resistant (MDR) microorganisms cause infections with higher mortality rates than those caused by susceptible bacteria. Thousands of people die from infections caused by antibiotic-resistant microorganisms. Furthermore, recent reports predict that antibiotic resistance could cause 300 million premature deaths by 2050. Resistance to all known antibiotics will emerge, resulting in an increase in untreatable infections and a lack of alternative antibiotics. (Munita,J.et al,HS Public Access.2016,4(2),1-37) Despite the many successes of beta-lactam antibiotics, bacteria have developed resistance to them, the most troublesome reason being a bacterial enzyme called beta-lactamase. This enzyme reacts with antibiotics and hydrolyzes the beta-lactam ring, thus inactivating the beta-lactam antibiotic. There are four classes of beta-lactamases in Gram-negative bacteria: serine beta-lactamases (SBLs) of classes A, C, and D, and MBLs (class B). SBL enzymes hydrolyze the β-lactam ring in a covalent mechanism using an active serine present in their catalytic site, whereas MBL enzymes require Zn metal to assist in coordination and hydroxide ions to hydrolyze the β-lactam ring. (Spencer, J., & Walsh, TR; Angewandte Chemie-International Edition, 2006, 45(7), 1022-1026; E. Zhang et al., 2018) Zinc-dependent class B metallo-beta-lactamases are mainly represented by NDM, VIM, and IMP types. IMP- and VIM-producing K. pneumonia were first observed in Japan in the 1990s and Southern Europe in 2001, respectively. IMP-positive strains still occur frequently in Japan and have also caused nosocomial outbreaks in China and Australia. However, the spread of IMP-producing Enterobacteriaceae elsewhere appears to be somewhat limited. VIM-producing Enterobacteriaceae can be frequently isolated in Mediterranean countries and have reached epidemic proportions in Greece. Isolations of VIM-producing strains remain rare in Northern Europe and the United States.In stark contrast, NDM-producing K. pneumonia isolates are characterized by their rapid spread from their origin in the Indian subcontinent to Western Europe, North America, Australia, and the Far East. Furthermore, the NDM gene has spread rapidly to various species other than K. pneumonia. To overcome the problem of increasing resistant bacteria, it is necessary to develop novel compounds such as β-lactamase inhibitors that can enhance the effectiveness of previously available antibiotics and are potent against both serine and MBL. Meredith A. Hackel's group discovered vaborbactam, a potent inhibitor of KPC and serine-lactamases. Vaborbactam has good efficacy against SBL but very low efficacy against MBL. (Hackel,MA,et al;2018,1-10) Zheng et al. (PLOS One 2013,8(5),e62955) disclose substituted 2,5-bistetrazolylmethyl-thiophenes and their use as β-lactamase inhibitors. (Zhang, YJ, et al; Chemical and Pharmaceutical Bulletin, 2019, 67(2), 135-142; Zhang, E. et al, Bioorganic and Medicinal Chemistry Letters, 2018, 28(2), 214-221).

[0005] Objective of the invention It is a primary object of the present invention to provide substituted tricyclic heterocyclic compounds of formula (I) and pharma- ceutically acceptable salts thereof.

[0006] Another object of the present invention is to provide substituted tricyclic heterocyclic compounds of formula (I) and pharma- ceutical acceptable salts thereof, which are useful as inhibitors of metallo-β-lactamase (MBL) enzymes and are useful in reducing or eliminating antibiotic resistant bacteria.

[0007] It is yet another object of the present invention to provide a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof.

[0008] It is yet another object of the present invention to provide a process for preparing the compounds of formula I. Summary of the Invention

[0009] Thus, the present invention provides a compound of formula I, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof.

[0010] [ka] During the ceremony, R1 is selected from the group consisting of: (i) -OH; (ii)-NR a R b (In the formula, R a and R b is independently, at each occurrence, selected from hydrogen, unsubstituted or substituted alkyl, and unsubstituted or substituted cycloalkyl and methoxy; or R a and R b may, together with the carbon atom to which they are attached, form a substituted or unsubstituted 3- to 7-membered saturated carbocyclic ring); (iii)-OR c (In the formula, R c is C 1~6 Alkyl, C 3~8 Cycloalkyl, C 3~8 Cycloalkyl, C 1~2 Alkyl, aryl, aryl-C 1~2 Alkyl, Heteroaryl, Heteroaryl-C 1~2 Alkyl, heterocyclyl or heterocyclyl-C 1~2 alkyl, each of which is optionally substituted by one or more substituents; (iv)-R d (In the formula, R d is independently, at each occurrence, selected from hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl; R2 may be the same or different in each occurrence and is independently selected from halogen, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, -C(O)OR e , -OC(O)OR e , -O(CR a R b )rC(O)OR e , -(CR a R b ) r -C(O)OR e , -C(O)R h , N.R. f R g , -C(O)NR f R g , -NR f C(O)R h , -NR f S(O)2R g , -S(O)0-2R e , and -S(O)NR f R g is selected from the group consisting of R a and R b may be the same or different in each occurrence and are independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl, or R a and R b may, together with the carbon atom to which they are attached, form an unsubstituted or substituted 3- to 7-membered saturated carbocyclic ring; R e may be the same or different in each occurrence and are independently selected from the group consisting of hydrogen, substituted or unsubstituted aryl, substituted or unsubstituted haloalkyl, and substituted or unsubstituted alkyl; R f and R g may be the same or different in each occurrence and independently represent hydrogen, substituted or unsubstituted alkyl, -(CRaRb) r -C(O)OR e, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted heterocyclylalkyl, or R f and R g may be taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted, saturated or unsaturated 3- to 10-membered cyclic ring, said unsaturated cyclic ring optionally having one or two double bonds, and in each occurrence, R h is a substituted or unsubstituted alkyl, or a substituted or unsubstituted aryl; "n" is an integer between 0 and 5 (inclusive), "r" is an integer between 1 and 3, inclusive; X1, X2, X3, or X5 are selected from C or N, with the proviso that only one or two of X1, X2, X3, or X5 may be N; R3 is hydrogen, halo, cyano, nitro, hydroxy, or -A 1 -B 1 -C 1 is selected from the group In the formula, A 1 is absent or the expression -[CR 1A R 1B ] P -, where p is an integer selected from 1 or 2, 3 or 4, and R 1A and R 1B are each independently hydrogen or C 1~2 alkyl, B 1 is absent or -O-, -C(O)-, -C(O)O-, -OC(O)-, -CH(OR 1C )-, -N(R 1C )-, N(R 1D )-C(O)-, -N(R 1D )-C(O)O-, -C(O)-N(R 1C )-, -N(R 1D )C(O)N(R1C )-, -S-, -SO-, -SO2-, -S(O)2N(R 1C )- or -N(R 1D )SO2-, where R 1C and R 1D are each independently selected from hydrogen or methyl; C 1 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Aryl, C 3~6 Cycloalkyl, C 3~6 cycloalkenyl, heterocyclyl, or heteroaryl; C 1 is optionally oxo, halo, cyano, nitro, hydroxy, carboxy, NR 1E R 1F , C 1~4 Alkoxy, C 1~4 Alkyl, C 3~8 Cycloalkyl, C 3~8 Cycloalkyl-C 1~3 Alkyl, C 1~4 Alkanoyl, C 1~4 Alkyl sulfonyl, aryl, aryloxy, aryl-C 1~2 Alkyl, heterocyclyl, heterocyclyloxy, heterocyclyl-C 1~2 Alkyl, heteroaryl, heteroaryloxy, heteroaryl-C 1~2 Alkyl, C(O)NR 1E R 1F , N.R. 1E C(O)R 1F , N.R. 1E S(O)2R 1F , and S(O)NR 1E R 1F and wherein R 1E and R 1F are each independently hydrogen, C 1~4 Alkyl or C 3~6 Cycloalkyl, or C 3~6 Cycloalkyl C 1~2 alkyl, or R 1Eand R 1F may be bonded together with the nitrogen atom to which they are attached to form a 4- to 7-membered heterocycle, C 1 Any alkyl, aryl, heterocyclyl, or heteroaryl group present within the above substituents may optionally be selected from the group consisting of halo, cyano, nitro, hydroxy, carboxy, NR 1G R 1H , C 1~2 Alkoxy, or C 1~2 Further substituted by alkyl, wherein R 1G and R 1H is hydrogen or C 1~2 alkyl, Or R 1C and C 1 may be joined together with the nitrogen atom to which they are attached to form a 4- to 7-membered heterocycle, which may optionally be selected from the group consisting of oxo, halo, cyano, nitro, hydroxy, carboxy, NR 1E R 1F , C 1~4 Alkoxy, C 1~4 Alkyl, C 3~8 Cycloalkyl, C 3~8 Cycloalkyl-C 1~3 Alkyl, C 1~4 Alkanoyl, C 1~4 Alkylsulfonyl, or C(O)NR 1E R 1F , N.R. 1E C(O)R 1F , N.R. 1E S(O)2R 1F , and S(O)NR 1E R 1F is replaced by R4 is hydrogen, cyano, halo, nitro, hydroxy, or -A 2 -B 2 -C 2 is selected from the group In the formula, A 2 is absent or the expression -[CR 2A R 2B ] q-, where q is an integer selected from 1 or 2, 3 or 4, and R 2A and R 2B are each independently hydrogen or C 1~2 alkyl, B 2 is absent or -O-, -C(O)-, -C(O)O-, -OC(O)-, -CH(OR 2C )-, -N(R 2C )-, N(R 2D )-C(O)-, -N(R 2D )-C(O)O-, -C(O)-N(R 2C )-, -N(R 2D )C(O)N(R 2C )-, -S-, -SO-, -SO2-, -S(O)2N(R 2C )- or -N(R 2D )SO2-, where R 2C and R 2D are each independently selected from hydrogen or methyl; C 2 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Aryl, C 3~6 Cycloalkyl, C 3~6 cycloalkenyl, heterocyclyl, or heteroaryl; C 2 is optionally oxo, halo, cyano, nitro, hydroxy, carboxy, NR 2E R 2F , C 1~4 Alkoxy, C 3~8 Cycloalkyl, C 1~4 Alkyl, C 3~8 Cycloalkyl-C 1~3 Alkyl, C 1~4 Alkylsulfonyl, C 1~4 Alkanoyl, aryl, aryloxy, aryl-C 1~2 Alkyl, heterocyclyl, heterocyclyloxy, heterocyclyl-C 1~2 Alkyl, heteroaryl, heteroaryloxy, heteroaryl-C 1~2 Alkyl, C(O)NR2E R 2F , N.R. 2E C(O)R 2F , N.R. 2E S(O)2R 2F , and S(O)NR 2E R 2F and wherein R 2E and R 2F are each independently hydrogen, C 1~4 Alkyl or C 3~6 Cycloalkyl, or C 3~6 Cycloalkyl C 1~2 alkyl, or R 2E and R 2F may be bonded together with the nitrogen atom to which they are attached to form a 4- to 7-membered heterocycle, C 2 Any alkyl, aryl, heterocyclyl, or heteroaryl group present within the above substituents may optionally be selected from the group consisting of halo, cyano, nitro, hydroxy, carboxy, NR 2G R 2H , C 1~2 Alkoxy, or C 1~2 Further substituted by alkyl, wherein R 2G and R 2H is hydrogen or C 1~2 alkyl, Or R 2C and C 2 may be joined together with the nitrogen atom to which they are attached to form a 4- to 7-membered heterocycle, which may optionally be selected from the group consisting of oxo, halo, cyano, nitro, hydroxy, carboxy, NR 2E R 2F , C 1~4 Alkoxy, C 1~4 Alkyl, C 3~8 Cycloalkyl, C 3~8 Cycloalkyl-C 1~3 Alkyl, C 1~4 Alkanoyl, C 1~4 Alkylsulfonyl, or C(O)NR 2E R 2F , N.R. 2E C(O)R2F , N.R. 2E S(O)2R 2F , and S(O)NR 2E R 2F is replaced by R5 is hydrogen, halo, cyano, hydroxy, nitro, or -A 3 -B 3 -C 3 is selected from the group In the formula, A 3 is absent or the expression -[CR 3A R 3B ] r -, where r is an integer selected from 1 or 2, 3 or 4, and R 3A and R 3B are each independently hydrogen or C 1~2 alkyl, B 3 is absent or -O-, -C(O)-, -C(O)O-, -OC(O)-, -CH(OR 3C )-, -N(R 3C )-, N(R 3D )-C(O)-, -N(R 3D )-C(O)O-, -C(O)-N(R 3C )-, -N(R 3D )C(O)N(R 3C )-, -S-, -SO-, -SO2-, -S(O)2N(R 3C )- or -N(R 3D )SO2-, where R 3C and R 3D are each independently selected from hydrogen or methyl; C 3 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Aryl, C 3~6 Cycloalkyl, C 3~6 cycloalkenyl, heteroaryl, or heterocyclyl; C 3 is optionally oxo, halo, cyano, nitro, hydroxy, carboxy, NR 3E R 3F , C1~4 Alkoxy, C 1~4 Alkyl, C 3~8 Cycloalkyl, C 3~8 Cycloalkyl-C 1~3 Alkyl, C 1~4 Alkanoyl, C 1~4 Alkyl sulfonyl, aryl, aryloxy, aryl-C 1~2 Alkyl, heterocyclyl, heterocyclyloxy, heterocyclyl-C 1~2 Alkyl, heteroaryl, heteroaryloxy, heteroaryl-C 1~2 Alkyl, C(O)NR 3E R 3F , N.R. 3E C(O)R 3F , N.R. 3E S(O)2R 3F , and S(O)NR 3E R 3F and wherein R 3E and R 3F are each independently hydrogen, C 1~4 Alkyl or C 3~6 Cycloalkyl, or C 3~6 Cycloalkyl C 1~2 alkyl, or R 3E and R 3F may be bonded together with the nitrogen atom to which they are attached to form a 4- to 7-membered heterocycle, C 3 Any alkyl, aryl, heterocyclyl, or heteroaryl group present within the above substituents may optionally be selected from the group consisting of halo, nitro, cyano, hydroxy, carboxy, NR 3G R 3H , C 1~2 Alkoxy, or C 1~2 Further substituted by alkyl, wherein R 3G and R 3H is hydrogen or C 1~2 alkyl, Or R 3C and C 3may be joined together with the nitrogen atom to which they are attached to form a 4- to 7-membered heterocycle, which may optionally be selected from the group consisting of oxo, halo, cyano, hydroxy, nitro, carboxy, NR 3E R 3F , C 1~4 Alkoxy, C 1~4 Alkyl, C 3~8 Cycloalkyl, C 3~8 Cycloalkyl-C 1~3 Alkyl, C 1~4 Alkanoyl, C 1~4 Alkylsulfonyl, or C(O)NR 3E R 3F , N.R. 3E C(O)R 3F , N.R. 3E S(O)2R 3F , and S(O)NR 3E R 3F is replaced by R6 is hydrogen, halo, cyano, nitro, hydroxy, or -A 4 -B 4 -C 4 is selected from the group In the formula, A 4 is absent or the expression -[CR 4A R 4B ] s -, where p is an integer selected from 1 or 2, 3 or 4, and R 4A and R 4B are each independently hydrogen or C 1~2 alkyl, B 4 is absent or -O-, -C(O)-, -C(O)O-, -OC(O)-, -CH(OR 4C )-, -N(R 4C )-, N(R 4D )-C(O)-, -N(R 4D )-C(O)O-, -C(O)-N(R 4C )-, -N(R 4D )C(O)N(R 4C )-, -S-, -SO-, -SO2-, -S(O)2N(R 4C )- or -N(R 4D)SO2-, where R 4C and R 4D are each independently selected from hydrogen or methyl; C 4 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Aryl, C 3~6 Cycloalkyl, C 3~6 cycloalkenyl, heterocyclyl, or heteroaryl; C 4 is optionally oxo, halo, cyano, nitro, hydroxy, carboxy, NR 4E R 4F , C 1~4 Alkoxy, C 1~4 Alkyl, C 3~8 Cycloalkyl, C 3~8 Cycloalkyl-C 1~3 Alkyl, C 1~4 Alkanoyl, C 1~4 Alkyl sulfonyl, aryl, aryloxy, aryl-C 1~2 Alkyl, heterocyclyl, heterocyclyloxy, heterocyclyl-C 1~2 Alkyl, heteroaryl, heteroaryloxy, heteroaryl-C 1~2 Alkyl, C(O)NR 4E R 4F , N.R. 4E C(O)R 4F , N.R. 4E S(O)2R 4F , and S(O)NR 4E R 4F and wherein R 4E and R 4F are each independently hydrogen, C 1~4 Alkyl or C 3~6 Cycloalkyl, or C 3~6 Cycloalkyl C 1~2 alkyl, or R 4E and R 4F may be bonded together with the nitrogen atom to which they are attached to form a 4- to 7-membered heterocycle, C4 Any alkyl, aryl, heterocyclyl, or heteroaryl group present within the above substituents may optionally be selected from the group consisting of halo, cyano, nitro, hydroxy, carboxy, NR 4G R 4H , C 1~2 Alkoxy, or C 1~2 Further substituted by alkyl, wherein R 4G and R 4H is hydrogen or C 1~2 alkyl, Or R 4C and C 4 may be joined together with the nitrogen atom to which they are attached to form a 4- to 7-membered heterocycle, which may optionally be selected from the group consisting of oxo, halo, cyano, nitro, hydroxy, carboxy, NR 4E R 4F , C 1~4 Alkoxy, C 1~4 Alkyl, C 3~8 Cycloalkyl, C 3~8 Cycloalkyl-C 1~3 Alkyl, C 1~4 Alkanoyl, C 1~4 Alkylsulfonyl, or C(O)NR 4E R 4F , N.R. 4E C(O)R 4F , N.R. 4E S(O)2R 4F , and S(O)NR 4E R 4F is replaced by R7 is hydrogen, halo, nitro, cyano, hydroxy, or -A 5 -B 5 -C 5 is selected from the group In the formula, A 5 is absent or the expression -[CR 5A R 5B ] t -, where "t" is an integer selected from 1 or 2, 3 or 4, and R 5A and R 5B are each independently hydrogen or C 1~2 alkyl, B 5 is absent or -O-, -C(O)-, -C(O)O-, -OC(O)-, -CH(OR 5C )-, -N(R 5C )-, N(R 5D )-C(O)-, -N(R 5D )-C(O)O-, -C(O)-N(R 5C )-, -N(R 5D )C(O)N(R 5C )-, -S-, -SO-, -SO2-, -S(O)2N(R 5C )- or -N(R 5D )SO2-, where R 5C and R 5D are each independently selected from hydrogen or methyl; C 5 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Aryl, C 3~6 Cycloalkyl, C 3~6 cycloalkenyl, heteroaryl, or heterocyclyl; C 5 is optionally oxo, cyano, halo, nitro, carboxy, hydroxy, NR 5E R 5F , C 1~4 Alkoxy, C 1~4 Alkyl, C 3~8 Cycloalkyl, C 3~8 Cycloalkyl-C 1~3 Alkyl, C 1~4 Alkanoyl, C 1~4 Alkyl sulfonyl, aryl, aryloxy, aryl-C 1~2 Alkyl, heterocyclyl, heterocyclyloxy, heterocyclyl-C 1~2 Alkyl, heteroaryl, heteroaryloxy, heteroaryl-C 1~2 Alkyl, C(O)NR 5E R 5F , N.R. 5E C(O)R 5F , N.R. 5E S(O)2R 5F , and S(O)NR 5E R5F and wherein R 5E and R 5F are each independently hydrogen, C 1~4 Alkyl or C 3~6 Cycloalkyl, or C 3~6 Cycloalkyl C 1~2 alkyl, or R 5E and R 5F may be bonded together with the nitrogen atom to which they are attached to form a 4- to 7-membered heterocycle, C 5 Any alkyl, aryl, heterocyclyl, or heteroaryl group present within the above substituents may optionally be selected from the group consisting of halo, cyano, nitro, hydroxy, carboxy, NR 5G R 5H , C 1~2 Alkoxy, or C 1~2 Further substituted by alkyl, wherein R 5G and R 5H is hydrogen or C 1~2 alkyl, Or R 5C and C 5 may be joined together with the nitrogen atom to which they are attached to form a 4- to 7-membered heterocycle, which may optionally be selected from the group consisting of oxo, halo, cyano, nitro, hydroxy, carboxy, NR 5E R 5F , C 1~4 Alkoxy, C 1~4 Alkyl, C 3~8 Cycloalkyl, C 3~8 Cycloalkyl-C 1~3 Alkyl, C 1~4 Alkanoyl, C 1~4 Alkylsulfonyl, or C(O)NR 5E R 5F , N.R. 5E C(O)R 5F , N.R. 5E S(O)2R 5F , and S(O)NR 5E R 5F is replaced by R8 and R9, which may be the same or different in each occurrence, are selected from the group consisting of hydrogen, hydroxy, halogen, cyano, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl, or R8 and R9, together with the carbon atom to which they are attached, may form a substituted or unsubstituted 3- to 7-membered saturated carbocyclic ring; R 10 and R 11 may be the same or different in each occurrence and are independently selected from hydrogen, halogen, cyano, hydroxy, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl, or R 10 and R 11 may be taken together with the carbon atom to which they are attached to form a substituted or unsubstituted 3- to 7-membered saturated carbocyclic ring.

[0011] In one embodiment of the invention, the compound of formula I is selected from the group consisting of: 1. Methyl 3-(3,5-dichlorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 2. Methyl 3-(3,5-dichlorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 3. Methyl 3-(5-fluoro-2-methoxyphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 4. Methyl 3-(2-methoxyphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 5. Methyl 3-(4-methoxyphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 6. Methyl 3-(3,4-difluorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 7. Methyl 3-(5-chloro-2-methoxyphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 8. Methyl 3-(4-(tert-butyl)phenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 9. Methyl 3-(4-fluorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 10. Methyl 3-phenyl-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 11. Methyl 3-(2-fluorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 12. Methyl 3-(3-fluorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 13. Methyl 3-(4-chlorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 14. Methyl 3-(2-chlorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 15. Methyl 3-(3-chlorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 16. Methyl 3-(2,4-dichlorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 17. Methyl 3-(2,3-difluorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 18. Methyl 3-(3,5-dimethylphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 19. Methyl 3-(2-fluoro-4-methylphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 20. Methyl 3-(2,3-dichlorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 21. Methyl 3-(pyridin-4-yl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 22. Methyl 3-(3,5-difluorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 23. Methyl 3-(pyrimidin-5-yl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 24. Methyl 3-(5-fluoropyridin-3-yl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 25. Methyl 3-(5-chloropyridin-3-yl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 26. Methyl 3-(4-fluoro-3-methoxyphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 27. Methyl 3-(3-chloro-5-methylphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 28. Methyl 3-(3-chloro-5-fluorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 29. Methyl 3-(3-chloro-5-methoxyphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 30. Methyl 3-(3,4,5-trichlorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 31. Methyl 3-(3,5-dimethoxyphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 32. Methyl 3-(3-fluoro-5-methoxyphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 33. Methyl 3-(2,3-dichlorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 34. 3-(5-Fluoro-2-methoxyphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid; 35. 3-(2-Methoxyphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid; 36. 3-(4-Methoxyphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid; 37. 3-(3,4-Difluorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid; 38. 3-(5-Chloro-2-methoxyphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid; 39. 3-(4-(tert-butyl)phenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid; 40. 3-(4-Fluorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid; 41. 3-(2-Fluorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid; 42. 3-(3-Fluorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid; 43. 3-(4-Chlorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid; 44. 3-(2-Chlorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid; 45. 3-(3-Chlorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid; 46. ​​3-(2,4-Dichlorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid; 47. 3-(2,3-Difluorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid; 48. 3-(3,5-Dimethylphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid; 49. 3-(2-Fluoro-4-methylphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid; 50. 3-(Pyridin-4-yl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid; 51. 3-(3,5-Difluorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid; 52. 3-(5-fluoropyridin-3-yl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid; 53. 3-(5-chloropyridin-3-yl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid; 54. 3-(2,3-Dichlorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid; 55. 3-(Pyrimidin-5-yl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid; 56. 3-(4-Fluoro-2-methoxyphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid; 57. 3-(3-chloro-5-methylphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid; 58. 3-(3-chloro-5-fluorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid; 59. 3-(3-chloro-5-methoxyphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid; 60. 3-(3,4,5-trichlorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid; 61. 3-(3,5-Dimethoxyphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid; 62. 3-(3-Fluoro-5-methoxyphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid; 63. 3-Phenyl-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid; 64. 3-(3-chloro-5-fluorophenyl)-5-methyl-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid; 65. 7-Bromo-3-(3,5-dichlorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid.

[0012] In one embodiment, the present invention provides a method for preparing a compound of formula I, comprising: i. reducing the tetralone of formula (1) with a reducing agent such as sodium borohydride to give a compound of formula (2);

[0013] [ka] ii. formylation of the compound of formula (2) obtained in step (i) using the in situ prepared Vilsmeier-Haack reagent / adduct to obtain a compound of formula (3);

[0014] [ka] iii. treating the aldehyde of formula (3) obtained in step (ii) with an azido ester compound of formula (4) in the presence of a base such as sodium ethoxide, sodium methoxide, and the like to obtain a compound of formula (5);

[0015] [ka] iv. cyclization of the compound of formula (5) in the presence of a suitable Lewis acid or under acidic conditions to give a compound of formula (6);

[0016] [ka] v. halogenating the compound of formula (6) using a halogenating agent such as NBS, NIS, etc. to obtain a halogenated compound of formula (7);

[0017] [ka] vi. coupling reaction of the halo compound of formula (7) with an aryl / heteroaryl boronic acid or aryl / heteroaryl boronic acid ester to obtain a compound of formula (Ia);

[0018] [ka] vii. converting the compound of formula (Ia) to the compound of formula (I) by hydrolysis of the corresponding ester using a base such as LiOH, K2CO3, NaOH,

[0019] [ka] viii. A process is provided, wherein in the acid of formula (I), -COOH may be converted to the corresponding amide, ester, etc., wherein R1 is the same as defined above.

[0020] In another embodiment of the invention is a compound of formula I in free form or in the form of a salt or a pharma- ceutically acceptable salt.

[0021] In another embodiment, the present invention provides pharmaceutical compositions comprising at least one compound of formula (I), optionally together with a pharma- ceutically acceptable excipient.

[0022] In yet another embodiment of the invention, the composition further comprises an effective amount of a beta-lactam antibiotic.

[0023] In yet another embodiment of the invention, the pharma- ceutically acceptable excipient is selected from the group consisting of water, saline, alcohol, polyethylene glycol, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, gum arabic, lower alkyl ethers of stearic acid or cellulose, salicylic acid, fatty acids, fatty acid amines, fatty acid mono- and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose, and polyvinylpyrrolidone.

[0024] In yet another embodiment of the invention, the composition is used as a beta-lactamase inhibitor or drug.

[0025] Yet another embodiment of the invention is the use of a compound of formula (I) or a pharma- ceutical acceptable salt thereof, for inhibiting beta-lactamase activity, in the manufacture of a medicament for inhibiting beta-lactamase activity, in combination with a beta-lactam antibiotic for treating a bacterial infection, or in combination with a beta-lactam antibiotic in the manufacture of a medicament for treating a bacterial infection.

[0026] In yet another embodiment, the present invention provides a zwitterion of the compound of formula I. [Brief description of the drawings]

[0027] [Figure 1] FIG. 1 depicts the process steps for preparing compounds of formula I. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0028] The present invention provides substituted tricyclic heterocyclic compounds of formula (I) and pharma- ceutically acceptable salts thereof.

[0029] [ka] Formula I

[0030] Compounds of formula (I) (wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , X1, X2, X3, X4, X5, and "n" are as defined herein above) can be prepared starting from commercially available tetralone of formula (1) following the procedure as shown in FIG. 1. Thus, the tetralone of formula (1) undergoes reduction using a suitable reducing agent such as sodium borohydride to give the compound of formula (2). The compound of formula (2) undergoes formylation using an in situ prepared Vilsmeier-Haack reagent / adduct to give the compound of formula (3). Further, the aldehyde of formula (3) is treated with an azido ester compound of formula (4) in the presence of a base such as sodium ethoxide, sodium methoxide, and the like to give the compound of formula (5). The compound of formula (5) undergoes cyclization in the presence of a suitable Lewis acid or under acidic conditions to give the compound of formula (6). The compound of formula (6) undergoes halogenation using a halogenating agent such as NBS, NIS, and the like to give the halogenated compound of formula (7). The halo compound of formula (7) undergoes a coupling reaction with a suitable aryl / heteroaryl boronic acid or aryl / heteroaryl boronic acid ester to obtain a compound of formula (Ia). The compound of formula (Ia) is further converted to a compound of formula (I) by hydrolyzing the corresponding ester with a base such as LiOH, K2CO3, NaOH, etc. In the acid of formula (I), -COOH may be converted to the corresponding amide, ester, etc.

[0031] The term "halogen" or "halo" means fluorine, chlorine, bromine, or iodine. The term "alkyl" refers to a hydrocarbon radical derived from an alkane (e.g., C), containing only carbon and hydrogen atoms in the backbone, no unsaturation, having 1 to 6 carbon atoms, and attached to the remainder of the molecule by a single bond. 1~6 Alkyl or C 1~6"alkyl" refers to a radical that is an alkyl group, representative radicals include, for example, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, and the like. Unless stated or explained to the contrary, all alkyl radicals described or claimed herein can be straight or branched.

[0032] The term "alkenyl" refers to a hydrocarbon radical containing 2 to 10 carbon atoms and containing at least one carbon-carbon double bond. Non-limiting examples of alkenyl groups include, for example, C 2~6 Alkenyl, C 2~4 Alkenyl, ethenyl, 1-propenyl, 2-propenyl (allyl), etc. Unless stated or explained to the contrary, all alkenyl groups described or claimed herein can be straight or branched.

[0033] The term "alkynyl" refers to a hydrocarbon radical containing 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond. Non-limiting examples of alkynyl groups include, for example, C 2~6 Alkynyl, C 2~4 Includes alkynyl, ethynyl, propynyl, butynyl, etc. Unless stated or explained to the contrary, all alkynyl groups described or claimed herein can be straight or branched.

[0034] The term "haloalkyl" refers to an alkyl group, as defined above, substituted by one or more halogen atoms, as defined above. For example, C 1~6 Haloalkyl or C 1~4Haloalkyl. Preferably, haloalkyl is monohaloalkyl, dihaloalkyl or polyhaloalkyl, including perhaloalkyl. Monohaloalkyl can have one iodine, bromine, chlorine or fluorine atom. Dihaloalkyl and polyhaloalkyl groups can be substituted with two or more of the same halogen atom or a combination of different halogen atoms. Preferably, polyhaloalkyl is substituted with up to 12 halogen atoms. Non-limiting examples of haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, etc. Perhaloalkyl refers to an alkyl where all hydrogen atoms are replaced with halogen atoms. Unless stated or explained to the contrary, all haloalkyl groups described or claimed herein can be linear or branched.

[0035] The term "alkoxy" refers to an alkyl group attached to the remainder of the molecule via an oxygen linkage. Representative examples of such groups include -OCH3 and -OC2H5. Unless stated or explained to the contrary, all alkoxy groups described or claimed herein may be straight or branched.

[0036] The term "alkoxyalkyl" refers to an alkoxy group, as defined above, directly attached to an alkyl group, as defined above, e.g., -CH2-O-CH3, -CH2-O-CH2CH3, -CH2CH2-O-CH3, and the like.

[0037] The term "cycloalkyl" refers to a non-aromatic monocyclic or polycyclic ring system having 3 to 12 carbon atoms, e.g., C 3~10 Cycloalkyl, C 3~6cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. Examples of polycyclic cycloalkyl groups include, but are not limited to, perhydronaphthyl, adamantyl, and norbornyl groups, bridged cyclic groups, or spiro bicyclic groups (e.g., spiro(4,4)non-2-yl), and the like.

[0038] The term "aryl" refers to aromatic radicals having 6 to 14 carbon atoms (including monocyclic, bicyclic, and tricyclic aromatic systems), such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, and biphenyl.

[0039] The term "heterocyclic ring" or "heterocyclyl ring" or "heterocyclyl", unless otherwise specified, refers to a non-aromatic substituted or unsubstituted 3-15 membered ring consisting of carbon atoms and one or more heteroatoms independently selected from N, O, or S. The heterocyclic ring may be a monocyclic, bicyclic, or tricyclic ring system, which may include fused, bridged, or spiro ring systems, and the nitrogen, carbon, oxygen, or sulfur atoms in the heterocyclic ring may be optionally oxidized to various oxidation states. In addition, the nitrogen atom may be optionally quaternized, the heterocyclic ring or heterocyclyl may optionally contain one or more olefinic bonds, and one or two carbon atoms in the heterocyclic ring or heterocyclyl may be interrupted by -CF2-, -C(O)-, -S(O)-, S(O)2, etc. In addition, the heterocyclic ring may be fused to an aromatic ring. Non-limiting examples of heterocyclic rings include azetidinyl, benzopyranyl, chromanyl, decahydroisoquinolyl, indolinyl, isoindolinyl, isochromanyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, octahydroindolyl, octahydroisoindolyl, perhydroisoindolyl, and the like. Examples of heterocyclic rings include bromoazepinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, piperidinyl, phenothiazinyl, phenoxazinyl, quinuclidinyl, tetrahydroisoquinolyl, tetrahydrofuryl, tetrahydropyranyl, thiazolinyl, thiazolidinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone indoline, benzodioxole, tetrahydroquinoline, tetrahydrobenzopyran, etc. The heterocyclic ring can be attached by any atom of the heterocyclic ring that results in the creation of a stable structure.

[0040] The term "heteroaryl" refers to a substituted or unsubstituted 5- to 14-membered aromatic heterocyclic ring having one or more heteroatoms independently selected from N, O, or S, unless otherwise specified. Heteroaryls can be monocyclic, bicyclic, or tricyclic ring systems. The heteroaryl ring can be attached by any atom of the heteroaryl ring that results in the creation of a stable structure. Non-limiting examples of heteroaryl rings include oxazolyl, isoxazolyl, imidazolyl, furyl, indolyl, isoindolyl, pyrrolyl, triazolyl, triazinyl, tetrazolyl, thienyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, carbazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl, quinoxalinyl, quinolyl, isoquinolyl, thiadiazolyl, indolizinyl, acridinyl, phenazinyl, phthalazinyl, and the like.

[0041] "Treating" or "treatment" of a condition, disorder, or condition includes: (a) preventing or delaying the appearance of clinical symptoms of a developing condition, disorder, or condition in a subject who may be afflicted with or predisposed to the condition, disorder, or condition, but who has not yet experienced or displayed clinical or subclinical symptoms of the condition, disorder, or condition; (b) inhibiting the condition, disorder, or condition, i.e., arresting or reducing the onset of the disease or at least one clinical or subclinical symptom thereof; (c) alleviating the disease, disorder, or condition, or at least one clinical or subclinical symptom thereof; or (d) palliating the disease, disorder, or condition, i.e., causing a reduction in the condition, disorder, or condition, or at least one clinical or subclinical symptom thereof.

[0042] The term "inhibitor" refers to a molecule that binds to an enzyme and partially or completely inhibits the activity of that enzyme.

[0043] The term "effective amount" refers to the amount of each active agent required to confer the desired effect (e.g., inhibition of MBL) on a subject, either alone or in combination with one or more other active agents. As those skilled in the art will recognize, the effective amount will vary depending on the particular condition being treated, the severity of the condition, individual patient parameters including age, size, health, weight, and sex, the nature of the concomitant treatment (if any), the duration of the treatment, the particular route of administration, and similar factors within the knowledge and expertise of the medical practitioner. These factors are well known to those skilled in the art and can be addressed with only routine experimentation. In general, it is preferred to use the maximum dose of each component or combination thereof, i.e., the highest safe dose based on sound medical judgment. However, those skilled in the art will understand that a patient may require a lower dose or tolerate a lower dose for medical, psychological, or virtually any other reason.

[0044] "Therapeutically effective amount" means the amount of a compound that, when administered to a subject for treating a disease, disorder, or condition, is sufficient to produce the effect for which it is administered in the subject. The "therapeutically effective amount" varies depending on the compound, the disease and its severity, and the age, weight, health, and responsiveness of the subject to be treated.

[0045] Pharmaceutically acceptable salts The compounds of the present invention can form salts with acids or bases. The compounds of the present invention can be sufficiently basic or acidic to form stable non-toxic acid or base salts, and may be suitable for administration as pharmaceutically acceptable salts. Non-limiting examples of pharmaceutically acceptable salts include inorganic / organic acid addition salts formed by addition of acids (including hydrochlorides). Non-limiting examples of pharmaceutically acceptable salts include inorganic / organic base addition salts formed by addition of bases. The compounds of the present invention can also form salts with amino acids. Pharmaceutically acceptable salts can be obtained by reacting a sufficiently basic compound, such as an amine, with a suitable acid, using standard procedures well known in the art.

[0046] Screening the compounds of the present invention for MBL inhibitory activity can be accomplished by using a variety of in vitro methods described herein below or known in the art.

[0047] Pharmaceutical Compositions The present invention relates to a pharmaceutical composition comprising a compound of formula (1) disclosed herein or a pharma- ceutical acceptable salt thereof. In particular, it is a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of formula (I) described herein and at least one pharma- ceutical acceptable excipient (e.g., carrier or diluent). Preferably, the contemplated pharmaceutical composition comprises a compound or compounds described herein in an amount sufficient to inhibit MBL and treat the diseases described herein when administered to a subject.

[0048] Contemplated subjects include, for example, living cells and mammals, including humans. The compounds of the present invention may be combined with a pharma- ceutically acceptable excipient (e.g., a carrier or diluent), diluted by a carrier, or enclosed within a carrier, which may take the form of a capsule, sachet, paper, or other container. Pharmaceutically acceptable excipients include pharmaceutical agents that do not themselves induce the production of antibodies harmful to the individual to whom the composition is administered and that may be administered without undue toxicity.

[0049] Suitable carriers or excipients include, but are not limited to, water, salt solutions, alcohol, polyethylene glycol, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, gum arabic, lower alkyl ethers of stearic acid or cellulose, salicylic acid, fatty acids, fatty acid amines, fatty acid mono- and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose, and polyvinylpyrrolidone.

[0050] The pharmaceutical composition may also contain one or more pharma- ceutically acceptable auxiliary agents, wetting agents, emulsifying agents, suspending agents, preservatives, salts for influencing osmotic pressure, buffers, sweetening agents, flavoring agents, coloring agents, or any combination of the foregoing.The pharmaceutical composition of the present invention may be formulated to provide quick, sustained, or delayed release of the active ingredient after administration to a subject by using procedures known in the art.

[0051] The pharmaceutical compositions described herein can be prepared by conventional techniques known in the art. For example, the active compound can be mixed with a carrier, diluted with a carrier, or enclosed in a carrier that can take the form of an ampoule, capsule, sachet, paper, or other container. When the carrier functions as a diluent, it can be a solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound. The active compound can be adsorbed into a particulate solid container, such as a sachet. The pharmaceutical composition can take conventional forms, such as capsules, tablets, caplets, oral disintegrating tablets, aerosols, solutions, suspensions, or products for topical application.

[0052] The route of administration can be any route that effectively transports the active compound of the present invention to the appropriate or desired site of action. Suitable routes of administration include, but are not limited to, oral, oral inhalation, nasal, pulmonary, buccal, subcutaneous, intradermal, transdermal, parenteral, rectal, depot, subcutaneous, intravenous, intraurethral, ​​intramuscular, intranasal, ocular (e.g., by eye drops), or topical (e.g., by topical ointment).

[0053] Oral solid formulations include, but are not limited to, tablets, caplets, capsules (soft or hard gelatin), orally disintegrating tablets, dragees (containing the active ingredient in powder or pellet form), troches, and lozenges. Tablets, dragees, or capsules with talc and / or carbohydrate carriers or binders or the like are particularly suitable for oral application. Liquid formulations include, but are not limited to, syrups, emulsions, suspensions, solutions, soft gelatin, and sterile injectable liquids, such as aqueous or non-aqueous liquid suspensions or solutions. For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions in which the active compound is dissolved in polyhydroxylated castor oil.

[0054] The pharmaceutical preparation is preferably in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate amounts of active components. The unit dosage form may be a packaged preparation containing discrete amounts of the preparation (for example, pocketed tablets, capsules, and powders in vials or ampoules). The unit dosage form may also be a capsule, tablet, caplet, cachet, or lozenge itself, or the appropriate number of any of these in packaged form.

[0055] When administered to a subject patient, the total daily dose of the compound of the present invention will of course depend on the mode of administration. For example, oral administration may require a total daily dose that is greater than that of intravenous administration (direct administration into blood). The amount of active ingredient in a unit dose preparation can vary or be adjusted in the range of 0.1mg to 1000mg for oral administration, and 1pg to 5000pg for inhalation administration, depending on the potency of the active ingredient or the mode of administration.

[0056] A person skilled in the relevant art can determine the appropriate dose of the compound to be used in the treatment of the diseases and disorders described herein. Generally, the therapeutic dose is identified by a dose-ranging study in subjects based on preliminary evidence from animal studies. The dose should be sufficient to provide the desired therapeutic benefit without causing undesirable side effects in the patient. For example, the daily dose of the MBL inhibitor can range from about 0.1 to about 30.0 mg / kg for oral administration. The mode of administration, dosage form, suitable pharmaceutical excipients, diluents, or carriers can also be fully used and adjusted by a person skilled in the art. All envisioned changes and modifications are within the scope of the present invention.

[0057] Treatment method The present invention provides compounds of formula (I) and pharmaceutical compositions thereof as MBL inhibitors for treating diseases, disorders or conditions associated with antimicrobial resistance (AMR). The present invention further provides a method of treating a disease, disorder or condition associated with antimicrobial resistance in a subject in need thereof by administering a therapeutically effective amount of a compound or pharmaceutical composition of the present invention to the subject.

[0058] In another aspect, the present invention relates to a method of treating a disease, disorder, or condition associated with MBL, AMR, or antibacterial agents, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof.

[0059] The present invention includes a compound of formula (I) or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a disease or disorder described herein. EXAMPLES

[0060] The following examples are offered by way of illustration and therefore should not be construed as limiting the scope of the invention.

[0061] General procedure for preparing intermediate 1 Methyl 3-iodo-4,5-dihydro-1H-benzo[g]indole-2-carboxylate

[0062] [ka]

[0063] Step 1: Preparation of 1,2,3,4-tetrahydronaphthalen-1-ol

[0064] [ka] NaBH4 (3.88 g, 102.61 mmol) was added to a stirred solution of 1-tetralone (15 g, 102.61 mmol) in methanol (256 mL). The reaction mixture was stirred for 1 h and then concentrated under reduced pressure to about 35 mL. Water was added to the reaction mixture (75 mL) and extracted with ethyl acetate (2 x 100 mL). The organic phase was washed with brine solution (40 mL), dried over Na2SO4 and filtered. The organic layer was concentrated to give the crude compound. The crude compound was purified by flash column chromatography (Biotage) using eluent (1:9, ethyl acetate:n-hexane) to give the title compound (15.1 g, 99.3% yield) as a pale yellow oil. LCMS (ESI): m / z = 148.2 (M) +

[0065] Step 2: Preparation of 3,4-dihydronaphthalene-2-carbaldehyde

[0066] [ka] To a stirred solution of 1,2,3,4-tetrahydronaphthalene-1-ol (15.4 g, 97.5 mmol) in DMF (39.22 mL) was added POCl3 (22.66 mL) dropwise at 0° C. and stirred for 1 h. The reaction mixture was allowed to warm to room temperature and stirred for an additional hour. The stirred solution was then heated at 100° C. overnight. The reaction mixture was quenched with water at room temperature and basified with 3 M NaOH. The reaction mixture was extracted with ethyl acetate (3×550 mL), washed with brine solution, dried over Na2SO4, and concentrated to give the crude compound. The crude compound was purified by flash column chromatography (Biotage) using eluent (1:9, ethyl acetate:n-hexane) to give 3,4-dihydronaphthalene-2-carbaldehyde (8.5 g, 52% yield) as a pale yellow oil. 1 H NMR(300MHz,DMSO-D6)δ=9.62(s,1H),7.51(s,1H),7.37-7.24(m,4H),2.79(t,J=8.58Hz,2H),2.42(t,J=8.58Hz,2H).

[0067] Step 3: Preparation of methyl (Z)-2-azido-3-(3,4-dihydronaphthalen-2-yl)acrylate

[0068] [ka] A round bottom flask purged and maintained under inert atmosphere was charged with 3,4-dihydronaphthalene-2-carbaldehyde (8.5 g, 53.95 mmol), methyl azidoacetate (15.5 g, 134.18 mmol, 1.18 mL) in dry MeOH (175 mL) at -15°C. After 15 min, a solution of NaOMe (26.34 mL) in MeOH (44 mL) was added dropwise over 20 min to the stirred mixture and stirred at -15°C for 90 min. It was further allowed to warm slowly to 4°C and stirred for 12 h. The reaction mixture was then poured into ice-cold saturated aqueous NH4Cl (215 mL). The resulting precipitate was isolated on a fritted funnel and washed with deionized water until the filtrate was clear. The solid was dissolved in DCM and dried over Na2SO4. The organic phase was filtered and evaporated in vacuo to give the crude compound. The crude compound was purified by flash column chromatography (Biotage) using eluent (1:9, ethyl acetate:n-hexane) to give methyl (Z)-2-azido-3-(3,4-dihydronaphthalen-2-yl)acrylate (9.65 g, 70% yield) as an oil containing traces of cyclized compound, which was used further in the next reaction.

[0069] Step 4: Preparation of methyl 4,5-dihydro-1H-benzo[g]indole-2-carboxylate

[0070] [ka] To a stirred solution of methyl 4,5-dihydro-1H-benzo[g]indole-2-carboxylate (9.654 g, 37.82 mmol) in DCM (55 mL), ZnI2 (0.604 g, 1.89 mmol) was added slowly and stirred at room temperature overnight. The resulting solution was filtered through a pad of Celite and concentrated under vacuum to give the crude compound. The crude compound was purified by flash column chromatography (Biotage) using eluent (2:8, ethyl acetate:n-hexane) to give methyl 4,5-dihydro-1H-benzo[g]indole-2-carboxylate (5.86 g, 68% yield) as a pale yellow solid. LCMS(ESI):m / z=228.1(M+H) + ;1 H NMR(300MHz,DMSO-D6)δ=12.08(s,1H),7.84(d,J=7.6Hz,1H),7.18(t,J=7.5Hz,2H),7.13-7. 07(m,1H),6.70-6.62(m,1H),3.75(s,3H),2.82(t,J=7.5Hz,2H),2.62(dd,J=8.5,6.5Hz,2H).

[0071] Step 5: Preparation of methyl 3-iodo-4,5-dihydro-1H-benzo[g]indole-2-carboxylate To a stirred solution of methyl 3-iodo-4,5-dihydro-1H-benzo[g]indole-2-carboxylate (5.86 g, 25.8 mmol) in DMF (60 mL) was added N-iodosuccinamide (6.38 g, 28.34 mmol). The resulting mixture was stirred at room temperature for 3 h and then concentrated in vacuo. The crude mixture was dissolved in DCM and washed with saturated NaHCO3. The organic extract was dried over Na2SO4, filtered and concentrated in vacuo. The crude compound was purified by column chromatography (Biotage) using eluent (2:8, ethyl acetate:n-hexane) to give methyl 3-iodo-4,5-dihydro-1H-benzo[g]indole-2-carboxylate (8.01 g, 88% yield) as a brown solid. LCMS(ESI): m / z=354.1(M+H) + ; 1 H NMR(300MHz,DMSO-D6)δ=12.42(s,1H),7.89(d,J=7.5Hz,1H),7.35-6.99(m,3H),3.79(s,3H),2.87(t,J=7.6Hz,2H),2.56-2.44(m,2H).

[0072] Example 1: Preparation of methyl 3-(3,5-dichlorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate

[0073] [ka] To a solution of methyl 3-iodo-4,5-dihydro-1H-benzo[g]indole-2-carboxylate (200 mg, 0.57 mmol), 3,5-dichlorophenylboronic acid (130 g, 0.68 mmol) in 1,4-dioxane (5.5 mL) was added aqueous Na2CO3 (120.8 mg, 1.14 mmol in 1.5 mL H2O) in a sealed tube at 25 °C and nitrogen gas was bubbled through the reaction mixture for 15 minutes. To this was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), tightly packed and the reaction mixture was heated at 80 °C with stirring for 16 hours. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to 25 °C and filtered through Celite. The filtrate was concentrated under reduced pressure to give the crude product. The crude compound thus obtained was purified by column chromatography (Biotage) using eluent (2:8, ethyl acetate:n-hexane) to give methyl 3-(3,5-dichlorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate (188 mg, 89% yield) as a solid. LCMS(ESI): m / z=370.0, 372(M-2H) - ; 1 H NMR(300MHz,DMSO-D6)δ=12.08(s,1H),7.93(d,J=7.2Hz,1H),7.51(s,1H),7.38(s,2H),7. 23-7.20(m,2H),7.18-7.13(m,1H),3.68(s,3H),2.83(t,J=7.23Hz,2H),2.56-2.51(m,2H).

[0074] Example 2: Preparation of 3-(3,5-dichlorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid

[0075] [ka] To a stirred solution of methyl 3-(3,5-dichlorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate (188 mg, 0.57 mmol) in THF (2.5 mL), MeOH (1.1 mL), and HO (1.1 mL) was added LiOH.HO (120 mg, 2.87 mmol). The resulting mixture was stirred at room temperature for 48 h. The reaction mixture was acidified to pH 2 with 2 M HCl and extracted with EtOAc (2×25 mL). The organic extracts were dried over NaSO, filtered, and concentrated in vacuo. The crude compound thus obtained was purified by column chromatography (Biotage) using eluent (2:8, ethyl acetate:n-hexane) to give 3-(3,5-dichlorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid (112 g, 60% yield) as a solid. LCMS(ESI): m / z=356.3(M-2H) - ; 1 H NMR (300 MHz, chloroform-D) δ = 9.37 (bs, 1H), 7.46-7.13 (m, 7H), 2.94 (t, J = 7.2 Hz, 2H), 2.66 (t, J = 7.2 Hz, 2H).

[0076] Example 3: Preparation of methyl 3-(5-fluoro-2-methoxyphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate

[0077] [ka] Following a procedure similar to that given for the compound of Example 1, substituting the appropriate boronic acid for 3,5-dichlorophenylboronic acid. LCMS(ESI): m / z=352.1(M+H) + ; 1H NMR (300MHz, chloroform-D) δ=9.33(bs,1H),7.39(d,J=7.6Hz,1H),7.29-7.14(m,3H),7.05-6.96( m,2H),6.91-6.84(m,1H),3.75(s,3H),3.73(s,3H),2.91(t,J=7.5Hz,2H),2.51-2.60(m,2H).

[0078] Example 4: Preparation of methyl 3-(2-methoxyphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate

[0079] [ka] Following a procedure similar to that given for the compound of Example 1, substituting the appropriate boronic acid for 3,5-dichlorophenylboronic acid. LCMS(ESI): m / z=334.1(M+H) + ; 1 H NMR (300 MHz, chloroform-D) δ = 9.30 (bs, 1H), 7.49-7.10 (m, 4H), 7.08-6.90 (m, 4H), 3.78 (s, 3H), 3.71 (s, 3H), 2.91 (t, J = 7.6 Hz, 2H), 2.61-2.57 (m 2H).

[0080] Example 5: Preparation of methyl 3-(4-methoxyphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate

[0081] [ka] Following a procedure similar to that given for the compound of Example 1, substituting the appropriate boronic acid for 3,5-dichlorophenylboronic acid. LCMS(ESI): m / z=334.1(M+H) + ; 1H NMR (300MHz, chloroform-D) δ=9.20(bs,1H),7.47-7.26(m,3H),7.24-7.05(m,3H),7.0 5-6.86(d,2H),3.86(s,3H),3.76(s,3H),2.92(t,J=7.9Hz,2H),2.69-2.67(m,2H).

[0082] Example 6: Preparation of methyl 3-(3,4-difluorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate

[0083] [ka] Following a procedure similar to that given for the compound of Example 1, substituting the appropriate boronic acid for 3,5-dichlorophenylboronic acid. LCMS(ESI):m / z=338.1(MH) - ; 1 H NMR (300 MHz, chloroform-D) δ = 9.27 (bs, 1H), 7.37-7.34 (m, 2H), 7.21 (dd, J = 10.3, 4.5 Hz, 2H), 6.99-6.88 (m, 2H), 6.81-6.74 (m, 1H), 3.78 (s, 3H), 2.93 (t, 2H), 2.67 (t, 2H).

[0084] Example 7: Preparation of methyl 3-(5-chloro-2-methoxyphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate

[0085] [ka] Following a procedure similar to that given for the compound of Example 1, substituting the appropriate boronic acid for 3,5-dichlorophenylboronic acid. LCMS(ESI):m / z=368.0(M+H) + ; 1H NMR (300 MHz, chloroform-D) δ = 9.25 (bs, 1H), 7.37 (d, J = 7.4 Hz, 1H), 7.28 (dd, J = 4.9, 2.4 Hz, 1H), 7.25 - 7.13 (m, 4H), 6.89 (d, J = 8.5 Hz 1H), 3.75 (s, 3H), 3.72 (s, 3H), 2.91 (t, J = 7.5 Hz, 2H), 2.61 - 2.51 (m, 2H).

[0086] Example 8: Preparation of methyl 3-(4-(tert-butyl)phenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate

[0087] [ka] Following a procedure similar to that given for the compound of Example 1, substituting the appropriate boronic acid for 3,5-dichlorophenylboronic acid. LCMS(ESI): m / z=360.2(M+H) + ; 1 H NMR (300 MHz, chloroform-D) δ = 9.23 (bs, 1H), 7.45-7.34 (m, 5H), 7.25-7.15 (m, 3H), 3.77 (s, 3H), 2.91 (t, J = 7.8 Hz, 2H), 2.72 (t, J = 7.8 Hz, 2H), 1.36 (s, 9H).

[0088] Example 9: Preparation of methyl 3-(4-fluorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate

[0089] [ka] Following a procedure similar to that given for the compound of Example 1, substituting the appropriate boronic acid for 3,5-dichlorophenylboronic acid. LCMS(ESI):m / z=322.1(M+H) +;1H NMR (300MHz, chloroform-D) δ=9.39-9.12(bs,1H),7.38(dd,J=8.9,5.7Hz,3H),7.25-7.14( m,3H),7.09(t,J=8.9Hz,2H),3.76(s,3H),2.93(t,J=7.8Hz,2H),2.67(t,J=7.8Hz,2H).

[0090] Example 10: Preparation of methyl 3-phenyl-4,5-dihydro-1H-benzo[g]indole-2-carboxylate

[0091] [ka] Following a procedure similar to that given for the compound of Example 1, substituting the appropriate boronic acid for 3,5-dichlorophenylboronic acid. LCMS(ESI):m / z=304.1(M+H) + ; 1 H NMR (300MHz, chloroform-D) δ=7.55-7.26(m,5H),7.25-7.22(m,4H),3.76(s,3H),2.92(t,J=7.8Hz,2H),2.68(t,J=7.8Hz,2H).

[0092] Example 11: Preparation of methyl 3-(2-fluorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate

[0093] [ka] Following a procedure similar to that given for the compound of Example 1, substituting the appropriate boronic acid for 3,5-dichlorophenylboronic acid. LCMS(ESI):m / z=322.1(M+H) + ; 1H NMR(500MHz,DMSO)δ=12.27(s,1H),8.04-7.87(m,1H),7.42-7.31(m,2H),7.29-7.2 0(m,4H),7.20-7.13(m,1H),3.65(s,3H),2.85(t,J=7.5Hz,2H),2.58-2.39(m,2H).

[0094] Example 12: Preparation of methyl 3-(3-fluorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate

[0095] [ka] Following a procedure similar to that given for the compound of Example 1, substituting the appropriate boronic acid for 3,5-dichlorophenylboronic acid. LCMS(ESI):m / z=322.1(M+H) + ; 1 H NMR(500MHz,DMSO)δ=12.19(s,1H),8.03-7.91(m,1H),7.47-7.37(m,1H),7.31- 7.22(m,2H),7.17-7.09(m,4H),3.69(s,3H),2.85(t,J=7.5Hz,2H),2.53(m,2H).

[0096] Example 13: Preparation of methyl 3-(4-chlorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate

[0097] [ka] Following a procedure similar to that given for the compound of Example 1, substituting the appropriate boronic acid for 3,5-dichlorophenylboronic acid. LCMS(ESI):m / z=338.1(M+H) + ; 1H NMR(500MHz,DMSO)δ=12.37-11.94(m,1H),7.97(d,J=7.1Hz,1H),7.48-7.41(m,2H),7.41-7.36(m,2H) ),7.25(d,J=2.7Hz,2H),7.17(d,J=0.9Hz,1H),3.68(s,3H),2.84(t,J=7.7Hz,2H),2.67-2.44(m,2H).

[0098] Example 14: Preparation of methyl 3-(2-chlorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate

[0099] [ka] Following a procedure similar to that given for the compound of Example 1, substituting the appropriate boronic acid for 3,5-dichlorophenylboronic acid. LCMS(ESI):m / z=338.1(M+H) + ; 1 H NMR(500MHz,DMSO)δ=12.24(bs,1H),7.96(d,J=7.7Hz,1H),7.51(dd,J=5.7,3.2Hz,1H),7.40-7.33(m ,3H),7.24(d,J=7.5Hz,2H),7.16-7.07(m,1H),3.61(s,3H),2.84(t,J=7.5Hz,2H),2.46-2.31(m,2H).

[0100] Example 15: Preparation of methyl 3-(3-chlorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate

[0101] [ka] Following a procedure similar to that given for the compound of Example 1, substituting the appropriate boronic acid for 3,5-dichlorophenylboronic acid. LCMS(ESI):m / z=338.1(M+H) + ; 1H NMR(500MHz,DMSO)δ=12.21(s,1H),8.05-7.91(m,1H),7.44-7.40(m,2H),7.38(dd,J=6.0,4.0Hz,1H),7.34-7.3 0(m,1H),7.28-7.23(m,2H),7.18(dd,J=7.3,1.1Hz,1H),3.69(s,3H),2.85(t,J=7.5Hz,2H),2.63-2.51(m,2H).

[0102] Example 16: Preparation of methyl 3-(2,4-dichlorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate

[0103] [ka] Following a procedure similar to that given for the compound of Example 1, substituting the appropriate boronic acid for 3,5-dichlorophenylboronic acid. LCMS(ESI):m / z=374.0(M+H) + ; 1 H NMR(500MHz,DMSO)δ=12.39(bs,1H),7.95(s,1H),7.68(d,J=2.1Hz,1H),7.43(d,J=2.1Hz,1H),7 .38(d,J=8.3Hz,1H),7.25(d,J=7.4Hz,2H),7.17(s,1H),3.63(s,3H),2.85(m,2H),2.45(m,2H).

[0104] Example 17: Preparation of methyl 3-(2,3-difluorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate

[0105] [ka] Following a procedure similar to that given for the compound of Example 1, substituting the appropriate boronic acid for 3,5-dichlorophenylboronic acid. LCMS(ESI): m / z=340.0(M+H) +

[0106] Example 18: Preparation of methyl 3-(3.5-dimethylphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate

[0107] [ka] Following a procedure similar to that given for the compound of Example 1, substituting the appropriate boronic acid for 3,5-dichlorophenylboronic acid. LCMS(ESI):m / z=332.1(M+H) + ; 1 H NMR(500MHz,DMSO)δ=12.04(s,1H),8.03-7.87(m,1H),7.24(t,J=6.6Hz,2H),7.16-7.10 (m,1H),6.98-6.86(m,3H),3.66(s,3H),2.83(t,J=7.5Hz,2H),2.52(m,2H),2.30(s,6H).

[0108] Example 19: Preparation of methyl 3-(2-fluoro-4-methylphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate

[0109] [ka] Following a procedure similar to that given for the compound of Example 1, substituting the appropriate boronic acid for 3,5-dichlorophenylboronic acid. LCMS(ESI): m / z=336.1(M+H) + ; 1 H NMR(500MHz,DMSO)δ=12.22(s,1H),8.01-7.88(m,1H),7.27-7.19(m,3H),7.18-7.13(m,1H) ,7.04(t,J=10.2Hz,2H),3.65(s,3H),2.84(t,J=7.5Hz,2H),2.63-2.47(m,2H),2.40(s,3H).

[0110] Example 20: Preparation of methyl 3-(2,3-chlorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate

[0111] [ka] Following a procedure similar to that given for the compound of Example 1, substituting the appropriate boronic acid for 3,5-dichlorophenylboronic acid. LCMS(ESI):m / z=372.0(M+H) + ,374.0(M+2H) + ; 1 H NMR(500MHz,DMSO)δ=12.32(s,1H),7.96(d,J=7.6Hz,1H),7.62(dd,J=7.9,1.6Hz,1H),7.38(t,J=7.8Hz,1H),7.33(dd,J= 7.6,1.6Hz,1H),7.25(d,J=7.4Hz,2H),7.20-7.14(m,1H),3.63(s,3H),2.85(t,J=7.5Hz,2H),2.39(t,J=7.5,4.5Hz,2H).

[0112] Example 21: Preparation of methyl 3-(pyridin-4-yl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate

[0113] [ka] Following a procedure similar to that given for the compound of Example 1, substituting the appropriate boronic acid for 3,5-dichlorophenylboronic acid. LCMS(ESI): m / z=305.1(M+H) + ; 1 H NMR(500MHz,MeOD)δ=8.53-8.39(m,2H),7.65-7.59(m,1H),7.44-7.35(m,2H),7.21 -7.12(m,2H),7.12-7.05(m,1H),3.67(s,3H),2.95-2.70(m,2H),2.70-2.39(m,2H).

[0114] Example 22: Preparation of methyl 3-(3,5-difluorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate

[0115] [ka] Following a procedure similar to that given for the compound of Example 1, substituting the appropriate boronic acid for 3,5-dichlorophenylboronic acid. LCMS(ESI)m / z:340.0[M+H] + ; 1 H NMR(500MHz,CDCl3)δ=9.34(bs,1H),7.40(d,J=7.2Hz,1H),7.28(d,J=7.4Hz,2H),7.23-7.19(m,1H ),6.93(dd,J=8.5,2.3Hz,2H),6.78(m,1H),3.79(s,3H),2.94(t,J=7.5Hz,2H),2.74-2.61(m,2H).

[0116] Example 23: Preparation of methyl 3-(pyrimidin-5-yl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate

[0117] [ka] Following a procedure similar to that given for the compound of Example 1, substituting the appropriate boronic acid for 3,5-dichlorophenylboronic acid. LCMS(ESI)m / z:306.0[M+H] + ; 1 H NMR(500MHz,DMSO)δ=12.45(bs,1H),9.13(s,1H),8.83(s,2H),7.99(d,J=7.0Hz,1H),7.2 7(t,J=6.9Hz,2H),7.20-7.17(m,1H),3.71(s,3H),2.88(t,J=7.5,2H),2.59-2.62(m,2H).

[0118] Example 24: Preparation of methyl 3-(5-fluoropyridin-3-yl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate

[0119] [ka] Following a procedure similar to that given for the compound of Example 1, substituting the appropriate boronic acid for 3,5-dichlorophenylboronic acid. LCMS(ESI)m / z:323.0[M+H] + ; 1 H NMR(500MHz,DMSO)δ=12.35(bs,1H),8.52(d,J=2.8Hz,1H),8.45(t,J=1.7Hz,1H),7.98(m,1H),7.77(m, 1H),7.26(t,J=6.6Hz,2H),7.21-7.15(m,1H),3.71(s,3H),2.87(t,J=7.5Hz,2H),2.59(t,J=7.5Hz,2H).

[0120] Example 25: Preparation of methyl 3-(5-chloropyridin-3-yl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate

[0121] [ka] Following a procedure similar to that given for the compound of Example 1, substituting the appropriate boronic acid for 3,5-dichlorophenylboronic acid. LCMS(ESI)m / z:339.0[M+H] + ; 1 H NMR(500MHz,DMSO)δ=12.38(s,1H),8.57(d,J=2.4Hz,1H),8.53(d,J=1.8Hz,1H),8.00-7.97(m,1H),7.97- 7.94(m,1H),7.28-7.24(m,2H),7.20-7.16(m,1H),3.71(s,3H),2.87(t,J=7.5Hz,2H),2.62-2.67(m,2H).

[0122] Example 26: Preparation of methyl 3-(4-fluoro-3-methoxyphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate

[0123] [ka] Following a procedure similar to that given for the compound of Example 1, substituting the appropriate boronic acid for 3,5-dichlorophenylboronic acid. LCMS(ESI)m / z:350.1[MH] -

[0124] Example 27: Preparation of methyl 3-(3-chloro-5-methylphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate

[0125] [ka] Following a procedure similar to that given for the compound of Example 1, substituting the appropriate boronic acid for 3,5-dichlorophenylboronic acid. LCMS(ESI)m / z:353.1[MH] - ;

[0126] Example 28: Preparation of methyl 3-(3-chloro-5-fluorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate

[0127] [ka] Following a procedure similar to that given for the compound of Example 1, substituting the appropriate boronic acid for 3,5-dichlorophenylboronic acid. LCMS(ESI)m / z:354.1[MH] - ; 1H NMR(500MHz,CDCl3)δ=9.31(bs,1H),7.39(d,J=7.6Hz,1H),7.30-7.26(m,2H),7.23-7 .18(m,2H),7.09-7.01(m,2H),3.79(s,3H),2.94(t,J=7.5Hz,2H),2.71-2.63(m,2H).

[0128] Example 29: Preparation of methyl 3-(3-chloro-5-methoxyphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate

[0129] [ka] Following a procedure similar to that given for the compound of Example 1, substituting the appropriate boronic acid for 3,5-dichlorophenylboronic acid. LCMS(ESI)m / z:368.0[M+H] + ; 1 H NMR(500MHz,CDCl3)δ=9.29(bs,1H),7.39(d,J=7.4Hz,1H),7.29-7.27(m,1H),7.25-7.23(m,1H),7.22-7.17(m,1H),7.00(t ,J=1.5Hz,1H),6.88(t,J=2.1Hz,1H),6.86-6.84(m,1H),3.83(s,3H),3.78(s,3H),2.93(t,J=7.5Hz,2H),2.71-2.65(m,2H).

[0130] Example 30: Preparation of methyl 3-(3,4,5-trichlorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate

[0131] [ka] Following a procedure similar to that given for the compound of Example 1, substituting the appropriate boronic acid for 3,5-dichlorophenylboronic acid. LCMS(ESI)m / z:405.9[MH] - ; 1H NMR(500MHz,CDCl3)δ=9.32(bs,1H),7.44(s,2H),7.39(d,J=7.5Hz,1H),7.32-7.2 7(m,2H),7.23-7.20(m,1H),3.80(s,3H),2.94(t,J=7.5Hz,2H),2.69-2.63(m,2H).

[0132] Example 31: Preparation of methyl 3-(3,5-dimethoxyphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate

[0133] [ka] Following a procedure similar to that given for the compound of Example 1, substituting the appropriate boronic acid for 3,5-dichlorophenylboronic acid. LCMS(ESI)m / z:364.1[M+H] + ; 1 H NMR(500MHz,CDCl3)δ=9.29(s,1H),7.39(d,J=7.4Hz,1H),7.28(s,1H),7.24(d,J=7.0Hz,1H),7.21-7.16(m,1H),6 .58(d,J=2.3Hz,2H),6.46(t,J=2.3Hz,1H),3.82(s,6H),3.78(s,3H),2.92(t,J=7.5Hz,2H),2.71(t,J=7.5Hz,2H).

[0134] Example 32: Preparation of methyl 3-(3-fluoro-5-methoxyphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate

[0135] [ka] Following a procedure similar to that given for the compound of Example 1, substituting the appropriate boronic acid for 3,5-dichlorophenylboronic acid. LCMS(ESI)m / z:350.1[MH] -

[0136] Example 33: Preparation of methyl 3-(2,3-dichlorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate

[0137] [ka] Following a procedure similar to that given for the compound of Example 1, substituting the appropriate boronic acid for 3,5-dichlorophenylboronic acid. LCMS(ESI)m / z:374.0[M+2H] + ; 1 H NMR(500MHz,DMSO)δ=12.32(bs,1H),7.96(d,J=7.6Hz,1H),7.62(dd,J=7.9,1.6Hz,1H),7.38(t,J=7.8Hz,1H),7. 34-7.30(m,1H),7.25(d,J=7.4Hz,2H),7.20-7.14(m,1H),3.63(s,3H),2.85(t,J=7.5Hz,2H),2.43-2.36(m,2H). By following procedures similar to those described in Example 2, the following Examples 34-66 were prepared.

[0138] Example 34: 3-(5-fluoro-2-methoxyphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid

[0139] [ka] LCMS(ESI):m / z=338.1(M+H) + ; 1 H NMR (300 MHz, chloroform-D) δ = 9.34 (bs, 1H), 7.48-7.29 (m, 2H), 7.23 (s, 2H), 7.09-6.95 (m, 2H), 6.95-6.80 (m, 1H), 3.77 (s, 3H), 2.98-2.89 (m, 2H), 2.69-2.43 (m, 2H).

[0140] Example 35: 3-(2-Methoxyphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid

[0141] [ka] LCMS(ESI): m / z=320.1(M+H) + ; 1 H NMR (300 MHz, chloroform-D) δ = 9.37 (bs, 1H), 7.42-6.96 (m, 8H), 3.80 (s, 3H), 2.91 (t, J = 7.5 Hz, 2H), 2.61-2.52 (m, 2H).

[0142] Example 36: 3-(4-Methoxyphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid

[0143] [ka] LCMS(ESI): m / z=320.1(M+H) + ; 1 H NMR (300MHz, chloroform-D) δ = 9.73 (bs, 1H), 7.67-6.73 (m, 8H), 3.81 (s, 3H), 2.92-2.84 (m, 2H), 2.70-2.64 (m, 2H)

[0144] Example 37: 3-(3,4-difluorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid

[0145] [ka] LCMS(ESI): m / z=326.0(M+H) + ; 1 H NMR (300 MHz, chloroform-D) δ = 9.49 (bs, 1H), 7.40 (d, J = 7.2 Hz, 1H), 7.35-7.01 (m, 3H), 7.09-6.87 (m, 2H), 6.79-6.76 (m, 1H), 2.96 (t, J = 7.8 Hz, 2H), 2.69 (t, J = 7.8 Hz, 2H).

[0146] Example 38: 3-(5-chloro-2-methoxyphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid

[0147] [ka] LCMS(ESI-):m / z=352.0(MH) - ; 1 H NMR(300MHz,DMSO-D6)δ=12.03(bs,1H),12.01(bs,1H),7.90(d,J=7.9Hz,1H),7.29-7.23(m,2H),7.16( s,1H),7.14-7.05(m,2H),7.04-6.98(m,1H),3.67(s,3H),2.78(t,J=7.4Hz,2H),2.37(t,J=7.5Hz,2H).

[0148] Example 39: 3-(4-(tert-butyl)phenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid

[0149] [ka] LCMS(ESI):m / z=346.1(M+H) + ; 1 H NMR (300 MHz, chloroform-D) δ = 9.42 (s, 1H), 7.41 (m, 4H), 7.23 (dd, J = 12.3, 7.1 Hz, 4H), 2.92 (t, J = 7.3 Hz, 2H), 2.71 (t, J = 7.3 Hz, 2H), 1.39 (s, 9H).

[0150] Example 40: 3-(4-fluorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid

[0151] [ka] LCMS(ESI):m / z=308.0(M+H) +

[0152] Example 41: 3-(2-fluorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid

[0153] [ka] LCMS(ESI):m / z=308.1(M+H) + ; 1 H NMR(500MHz,MeOD)δ=7.60-7.55(m,1H),7.25-7.17(m,2H),7.15-7.07(m,2H),7.07-6.95(m,3H),2.76(t,J=7.5Hz,2H),2.41(t,J=7.5Hz,2H).

[0154] Example 42: 3-(3-fluorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid

[0155] [ka] LCMS(ESI):m / z=308.1(M+H) + ; 1 H NMR(500MHz,MeOD)δ=7.61-7.56(m,1H),7.24(m,1H),7.16-7.08(m,2H),7.08-6.99(m,3H),6.93-6.86(m,1H),2.89-2.67(m,2H),2.49(m,2H).

[0156] Example 43: 3-(4-chlorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid

[0157] [ka] LCMS(ESI):m / z=322.0(M+H) + ; 1H NMR(500MHz,DMSO)δ=12.23(bs,1H),8.03-7.95(m,1H),7.45-7.35(m,4H),7.27-7.20(m,2H),7.18-7.12(m,1H),2.77 -2 .89(m,2H),2.63-2.41(m,2H).

[0158] Example 44: 3-(2-chlorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid

[0159] [ka] LCMS(ESI): m / z=324.1(M+H) + ; 1 H NMR(500MHz,MeOD)δ=7.56(d,J=7.5Hz,1H),7.33-7.29(m,1H),7.20-7.09(m, 4H),7.07(d,J=7.2Hz,1H),7.00(m,1H),2.81-2.67(m,2H),2.40-2.20(m,2H).

[0160] Example 45: 3-(3-chlorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid

[0161] [ka] LCMS(ESI): m / z=324.1(M+H) + ; 1 H NMR(500MHz,MeOD)δ=7.58(d,J=7.5Hz,1H),7.27(dd,J=5.9,4.2Hz,1H),7.24-7.1 9(m,1H),7.19-7.08(m,4H),7.03(dd,J=7.4,1.1Hz,1H),2.77(m,2H),2.47(m,2H).

[0162] Example 46: 3-(2,4-dichlorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid

[0163] [ka] LCMS(ESI): m / z=360.0(M+H) + ; 1 H NMR(500MHz,MeOD)δ=7.58(d,J=7.6Hz,1H),7.43-7.36(m,1H),7.24-7.18(m,2H),7.13(dd,J =15.5,7.6Hz,2H),7.04(dd,J=7.4,1.2Hz,1H),2.78(t,J=7.6Hz,2H),2.78(t,J=7.6Hz,2H).

[0164] Example 47: 3-(2,3-difluorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid

[0165] [ka] LCMS(ESI): m / z=326.1(M+H) + ; 1 H NMR(500MHz,MeOD)δ=7.59(d,J=7.6Hz,1H),7.23-6.94(m,6H),2.81(m,2H),2.65-2.31(m,2H).

[0166] Example 48: 3-(3.5-dimethylphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid

[0167] [ka] LCMS(ESI): m / z=318.1(M+H) + ; 1 H NMR(500MHz,MeOD)δ=7.57(d,J=7.1Hz,1H),7.18-7.07(m,2H),7.07-6.97(m,1H),6. 88(d,J=18.7Hz,2H),6.80(s,1H),2.82-2.68(m,2H),2.51-2.41(m,2H),2.23(s,6H).

[0168] Example 49: 3-(2-fluoro-4-methylphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid

[0169] [ka] LCMS(ESI):m / z=322.1(M+H) + ; 1 H NMR(500MHz,MeOD)δ=7.56(d,J=7.6Hz,1H),7.10(dd,J=19.7,7.7Hz,3H),7.02(ddd,J=15 .1,12.1,11.0Hz,1H),6.87(m,2H),2.75(t,J=7.5Hz,2H),2.45-2.35(m,2H),2.25(s,3H).

[0170] Example 50: 3-(2,3-dichlorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid

[0171] [ka] LCMS(ESI)m / z:360.0[M+2H] + ; 1 H NMR(500MHz,MeOD)δ=7.58(d,J=7.6Hz,1H),7.41-7.35(m,1H),7.18-7.15(m,2H),7 .14-7.09(m,2H),7.04(dd,J=7.4,1.2Hz,1H),2.82-2.73(m,2H),2.38-2.28(m,2H).

[0172] Example 51: 3-(pyridin-4-yl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid

[0173] [ka] LCMS(ESI): m / z=291.1(M+H) + ; 1H NMR(500MHz,MeOD)δ=8.41(d,J=6.0Hz,2H),7.59(d,J=7.7Hz,1H),7.42-7.37(m,2H), 7.14(d,J=9.3Hz,2H),7.07(d,J=7.4Hz,1H),2.81(t,J=7.5Hz,2H),2.59-2.50(m,2H).

[0174] Example 52: 3-(3,5-difluorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid

[0175] [ka] LCMS(ESI)m / z:324.0[M-2H] - ; 1 H NMR(500MHz,MeOD)δ=7.59(d,J=7.7Hz,2H),7.17-7.11(m,2H),7.07-7.04(m, 1H),6.88-6.86(m,2H),6.75(m,1H),2.80(t,J=7.5Hz,1H),2.55-2.50(m,1H).

[0176] Example 53: 3-(5-fluoropyridin-3-yl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid

[0177] [ka] LCMS(ESI)m / z:309.0[M+H] + ; 1 H NMR(500MHz,MeOD)δ=8.32(s,1H),8.27(d,J=2.6Hz,1H),7.63-7.58(m,2H),7 .17-7.13(m,2H),7.09-7.04(m,1H),2.82(t,J=7.5Hz,1H),2.56-2.53(m,1H).

[0178] Example 54: 3-(5-chloropyridin-3-yl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid

[0179] [ka] LCMS(ESI)m / z:325.0[M+H] + ; 1 H NMR(500MHz,DMSO)δ=12.44(s,1H),12.26(s,1H),8.54(dd,J=9.0,1.7Hz,2H),7.98(d,J=7.6Hz,1H),7.9 5-7.92(m,1H),7.24(t,J=7.5Hz,2H),7.16(t,J=7.3Hz,1H),2.86(t,J=7.4Hz,2H),2.58(t,J=7.5Hz,2H).

[0180] Example 55: 3-(pyrimidin-5-yl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid

[0181] [ka] LCMS(ESI)m / z:292.3 [M+H] +

[0182] Example 56: 3-(4-fluoro-2-methoxyphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid

[0183] [ka] LCMS(ESI)m / z:336.1[MH] - ; 1 H NMR(500MHz,MeOD)δ=7.55(d,J=7.5Hz,1H),7.15-7.04(m,3H),7.02(t,J=7.0Hz,1H),6.68(dd,J=1 1.2,2.3Hz,1H),6.59-6.54(m,1H),3.69-3.61(s,3H),2.75(t,J=7.5Hz,2H),2.35(t,J=7.5Hz,2H).

[0184] Example 57: 3-(3-chloro-5-methylphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid

[0185] [ka] LCMS(ESI)m / z:337.8,339.5[M+H] + ; 1 H NMR(500MHz,MeOD)δ=7.70(d,J=7.1Hz,1H),7.27-7.21(m,2H),7.18(s,1H),7.17-7. 14(m,1H),7.13-7.10(m,2H),2.89(t,J=7.5Hz,2H),2.63-2.55(m,2H),2.37(s,3H).

[0186] Example 58: 3-(3-chloro-5-fluorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid

[0187] [ka] LCMS(ESI)m / z:340.0[MH] - ; 1 H NMR(500MHz,MeOD)δ=7.58(d,J=7.6Hz,1H),7.17-7.09(m,3H),7.07-7.02(m,1H),7.02-6.94(m,2H),2.78(t,J=7.5Hz,2H),2.53-2.44(m,2H).

[0188] Example 59: 3-(3-chloro-5-methoxyphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid

[0189] [ka] LCMS(ESI)m / z:352.0[MH] - ; 1H NMR(500MHz,MeOD)δ=7.57(d,J=7.5Hz,1H),7.16-7.07(m,2H),7.05-7.00(m,1H),6.86 -6.82(m,1H),6.79-6.72(m,2H),3.69(s,3H),2.77(t,J=7.5Hz,2H),2.52-2.43(m,2H).

[0190] Example 60: 3-(3,4,5-dichlorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid

[0191] [ka] LCMS(ESI)m / z:390.0,391.9[MH] - ; 1 H NMR(500MHz,MeOD)δ=7.59(d,J=7.6Hz,1H),7.41(s,2H),7.17-7.11(m,2H),7.09-7.04(m,1H),2.81(t,J=7.5Hz,2H),2.52(t,J=7.5Hz,2H).

[0192] Example 61: 3-(3,5-dimethoxyphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid

[0193] [ka] LCMS(ESI)m / z:348.1[MH] - ; 1 H NMR(500MHz,DMSO)δ=11.98(s,1H),7.96(s,1H),7.35-7.05(m,3H),6.60-6.35(m,3H),3.75(s,6H),2.8-2.7(m,2H),2.65-2.55(m,2H).

[0194] Example 62: 3-(3-fluoro-5-methoxyphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid

[0195] [ka] LCMS(ESI)m / z:336.1[MH] - ; 1 H NMR(500MHz,MeOD)δ=7.58(d,J=7.6Hz,1H),7.15-7.08(m,2H),7.05-7.01(m,1H),6.66-6.63(m, 1H),6.61-6.56(m,1H),6.52-6.48(m,1H),3.70(s,3H),2.77(t,J=7.5Hz,2H),2.53-2.46(m,2H).

[0196] Example 63: 3-Phenyl-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid

[0197] [ka] LCMS(ESI)m / z:290.2[M+H] + ; 1 H NMR(500MHz,MeOD)δ=7.58(d,J=7.7Hz,1H),7.30-7.26(m,2H),7.26-7.23(m,2H),7.19-7. 165(m,1H),7.16-7.10(m,2H),7.06-7.01(m,1H),2.78(t,J=7.5Hz,2H),2.53-2.46(m,2H).

[0198] Example 64: 3-(3-chloro-5-fluorophenyl)-5-methyl-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid

[0199] [ka] LCMS(ESI)m / z:356.3[M+H] + ; 1H NMR(500MHz,MeOD)δ=7.61(dd,J=7.5,1.1Hz,1H),7.18-7.12(m,2H),7.11-7.07(m,2H),7.03-6.99(m,1H),6.98- 6.95(m,1H),2.97-2.94(m,1H),2.69(dd,J=15.4,6.1Hz,1H),2.31(dd,J=15.4,5.8Hz,1H),1.09(d,J=7.0Hz,3H).

[0200] Example 65: 7-Bromo-3-(3,5-dichlorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid

[0201] [ka] LCMS(ESI)m / z:[M+H] + 435.1

[0202] Hypothetical Example The following list of Examples 66-75 shown in Table-1 can be prepared by following procedures similar to those described in Example 1, then Example 2, by using Intermediate 1 and the appropriately substituted boronic acid / ester.

[0203] [Table 1]

[0204] Biological assays Enzyme activity: IC 50 Quantification of Class B beta-lactamase activity was measured in a fluorometric assay with the in-house synthesized fluorescent cephalosporin substrate FC5 (Berkel, et. al. J. Med. Chem. 2013, 56(17), 6945) in the presence of test inhibitors. Enzymes (NDM-1, IMP-1) and substrates were diluted in 20 mM HEPES, pH 7.4, supplemented with 300 mM NaCl and 10 μM ZnSO4. In the assay, the final enzyme concentrations were 50 pM for NDM-1 and 100 pM for IMP-1, and the final FC5 concentrations were 1.5 M for NDM-1 and 10 M for IMP-1. Test inhibitors / compounds were dissolved in dimethyl sulfoxide (DMSO) and diluted in assay buffer (20 mM HEPES, pH 7.4 supplemented with 5% DMSO, 300 mM NaCl, and 10 μM ZnSO4) to give a final concentration range of 0.008 μM to 25 μM. Assays were performed in 96-well microplates (flat bottom, black). Test inhibitors were incubated with MBL enzyme for 10 min at room temperature, then substrate was added and fluorescence was immediately recorded in a microplate reader (λex 380 nm, λem 460 nm). Initial rate data plotted against inhibitor concentration were used to calculate IC using GraphPad Prism 9 software. 50 The half maximal inhibitory concentrations were calculated using a curve fitting model. Representative compounds of the present invention demonstrate inhibition of class B β-lactamases in this assay. For example, the compounds of Examples 2, 34-64 were tested in this assay and showed the IC values ​​shown in Table 1. 50 It was found to have value.

[0205] [Table 2]

[0206] in vitro pharmacological activity Antibiotic activity of imipenem and meropenem against NDM-1 expressing bacteria in the presence of representative compounds of the present invention Bacterial strains The strains included in this study were Klebsiella pneumoniae ATCC BAA-2146 (Himedia®, India) which contains the New Delhi metallo-β-lactamase (NDM-1) gene. Quality control reference strains Escherichia coli ATCC 25922 and Pseudomonas aeruginosa ATCC 27853 were obtained from Himedia® (India).

[0207] Minimum inhibitory concentration (MIC) MIC values ​​were determined by broth microdilution in sterile 96-well polystyrene flat-bottom microtiter plates (Cole-Parmer®) according to Clinical and Laboratory Standards Institute (CLSI) guidelines (CLSI; Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; Clinical Laboratory Standards Institute, M07-A09, 2012). The method involved the use of BBL™ Cation-adjusted Mueller-Hinton II Broth (CA-MHB; BD) with a concentration of 5 × 10 strain (Klebsiella pneumoniae ATCC BAA-2146) at 10–200 μg / ml. 5 After incubation with various concentrations of imipenem, meropenem (Alfa Aesar), or test compound for 16–18 h at 37 °C, the MIC was defined as the lowest concentration of antibiotic or test compound at which there was no visible growth.

[0208] Checkerboard synergy assay The fold modulating activity of the test compounds in combination with imipenem or meropenem was confirmed against Klebsiella pneumoniae ATCC BAA-2146 strain by broth-microdilution checkerboard synergy assay. 5Bacterial inoculum in CFU / mL was added along with serial two-fold dilutions of antibiotics (128-2 μg / mL) and test compounds (32-4 μg / mL) in a total volume of 200 μL in CA-MHB. Dimethyl sulfoxide (DMSO, ≤2.5%) was included as a vehicle control. After incubation at 37°C for 16-18 hours, the MICs of antibiotics and drug combinations were determined visually.

[0209] [Table 3]

[0210] Thus, the above in vitro assay methods indicate that the compounds of the present invention have inhibition against MBL (NDM-1 and IMP-1) in biochemical assays and are found to exhibit synergistic effects in carbapenem resistant strains in combination with beta-lactam antibiotics, thereby making them useful for the treatment of diseases and disorders associated with the regulation of MBL and antibiotic resistance.

[0211] Compound testing results demonstrated that the substituted tricyclic compounds of formula (I) are capable of inhibiting clinically relevant MBL. The substituted tricyclic-based scaffolds described in this invention can be developed as broad-spectrum, high-affinity inhibitors that target multiple beta-lactamases in resistant bacteria and can be combined with beta-lactam antibiotics to treat infections caused by multidrug-resistant bacteria.

[0212] Using the above-mentioned assays, the compounds were found to exhibit fold modulating activity with antibiotics and were therefore found to be particularly well suited for the treatment of diseases or disorders as mentioned herein above.

[0213] Advantages of the Invention As we reach the point where patients infected with multi-drug resistant bacteria are concerned, there is no magic pellet. The present invention relates to small molecule compounds that inhibit the MBL enzyme and the fold modulation of the trump card carbapenem (β-lactam antibiotic) class of antibiotics. These inhibitors can help preserve antibiotic activity in the event of resistant bacteria emergence, and thus can be beneficial to the entire world where there is a huge unmet medical need.

Claims

1. A compound of formula I, [Case 1] Formula I A stereoisomer thereof, or a pharma- ceutically acceptable salt thereof. During the ceremony, R １ is selected from the group consisting of: (i) -OH; (ii) -NR ａ R ｂ (In the formula, R ａ and R ｂ is independently, at each occurrence, selected from hydrogen, unsubstituted or substituted alkyl, and unsubstituted or substituted cycloalkyl and methoxy, or R ａ and R ｂ may be taken together with the carbon atom to which they are attached to form a substituted or unsubstituted 3- to 7-membered saturated carbocyclic ring; (iii) -OR ｃ (In the formula, R ｃ is C １～６ Alkyl, C ３～８ Cycloalkyl, C ３～８ Cycloalkyl, C １～２ Alkyl, aryl, aryl-C １～２ Alkyl, Heteroaryl, Heteroaryl-C １～２ Alkyl, heterocyclyl or heterocyclyl-C １～２ alkyl, each of which is optionally substituted by one or more substituents; (iv) -R ｄ (In the formula, R ｄ is independently, at each occurrence, selected from hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl; R ２ may be the same or different in each occurrence and independently represent halogen, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, -C(O)OR ｅ , -OC(O)OR ｅ , -O(CR ａ R ｂ)r-C(O)OR ｅ , -(CR ａ R ｂ ) ｒ -C(O)OR ｅ , -C(O)R ｈ , N.R. ｆ R ｇ , -C(O)NR ｆ R ｇ , -NR ｆ C(O)R ｈ , -NR ｆ S (O) ２ R ｇ , -S(O) ０ - ２ R ｅ , and -S(O) ２ N.R. ｆ R ｇ is selected from the group consisting of R ａ and R ｂ may be the same or different in each occurrence and are independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl, or R ａ and R ｂ may be taken together with the carbon atom to which they are attached to form an unsubstituted or substituted 3- to 7-membered saturated carbocyclic ring; R ｅ may be the same or different in each occurrence and are independently selected from the group consisting of hydrogen, substituted or unsubstituted aryl, substituted or unsubstituted haloalkyl, and substituted or unsubstituted alkyl; R ｆ and R ｇ may be the same or different in each occurrence and are independently hydrogen, substituted or unsubstituted alkyl, -(CRaRb) ｒ -C(O)OR ｅ, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted heterocyclylalkyl, or R ｆ and R ｇ may be taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted, saturated or unsaturated 3- to 10-membered cyclic ring, said unsaturated cyclic ring optionally having one or two double bonds, and in each occurrence, R ｈ is a substituted or unsubstituted alkyl, or a substituted or unsubstituted aryl; "n" is an integer from 0 to 5, inclusive; "r" is an integer from 1 to 3, inclusive; X １ , X ２ , X ３ , or X ５ is selected from C or N, with the proviso that X １ , X ２ , X ３ , or X ５ may be N; R ３ is hydrogen, halo, cyano, nitro, hydroxy, or -A １ -B １ -C １ is selected from the group In the formula, A １ is absent or of the formula -[CR １Ａ R １Ｂ ] Ｐ -, where p is an integer selected from 1 or 2, 3 or 4, and R １Ａ and R １Ｂ are each independently hydrogen or C １～２ alkyl, B １ is absent or -O-, -C(O)-, -C(O)O-, -OC(O)-, -CH(OR １Ｃ ) -, -N(R １Ｃ) -, N(R １Ｄ )-C(O)-,-N(R １Ｄ )-C(O)O-, -C(O)-N(R １Ｃ ) -, -N(R １Ｄ ) C(O)N(R １Ｃ )-, -S-, -SO-, -SO ２ -, -S(O) ２ N (R １Ｃ )- or -N(R １Ｄ ) S.O. ２ -, wherein R １Ｃ and R １Ｄ are each independently selected from hydrogen or methyl; C １ is hydrogen, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, aryl, C ３～６ Cycloalkyl, C ３～６ cycloalkenyl, heterocyclyl, or heteroaryl; C １ is optionally oxo, halo, cyano, nitro, hydroxy, carboxy, NR １Ｅ R １Ｆ , C １～４ Alkoxy, C １～４ Alkyl, C ３～８ Cycloalkyl, C ３～８ Cycloalkyl-C １～３ Alkyl, C １～４ Alkanoyl, C １～４ Alkyl sulfonyl, aryl, aryloxy, aryl-C １～２ Alkyl, heterocyclyl, heterocyclyloxy, heterocyclyl-C １～２ Alkyl, heteroaryl, heteroaryloxy, heteroaryl-C １～２ Alkyl, C(O)NR １Ｅ R １Ｆ , N.R. １Ｅ C(O)R １Ｆ , N.R. １Ｅ S (O) ２ R １Ｆ , and S(O) ２ N.R. １Ｅ R １Ｆand further substituted by one or more substituents independently selected from １Ｅ and R １Ｆ are each independently hydrogen, C １～４ Alkyl or C ３～６ Cycloalkyl, or C ３～６ Cycloalkyl C １～２ alkyl, or R １Ｅ and R １Ｆ may be linked together with the nitrogen atom to which they are attached to form a 4- to 7-membered heterocycle; C １ Any alkyl, aryl, heterocyclyl, or heteroaryl group present within the above substituents may optionally be selected from the group consisting of halo, cyano, nitro, hydroxy, carboxy, NR １Ｇ R １Ｈ , C １～２ Alkoxy, or C １～２ Further substituted by alkyl, wherein R １Ｇ and R １Ｈ is hydrogen or C １～２ alkyl, Or R １Ｃ and C １ may be joined together with the nitrogen atom to which they are attached to form a 4- to 7-membered heterocycle, which may optionally be selected from the group consisting of oxo, halo, cyano, nitro, hydroxy, carboxy, NR １Ｅ R １Ｆ , C １～４ Alkoxy, C １～４ Alkyl, C ３～８ Cycloalkyl, C ３～８ Cycloalkyl-C １～３ Alkyl, C １～４ Alkanoyl, C １～４ Alkylsulfonyl, or C(O)NR １Ｅ R １Ｆ , N.R. １Ｅ C(O)R １Ｆ , N.R. １Ｅ S (O) ２ R １Ｆ , and S(O) ２ N.R. １Ｅ R １Ｆ is replaced by R ４ is hydrogen, cyano, halo, nitro, hydroxy, or -A ２ -B ２ -C ２ is selected from the group In the formula, A ２ is absent or of the formula -[CR ２Ａ R ２Ｂ ] ｑ -, where q is an integer selected from 1 or 2, 3 or 4, and R ２Ａ and R ２Ｂ are each independently hydrogen or C １～２ alkyl, B ２ is absent or -O-, -C(O)-, -C(O)O-, -OC(O)-, -CH(OR ２Ｃ ) -, -N(R ２Ｃ ) -, N(R ２Ｄ )-C(O)-,-N(R ２Ｄ )-C(O)O-, -C(O)-N(R ２Ｃ ) -, -N(R ２Ｄ ) C(O)N(R ２Ｃ )-, -S-, -SO-, -SO ２ -, -S(O) ２ N (R ２Ｃ )- or -N(R ２Ｄ ) S.O. ２ -, wherein R ２Ｃ and R ２Ｄ are each independently selected from hydrogen or methyl; C ２ is hydrogen, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, aryl, C ３～６ Cycloalkyl, C ３～６ cycloalkenyl, heterocyclyl, or heteroaryl; C ２ is optionally oxo, halo, cyano, nitro, hydroxy, carboxy, NR ２Ｅ R ２Ｆ , C １～４ Alkoxy, C ３～８ Cycloalkyl, C １～４Alkyl, C ３～８ Cycloalkyl-C １～３ Alkyl, C １～４ Alkylsulfonyl, C １～４ Alkanoyl, aryl, aryloxy, aryl-C １～２ Alkyl, heterocyclyl, heterocyclyloxy, heterocyclyl-C １～２ Alkyl, heteroaryl, heteroaryloxy, heteroaryl-C １～２ Alkyl, C(O)NR ２Ｅ R ２Ｆ , N.R. ２Ｅ C(O)R ２Ｆ , N.R. ２Ｅ S (O) ２ R ２Ｆ , and S(O) ２ N.R. ２Ｅ R ２Ｆ and further substituted by one or more substituents independently selected from ２Ｅ and R ２Ｆ are each independently hydrogen, C １～４ Alkyl or C ３～６ Cycloalkyl, or C ３～６ Cycloalkyl C １～２ alkyl, or R ２Ｅ and R ２Ｆ may be linked together with the nitrogen atom to which they are attached to form a 4- to 7-membered heterocycle; C ２ Any alkyl, aryl, heterocyclyl, or heteroaryl group present within the above substituents may optionally be selected from the group consisting of halo, cyano, nitro, hydroxy, carboxy, NR ２Ｇ R ２Ｈ , C １～２ Alkoxy, or C １～２ Further substituted by alkyl, wherein R ２Ｇ and R ２Ｈ is hydrogen or C １～２ alkyl, Or R ２Ｃ and C ２may be joined together with the nitrogen atom to which they are attached to form a 4- to 7-membered heterocycle, which may optionally be selected from the group consisting of oxo, halo, cyano, nitro, hydroxy, carboxy, NR ２Ｅ R ２Ｆ , C １～４ Alkoxy, C １～４ Alkyl, C ３～８ Cycloalkyl, C ３～８ Cycloalkyl-C １～３ Alkyl, C １～４ Alkanoyl, C １～４ Alkylsulfonyl, or C(O)NR ２Ｅ R ２Ｆ , N.R. ２Ｅ C(O)R ２Ｆ , N.R. ２Ｅ S (O) ２ R ２Ｆ , and S(O) ２ N.R. ２Ｅ R ２Ｆ is replaced by R ５ is hydrogen, halo, cyano, hydroxy, nitro, or -A ３ -B ３ -C ３ is selected from the group In the formula, A ３ is absent or of the formula -[CR ３Ａ R ３Ｂ ] ｒ -, where r is an integer selected from 1 or 2, 3 or 4, and R ３Ａ and R ３Ｂ are each independently hydrogen or C １～２ alkyl, B ３ is absent or -O-, -C(O)-, -C(O)O-, -OC(O)-, -CH(OR ３Ｃ ) -, -N(R ３Ｃ ) -, N(R ３Ｄ )-C(O)-,-N(R ３Ｄ )-C(O)O-, -C(O)-N(R ３Ｃ ) -, -N(R ３Ｄ ) C(O)N(R ３Ｃ )-, -S-, -SO-, -SO ２-, -S(O) ２ N (R ３Ｃ )- or -N(R ３Ｄ ) S.O. ２ -, wherein R ３Ｃ and R ３Ｄ are each independently selected from hydrogen or methyl; C ３ is hydrogen, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, aryl, C ３～６ Cycloalkyl, C ３～６ cycloalkenyl, heteroaryl, or heterocyclyl; C ３ is optionally oxo, halo, cyano, nitro, hydroxy, carboxy, NR ３Ｅ R ３Ｆ , C １～４ Alkoxy, C １～４ Alkyl, C ３～８ Cycloalkyl, C ３～８ Cycloalkyl-C １～３ Alkyl, C １～４ Alkanoyl, C １～４ Alkyl sulfonyl, aryl, aryloxy, aryl-C １～２ Alkyl, heterocyclyl, heterocyclyloxy, heterocyclyl-C １～２ Alkyl, heteroaryl, heteroaryloxy, heteroaryl-C １～２ Alkyl, C(O)NR ３Ｅ R ３Ｆ , N.R. ３Ｅ C(O)R ３Ｆ , N.R. ３Ｅ S (O) ２ R ３Ｆ , and S(O) ２ N.R. ３Ｅ R ３Ｆ and further substituted by one or more substituents independently selected from ３Ｅ and R ３Ｆ are each independently hydrogen, C １～４ Alkyl or C ３～６ Cycloalkyl, or C ３～６ Cycloalkyl C １～２alkyl, or R ３Ｅ and R ３Ｆ may be linked together with the nitrogen atom to which they are attached to form a 4- to 7-membered heterocycle; C ３ Any alkyl, aryl, heterocyclyl, or heteroaryl group present within the above substituents may optionally be selected from the group consisting of halo, nitro, cyano, hydroxy, carboxy, NR ３Ｇ R ３Ｈ , C １～２ Alkoxy, or C １～２ Further substituted by alkyl, wherein R ３Ｇ and R ３Ｈ is hydrogen or C １～２ alkyl, Or R ３Ｃ and C ３ may be joined together with the nitrogen atom to which they are attached to form a 4- to 7-membered heterocycle, which may optionally be selected from the group consisting of oxo, halo, cyano, hydroxy, nitro, carboxy, NR ３Ｅ R ３Ｆ , C １～４ Alkoxy, C １～４ Alkyl, C ３～８ Cycloalkyl, C ３～８ Cycloalkyl-C １～３ Alkyl, C １～４ Alkanoyl, C １～４ Alkylsulfonyl, or C(O)NR ３Ｅ R ３Ｆ , N.R. ３Ｅ C(O)R ３Ｆ , N.R. ３Ｅ S (O) ２ R ３Ｆ , and S(O) ２ N.R. ３Ｅ R ３Ｆ is replaced by R ６ is hydrogen, halo, cyano, nitro, hydroxy, or -A ４ -B ４ -C ４ is selected from the group In the formula, A ４ is absent or of the formula -[CR ４Ａ R ４Ｂ ] ｓ -, where p is an integer selected from 1 or 2, 3 or 4, and R ４Ａ and R ４Ｂ are each independently hydrogen or C １～２ alkyl, B ４ is absent or -O-, -C(O)-, -C(O)O-, -OC(O)-, -CH(OR ４Ｃ ) -, -N(R ４Ｃ ) -, N(R ４Ｄ )-C(O)-,-N(R ４Ｄ )-C(O)O-, -C(O)-N(R ４Ｃ ) -, -N(R ４Ｄ ) C(O)N(R ４Ｃ )-, -S-, -SO-, -SO ２ -, -S(O) ２ N (R ４Ｃ )- or -N(R ４Ｄ ) S.O. ２ -, wherein R ４Ｃ and R ４Ｄ are each independently selected from hydrogen or methyl; C ４ is hydrogen, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, aryl, C ３～６ Cycloalkyl, C ３～６ cycloalkenyl, heterocyclyl, or heteroaryl; C ４ is optionally oxo, halo, cyano, nitro, hydroxy, carboxy, NR ４Ｅ R ４Ｆ , C １～４ Alkoxy, C １～４ Alkyl, C ３～８ Cycloalkyl, C ３～８ Cycloalkyl-C １～３ Alkyl, C １～４ Alkanoyl, C １～４ Alkyl sulfonyl, aryl, aryloxy, aryl-C １～２ Alkyl, heterocyclyl, heterocyclyloxy, heterocyclyl-C １～２ Alkyl, heteroaryl, heteroaryloxy, heteroaryl-C １～２ Alkyl, C(O)NR ４Ｅ R ４Ｆ , N.R. ４Ｅ C(O)R ４Ｆ , N.R. ４Ｅ S (O) ２ R ４Ｆ , and S(O) ２ N.R. ４Ｅ R ４Ｆ and further substituted by one or more substituents independently selected from ４Ｅ and R ４Ｆ are each independently hydrogen, C １～４ Alkyl or C ３～６ Cycloalkyl, or C ３～６ Cycloalkyl C １～２ alkyl, or R ４Ｅ and R ４Ｆ may be linked together with the nitrogen atom to which they are attached to form a 4- to 7-membered heterocycle; C ４ Any alkyl, aryl, heterocyclyl, or heteroaryl group present within the above substituents may optionally be selected from the group consisting of halo, cyano, nitro, hydroxy, carboxy, NR ４Ｇ R ４Ｈ , C １～２ Alkoxy, or C １～２ Further substituted by alkyl, wherein R ４Ｇ and R ４Ｈ is hydrogen or C １～２ alkyl, Or R ４Ｃ and C ４ may be joined together with the nitrogen atom to which they are attached to form a 4- to 7-membered heterocycle, which may optionally be selected from the group consisting of oxo, halo, cyano, nitro, hydroxy, carboxy, NR ４Ｅ R ４Ｆ , C １～４ Alkoxy, C １～４ Alkyl, C ３～８ Cycloalkyl, C ３～８ Cycloalkyl-C １～３ Alkyl, C １～４ Alkanoyl, C １～４ Alkylsulfonyl, or C(O)NR ４Ｅ R ４Ｆ , N.R. ４Ｅ C(O)R ４Ｆ , N.R. ４Ｅ S (O) ２ R ４Ｆ , and S(O) ２ N.R. ４Ｅ R ４Ｆ is replaced by R ７ is hydrogen, halo, nitro, cyano, hydroxy, or -A ５ -B ５ -C ５ is selected from the group In the formula, A ５ is absent or of the formula -[CR ５Ａ R ５Ｂ ] ｔ -, where "t" is an integer selected from 1 or 2, 3 or 4, and R ５Ａ and R ５Ｂ are each independently hydrogen or C １～２ alkyl, B ５ is absent or -O-, -C(O)-, -C(O)O-, -OC(O)-, -CH(OR ５Ｃ ) -, -N(R ５Ｃ ) -, N(R ５Ｄ )-C(O)-,-N(R ５Ｄ )-C(O)O-, -C(O)-N(R ５Ｃ ) -, -N(R ５Ｄ ) C(O)N(R ５Ｃ )-, -S-, -SO-, -SO ２ -, -S(O) ２ N (R ５Ｃ )- or -N(R ５Ｄ ) S.O. ２ -, wherein R ５Ｃ and R ５Ｄ are each independently selected from hydrogen or methyl; C ５ is hydrogen, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６Alkynyl, aryl, C ３～６ Cycloalkyl, C ３～６ cycloalkenyl, heteroaryl, or heterocyclyl; C ５ is optionally oxo, cyano, halo, nitro, carboxy, hydroxy, NR ５Ｅ R ５Ｆ , C １～４ Alkoxy, C １～４ Alkyl, C ３～８ Cycloalkyl, C ３～８ Cycloalkyl-C １～３ Alkyl, C １～４ Alkanoyl, C １～４ Alkyl sulfonyl, aryl, aryloxy, aryl-C １～２ Alkyl, heterocyclyl, heterocyclyloxy, heterocyclyl-C １～２ Alkyl, heteroaryl, heteroaryloxy, heteroaryl-C １～２ Alkyl, C(O)NR ５Ｅ R ５Ｆ , N.R. ５Ｅ C(O)R ５Ｆ , N.R. ５Ｅ S (O) ２ R ５Ｆ , and S(O) ２ N.R. ５Ｅ R ５Ｆ and further substituted by one or more substituents independently selected from ５Ｅ and R ５Ｆ are each independently hydrogen, C １～４ Alkyl or C ３～６ Cycloalkyl, or C ３～６ Cycloalkyl C １～２ alkyl, or R ５Ｅ and R ５Ｆ may be linked together with the nitrogen atom to which they are attached to form a 4- to 7-membered heterocycle; C ５ Any alkyl, aryl, heterocyclyl, or heteroaryl group present within the above substituents may optionally be selected from the group consisting of halo, cyano, nitro, hydroxy, carboxy, NR ５Ｇ R ５Ｈ , C １～２ Alkoxy, or C １～２ Further substituted by alkyl, wherein R ５Ｇ and R ５Ｈ is hydrogen or C １～２ alkyl, Or R ５Ｃ and C ５ may be joined together with the nitrogen atom to which they are attached to form a 4- to 7-membered heterocycle, which may optionally be selected from the group consisting of oxo, halo, cyano, nitro, hydroxy, carboxy, NR ５Ｅ R ５Ｆ , C １～４ Alkoxy, C １～４ Alkyl, C ３～８ Cycloalkyl, C ３～８ Cycloalkyl-C １～３ Alkyl, C １～４ Alkanoyl, C １～４ Alkylsulfonyl, or C(O)NR ５Ｅ R ５Ｆ , N.R. ５Ｅ C(O)R ５Ｆ , N.R. ５Ｅ S (O) ２ R ５Ｆ , and S(O) ２ N.R. ５Ｅ R ５Ｆ is replaced by R ８ and R ９ is selected from the group which may be the same or different at each occurrence and is independently selected from the group consisting of hydrogen, hydroxy, halogen, cyano, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl; or R ８ and R ９ may be taken together with the carbon atom to which they are attached to form a substituted or unsubstituted 3- to 7-membered saturated carbocyclic ring; R １０ and R １１ may be the same or different in each occurrence and are independently selected from hydrogen, halogen, cyano, hydroxy, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl, or R １０ and R １１ may be taken together with the carbon atom to which they are attached to form a substituted or unsubstituted 3- to 7-membered saturated carbocyclic ring.

2. The compound of claim 1, wherein the compound of formula I is selected from the group consisting of:

1. Methyl 3-(3,5-dichlorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 2. Methyl 3-(3,5-dichlorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 3. Methyl 3-(5-fluoro-2-methoxyphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 4. Methyl 3-(2-methoxyphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 5. Methyl 3-(4-methoxyphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 6. Methyl 3-(3,4-difluorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 7. Methyl 3-(5-chloro-2-methoxyphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 8. Methyl 3-(4-(tert-butyl)phenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 9. Methyl 3-(4-fluorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 10. Methyl 3-phenyl-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 11. Methyl 3-(2-fluorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 12. Methyl 3-(3-fluorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 13. Methyl 3-(4-chlorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 14. Methyl 3-(2-chlorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 15. Methyl 3-(3-chlorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 16. Methyl 3-(2,4-dichlorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 17. Methyl 3-(2,3-difluorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 18. Methyl 3-(3,5-dimethylphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 19. Methyl 3-(2-fluoro-4-methylphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 20. Methyl 3-(2,3-dichlorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 21. Methyl 3-(pyridin-4-yl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 22. Methyl 3-(3,5-difluorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 23. Methyl 3-(pyrimidin-5-yl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 24. Methyl 3-(5-fluoropyridin-3-yl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 25. Methyl 3-(5-chloropyridin-3-yl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 26. Methyl 3-(4-fluoro-3-methoxyphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 27. Methyl 3-(3-chloro-5-methylphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 28. Methyl 3-(3-chloro-5-fluorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 29. Methyl 3-(3-chloro-5-methoxyphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 30. Methyl 3-(3,4,5-trichlorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 31. Methyl 3-(3,5-dimethoxyphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 32. Methyl 3-(3-fluoro-5-methoxyphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 33. Methyl 3-(2,3-dichlorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylate; 34. 3-(5-fluoro-2-methoxyphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid; 35. 3-(2-Methoxyphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid; 36. 3-(4-Methoxyphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid; 37. 3-(3,4-difluorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid; 38. 3-(5-chloro-2-methoxyphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid; 39. 3-(4-(tert-butyl)phenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid; 40. 3-(4-fluorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid; 41. 3-(2-fluorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid; 42. 3-(3-fluorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid; 43. 3-(4-chlorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid; 44. 3-(2-chlorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid; 45. 3-(3-chlorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid; 46. ​​3-(2,4-dichlorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid; 47. 3-(2,3-difluorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid; 48. 3-(3,5-dimethylphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid; 49. 3-(2-fluoro-4-methylphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid; 50. 3-(Pyridin-4-yl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid; 51. 3-(3,5-difluorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid; 52. 3-(5-fluoropyridin-3-yl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid; 53. 3-(5-chloropyridin-3-yl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid; 54. 3-(2,3-dichlorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid; 55. 3-(pyrimidin-5-yl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid; 56. 3-(4-fluoro-2-methoxyphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid; 57. 3-(3-chloro-5-methylphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid; 58. 3-(3-chloro-5-fluorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid; 59. 3-(3-chloro-5-methoxyphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid; 60. 3-(3,4,5-trichlorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid; 61. 3-(3,5-dimethoxyphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid; 62. 3-(3-fluoro-5-methoxyphenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid; 63. 3-Phenyl-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid; 64. 3-(3-chloro-5-fluorophenyl)-5-methyl-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid; 65. 7-Bromo-3-(3,5-dichlorophenyl)-4,5-dihydro-1H-benzo[g]indole-2-carboxylic acid.

3. A process for preparing a compound of formula I according to claim 1, comprising the steps of: i. reducing the tetralone of formula (1) using a reducing agent such as sodium borohydride to obtain a compound of formula (2); [Case 2] ii. formylation of the compound of formula (2) obtained in step (i) with the in situ prepared Vilsmeier-Haack reagent / adduct to obtain a compound of formula (3); [C3] iii. Treating the aldehyde of formula (3) obtained in step (ii) with an azido ester compound of formula (4) in the presence of a base such as sodium ethoxide, sodium methoxide, etc. to obtain a compound of formula (5); [C4] iv. cyclizing the compound of formula (5) in the presence of a suitable Lewis acid or under acidic conditions to obtain a compound of formula (6); [C5] v. halogenating the compound of formula (6) using a halogenating agent such as NBS, NIS, etc. to obtain the halogenated compound of formula (7); [C6] vi. coupling the halo compound of formula (7) with an aryl / heteroaryl boronic acid or aryl / heteroaryl boronic acid ester to obtain a compound of formula (Ia); [C7] vii. LiOH, K ２ CO ３ and converting the compound of formula (Ia) to a compound of formula (I) by hydrolysis of the corresponding ester using a base such as NaOH, [C8] The process, wherein in the acid of formula (I), -COOH may be converted to the corresponding amide, ester, etc., wherein R1 is the same as defined above.

4. 2. A compound of formula I according to claim 1 in free form, in the form of a salt, or in the form of a pharma- ceutically acceptable salt.

5. A pharmaceutical composition comprising at least one compound of formula (I), optionally together with a pharma- ceutically acceptable excipient.

6. 10. The pharmaceutical composition of claim 1, wherein the composition further comprises an effective amount of a beta-lactam antibiotic.

7. The pharmaceutical composition of claim 1, wherein the composition is used as a beta-lactamase inhibitor or drug.

8. 2. Use of a compound of formula (I) or a pharma- ceutical acceptable salt thereof for inhibiting beta-lactamase activity, in the manufacture of a medicament for inhibiting beta-lactamase activity, in combination with a beta-lactam antibiotic for treating a bacterial infection, or in combination with a beta-lactam antibiotic in the manufacture of a medicament for treating a bacterial infection.

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