Benzothiazole analogues and their use as boosters of antituberculous drugs - Patents.com

Abstract

The present invention relates to new norbornene analogues of formula (I) having a norbornene moiety at R5 and to their use as drugs, in particular for the prevention and / or treatment of mycobacterial infections or diseases caused by infection with mycobacteria.

Description

[Technical Field]

[0001] The present invention relates to new benzothiazole analogues and their use as drugs, in particular for the prevention and / or treatment of mycobacterial infections or diseases caused by mycobacterial infections, more particularly Mycobacterium tuberculosis infections. [Background technology]

[0002] background Tuberculosis (TB) is the leading cause of death from a single infectious pathogen worldwide. According to the World Health Organization (WHO), TB caused 1.5 million deaths in 2019 and continues to affect 10 million people annually. Furthermore, one-third of the world's population has latent TB infection, and 10% will have active TB [Global Tuberculosis Report 2019 - WHO].

[0003] Although various treatments are currently available to treat susceptible tuberculosis, the rapid and global emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains has become alarming, forcing the scientific community to develop new alternative strategies.

[0004] MDR-TB is characterized by resistance to two key first-line drugs (isoniazid and rifampicin), while XDR-TB is defined as MDR-TB that is additionally resistant to fluoroquinolones and at least two injectable second-line drugs. Treatment duration, which ranges from 6 to 9 months in the best case scenario, can extend to more than 24 months in the worst case scenario and is associated with numerous side effects that lead to patient noncompliance. Therefore, treatment duration and the complexity of the dosing regimen are part of the challenge.

[0005] Over the past decade, much of the research in drug discovery has been focused on discovering new families of active antituberculosis drugs. One common feature shared by both new and old antituberculosis drugs is that they are prodrugs, meaning that they are active only upon bioactivation in mycobacteria. Therefore, mutations in the bioactivation pathway have long been observed in clinical strains of M. tuberculosis that have developed resistance to prodrugs.

[0006] As a result, the inventors have developed molecules capable of triggering alternative bioactivation pathways in bacteria. A non-exhaustive list of the potential benefits of such molecules includes: i) enhancing the efficacy of existing prodrugs, ii) improving their therapeutic index, iii) shortening treatment duration, iv) inhibiting the emergence of resistant bacteria, and v) resensitizing clinical strains resistant to prodrugs.

[0007] The present invention describes the discovery of a new chemical series of benzothiazole analogs, herein referred to as Smart-Nims, that can reprogram the bioactivation of nitroimidazole antituberculosis prodrugs. These Smart-Nim molecules i.) enhance the susceptibility of M. tuberculosis to nitroimidazoles and ii.) restore susceptibility to nitroimidazoles in clinical strains of M. tuberculosis that are resistant to this antibiotic class.

[0008] Detailed Description Thus, the present invention provides a compound of formula (I): [ka] [In formula: R1 is ·-H; ·-OH; ·Straight-chain or branched-(C1-C6) alkyl; and ·Straight-chain or branched-(C1-C6)alkoxy(C2-C6)alkynyl; is selected from R2 is ·-H; ·Straight-chain or branched-(C1-C6) alkyl; ·Straight-chain or branched-(C1-C6)alkoxy; and Halogen atoms; is selected from R3 is ·-H; Halogen atoms; linear or branched -(C1-C6) alkyl optionally substituted by one or more halogen atoms; linear or branched -(C1-C6)alkoxy optionally substituted by one or more halogen atoms; ·Straight or branched chain -(C2-C8)alkynyl; · linear or branched chain -(C1-C6)alkoxy-(C2-C6)alkynyl; ·-OR; ·-NHR; ·-(C2-C8)cycloalkyl; ·Straight or branched chain -(C2-C6)alkynyl-(C6-C 10 )aryl; ·Straight or branched chain -(C1-C6) alkyl-(C6-C 10 )aryl; - one or more -OH, halogen atoms, linear or branched -(C1-C6) alkyl optionally substituted by one or more halogen atoms; linear or branched -(C1-C6) alkoxy optionally substituted by one or more halogen atoms, -(C6-C 10 )aryl; Heteroaryl containing 3 to 10 ring members and having at least one heteroatom selected from O, N or S; optionally substituted by one or more halogen atoms, linear or branched -(C1-C6) alkyl optionally substituted by one or more halogen atoms; · linear or branched chain -(C2-C6)alkynyl-(C2-C6)cycloalkyl; ·Straight or branched chain - (C6-C 10 )aryl-(C1-C6)alkoxy-(C2-C6)alkynyl; ·-NO2; · Linear or branched chain -SO2(C1-C3) alkyl; ·-CN; ·-COO-(C1-C3)alkyl; is selected from R is ·-H; linear or branched -(C1-C6) alkyl optionally substituted by one or more halogen atoms; ·-(C6-C 10 )aryl optionally substituted by one or more halogen atoms, —OH, straight or branched chain —(C1-C6)alkyl optionally substituted by one or more halogen atoms, —(C1-C6)alkoxy optionally substituted by one or more halogen atoms; 10 )aryl; Heteroaryl containing 3 to 10 ring members and having at least one heteroatom selected from O, N or S; one or more halogen atoms, linear or branched -(C1-C6) alkyl optionally substituted with one or more halogen atoms; linear or branched -(C1-C6) alkoxy optionally substituted with one or more halogen atoms; the above heteroaryl optionally substituted with -CN; Selected from or R2 and R3 are linked together to form an -O-(C1-C6)alkyl-O- group; R4 is H and R5 is [ka] or R4 and R5, together with the nitrogen atom to which they are attached, [ka] form] or a pharmaceutically acceptable salt or optical isomer, racemate, diastereoisomer, enantiomer or tautomer thereof; However, the following compounds: - 3-[(1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-methyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(4-methyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(5,6-dimethyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-bromo-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-chloro-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(4,6-dimethyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-ethoxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-nitro-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-methylsulfonyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-(6-methyl-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - (1R,2S,6R,7S)-4-(6-ethoxy-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 2-[(6-ethyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-3-carboxylic acid; - 2-[(6-fluoro-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-3-carboxylic acid; - 2-[(5-ethoxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-3-carboxylic acid; - 2-(1,3-benzothiazol-2-yl)-4-ethyl-3a,4,7,7a-tetrahydroisoindole-1,3-dione; - 2-(5-chloro-6-methyl-1,3-benzothiazol-2-yl)-4-ethyl-3a,4,7,7a-tetrahydroisoindole-1,3-dione; - 4-ethyl-2-(4-methyl-1,3-benzothiazol-2-yl)-3a,4,7,7a-tetrahydroisoindole-1,3-dione; - 2-(6-bromo-1,3-benzothiazol-2-yl)-4-ethyl-3a,4,7,7a-tetrahydroisoindole-1,3-dione; - 4-ethyl-2-(6-methoxy-1,3-benzothiazol-2-yl)-3a,4,7,7a-tetrahydroisoindole-1,3-dione The present invention relates to the above compounds, salts or isomers, excluding:

[0009] In particular, the present invention provides compounds of formula (I): [ka] [In formula: R1 is ·-H; ·-OH; ·Straight-chain or branched-(C1-C6) alkyl; and ·Straight-chain or branched-(C1-C6)alkoxy(C2-C6)alkynyl; is selected from R2 is ·-H; ·Straight-chain or branched-(C1-C6) alkyl; ·Straight-chain or branched-(C1-C6)alkoxy; and Halogen atoms; is selected from R3 is ·-H; Halogen atoms; linear or branched -(C1-C6) alkyl optionally substituted by one or more halogen atoms; linear or branched -(C1-C6)alkoxy optionally substituted by one or more halogen atoms; ·Straight or branched chain -(C2-C8)alkynyl; · linear or branched chain -(C1-C6)alkoxy-(C2-C6)alkynyl; ·-OR; ·-NHR; ·-(C2-C8)cycloalkyl; ·Straight or branched chain -(C2-C6)alkynyl-(C6-C 10 )aryl; ·Straight or branched chain -(C1-C6) alkyl-(C6-C 10 )aryl; one or more -OH, halogen atoms, linear or branched -(C1-C6) alkyl optionally substituted with one or more halogen atoms; linear or branched -(C1-C6) alkoxy optionally substituted with one or more halogen atoms; -NRaRb, -(C6-C 10 )aryl; Straight or branched chain (C2-C6) alkynyl-(C2-C6) cycloalkyl Heteroaryl containing 3 to 10 ring members and having at least one heteroatom selected from O, N or S; optionally substituted by one or more halogen atoms, linear or branched -(C1-C6) alkyl optionally substituted by one or more halogen atoms; · linear or branched chain -(C2-C6)alkynyl-(C2-C6)cycloalkyl; ·Straight or branched chain - (C6-C 10 )aryl-(C1-C6)alkoxy-(C2-C6)alkynyl; ·-NO2; · Linear or branched chain -SO2(C1-C3) alkyl; ·-CN; ·-COO-(C1-C3)alkyl; is selected from R is ·-H; linear or branched -(C1-C6) alkyl optionally substituted by one or more halogen atoms; ·-(C6-C 10 )aryl optionally substituted by one or more halogen atoms, —OH, straight or branched chain —(C1-C6)alkyl optionally substituted by one or more halogen atoms, —(C1-C6)alkoxy optionally substituted by one or more halogen atoms; 10 )aryl; Heteroaryl containing 3 to 10 ring members and having at least one heteroatom selected from O, N or S; one or more halogen atoms, linear or branched -(C1-C6) alkyl optionally substituted with one or more halogen atoms; linear or branched -(C1-C6) alkoxy optionally substituted with one or more halogen atoms; the above heteroaryl optionally substituted with -CN; is selected from Ra and Rb are the same or different, ·-H; linear or branched (C1-C6) alkyl, in which one of the carbon atoms of the alkyl group may be replaced by a heteroatom; Selected from or Ra and Rb are joined together to form a heterocycloalkyl containing 3 to 10 ring members; optionally substituted by one or more of: straight or branched chain -(C1-C6)alkyl, -COO-(C1-C3)alkyl, -NRcRd; oxo (=O); Rc and Rd are the same or different; ·-H; and ·Straight-chain or branched-(C1-C6) alkyl; Selected from or R2 and R3 are linked together to form an -O-(C1-C6)alkyl-O- group; R4 is H and R5 is [ka] or R4 and R5, together with the nitrogen atom to which they are attached, [ka] form] or a pharmaceutically acceptable salt or optical isomer, racemate, diastereoisomer, enantiomer or tautomer thereof; However, the following compounds: - 3-[(1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-methyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(4-methyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(5,6-dimethyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-bromo-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-chloro-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(4,6-dimethyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-ethoxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-nitro-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-methylsulfonyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 4-(6-methyl-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 2-[(6-ethyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-3-carboxylic acid; - 2-[(6-fluoro-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-3-carboxylic acid; - 2-[(5-ethoxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-3-carboxylic acid; - (2-(benzo[d]thiazol-2-yl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindole-1,3(2H)-dione - 2-(5-chloro-6-methylbenzo[d]thiazol-2-yl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindole-1,3(2H)-dione - 2-(4-methylbenzo[d]thiazol-2-yl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindole-1,3(2H)-dione - 2-(6-bromobenzo[d]thiazol-2-yl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindole-1,3(2H)-dione - 2-(6-methoxybenzo[d]thiazol-2-yl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindole-1,3(2H)-dione; - 3-[(6-methoxy-1,3-benzothiazol-2-yl)carbamoyl]norbornane-2-carboxylic acid; 4-(6-methoxy-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 4-(5-chloro-6-methyl-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 4-(4-methyl-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 4-(6-bromo-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 4-(4-methyl-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]decane-3,5-dione The present invention relates to the above compounds, salts or isomers, excluding:

[0010] In one embodiment, (3aS,4R,7S,7aS)-[2-(2-benzothiazolyl)]-4,7-methano-1H-isoindole-1,3-(2H)-dione and / or -4-(6-ethoxy-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione are also excluded.

[0011] The present invention also relates to a pharmaceutical composition comprising a compound of formula (I) as described above and a pharmaceutically acceptable excipient.

[0012] The present invention further provides a compound of formula (I): [ka] [In formula: R1 is ·-H; ·-OH; ·Straight-chain or branched-(C1-C6) alkyl; and ·Straight-chain or branched-(C1-C6)alkoxy(C2-C6)alkynyl; is selected from R2 is ·-H; ·Straight-chain or branched-(C1-C6) alkyl; ·Straight-chain or branched-(C1-C6)alkoxy; and Halogen atoms; is selected from R3 is ·-H; Halogen atoms; linear or branched -(C1-C6) alkyl optionally substituted by one or more halogen atoms; linear or branched -(C1-C6)alkoxy optionally substituted by one or more halogen atoms; ·Straight or branched chain -(C2-C8)alkynyl; · linear or branched chain -(C1-C6)alkoxy-(C2-C6)alkynyl; ·-OR; ·-NHR; ·-(C2-C8)cycloalkyl; ·Straight or branched chain -(C2-C6)alkynyl-(C6-C 10 )aryl; ·Straight or branched chain -(C1-C6) alkyl-(C6-C 10 )aryl; - optionally substituted by one or more -OH, halogen atoms, linear or branched -(C1-C6) alkyl optionally substituted by one or more halogen atoms, linear or branched -(C1-C6) alkoxy optionally substituted by one or more halogen atoms, -(C6-C 10 )aryl; Heteroaryl containing 3 to 10 ring members and having at least one heteroatom selected from O, N or S; optionally substituted by one or more halogen atoms, linear or branched -(C1-C6) alkyl optionally substituted by one or more halogen atoms; · linear or branched chain -(C2-C6)alkynyl-(C2-C6)cycloalkyl; ·Straight or branched chain - (C6-C 10 )aryl-(C1-C6)alkoxy-(C2-C6)alkynyl; ·-NO2; · Linear or branched chain -SO2(C1-C3) alkyl; ·-CN; ·-COO-(C1-C3)alkyl; is selected from R is ·-H; linear or branched -(C1-C6) alkyl optionally substituted by one or more halogen atoms; ·-(C6-C 10)aryl optionally substituted by one or more halogen atoms, —OH, straight or branched chain —(C1-C6)alkyl optionally substituted by one or more halogen atoms, —(C1-C6)alkoxy optionally substituted by one or more halogen atoms, 10 )aryl; Heteroaryl containing 3 to 10 ring members and having at least one heteroatom selected from O, N or S; one or more halogen atoms, linear or branched -(C1-C6) alkyl optionally substituted with one or more halogen atoms; linear or branched -(C1-C6) alkoxy optionally substituted with one or more halogen atoms; the above heteroaryl optionally substituted with -CN; Selected from or R2 and R3 are linked together to form an -O-(C1-C6)alkyl-O- group; R4 is H and R5 is [ka] or R4 and R5, together with the nitrogen atom to which they are attached, [ka] form] or a pharmaceutically acceptable salt or optical isomer, racemate, diastereoisomer, enantiomer or tautomer thereof; It relates to said compounds, salts or isomers for use as a medicament, in particular for the treatment of a mycobacterial infection or in the treatment of a disease caused by an infection with a mycobacterium, more particularly wherein the mycobacterial infection is a Mycobacterium tuberculosis infection.

[0013] In particular, the present invention further provides compounds of formula (I): [ka] [In formula: R1 is ·-H; ·-OH; ·Straight-chain or branched-(C1-C6) alkyl; and ·Straight-chain or branched-(C1-C6)alkoxy(C2-C6)alkynyl; is selected from R2 is ·-H; ·Straight-chain or branched-(C1-C6) alkyl; ·Straight-chain or branched-(C1-C6)alkoxy; and Halogen atoms; is selected from R3 is ·-H; Halogen atoms; linear or branched -(C1-C6) alkyl optionally substituted by one or more halogen atoms; linear or branched -(C1-C6)alkoxy optionally substituted by one or more halogen atoms; ·Straight or branched chain -(C2-C8)alkynyl; · linear or branched chain -(C1-C6)alkoxy-(C2-C6)alkynyl; ·-OR; ·-NHR; ·-(C2-C8)cycloalkyl; ·Straight or branched chain -(C2-C6)alkynyl-(C6-C 10 )aryl; ·Straight or branched chain -(C1-C6) alkyl-(C6-C 10 )aryl; one or more -OH, halogen atoms, linear or branched -(C1-C6) alkyl optionally substituted with one or more halogen atoms, linear or branched -(C1-C6) alkoxy optionally substituted with one or more halogen atoms, -NRaRb, -(C6-C 10 )aryl; Heteroaryl containing 3 to 10 ring members and having at least one heteroatom selected from O, N or S; optionally substituted by one or more halogen atoms, linear or branched -(C1-C6) alkyl optionally substituted by one or more halogen atoms; · linear or branched chain -(C2-C6)alkynyl-(C2-C6)cycloalkyl; ·Straight or branched chain - (C6-C 10 )aryl-(C1-C6)alkoxy-(C2-C6)alkynyl; ·-NO2; · Linear or branched chain -SO2(C1-C3) alkyl; ·-CN; ·-COO-(C1-C3)alkyl; is selected from R is ·-H; linear or branched -(C1-C6) alkyl optionally substituted by one or more halogen atoms; ·-(C6-C 10 )aryl optionally substituted by one or more halogen atoms, —OH, straight or branched chain —(C1-C6)alkyl optionally substituted by one or more halogen atoms, —(C1-C6)alkoxy optionally substituted by one or more halogen atoms, 10 )aryl; Heteroaryl containing 3 to 10 ring members and having at least one heteroatom selected from O, N or S; one or more halogen atoms, linear or branched -(C1-C6) alkyl optionally substituted with one or more halogen atoms; linear or branched -(C1-C6) alkoxy optionally substituted with one or more halogen atoms; the above heteroaryl optionally substituted with -CN; is selected from Ra and Rb are the same or different, ·-H; linear or branched (C1-C6) alkyl, in which one of the carbon atoms of the alkyl group may be replaced by a heteroatom; Selected from or Ra and Rb are joined together to form a heterocycloalkyl containing 3 to 10 ring members; optionally substituted by one or more of: straight or branched chain -(C1-C6)alkyl, -COO-(C1-C3)alkyl, -NRcRd; oxo (=O); Rc and Rd are the same or different; ·-H; and ·Straight-chain or branched-(C1-C6) alkyl; Selected from or R2 and R3 are linked together to form an —O—(C1-C6)alkyl-O— group: R4 is H and R5 is [ka] or R4 and R5, together with the nitrogen atom to which they are attached, [ka] form] or a pharmaceutically acceptable salt or optical isomer, racemate, diastereoisomer, enantiomer or tautomer thereof; However, the following compounds: 3-[(6-methylsulfonyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; Except for The present invention relates to said compounds, salts or isomers for use as a medicament, in particular for the treatment of a mycobacterial infection or in the treatment of a disease caused by an infection with a mycobacterium, more particularly the mycobacterial infection is a Mycobacterium tuberculosis infection.

[0014] In one embodiment, (3aS,4R,7S,7aS)-[2-(2-benzothiazolyl)]-4,7-methano-1H-isoindole-1,3-(2H)-dione and / or bicyclo[2.2.1]hept-5-ene-2,3-dicarboximide-N-[2-(6-methylbenzo)thiazolyl] are also excluded.

[0015] Terms used hereinbefore or hereinafter in connection with compounds of formula (I) have the following meanings ascribed to them, unless otherwise specified:

[0016] "H" refers to hydrogen.

[0017] "OH" refers to hydroxyl.

[0018] "CN" refers to carbonitrile.

[0019] "NO2" refers to a nitro group.

[0020] "Oxo" refers to =O;

[0021] "SO2(C1-C3)alkyl" specifically refers to SO2CH3.

[0022] "COO-(C1-C3)alkyl" refers specifically to COOCH3 or COOC(CH3)3.

[0023] "Halogen" refers to a fluorine, chlorine, bromine, or iodine atom.

[0024] "Alkyl" refers to an aliphatic hydrocarbon group (C1-C6) alkyl or (C1-C3) alkyl, which may be linear or branched, having 1 to 6 or 1 to 3 carbon atoms in the chain, unless otherwise specified. In particular, the alkyl group is a (C1-C3) alkyl having 1 to 3 carbon atoms in the chain. Branched chain means that one or more alkyl groups, such as methyl, ethyl, or propyl, are attached to a linear alkyl chain. Exemplary alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, 2,2-dimethylbutyl, n-pentyl, and n-hexyl, particularly methyl or ethyl. As previously mentioned, the alkyl may be substituted with one or more halogen atoms; for example, (C1-C3)halogenoalkyl, which is an alkyl having 1 to 3 carbon atoms in the chain, has one or more hydrogen atoms replaced with a halogen atom, such as a fluorine, chlorine, bromine, or iodine atom, particularly one or more fluorine atoms. Exemplary halogenoalkyl include trifluoromethyl. When it is specified that one of the carbon atoms of an alkyl group may be replaced by a heteroatom, this means that one of the carbon atoms of the chain may be replaced by a heteroatom, such as O, N, or S, particularly N or O.

[0025] "Alkoxy" refers to an alkyl group as defined above that is single-bonded to an oxygen atom. Examples of straight or branched (C1-C6) alkoxy include methoxy (CHO-) and ethoxy (CHCHO-). The alkoxy may be substituted with one or more fluorine atoms, such as trifluoromethoxy.

[0026] "Alkynyl," unless otherwise specified, refers to an aliphatic hydrocarbon group (C2-C8)alkynyl or (C2-C6)alkynyl containing a carbon-carbon triple bond and having 2 to 8 or 2 to 6 carbon atoms in the chain, which may be straight or branched. Preferred alkynyl groups are (C2-C6)alkynyl groups having 2 to 6 carbon atoms in the chain. Exemplary alkynyl groups include ethynyl, propynyl, but-1-ynyl, but-2-ynyl, and 3,3-dimethylbut-1-ynyl.

[0027] "Cycloalkyl" refers to a saturated monocyclic or bicyclic non-aromatic hydrocarbon ring of 2 to 8 carbon atoms or 2 to 6 carbon atoms, preferably 3 to 6 carbon atoms, which may contain one or more unsaturations. Specific examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, and cyclohexenyl. Preferably, the cycloalkyl group is cyclohexyl or cyclopropyl.

[0028] "Aryl" refers to an aromatic monocyclic or polycyclic hydrocarbon ring system of 6 to 10 carbon atoms, preferably 6 carbon atoms. Exemplary aryl groups include phenyl, naphthyl, benzyl, phenanthryl, biphenyl, and especially phenyl. The aryl or phenyl may be substituted with one or more halogen atoms, such as fluorine, bromine, iodine, or chlorine; (C1-C6) alkyl or (C1-C3) alkyl, such as methyl, optionally substituted with 1 to 3 halogen atoms, especially fluorine (e.g., trifluoromethyl); -OH; (C1-C6) alkoxy or (C1-C3) alkoxy, such as methoxy, optionally substituted with 1 to 3 halogen atoms, especially fluorine (e.g., trifluoromethoxy).

[0029] "Heteroaryl" refers to a 3-10 aromatic monocyclic, bicyclic, or polycyclic ring in which at least one ring member is a heteroatom. The heteroatom can be O, S, or N. In particular, each ring contains 1-3 heteroatoms. Examples include pyrrolyl, pyridyl, quinolyl, furan, thiophene, pyrimidinyl, pyrazolyl, pyrazinyl, indolyl, and imidazolyl, in particular pyridyl, thiophene, quinolyl, or pyrimidinyl. The heteroaryl may be substituted by a halogen atom, such as fluorine, bromine, iodine, or chlorine, especially fluorine or bromine; (C1-C6) alkyl, such as methyl, optionally substituted with one or more halogen atoms, especially three fluorine atoms (e.g., trifluoromethyl); (C1-C6) alkoxy, such as methoxy, or (C1-C3) alkoxy, optionally substituted with one to three halogen atoms, especially fluorine (e.g., trifluoromethoxy); or CN.

[0030] "Heterocycloalkyl" or "heterocycle" refers to a saturated or partially unsaturated, non-aromatic, stable 3- to 10-membered monocyclic, bicyclic, or polycyclic ring, in which at least one ring member is a nitrogen atom. The ring may contain more than one nitrogen atom and may contain other heteroatoms such as oxygen or sulfur atoms. Suitable heterocycles are disclosed, for example, in "Handbook of Chemistry and Physics," 76th Edition, CRC Press, Inc., 1995-1996, pages 225 to 226, the disclosure of which is incorporated herein by reference. Examples of heterocycloalkyl include, but are not limited to, piperazine, diazepane, piperidine, pyrrolidine, imidazolidine, morpholine, azetidine, diazabicyclooctanyl, diazabicycloheptanyl, and azabicyclohexanyl, particularly piperazine, morpholine, pyrrolidine, and piperidine. The heterocycloalkyl is optionally substituted with one or more linear or branched chain -(C-C)alkyl, -COO-(C-C)alkyl, -NRcRd; oxo (=O); Rc and Rd are the same or different and are selected from -H and linear or branched chain -(C-C)alkyl. The term "substituted" generally refers to substitution with one or more substituents, which may be the same or different and are specified herein, unless otherwise specified.

[0031] The compounds of formula (I) described herein may contain one or more asymmetric carbon atoms. They can therefore exist in the form of enantiomers or diastereoisomers. These enantiomers and diastereoisomers, as well as mixtures thereof, including racemic mixtures, form part of the present invention.

[0032] The compounds of formula (I) described herein can be provided in the form of a free base or in the form of an addition salt with an acid or amine, which also form part of the present invention.

[0033] These salts are advantageously prepared with pharmaceutically acceptable amines, although salts with other amines, for example those useful in the purification or isolation of the compounds of formula (I) described herein, also form part of the present invention.

[0034] As used herein, the phrase "pharmaceutically acceptable" refers to a compound, material, excipient, composition or dosage form that is, within the scope of sound medical judgment, suitable for contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other significant complication, and is commensurate with a reasonable benefit / risk ratio.

[0035] As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds in which the parent compound is modified by making its acid or base salt. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound, for example, formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc., including mono-, di-, or tri-salts; and salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, tartaric acid, citric acid, methanesulfonic acid, benzenesulfonic acid, glucuronic acid, glutamic acid, benzoic acid, salicylic acid, toluenesulfonic acid, oxalic acid, fumaric acid, maleic acid, and lactic acid. Further additional salts include ammonium salts such as tromethamine, meglumine, and epolamine, and metal salts such as sodium, potassium, calcium, zinc, or magnesium.

[0036] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or free base form of these compounds with a stoichiometric amount of an appropriate base or acid in water or an organic solvent, or in a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 20 th ed., Mack Publishing Company, Easton, PA, 2000, the disclosure of which is incorporated herein by reference.

[0037] compound As already mentioned, the compounds of the present invention have the formula (I): [ka] [In formula: R1 is ·-H; ·-OH; ·Straight-chain or branched-(C1-C6) alkyl; and ·Straight-chain or branched-(C1-C6)alkoxy(C2-C6)alkynyl; and / or R2 is ·-H; ·Straight-chain or branched-(C1-C6) alkyl; ·Straight-chain or branched-(C1-C6)alkoxy; and Halogen atoms; and / or R3 is ·-H; Halogen atoms; linear or branched -(C1-C6) alkyl optionally substituted by one or more halogen atoms; linear or branched -(C1-C6)alkoxy optionally substituted by one or more halogen atoms; ·Straight or branched chain -(C2-C8)alkynyl; · linear or branched chain -(C1-C6)alkoxy-(C2-C6)alkynyl; ·-OR; ·-NHR; ·-(C2-C8)cycloalkyl; ·Straight or branched chain -(C2-C6)alkynyl-(C6-C 10 )aryl; ·Straight or branched chain -(C1-C6) alkyl-(C6-C 10 )aryl; one or more -OH, halogen atoms, linear or branched -(C1-C6) alkyl optionally substituted with one or more halogen atoms, linear or branched -(C1-C6) alkoxy optionally substituted with one or more halogen atoms, -NRaRb, -(C6-C 10 )aryl; Heteroaryl containing 3 to 10 ring members and having at least one heteroatom selected from O, N or S; optionally substituted by one or more halogen atoms, linear or branched -(C1-C6) alkyl optionally substituted by one or more halogen atoms; · linear or branched chain -(C2-C6)alkynyl-(C2-C6)cycloalkyl; ·Straight or branched chain - (C6-C 10 )aryl-(C1-C6)alkoxy-(C2-C6)alkynyl; ·-NO2; · Linear or branched chain -SO2(C1-C3) alkyl; ·-CN; ·-COO-(C1-C3)alkyl; is selected from R is ·-H; linear or branched -(C1-C6) alkyl optionally substituted by one or more halogen atoms; ·-(C6-C 10 )aryl optionally substituted by one or more halogen atoms, —OH, straight or branched chain —(C1-C6)alkyl optionally substituted by one or more halogen atoms, —(C1-C6)alkoxy optionally substituted by one or more halogen atoms; 10 )aryl; Heteroaryl containing 3 to 10 ring members and having at least one heteroatom selected from O, N or S; one or more halogen atoms, linear or branched -(C1-C6) alkyl optionally substituted with one or more halogen atoms; (C1-C6) alkoxy optionally substituted with one or more halogen atoms; the above heteroaryl optionally substituted with -CN; is selected from Ra and Rb are the same or different, ·-H; linear or branched (C1-C6) alkyl, in which one of the carbon atoms of the alkyl group may be replaced by a heteroatom; Selected from or Ra and Rb are joined together to form a heterocycloalkyl containing 3 to 10 ring members, optionally substituted by one or more of: straight or branched chain -(C1-C6)alkyl, -COO-(C1-C3)alkyl, -NRcRd; oxo; Rc and Rd are the same or different; ·-H; and ·Straight-chain or branched-(C1-C6) alkyl; Selected from or R2 and R3 are linked together to form an —O—(C1-C6)alkyl-O— group; and / or R4 is H and R5 is [ka] or R4 and R5, together with the nitrogen atom to which they are attached, [ka] form] or a pharmaceutically acceptable salt or optical isomer, racemate, diastereoisomer, enantiomer or tautomer thereof; However, the following compounds: - 3-[(1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-methyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(4-methyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(5,6-dimethyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-bromo-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-chloro-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(4,6-dimethyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-ethoxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-nitro-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-methylsulfonyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 4-(6-methyl-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 2-[(6-ethyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-3-carboxylic acid; - 2-[(6-fluoro-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-3-carboxylic acid; - 2-[(5-ethoxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-3-carboxylic acid; - (2-(benzo[d]thiazol-2-yl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindole-1,3(2H)-dione - 2-(5-chloro-6-methylbenzo[d]thiazol-2-yl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindole-1,3(2H)-dione - 2-(4-methylbenzo[d]thiazol-2-yl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindole-1,3(2H)-dione - 2-(6-bromobenzo[d]thiazol-2-yl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindole-1,3(2H)-dione - 2-(6-methoxybenzo[d]thiazol-2-yl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindole-1,3(2H)-dione; - 3-[(6-methoxy-1,3-benzothiazol-2-yl)carbamoyl]norbornane-2-carboxylic acid; - 4-(6-methoxy-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 4-(5-chloro-6-methyl-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 4-(4-methyl-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 4-(6-bromo-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 4-(4-methyl-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]decane-3,5-dione and the compounds, salts or isomers thereof, excluding:

[0038] In one embodiment, (3aS,4R,7S,7aS)-[2-(2-benzothiazolyl)]-4,7-methano-1H-isoindole-1,3-(2H)-dione and / or 4-(6-ethoxy-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione are also excluded.

[0039] In particular, the compound is - 3-[(6-methyl-1,3-benzothiazol-2-yl)carbamoyl]norbornane-2-carboxylic acid; - (1S,2S,6R,7R)-4-(6-methyl-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]decane-3,5-dione; - 3-[(5-methoxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-methoxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(5,6-dimethoxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-(6,7-dihydro-[1,4]dioxino[2,3-f][1,3]benzothiazol-2-ylcarbamoyl)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-ethyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-tert-butyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(4,5-dimethyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-phenoxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-(6-phenoxy-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 3-[(6-benzyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[[6-(4-fluorophenoxy)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[[6-[4-(trifluoromethyl)phenoxy]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-[6-[4-(trifluoromethyl)phenoxy]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 3-[[6-(4-pyridyloxy)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[[6-[[3-(trifluoromethyl)-2-pyridyl]oxy]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-[6-[[3-(trifluoromethyl)-2-pyridyl]oxy]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 3-[[6-[[4-(trifluoromethyl)-2-pyridyl]oxy]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-[6-[[4-(trifluoromethyl)-2-pyridyl]oxy]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 3-[[6-[(4-methyl-2-pyridyl)oxy]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 2-[[2-[(1R,2S,6R,7S)-3,5-dioxo-4-azatricyclo[5.2.1.02,6]dec-8-en-4-yl]-1,3-benzothiazol-6-yl]oxy]pyridine-4-carbonitrile; - 3-[[6-[[2-(trifluoromethyl)-4-pyridyl]oxy]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-[6-[[6-(trifluoromethyl)-2-pyridyl]oxy]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 3-[[6-[[5-(trifluoromethyl)-2-pyridyl]oxy]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-[6-[[5-(trifluoromethyl)-2-pyridyl]oxy]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 3-[[6-[(5-bromo-2-pyridyl)oxy]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-cyano-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-methoxycarbonyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-fluoro-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[[6-(trifluoromethyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 3-[(5-bromo-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-iodo-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-hydroxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-phenyl-1,3-benzothiazol-2-yl)carbamoyl]-7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-cyclohexyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[[6-(p-tolyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[[6-(4-methoxyphenyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[[6-(4-chlorophenyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[[6-(3,4-dichlorophenyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[[6-[2-(trifluoromethyl)phenyl]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-[6-[2-(trifluoromethyl)phenyl]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 3-[[6-[3-(trifluoromethyl)phenyl]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[[6-[4-(trifluoromethyl)phenyl]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-[6-[4-(trifluoromethyl)phenyl]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 3-[[6-[4-(trifluoromethoxy)phenyl]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-[6-(4-hydroxyphenyl)-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 3-[[6-(4-pyridyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-[6-(6-fluoro-3-pyridyl)-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 3-[[6-[6-(trifluoromethyl)-3-pyridyl]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-[6-[6-(trifluoromethyl)-3-pyridyl]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 3-[(6-pyrimidin-5-yl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[[6-(6-quinolyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 4-[6-(3-thienyl)-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 3-[[6-(3-furyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-[6-(3-furyl)-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 4-[6-(4-prop-2-ynoxyphenyl)-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - (1R,2S,6R,7S)-4-(6-ethynyl-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - (1R,2S,6R,7S)-4-(6-prop-2-ynoxy-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - (1R,2S,3R,4S)-3-[(4-hydroxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(4-prop-2-ynoxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-(4-prop-2-ynoxy-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 3-[[6-(2-phenylethynyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[[6-(3,3-dimethylbut-1-ynyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[[6-(2-cyclopropylethynyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - [2-Hydroxy-1,1-bis(hydroxymethyl)ethyl]ammonium; (1R,2S,3R,4S)-3-[(6-phenoxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylate; - (1R,2S,6R,7S)-4-[6-[(4-methyl-2-pyridyl)oxy]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - (1R,2S,6R,7S)-4-[6-[(2-chloro-4-pyridyl)oxy]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 3-[[6-[6-(trifluoromethyl)-3-pyridyl]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-(6-anilino-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; 4-[6-(2-pyridylamino)-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; and - 3-[[6-[(4-methyl-2-pyridyl)amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[[6-[(4-fluoro-2-pyridyl)amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[[6-[(5-fluoro-2-pyridyl)amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 4-[6-[(5-fluoro-2-pyridyl)amino]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 3-[[6-[(6-fluoro-2-pyridyl)amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 4-[6-[(6-fluoro-2-pyridyl)amino]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 4-[6-[[2-(trifluoromethyl)-4-pyridyl]amino]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 3-[[6-[[5-(trifluoromethyl)-3-pyridyl]amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 4-[6-[(2-methoxy-4-pyridyl)amino]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 3-[[6-[[5-(trifluoromethoxy)-2-pyridyl]amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 4-[6-[[5-(trifluoromethoxy)-2-pyridyl]amino]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 4-[6-[[5-(trifluoromethyl)-2-pyridyl]amino]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 3-[[6-[[5-(trifluoromethyl)-2-pyridyl]amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 4-[6-[[6-(trifluoromethyl)-2-pyridyl]amino]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 4-[6-[(2-fluoro-4-pyridyl)amino]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 3-[[6-[(2-fluoro-4-pyridyl)amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[[6-[4-(1-piperidyl)anilino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - tert-butyl 4-[4-[2-[(1R,2S,6R,7S)-3,5-dioxo-4-azatricyclo[5.2.1.02,6]dec-8-en-4-yl]-1,3-benzothiazol-6-yl]phenyl]piperazine-1-carboxylate; - 4-[6-(4-morpholinophenyl)-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; or a pharmaceutically acceptable salt thereof, or an optical isomer, racemate, diastereoisomer, enantiomer or tautomer thereof.

[0040] In one embodiment, the compound of formula (I) is R1 is H; and / or R2 is H; and / or R3, ·Straight or branched chain -(C2-C6)alkynyl; · straight-chain or branched-(C1-C6)alkoxy substituted by one or more halogen atoms; NHR ·-OR; one or more linear or branched -(C1-C6)alkyl optionally substituted by one or more halogen atoms, linear or branched -(C1-C6)alkoxy optionally substituted by one or more halogen atoms, -NRaRb optionally substituted by -(C6-C 10 )aryl; is selected from R, · linear or branched-(C1-C6) alkyl substituted by one or more halogen atoms; - one or more linear or branched -(C-C) alkyl optionally substituted by one or more halogen atoms, -(C-C 10 )aryl; Heteroaryl containing 3 to 10 ring members and having at least one heteroatom selected from O, N or S; optionally substituted by one or more linear or branched -(C1-C6) alkyls optionally substituted by one or more halogen atoms; is selected from, and Ra and Rb are joined together to form a heterocycloalkyl containing 3 to 10 ring members; optionally substituted by one or more of a straight or branched chain -(C1-C6)alkyl, -COO-(C1-C3)alkyl, -NRcRd; oxo; Rc and Rd are the same or different, ·-H; and ·Straight-chain or branched-(C1-C6) alkyl; Selected from It is characterized by:

[0041] In particular, the compound of formula (I) R1 is H; and / or R2 is H; and / or R3, linear or branched -(C1-C3)alkoxy substituted by one or more fluorine atoms, preferably trifluoromethoxy; ·3,3-dimethylbut-1-ynyl; ·-OR; ·-NHR; phenyl optionally substituted by one or more trifluoromethyl, methoxy, trifluoromethoxy and / or piperidyl; is selected from, and R, linear or branched (C1-C3) alkyl substituted by one or more halogen atoms, preferably one or more fluoro atoms; phenyl optionally substituted by one or more methyl and / or trifluoromethyl; Heteroaryl containing 6 ring members and having at least one nitrogen atom as heteroatom, said heteroaryl being optionally substituted by one or more trifluoromethyl, trifluoromethoxy and / or fluorine; for example, pyridyl substituted by one or more trifluoromethyl, trifluoromethoxy and / or fluorine. Selected from It is characterized by:

[0042] More particularly, the compound of formula (I) is - 3-[[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 3-[[6-(3,3-dimethylbut-1-ynyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[[6-(4-methoxyphenyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[[6-[4-(trifluoromethoxy)phenyl]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[[6-[4-(trifluoromethyl)phenyl]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-[6-[4-(trifluoromethyl)phenyl]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 3-[(6-phenoxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-(6-phenoxy-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - [2-Hydroxy-1,1-bis(hydroxymethyl)ethyl]ammonium; (1R,2S,3R,4S)-3-[(6-phenoxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylate; - 3-[[6-[[4-(trifluoromethyl)-2-pyridyl]oxy]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[[6-[(4-fluoro-2-pyridyl)amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[[6-[(5-fluoro-2-pyridyl)amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[[6-[(6-fluoro-2-pyridyl)amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 4-[6-[[2-(trifluoromethyl)-4-pyridyl]amino]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 3-[[6-[[5-(trifluoromethoxy)-2-pyridyl]amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 4-[6-[[5-(trifluoromethyl)-2-pyridyl]amino]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 4-[6-[[6-(trifluoromethyl)-2-pyridyl]amino]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 3-[[6-[4-(1-piperidyl)anilino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; or a pharmaceutically acceptable salt thereof, or an optical isomer, racemate, diastereoisomer, enantiomer or tautomer thereof.

[0043] The compounds provided herein can be formulated into pharmaceutical compositions, optionally by mixing with one or more pharmaceutically acceptable excipients.

[0044] Therefore, the present invention also relates to a pharmaceutical composition comprising a compound of formula (I) as defined in this section and a pharmaceutically acceptable excipient.

[0045] In particular, said pharmaceutical composition further comprises at least one other antimycobacterial agent.

[0046] Antimycobacterial agents are well known in the art.Antimycobacterial agents or antituberculous agents include rifampicin, rifabutin, isoniazid, ethambutol, streptomycin, amikacin, kanamycin, moxifloxacin, pyrazinamide, bedaquiline, linezolid, stezolid, nitroimidazole compounds, such as pretomanid and delamanid.In the context of the present invention, nitroimidazole compounds, such as pretomanid and delamanid, are particularly considered.Antimycobacterial agents are currently most often prescribed in combination with other drugs.

[0047] In one embodiment, the pharmaceutical composition comprises two, three, four, five, six, or seven additional anti-tuberculosis agents. For example, in the treatment of multidrug-resistant tuberculosis, it is common to administer a combination of four or more drugs to a patient. For example, in the treatment of drug-susceptible tuberculosis, it is common to administer a combination of three or four drugs to a patient.

[0048] Pretonamid (CAS number: 187235-37-6) has the formula: [ka] It is known as an antibiotic used to treat multidrug-resistant tuberculosis, and is commonly used together with bedaquiline and linezolid.

[0049] Delamanid (CAS number: 681492-22-8) has the formula: [ka] It is sold under the trade name Deltyba® and is commonly used in conjunction with other anti-tuberculosis drugs to treat active multidrug-resistant tuberculosis.

[0050] Such compositions may be prepared for oral use, especially in the form of tablets or capsules, and particularly orally disintegrating (lyoc) tablets; or for parenteral use, especially in the form of liquid solutions, suspensions or emulsions.

[0051] The composition can be prepared by any method known in the pharmaceutical art, for example, as described in Remington: The Science and Practice of Pharmacy, 20th ed.; Gennaro, AR, Ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2000. Pharmaceutically compatible binders and / or adjuvants can be included as part of the composition. Oral compositions generally contain an inert diluent or edible carrier. They can be administered in unit dosage form, and the term "unit dosage" refers to a single dosage that can be administered to a patient and is easy to handle and package, and remains as a physically and chemically stable unit dosage, containing the active compound itself or as a pharmaceutically acceptable composition.

[0052] Tablets, pills, powders, capsules, lozenges, etc. may contain one or more of the following ingredients or compounds of a similar nature: binders, such as microcrystalline cellulose or tragacanth gum; diluents, such as starch or lactose; disintegrants, such as starch and cellulose derivatives; lubricants, such as magnesium stearate; glidants, such as colloidal silicon dioxide; sweeteners, such as sucrose or saccharin; or flavoring agents, such as peppermint or methyl salicylate. Capsules can be in the form of hard or soft capsules (generally made from gelatin compounds optionally mixed with plasticizers), as well as starch capsules. In addition, dosage unit forms can contain various other materials that modify the physical form of the dosage unit, such as coatings of sugar, shellac, or enteric agents. Other oral dosage forms, such as syrups or elixirs, may contain sweeteners, preservatives, dyes, colorings, and flavoring agents. In addition, the active compounds may be incorporated into fast dissolving, modified release, or sustained release preparations and formulations, such sustained release formulations preferably being biphasic.

[0053] Liquid preparations for administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Liquid compositions may also contain binders, buffers, preservatives, chelating agents, sweeteners, flavorings, and coloring agents. Non-aqueous solvents include alcohols, propylene glycol, polyethylene glycol, acrylate copolymers, vegetable oils such as olive oil, and organic esters such as ethyl oleate. Aqueous carriers include mixtures of alcohols and water, hydrogels, buffered media, and saline. Biocompatible, biodegradable lactide polymers, lactide / glycolide copolymers, or polyoxyethylene-polyoxypropylene copolymers may be particularly useful excipients for controlling the release of active compounds. Intravenous vehicles may include fluid and nutrient replenishers, electrolyte replenishers, such as those based on Ringer's dextrose, and the like.

[0054] Examples of modes of administration include parenteral, eg, subcutaneous, intramuscular, intravenous, intradermal, as well as oral administration.

[0055] Compounds for Use As already mentioned, the present invention also provides compounds of formula (I): [ka] [In formula: R1 is ·-H; ·-OH; ·Straight-chain or branched-(C1-C6) alkyl; and ·Straight-chain or branched-(C1-C6)alkoxy(C2-C6)alkynyl; and / or R2 is ·-H; ·Straight-chain or branched-(C1-C6) alkyl; ·Straight-chain or branched-(C1-C6)alkoxy; and Halogen atoms; and / or R3 is ·-H; Halogen atoms; linear or branched -(C1-C6) alkyl optionally substituted by one or more halogen atoms; linear or branched -(C1-C6)alkoxy optionally substituted by one or more halogen atoms; ·Straight or branched chain -(C2-C8)alkynyl; · linear or branched chain -(C1-C6)alkoxy-(C2-C6)alkynyl; ·-OR; ·NHR; ·-(C2-C8)cycloalkyl; ·Straight or branched chain -(C2-C6)alkynyl-(C6-C 10 )aryl; ·Straight or branched chain -(C1-C6) alkyl-(C6-C 10 )aryl; one or more -OH, halogen atoms, linear or branched -(C1-C6) alkyl optionally substituted with one or more halogen atoms, linear or branched (C1-C6) alkoxy optionally substituted with one or more halogen atoms, -NRaRb, -(C6-C 10 )aryl; Heteroaryl containing 3 to 10 ring members and having at least one heteroatom selected from O, N or S; optionally substituted by one or more halogen atoms, linear or branched -(C1-C6) alkyl optionally substituted by one or more halogen atoms; linear or branched chain -(C2-C6)alkynyl-(C2-C6)cycloalkyl, ·Straight or branched chain - (C6-C 10 )aryl-(C1-C6)alkoxy-(C2-C6)alkynyl; ·-NO2; · Linear or branched chain -SO2(C1-C3) alkyl; ·-CN; ·-COO-(C1-C3)alkyl; is selected from R is ·-H; linear or branched -(C1-C6) alkyl optionally substituted by one or more halogen atoms; ·-(C6-C 10 )aryl optionally substituted by one or more halogen atoms, —OH, straight or branched chain —(C1-C6)alkyl optionally substituted by one or more halogen atoms, —(C1-C6)alkoxy optionally substituted by one or more halogen atoms, 10 )aryl; Heteroaryl containing 3 to 10 ring members and having at least one heteroatom selected from O, N or S; one or more halogen atoms, linear or branched -(C1-C6) alkyl optionally substituted with one or more halogen atoms; linear or branched -(C1-C6) alkoxy optionally substituted with one or more halogen atoms; the above heteroaryl optionally substituted with -CN; is selected from Ra and Rb are the same or different, ·-H; linear or branched (C1-C6) alkyl, in which one of the carbon atoms of the alkyl group may be replaced by a heteroatom; Selected from or Ra and Rb are joined together to form a heterocycloalkyl containing 3 to 10 ring members, optionally substituted by one or more of: straight or branched chain -(C1-C6)alkyl, -COO-(C1-C3)alkyl, -NRcRd; oxo; Rc and Rd are the same or different; ·-H; ·Straight-chain or branched-(C1-C6) alkyl; Selected from or R2 and R3 are linked together to form an —O—(C1-C6)alkyl-O— group; and / or R4 is H and R5 is [ka] or R4 and R5, together with the nitrogen atom to which they are attached, [ka] form] or a pharmaceutically acceptable salt or optical isomer, racemate, diastereoisomer, enantiomer or tautomer thereof; However, the following compounds: 3-[(6-methylsulfonyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; Except, The present invention relates to said compounds, salts or isomers for use as a medicament.

[0056] In one embodiment, (3aS,4R,7S,7aS)-[2-(2-benzothiazolyl)]-4,7-methano-1H-isoindole-1,3-(2H)-dione and / or bicyclo[2.2.1]hept-5-ene-2,3-dicarboximide-N-[2-(6-methylbenzo)thiazolyl] are also excluded.

[0057] In particular, the compound of formula (I) - 3-[(1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-methyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 4-(6-methyl-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 3-[(6-methyl-1,3-benzothiazol-2-yl)carbamoyl]norbornane-2-carboxylic acid; - (1S,2S,6R,7R)-4-(6-methyl-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]decane-3,5-dione; - 3-[(5-methoxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-methoxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-ethoxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-(6-ethoxy-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 3-[(5,6-dimethoxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-(6,7-dihydro-[1,4]dioxino[2,3-f][1,3]benzothiazol-2-ylcarbamoyl)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-ethyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-tert-butyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(4,6-dimethyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(5,6-dimethyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(4,5-dimethyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(4-methyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-phenoxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-(6-phenoxy-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 3-[(6-benzyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[[6-(4-fluorophenoxy)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[[6-[4-(trifluoromethyl)phenoxy]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-[6-[4-(trifluoromethyl)phenoxy]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 3-[[6-(4-pyridyloxy)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[[6-[[3-(trifluoromethyl)-2-pyridyl]oxy]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-[6-[[3-(trifluoromethyl)-2-pyridyl]oxy]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 3-[[6-[[4-(trifluoromethyl)-2-pyridyl]oxy]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-[6-[[4-(trifluoromethyl)-2-pyridyl]oxy]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 3-[[6-[(4-methyl-2-pyridyl)oxy]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 2-[[2-[(1R,2S,6R,7S)-3,5-dioxo-4-azatricyclo[5.2.1.02,6]dec-8-en-4-yl]-1,3-benzothiazol-6-yl]oxy]pyridine-4-carbonitrile; - 3-[[6-[[2-(trifluoromethyl)-4-pyridyl]oxy]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-[6-[[6-(trifluoromethyl)-2-pyridyl]oxy]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 3-[[6-[[5-(trifluoromethyl)-2-pyridyl]oxy]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-[6-[[5-(trifluoromethyl)-2-pyridyl]oxy]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 3-[[6-[(5-bromo-2-pyridyl)oxy]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-nitro-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-methylsulfonyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-cyano-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-methoxycarbonyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-fluoro-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[[6-(trifluoromethyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 3-[(6-chloro-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-bromo-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(5-bromo-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-iodo-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-hydroxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-phenyl-1,3-benzothiazol-2-yl)carbamoyl]-7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-cyclohexyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[[6-(p-tolyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[[6-(4-methoxyphenyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[[6-(4-chlorophenyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[[6-(3,4-dichlorophenyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[[6-[2-(trifluoromethyl)phenyl]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-[6-[2-(trifluoromethyl)phenyl]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 3-[[6-[3-(trifluoromethyl)phenyl]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[[6-[4-(trifluoromethyl)phenyl]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-[6-[4-(trifluoromethyl)phenyl]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 3-[[6-[4-(trifluoromethoxy)phenyl]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-[6-(4-hydroxyphenyl)-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 3-[[6-(4-pyridyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-[6-(6-fluoro-3-pyridyl)-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 3-[[6-[6-(trifluoromethyl)-3-pyridyl]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-[6-[6-(trifluoromethyl)-3-pyridyl]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 3-[(6-pyrimidin-5-yl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[[6-(6-quinolyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 4-[6-(3-thienyl)-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 3-[[6-(3-furyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-[6-(3-furyl)-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 4-[6-(4-prop-2-ynoxyphenyl)-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - (1R,2S,6R,7S)-4-(6-ethynyl-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - (1R,2S,6R,7S)-4-(6-prop-2-ynoxy-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - (1R,2S,3R,4S)-3-[(4-hydroxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(4-prop-2-ynoxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-(4-prop-2-ynoxy-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 3-[[6-(2-phenylethynyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[[6-(3,3-dimethylbut-1-ynyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[[6-(2-cyclopropylethynyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - [2-Hydroxy-1,1-bis(hydroxymethyl)ethyl]ammonium; (1R,2S,3R,4S)-3-[(6-phenoxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylate; - (1R,2S,6R,7S)-4-[6-[(4-methyl-2-pyridyl)oxy]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - (1R,2S,6R,7S)-4-[6-[(2-chloro-4-pyridyl)oxy]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 3-[[6-[6-(trifluoromethyl)-3-pyridyl]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-(6-anilino-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; 4-[6-(2-pyridylamino)-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; and - 3-[[6-[(4-methyl-2-pyridyl)amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[[6-[(4-fluoro-2-pyridyl)amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[[6-[(5-fluoro-2-pyridyl)amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 4-[6-[(5-fluoro-2-pyridyl)amino]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 3-[[6-[(6-fluoro-2-pyridyl)amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 4-[6-[(6-fluoro-2-pyridyl)amino]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 4-[6-[[2-(trifluoromethyl)-4-pyridyl]amino]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 3-[[6-[[5-(trifluoromethyl)-3-pyridyl]amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 4-[6-[(2-methoxy-4-pyridyl)amino]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 3-[[6-[[5-(trifluoromethoxy)-2-pyridyl]amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 4-[6-[[5-(trifluoromethoxy)-2-pyridyl]amino]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 4-[6-[[5-(trifluoromethyl)-2-pyridyl]amino]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 3-[[6-[[5-(trifluoromethyl)-2-pyridyl]amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 4-[6-[[6-(trifluoromethyl)-2-pyridyl]amino]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 4-[6-[(2-fluoro-4-pyridyl)amino]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 3-[[6-[(2-fluoro-4-pyridyl)amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[[6-[4-(1-piperidyl)anilino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - tert-butyl 4-[4-[2-[(1R,2S,6R,7S)-3,5-dioxo-4-azatricyclo[5.2.1.02,6]dec-8-en-4-yl]-1,3-benzothiazol-6-yl]phenyl]piperazine-1-carboxylate; - 4-[6-(4-morpholinophenyl)-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; or a pharmaceutically acceptable salt thereof, or an optical isomer, racemate, diastereoisomer, enantiomer or tautomer thereof.

[0058] More particularly, the compound of formula (I) is R1 is H; and / or R2 is H; and / or R3, linear or branched -(C1-C6) alkyl optionally substituted by one or more halogen atoms; linear or branched -(C1-C6)alkoxy optionally substituted by one or more halogen atoms; ·Straight or branched chain (C2-C6) alkynyl; ·-OR; ·-NHR; one or more linear or branched -(C1-C6)alkyl optionally substituted by one or more halogen atoms, linear or branched -(C1-C6)alkoxy optionally substituted by one or more halogen atoms, optionally substituted by NRaRb, -(C6-C 10 )aryl; is selected from R, linear or branched -(C1-C6) alkyl optionally substituted by one or more halogen atoms; - one or more linear or branched -(C-C) alkyl optionally substituted by one or more halogen atoms, -(C-C 10 )aryl; Heteroaryl containing 3 to 10 ring members and having at least one heteroatom selected from O, N or S; optionally substituted by one or more linear or branched -(C1-C6) alkyls optionally substituted by one or more halogen atoms; is selected from, and Ra and Rb are joined together to form a heterocycloalkyl containing 3 to 10 ring members; optionally substituted by one or more of a straight or branched chain -(C1-C6)alkyl, -COO-(C1-C3)alkyl, -NRcRd; oxo; Rc and Rd are the same or different, ·-H; and Straight or branched chain (C1-C6) alkyl Selected from It is characterized by:

[0059] More particularly, the compound of formula (I) is R1 is H; and / or R2 is H; and / or R3, linear or branched (C1-C3) alkyl, preferably methyl; linear or branched-(C1-C3)alkoxy, preferably ethoxy; linear or branched -(C1-C3)alkoxy substituted by fluorine atoms, preferably trifluoromethoxy; ·3,3-dimethylbut-1-ynyl; ·-OR; ·-NHR; phenyl optionally substituted by one or more trifluoromethyl, methoxy, trifluoromethoxy and / or piperidyl; is selected from, and R, linear or branched -(C1-C3) alkyl optionally substituted by one or more halogen atoms, preferably one or more fluoro atoms; phenyl optionally substituted by one or more methyl and / or trifluoromethyl; Heteroaryl containing 6 ring members and having at least one nitrogen atom as heteroatom, said heteroaryl being optionally substituted by one or more trifluoromethyl, trifluoromethoxy and / or fluorine; for example, pyridyl substituted by one or more trifluoromethyl, trifluoromethoxy and / or fluorine. Selected from It is characterized by:

[0060] In one embodiment, the compound of formula (I) is - 3-[(6-ethoxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-(6-ethoxy-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 3-[[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 3-[[6-(3,3-dimethylbut-1-ynyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[[6-(4-methoxyphenyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[[6-[4-(trifluoromethoxy)phenyl]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[[6-[4-(trifluoromethyl)phenyl]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-[6-[4-(trifluoromethyl)phenyl]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 3-[(6-methyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 4-(6-methyl-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 3-[(6-phenoxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-(6-phenoxy-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - [2-Hydroxy-1,1-bis(hydroxymethyl)ethyl]ammonium; (1R,2S,3R,4S)-3-[(6-phenoxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylate; - 3-[[6-[[4-(trifluoromethyl)-2-pyridyl]oxy]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[[6-[(4-fluoro-2-pyridyl)amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[[6-[(5-fluoro-2-pyridyl)amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[[6-[(6-fluoro-2-pyridyl)amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 4-[6-[[2-(trifluoromethyl)-4-pyridyl]amino]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 3-[[6-[[5-(trifluoromethoxy)-2-pyridyl]amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 4-[6-[[5-(trifluoromethyl)-2-pyridyl]amino]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 4-[6-[[6-(trifluoromethyl)-2-pyridyl]amino]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 3-[[6-[4-(1-piperidyl)anilino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; or a pharmaceutically acceptable salt thereof, or an optical isomer, racemate, diastereoisomer, enantiomer or tautomer thereof.

[0061] As already mentioned, the compounds can be used to prevent and / or treat mycobacterial infections.

[0062] Mycobacterial infections are well known in the art and are caused by infection with mycobacteria.

[0063] The mycobacterium can be a member of one of the following mycobacterial groups: Mycobacterium tuberculosis complex (MTC), Mycobacterium avium complex (MAC), Mycobacterium gordonae clade, Mycobacterium kansasii clade, Mycobacterium chelonae clade, Mycobacterium fortuitum clade, Mycobacterium parafortuitum clade, or Mycobacterium vaccae clade. The mycobacteria may also be Mycobacterium ulcerans or Mycobacterium leprae.

[0064] In particular, the mycobacteria are members of the Mycobacterium tuberculosis complex (MTC), which includes Mycobacterium tuberculosis, Mycobacterium africanum, Mycobacterium bovis, Mycobacterium bovis BCG, Mycobacterium canetti, Mycobacterium caprae, Mycobacterium microti, and Mycobacterium pinnipedii.

[0065] These mycobacteria are the causative agents of tuberculosis in humans and animals. Mycobacterium tuberculosis is the primary cause of tuberculosis in humans.

[0066] More specifically, the infection is a Mycobacterium tuberculosis infection. In other words, the mycobacterial infection is caused by infection with Mycobacterium tuberculosis.

[0067] In one embodiment, the M. tuberculosis is multidrug resistant. In another embodiment, the M. tuberculosis is resistant to nitroimidazole compounds, such as pretomanid and / or delamanid.

[0068] These two drugs are defined in the previous section.

[0069] In another aspect, the present invention relates to a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease caused by infection with mycobacteria.

[0070] In particular, the mycobacteria are selected from those described herein above.

[0071] For example, mycobacterial infections include the following: Mycobacterium tuberculosis, Mycobacterium africanum, Mycobacterium bovis, Mycobacterium bovis BCG, Mycobacterium canettii, Mycobacterium caprae, Mycobacterium microti, Mycobacterium pinnipedii, Mycobacterium avium, Mycobacterium avium paratuberclosis, Mycobacterium avium silaticum, Mycobacterium avium hominissuis, Mycobacterium colombiense, Mycobacterium columbiense, Mycobacterium indicus pranii, Mycobacterium asiaticum, Mycobacterium gordonae, Mycobacterium gastri, Mycobacterium kansasii, Mycobacterium abscessus, Mycobacterium borletii, Mycobacterium coronae, Mycobacterium boenickei, Mycobacterium brisbanense, Mycobacterium cosmeticum cosmeticum), Mycobacterium fortuitum, Mycobacterium fortuitum subsp. acetamidriticum, Mycobacterium houstonense, Mycobacterium mageritense, Mycobacterium newolleansenseneworleansense, Mycobacterium peregrinum, Mycobacterium porcinum, Mycobacterium senegalense, Mycobacterium septicum, Mycobacterium austroafricanum, Mycobacterium diernhoferi, Mycobacterium frederiksbergense, Mycobacterium hodleri, Mycobacterium neoaurum It can be caused by infection with a mycobacterium selected from Mycobacterium neoaurum, Mycobacterium parafortuitum, Mycobacterium ulcerans, and Mycobacterium leprae.

[0072] Diseases caused by infection with mycobacteria include tuberculosis (e.g., due to Mycobacterium tuberculosis), leprosy (e.g., due to Mycobacterium leprae), Johne's disease (e.g., due to Mycobacterium avium subsp. paratuberculosis), Buruli or Barnsdale ulcer (e.g., due to Mycobacterium ulcerans), Crohn's disease (e.g., due to Mycobacterium avium subsp. paratuberculosis), lung disease or infection, pneumonia, bursae, synovial fluid, tendon sheaths, localized abscesses, lymphadenitis, skin and soft tissue infections, Lady Windermere's disease, and other conditions. These include, but are not limited to, Windermere syndrome (e.g., caused by Mycobacterium avium complex (MAC)), MAC lung disease, disseminated Mycobacterium avium complex (DMAC), disseminated Mycobacterium avium intracellulare complex (DMAIC), hot tub lung (e.g., caused by Mycobacterium avium complex), MAC mastitis, MAC pyomyositis, or granulomatous disease.

[0073] In particular, in the context of the present invention, the disease is tuberculosis.

[0074] In one embodiment, therefore, the present invention also relates to a method of treating a mycobacterial infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) described in this section, or a pharmaceutically acceptable salt thereof.

[0075] As used herein, a mycobacterial infection is one caused by infection with mycobacteria, which are as defined herein above.

[0076] In one embodiment, the present invention relates to a method for treating a Mycobacterium tuberculosis infection.

[0077] In another embodiment, the present invention relates to a method of treating a disease caused by infection with mycobacteria in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0078] In particular, in the context of the present invention, the disease is tuberculosis.

[0079] In one embodiment, the compound is used in combination with at least one other antimycobacterial agent.

[0080] Antimycobacterial agents are well known in the art.Antimycobacterial agents or antituberculous agents include rifampicin, rifabutin, isoniazid, ethambutol, streptomycin, amikacin, kanamycin, moxifloxacin, pyrazinamide, bedaquiline, linezolid, stezolid, nitroimidazole compounds such as pretomanid and delamanid.In the context of the present invention, nitroimidazole compounds such as pretomanid and delamanid are particularly considered.

[0081] Antimycobacterial agents are currently most commonly prescribed in combination.

[0082] In one embodiment, the combination includes two, three, four, five, six, or seven additional anti-tuberculosis agents. For example, in the treatment of multidrug-resistant tuberculosis, it is common to administer a combination of four or more drugs to a patient. For example, in the treatment of drug-susceptible tuberculosis, it is common to administer a combination of three or four drugs to a patient.

[0083] In particular, the combination includes pletonamide and / or delamanid.

[0084] Pletonamide (CAS number: 187235-37-6) has the formula: [ka] It is known as an antibiotic used to treat multidrug-resistant tuberculosis, and is commonly used together with bedaquiline and linezolid.

[0085] Delamanid (CAS number: 681492-22-8) has the formula: [ka] It is sold under the trade name Deltyba® and is commonly used in conjunction with other anti-tuberculosis drugs to treat active multidrug-resistant tuberculosis.

[0086] In another aspect, the present invention also relates to the combination of (a) a compound of formula (I) as defined in this section and (b) at least one other antimycobacterial agent.

[0087] Antimycobacterial agents are as defined herein.

[0088] The terms "treat," "treating," "treated," or "treatment," as used in the context of the present invention, refer to therapeutic treatment aimed at eliminating or alleviating symptoms. Beneficial or desired clinical results include, but are not limited to, elimination of symptoms, alleviation of symptoms, reduction in the extent of the condition, stabilization (i.e., not worsening) of the condition, or delay or slowing of the progression of the condition.

[0089] The terms "prevent," "prevention," "preventing," or "prevented," as used in the context of the present invention, refer to the prevention of the onset, recurrence, or spread of a disease or disorder or infection, or one or more symptoms thereof. In certain embodiments, the term refers to treatment with or administration of a compound provided herein before the onset of symptoms, particularly to a patient at risk of a disease or disorder or infection provided herein. The term encompasses the suppression or reduction of symptoms of a particular disease or disorder or infection. Subjects with a family history of a disease or disorder or infection are particularly, in certain embodiments, candidates for a preventative regimen. In addition, subjects with a history of recurrent symptoms are also potential candidates for prevention. In this regard, the term "prevention" can be used interchangeably with the term "prophylactic treatment."

[0090] In particular, a subject in need of treatment for a mycobacterial infection or a disease caused by infection with mycobacteria is a subject suffering from such a disease or infection.

[0091] In the context of the present invention, the identification of subjects in need of treatment for the diseases and conditions described herein is carried out as described above and is well within the ability and knowledge of those skilled in the art.A clinician skilled in the art can easily identify subjects in need of such treatment by the techniques described above.In particular, the prevention and / or treatment described herein relates to subjects who have already been administered or are simultaneously taking at least one antimycobacterial agent, more particularly at least one antituberculosis agent, preferably pretomanid and / or delamanid.In the above context, the compound represented by formula (I) described herein can act as a booster for the antimycobacterial agent.

[0092] By "booster" it is meant that the compound of formula (I) according to the invention increases the efficacy of an antimycobacterial agent.

[0093] Therapeutically effective amount can be easily determined by the diagnostician skilled in the art by using conventional techniques and observing the results obtained under similar circumstances.When determining therapeutically effective amount, the diagnostician will consider many factors, including but not limited to the species of the subject; its size, age and general health condition; the specific disease involved; the extent or severity of the disease involved; the response of each individual subject; the specific compound to be administered; the mode of administration; the bioavailability characteristics of the administered preparation; the selected dosing schedule; the use of concomitant drugs; and other relevant circumstances.

[0094] As used herein, "effective amount" refers to an amount effective in reducing, eliminating, treating, or controlling the symptoms of the diseases and conditions described herein. The term "controlling" is intended to refer to all processes that may include slowing, interrupting, preventing, or halting the progression of the diseases and conditions described herein, but does not necessarily refer to the complete elimination of all symptoms of the disease or condition, and is intended to include preventative treatment and chronic use.

[0095] The term "patient" or "subject," unless otherwise specified, refers to a warm-blooded animal, such as a mammal, male or female, particularly a human, who is suffering from or may be suffering from one or more of the diseases and conditions described herein.

[0096] In particular, the compounds of the combination according to the invention may be administered separately, sequentially or simultaneously. More particularly, when a combination is envisaged, the compounds of formula (I) described herein may be administered simultaneously with at least one antimycobacterial agent, or the at least one antimycobacterial agent may be administered first.

[0097] The amount of a compound of the present invention required to achieve a desired biological effect will vary depending on numerous factors, including the dosage of the drug to be administered, the chemical properties (e.g., hydrophobicity) of the compound employed, the potency of the compound, the type of resistance, the state of resistance in the patient, and the route of administration.

[0098] The compounds provided herein can be formulated into pharmaceutical compositions, optionally by mixing with one or more pharmaceutically acceptable excipients.

[0099] Such compositions may be prepared for oral use, especially in the form of tablets or capsules, and particularly orally disintegrating (lyoc) tablets; or for parenteral use, especially in the form of liquid solutions, suspensions or emulsions.

[0100] The compositions are described, for example, in Remington: The Science and Practice of Pharmacy, 20 th The composition can be prepared by any method known in the pharmaceutical arts, such as those described in "Pharmaceutical Preparations for Infectious Diseases" (ed.); Gennaro, AR, Ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2000. Pharmaceutically compatible binders and / or adjuvants can be included as part of the composition. Oral compositions generally contain an inert diluent or edible carrier. They can be administered in unit dosage form, and the term "unit dosage" refers to a single dosage that can be administered to a patient and is easy to handle and package, and remains as a physically and chemically stable unit dosage containing the active compound itself or as a pharmaceutically acceptable composition.

[0101] Tablets, pills, powders, capsules, lozenges, etc. may contain one or more of the following ingredients or compounds of a similar nature: binders, such as microcrystalline cellulose or tragacanth gum; diluents, such as starch or lactose; disintegrants, such as starch and cellulose derivatives; lubricants, such as magnesium stearate; glidants, such as colloidal silicon dioxide; sweeteners, such as sucrose or saccharin; or flavoring agents, such as peppermint or methyl salicylate. Capsules can be in the form of hard or soft capsules (generally made from gelatin compounds optionally mixed with plasticizers), as well as starch capsules. In addition, dosage unit forms can contain various other materials that modify the physical form of the dosage unit, such as coatings of sugar, shellac, or enteric agents. Other oral dosage forms, such as syrups or elixirs, may contain sweeteners, preservatives, dyes, colorings, and flavoring agents. In addition, the active compound may be incorporated into fast dissolving, modified release, or sustained release preparations or formulations, such sustained release formulations preferably being biphasic.

[0102] Liquid preparations for administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Liquid compositions may also contain binders, buffers, preservatives, chelating agents, sweeteners, flavorings, and coloring agents. Non-aqueous solvents include alcohols, propylene glycol, polyethylene glycol, acrylate copolymers, vegetable oils such as olive oil, and organic esters such as ethyl oleate. Aqueous carriers include mixtures of alcohols and water, hydrogels, buffered media, and saline. Biocompatible, biodegradable lactide polymers, lactide / glycolide copolymers, or polyoxyethylene-polyoxypropylene copolymers may be particularly useful excipients for controlling the release of active compounds. Intravenous vehicles may include fluid and nutrient replenishers, electrolyte replenishers, such as those based on Ringer's dextrose, and the like.

[0103] Examples of modes of administration include parenteral, eg, subcutaneous, intramuscular, intravenous, intradermal, as well as oral administration.

[0104] Preparation process The present invention also relates to processes for the preparation of the compounds of formula (I) described herein.

[0105] The compounds and processes of the present invention can be prepared in a number of ways well known to those skilled in the art. Compounds can be synthesized, for example, by the application or adaptation of the methods described below, or variations thereof, as will be well understood by those skilled in the art. Suitable modifications and substitutions will be readily apparent and well known to those skilled in the art, or may be readily obtained from the scientific literature.

[0106] It is well understood that the compounds of the present invention may contain one or more asymmetrically substituted carbon atoms and may be isolated in optically active or racemic forms.Thus, unless a specific stereochemistry or isomeric form is specified, all chiral, diastereomeric, racemic, and isomeric forms of the structure are intended.How to prepare and isolate such optically active forms is well known in the art.

[0107] For example, mixtures of stereoisomers can be separated by standard techniques, including, but not limited to, resolution of racemic forms, normal-phase, reverse-phase and chiral chromatography, preferential salt formation, recrystallization, etc., or by either chiral synthesis from chiral starting materials or by planned synthesis of targeted chiral centers.

[0108] The compounds of the present invention can be prepared by a variety of synthetic routes. The reagents and starting materials are commercially available or readily synthesized by well-known techniques by those skilled in the art. All substituents are as previously defined unless otherwise indicated.

[0109] In the reactions described later herein, reactive functional groups, such as hydroxyl, amino, imino, thio, or carboxy groups, may need to be protected if desired in the final product to avoid unwanted participation in the reaction. Conventional protecting groups may be used according to standard practice, see, for example, TW Greene and PGM Wuts in Protective Groups in Organic Chemistry, 4th ed. (2007), John Wiley & Sons Inc., 1999; JFW McOmie in Protective Groups in Organic Chemistry, Plenum Press, 1973.

[0110] The compound thus prepared can be recovered from the reaction mixture by conventional means. For example, the compound can be recovered by distilling off the solvent from the reaction mixture, or, if necessary, by distilling off the solvent from the reaction mixture, pouring the residue into water, followed by extraction with a water-immiscible organic solvent and distilling off the solvent from the extract. Furthermore, if desired, the product can be further purified by various well-known techniques, such as recrystallization, reprecipitation, or various chromatographic techniques, particularly column chromatography or preparative thin-layer chromatography.

[0111] The reactions can be carried out by one skilled in the art by applying or adapting the methods illustrated in the examples set out herein below.

[0112] In particular, compounds of formula (I) can be prepared according to the protocols described in the experimental section below.

[0113] Additionally, the process of the present invention may include the additional step of isolating the compound of formula (I), which may be accomplished by any of the conventional means known to those skilled in the art, such as the recovery methods described above.

[0114] Generally, the starting products are commercially available, mainly from Aldrich or Acros or other typical chemical suppliers, or may be obtained by application or adaptation of any known method or method described in the Examples.

[0115] In the context of the present invention, "a compound for use for prevention and / or treatment" should be understood as equivalent to "use of a compound for prevention and / or treatment" and "use of a compound for the manufacture of a medicament for prevention and / or treatment".

[0116] The present invention is further illustrated by the following figures and examples. [Example]

[0117] Part A: Synthesis of compounds of the present invention The compounds of the present invention can be prepared by processes (a) to (c);

[0118] (a) Reaction of an appropriate anhydride with a substituted 2-aminobenzothiazole in the presence or absence of a base, as shown in Scheme 1.

[0119] (b) Cyclization using a dehydrating agent such as T3P, as shown in Scheme 2.

[0120] (c) Alkylation using alkyl halide derivatives in the presence of a base, as shown in Scheme 3.

[0121] [ka]

[0122] [ka]

[0123] [ka]

[0124] The synthesis of 2-aminobenzothiazole derivatives can be carried out by processes (d) to (h);

[0125] (d) A Hugerschoff-type reaction in which aniline is reacted with ammonium thiocyanate in the presence of bromine and acetic acid, as shown in Scheme 3.

[0126] [ka]

[0127] (e) Reaction of hydroxy-substituted 2-aminobenzothiazoles with halogenated pyridines in the presence of a base, as shown in Scheme 5. [ka]

[0128] (f) Sonogashira-type reaction of 2-aminobenzothiazole substituted with a halogen atom with a terminal alkyne in the presence of palladium, copper iodide, and a base, as shown in Scheme 6.

[0129] [ka]

[0130] (g) Suzuki-type reaction of halogen-substituted 2-aminobenzothiazole with boronic acid in the presence of palladium and a base, as shown in Scheme 7.

[0131] [ka]

[0132] (h) Reaction of Boc-protected 2-aminobenzothiazoles substituted with halogen atoms with aminopyridines in the presence of palladium, phosphine and base as shown in Scheme 8 via Buchwald-type reaction.

[0133] [ka]

[0134] Method X: HPLC-MS analysis was performed on an LC-MS Waters Alliance Micromass ZQ 2000 system equipped with a Waters 2747 sample manager, a Waters 2695 separation module, a Waters 2996 photodiode array detector (210–400 nm at 1.2 nm resolution), and a Waters Micromass ZQ2000 detector (scans 100–800). An XBridge C18 column (3.5 μm particle size, 50 mm × 4.6 mm) was used for the HPLC analysis. The injection volume was 20 μL. For the 5-minute analysis, elution was performed with 100% HO / 0.1% ammonium formate to 2% HO / 98% CH3CN / 0.1% ammonium formate (or HCOOH), pH 3.8, over 3.5 minutes. A flow rate of 2 mL / min was used. For the 30-minute analysis, elution was performed with 100% HO / 0.1% ammonium formate (or HCOOH) to 2% HO / 98% CHCN / 0.1% ammonium formate at pH 3.8 over 7 minutes. A flow rate of 1 mL / min was used. Purity (%) was determined by reverse-phase HPLC (30-minute analysis) with UV detection (215 nm).

[0135] HRMS analysis was performed on an LCT Premier XE Micromass using a C18 X-Bridge column (particle size 3.5 μm, dimensions 50 mm x 4.6 mm). A gradient was used starting from 98% H2O 5 mM ammonium formate (pH = 3.8) and reaching 100% CH3CN 5 mM ammonium formate (pH = 3.8) within 3 min at a flow rate of 1 mL / min.

[0136] The invention will now be illustrated by the following non-limiting examples.

[0137] Example 1: 3-[(6-methyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (1 g, 6.1 mmol) in THF (4 mL) was added 6-methyl-1,3-benzothiazol-2-amine (1 g, 6.1 mmol). The mixture was heated under reflux, and after 16 h, a precipitate was observed. The reaction was cooled to room temperature, and the precipitate was removed by filtration and washed with THF to give the title compound as a white powder (1.5 g, 77%). 1 H NMR (300 MHz, DMSO-d6) δ = 12.15 (s, 1H), 11.8 (s, 1H), 7.69 (br s, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.20 (dd, J = 8.5, 1.6 Hz, 1H), 6.14 (br s, 2H), 3.45 (dd, J = 10.4, 3.3 Hz, 1H), 3.35 (dd, J = 9.9 Hz, 3.2 Hz, 1H), 3.11 (s, 1H), 3.06 (s 1H), 2.38 (s, 3H), 1.32 (dd, J = 17.2, 8.2 Hz, 2H). LC-MS: Method X, RT = 3.92 min (10 min run), MS (ESI) m / z:329 (M+H) + ; 327 (MH RT = 2.47 min (5 min run), MS (ESI) m / z:329 (M+H) + ; 327 (MH) - HRMS (ES+) C17H17N2O3S [M+H] + Calculated value: 329.0960 Measured value: 329.0963

[0138] Purification of the two enantiomers of Example 1 was achieved by SFC (supercritical fluid chromatography). The sample was solubilized at a concentration of 8 mg / mL in a 50 / 50 DCM / MeOH mixture and filtered prior to injection. 100 μL was injected onto the IA column at a flow rate of 3 mL / min with 10% methanol as the co-solvent. Fractions were collected with acetonitrile and then lyophilized to give both enantiomers, Examples 1a and 1b.

[0139] Example 2: (1R,2S,6R,7S)-4-(6-methyl-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione [ka] To a solution of 3-[(6-methyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid (compound from Example 1, 3.9 g, 12 mmol) in EtOAc (20 mL) was added T3P (50% in AcOEt, 28.22 mL, 95 mmol). The solution was stirred under reflux for 4 hours. The organic layer was washed twice with water, dried, filtered, and evaporated under reduced pressure to give the title compound as a white powder (3.1 g, 84% yield). 1 H NMR (300 MHz, DMSO-d6) δ = 7.89 (s, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.36 (ddd, J = 8.4, 1.7, 0.6 Hz, 1H), 6.22 (t, J = 1.8 Hz, 2H), 3.62 (dd, J = 3.0, 1.6 Hz, 2H), 3.43 - 3.36 (m, 2H), 2.45 (s, 3H), 1.66 - 1.58 (m, 2H). LC-MS: Method X, RT = 2.82 min, MS (ESI) m / z:311 (M+H) + HRMS (ES+) C17H15N2O2S [M+H] + Calculated value: 311.0854 Measured value: 311.0850

[0140] Example 3: 3-[(6-methyl-1,3-benzothiazol-2-yl)carbamoyl]norbornane-2-carboxylic acid [ka] To a solution of 3-[(6-methyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid (100 mg, 0.305 mmol) in MeOH (1 mL) at 0° C. was added a solution of hydrazine (923 μL, 12.2 mmol) and hydrogen peroxide (4933 μL, 0.152 mmol). The mixture was stirred at 0° C. for 20 minutes. The reaction was then acidified to pH 4 with ammonium formate. The precipitate was filtered and washed with DCM. The filtrate was evaporated under reduced pressure to give the title compound as a white powder (5.9 mg, 6%). 1 H NMR (300 MHz, DMSO-d6) δ = 12.17 (s, 1H), 11.9 (s, 1H), 7.73 (s, 1H), 7.59 (d, J = 8.2 Hz, 1H), 7.22 (dd, J = 8.2, 1.1 Hz, 1H), 3.20 (dd, J = 11.7, 4.3 Hz, 1H), 2.98 (dd, J = 11.7, 2.9 Hz, 1H), 2.58 (s, 1H,), 2.40 (s, 4H), 1.88-1.80 (m, 1H) ’ ), 1.61 (m, 1H), 1.47 (d, J = 9.7 Hz, 1H), 1.34 (m, 3H). LC-MS: Method X, RT = 2.56 min, MS (ESI) m / z:331 (M+H) + ; 329 (MH) - HRMS (ES+) C17H19N2O3S [M+H] + Calculated value: 331.1116 Measured value: 331.1106

[0141] Example 4: (1S,2S,6R,7R)-4-(6-methyl-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]decane-3,5-dione [ka]

[0142] Step 1: (1S,2S,6R,7R)-4-oxatricyclo[5.2.1.02,6]decane-3,5-dione [ka] To a solution of (2S,6R)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (50 mg, 0.305 mmol) in MeOH (4 mL) was added ammonium formate (57.6 mg, 0.313 mmol) and Pd / C (32.4 mg, 0.003 mmol). The reaction was heated under reflux overnight. The reaction was then cooled to room temperature and filtered through a pad of Celite. The filtrate was evaporated and carried on to the next step without further purification (yellow oil, 40.0 mg). LC-MS: Method X, RT = 2.05 min, MS (ESI) m / z:167 (M+H) +

[0143] Step 2: (1S,2S,6R,7R)-4-(6-methyl-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]decane-3,5-dione [ka] To a solution of (2S,6R)-4-oxatricyclo[5.2.1.02,6]decane-3,5-dione (40 mg, 0.241 mmol) in THF (0.2 mL) was added dropwise a solution of 6-methyl-1,3-benzothiazol-2-amine (43.5 mg, 0.265 mmol) in THF (2.3 mL). After 48 h, the reaction mixture was heated under reflux for an additional 32 h. The reaction was then cooled to room temperature and evaporated under reduced pressure. The crude product was purified by reverse column chromatography (C18, 20 / 80 ACN-ammonium formate / water-ammonium formate to 100% water-ammonium formate over 40 min). The collected fractions were lyophilized and dried to give the title compound as a white solid (7.5 mg, 8% over two steps). 1 H NMR (300 MHz, DMSO-d6) δ = 7.92 (m, J = 8.2, 1.2 Hz, 2H), 7.38 (dd, J = 8.2, 1.2 Hz, 1H), 3.37 (m, 2H), 2.71 (s, 2H), 2.47(s, 3H), 1.70 (d, J = 9.6 Hz, 1H), 1.61-1.55 (m, 3H), 1.29-1.23 (m, 2H). LC-MS: Method X, RT = 2.84 min, MS (ESI) m / z:313 (M+H) + HRMS (ES+) C17H17N2O2S [M+H] + Calculated value: 313.1011 Measured value: 313.1012

[0144] Example 5: 3-[(5-methoxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (100 mg, 0.61 mmol) in THF (10 mL) was added 5-methoxy-1,3-benzothiazol-2-amine (110 mg, 0.61 mmol), and the mixture was stirred under reflux overnight. Since the reaction was not complete, DIEA was added (105.4 μl, 0.61 mmol), and the reaction was stirred under reflux. After 7 h, the solvent was evaporated under reduced pressure. The crude product was solubilized with cooled aqueous KCO / KOH solution and then filtered. The aqueous phase was acidified to pH 1 by the addition of 1 M HCl solution, giving a milky white precipitate. The precipitate was recrystallized from AcOEt / EtOH to give the title compound as a white solid (16.4 mg, 8%). 1H NMR (300 MHz, DMSO-d6) δ = 12.21 (brs, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.23 (d, J = 1.7 Hz, 1H), 6.89 (dd, J = 8.6, 1.9 Hz, 1 H), 6.15 (s, 2 H), 3.80 (s, 3 H), 3.48-3.38 (m, 2 H), 3.09 (d, J = 13.4 Hz, 2 H), 1.33 (q, J = 8.3 Hz, 2 H). LC-MS: Method X, RT = 8.30 min (30 min run), MS (ESI) m / z:345 (M+H) + ; 343 (MH) - HRMS (ES+) C17H17N2O4S [M+H] + Calculated value: 345.0909 Measured value: 345.0912.

[0145] Example 6: 3-[(6-methoxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (20 mg, 0.122 mmol) in THF (0.1 mL), 6-methoxy-1,3-benzothiazol-2-amine (24.2 mg, 0.134 mmol) was added, and the reaction mixture was heated under reflux. After 3 h, the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography (100 DCM to 70 / 30 DCM / DCM-MeOH (90 / 10)) to give the title compound as a white solid (4.6 mg, 11%). 1H NMR (300 MHz, DMSO-d6) δ = 12.11 (s, 1H), 11.87 (s, 1H), 7.58 (d, J = 8.9 Hz, 1H), 7.51 (d, J = 2.5 Hz, 1H), 7.01-6.97 (dd, J = 8.9, 2.5 Hz, 1H), 6.16 (t, J = 1.3 Hz, 2H), 3.79 (s, 3H), 3.48-43 (dd, J = 10.2, 3.3 Hz, 1H), 3.38-33 (dd, J = 10.2, 3.30 Hz, 1H), 3.12 (s, 2H), 3.07 (s, 2H), 1.37-29 (q, J = 16.9, 8.2 Hz, 2H). LC-MS: Method X, RT = 8.15 min (30 min run), MS (ESI) m / z:345 (M+H) + ; 343 (MH) - HRMS (ES+) C17H17N2O4S [M+H] + Calculated value: 345.0909 Measured value: 345.0910.

[0146] Example 7: 3-[(6-ethoxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (115 mg, 0.7 mmol) in THF (2 mL) was added 6-ethoxy-1,3-benzothiazol-2-amine (136 mg, 0.7 mmol), and the mixture was stirred under reflux. After 4 h, the observed precipitate was filtered, washed with THF, and dried to give the title compound as a white solid (81 mg, 32%). 1H NMR (300 MHz, DMSO-d6) δ = 12.10 (s, 1H), 11.85 (s, 1H), 7.57 (d, J = 8.7 Hz, 1H), 7.49 (d, J = 2.6 Hz, 1H), 6.99 (dd, J = 8.7, 2.5 Hz, 1H), 6.16 (br s, 2H), 4.05 (q, J = 6.9 Hz, 2H), 3.46 (dd, J = 10.2, 3.2 Hz, 1H,), 3.35 (dd, J = 10.2, 3.2 Hz, 1H), 3.12 (s, 1H), 3.07 (s, 1H), 1.40 - 11.27 (m, 5 H). LC-MS: Method X, RT = 4.34 min (10 min run), MS (ESI) m / z:359 (M+H) + ; 357 (MH) - HRMS (ES+) C18H19N2O4S [M+H] + Calculated value: 359.1066 Measured value: 359.1073.

[0147] Example 8: (1R,2S,6R,7S)-4-(6-ethoxy-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione [ka] To a solution of 3-[(6-ethoxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid (164 mg, 0.458 mmol) in AcOEt (2 mL) was added T3P (50% in AcOEt, 545 μL, 0.915 mmol). The reaction was stirred at room temperature for 5 h. The observed precipitate was filtered. AcOEt was added to the filtrate and washed twice with water. The organic layer was dried, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (100% cyclohexane to 50 / 50 cyclohexane / AcOEt) to give the title compound (55 mg, 35%). 1H NMR (300 MHz, DMSO-d6) δ = 7.87 (d, J = 8.9 Hz, 1H), 7.66 (d, J = 2.5 Hz, 1H), 7.11 (dd, J = 8.6, 2.4 Hz, 1H), 6.21 (t, J = 1.8 Hz, 2H), 4.09 (q, J = 7.0 Hz, 2H), 3.60 (dd, J = 2.7, 1.5 Hz, 2H), 3.37 (s, 2H), 1.62 (br s, 2H), 1.35 (t, J = 7.0 Hz, 3H). LC-MS: Method X, RT = 4.58 min (10 min run), MS (ESI) m / z:341 (M+H) + HRMS (ES+) C18H17N2O3S [M+H] + Calculated value: 341.0960 Measured value: 341.0963

[0148] Example 9: 3-[(5,6-dimethoxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (78.1 mg, 0.476 mmol) in THF (3 mL) was added 5,6-dimethoxy-1,3-benzothiazol-2-amine (100 mg, 0.476 mmol), and the mixture was stirred under reflux. After 6 h, the observed precipitate was filtered, washed with THF, and dried to give the title compound as a light brown solid (85 mg, 48%). 1H NMR (300 MHz, DMSO-d6) δ = 12.07 (s, 1H), 11.81 (s, 1H), 7.48 (s, 1H), 7.25 (s, 1H), 6.15 (br s, 2H), 3.81 (s, 3H), 3.79 (s, 3H), 3.47 (dd, J = 9.8, 2.6 Hz, 1H), 3.35 (dd, J = 9.8, 2.8 Hz, 1H), 3.11 (s, 1H), 3.06 (s, 1H), 1.43 - 1.25 (m, 2H). LC-MS: Method X, RT = 3.38 min (10 min run), MS (ESI) m / z:375 (M+H) + ; 373 (MH) - HRMS (ES+) C18H19N2O5S [M+H] + Calculated value: 375.1015 Measured value: 375.1022

[0149] Example 10: 3-(6,7-dihydro-[1,4]dioxino[2,3-f][1,3]benzothiazol-2-ylcarbamoyl)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka] To a solution of 6,7-dihydro-[1,4]dioxino[2,3-f][1,3]benzothiazol-2-amine (146 mg, 0.7 mmol) in THF (3 mL) cooled to 0 °C was added NaH (9.7 mg, 0.7 mmol). The solution was then added dropwise to a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (115 mg, 0.7 mmol) in THF (3 mL). The reaction mixture was heated under reflux. After 4 h, the reaction was cooled to room temperature and THF was added. The observed precipitate was filtered, washed with THF, and dried to give the title compound as a white solid (84 mg, 32%). 1H NMR (300 MHz, DMSO-d6) δ = 12.10 (s, 1H), 11.83 (s, 1H), 7.38 (s, 1H), 7.14 (s, 1H), 6.13 (m, 2H), 4.25 (s, 4H), 3.44 (dd, J = 10.0, 2.7 Hz, 1H), 3.33 (m, 1H), 3.10 (s, 1H), 3.06 (s, 1H), 1.31 (dd, J = 16.7, 8.1 Hz, 2H). LC-MS: Method X, RT = 3.58 min (10 min run), MS (ESI) m / z:373 (M+H) + ; 371 (MH) - HRMS (ES+) C18H17N2O5S [M+H] + Calculated value: 373.0858 Measured value: 373.0866

[0150] Example 11: 3-[(6-ethyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka] To a solution of 6-ethyl-1,3-benzothiazol-2-amine (125 mg, 0.7 mmol) in THF (3 mL) cooled to 0 °C was added NaH (9.6 mg, 0.7 mmol). The solution was then added dropwise to a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (115 mg, 0.7 mmol) in THF (3 mL). The reaction mixture was heated under reflux. After 4 h, the reaction was cooled to room temperature and THF was added. The observed precipitate was filtered, washed with THF, and dried. ACN was added, and the precipitate was filtered, concentrated, and dried to give the title compound as a white solid (120 mg, 50%). 1H NMR (300 MHz, DMSO-d6) δ = 12.22 (s, 1H), 11.91 (s, 1H), 7.73 (d, J = 1.2 Hz, 1H), 7.59 (d, J = 8.2 Hz, 1H), 7.24 (dd, J = 8.2, 1.6 Hz, 1H), 6.14 (s, 2H), 3.46 (dd, J = 10.2, 3.5 Hz, 1H), 3.35 (dd, J = 10.2, 3.3 Hz, 1H), 3.11 (s, 1H), 3.06 (s, 1H), 2.69 (q, J = 7.6 Hz, 2H), 1.32 (q, J = 8.4 Hz, 2H), 1.21 (t, J = 7.6 Hz, 3H). LC-MS: Method X, RT = 4.62 min (10 min run), MS (ESI) m / z:343 (M+H) + ; 341 (MH) - HRMS (ES+) C18H19N2O3S [M+H] + Calculated value: 343.1116 Measured value: 343.1106

[0151] Example 12: 3-[(6-tert-butyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (115 mg, 0.7 mmol) in THF (3 mL) was added 6-tert-butyl-1,3-benzothiazol-2-amine (144 mg, 0.7 mmol), and the mixture was stirred under reflux. After 3 h, the observed precipitate was filtered, washed with ACN, and dried to give the title compound as a white solid (79 mg, 30%). 1H NMR (300 MHz, DMSO-d6) δ = 12.15 (brs, 1H), 11.91 (brs, 1H), 7.91 (s, 1H), 7.61 (d, J = 8.3 Hz, 1H), 7.46 (d, J = 7.6 Hz, 1H), 6.16 (s, 2H), 3.46 (d, J = 10.3 Hz, 1H), 3.34 (d, J = 10.2 Hz, 1H), 3.13 (s, 1H), 3.08 (s, 1H), 1.33 (br s, 11H). LC-MS: Method X, RT = 5.10 min (10 min run), MS (ESI) m / z:371 (M+H) + ; 369 (MH) -

[0152] Example 13: 3-[(4,6-dimethyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka] To a solution of 4,6-dimethyl-1,3-benzothiazol-2-amine (125 mg, 0.7 mmol) in THF (3 mL) cooled to 0 °C was added NaH (26.8 mg, 0.7 mmol). The solution was then added dropwise to a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (115 mg, 0.7 mmol) in THF (3 mL). The reaction mixture was heated under reflux overnight. The reaction was then cooled to room temperature and evaporated under reduced pressure. ACN was added, and the observed precipitate was filtered, concentrated, and dried to give the title compound as a white solid (72 mg, 30%). 1H NMR (300 MHz, DMSO-d6) δ = 12.28 (brs, 1H), 11.95 (brs, 1H), 7.51 (s, 1H), 7.03 (s, 1H), 6.14 (s, 2H), 3.45 (dd, J = 10.8, 3.2 Hz, 1H), 3.34 (dd, J = 10.8, 3.2 Hz, 1H), 3.10 (s, 1H), 3.06 (s, 1H), 2.5 (s, 3H), 2.34 (s, 3H), 1.30 (m, 2H) LC-MS: Method X, RT = 4.68 min (10 min run), MS (ESI) m / z:343 (M+H) + ; 341 (MH) - HRMS (ES+) C18H19N2O3S [M+H] + Calculated value: 343.1116 Measured value: 343.1107

[0153] Example 14: 3-[(5,6-dimethyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka] Commercially available. Purchased from Vitas-M Laboratory.

[0154] Example 15: 3-[(4,5-dimethyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka] To a solution of 4,5-dimethyl-1,3-benzothiazol-2-amine (125 mg, 0.7 mmol) in THF (3 mL) cooled to 0 °C was added NaH (9.66 mg, 0.42 mmol). The solution was then added dropwise to a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (115 mg, 0.7 mmol) in THF (3 mL). The reaction mixture was heated under reflux. After 4 h, THF was added and the observed precipitate was filtered, washed with ACN and THF, and dried to give the title compound as a white solid (103 mg, 43%). 1 H NMR (300 MHz, DMSO-d6) δ = 12.25 (brs, 1H), 11.91 (brs, 1H), 7.60 (d, J = 7.9 Hz, 1H), 7.08 (d, J = 8.3 Hz, 1H), 6.15 (t, J = 1.2 Hz, 2H), 3.47 (dd, J = 10.0, 3.3 Hz, 1H), 3.36 (dd, J = 10.0, 3.4 Hz, 1H), 3.12 (s, 1H), 3.08 (s, 1H), 2.49 (s, 3H), 2.33 (s, 3H), 1.33 (m, 2H). LC-MS: Method X, RT = 4.72 min (10 min run), MS (ESI) m / z:343 (M+H) + ; 341 (MH) - HRMS (ES+) C18H19N2O3S [M+H] + Calculated value: 343.1116 Measured value: 343.1102

[0155] Example 16: 3-[(4-methyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (115 mg, 0.7 mmol) in THF (3 mL) was added 4-methyl-1,3-benzothiazol-2-amine (115 mg, 0.7 mmol), and the mixture was stirred under reflux. After 3 h, the observed precipitate was filtered, washed with THF and ACN, and dried to give the title compound as a white solid (117 mg, 51%). 1H NMR (300 MHz, DMSO-d6) δ = 12.32 (brs, 1H) 11.85 (brs, 1H), 7.73 (d, J = 7.3 Hz, 1H), 7.22 (d, J = 6.9 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 6.22 - 6.09 (m, 2H), 3.47 (dd, J = 10.2, 3.1 Hz, 1H), 3.37 (dd, J = 10.1, 3.1 Hz, 1H), 3.12 (s, 1H), 3.08 (s, 1H), 2.55 (s, 3H) 1.41 - 1.25 (m, 2H). LC-MS: Method X, RT = 4.00 min (10 min run), MS (ESI) m / z:329 (M+H) + ; 327 (MH) - HRMS (ES+) C17H17N2O3S [M+H] + Calculated value: 329.0960 Measured value: 329.0966

[0156] Example 17: 3-[(6-phenoxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (696 mg, 4.2 mmol) in THF (5 mL) was added 6-phenoxy-1,3-benzothiazol-2-amine (1.0 g, 4.1 mmol). The mixture was stirred under reflux overnight. The observed precipitate was then filtered, washed with ACN and THF, and dried to give the title compound as a white solid (1.39 g, 83%). 1H NMR (300 MHz, DMSO-d6) δ = 12.24 (s, 1H), 12.00 (s, 1H), 7.71 (d, J = 8.7 Hz, 1H), 7.64 (d, J = 2.4 Hz, 1H), 7.42 - 7.33 (m, 2H), 7.71 - 7.07 (m, 2H), 7.04 - 6.98 (m, 2H), 6.16 (s, 2H), 3.47 (dd, J = 10.0, 3.0 Hz, 1H), 3.38 (dd, J = 10.0, 3.1 Hz, 1H), 3.13 (s, 1H), 3.09 (s, 1H), 1.37 (d, J = 8.3 Hz), 1.31 (dt, J = 8.9, 2.3 Hz, 1H). LC-MS: Method X, RT = 4.62 min (10 min run), MS (ESI) m / z:407 (M+H) + ; 405 (MH) - HRMS (ES+) C22H19N2O4S [M+H] + Calculated value: 407.1066 Measured value: 407.1064

[0157] Example 18: [2-Hydroxy-1,1-bis(hydroxymethyl)ethyl]ammonium; (1R,2S,3R,4S)-3-[(6-phenoxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylate [ka] To a solution of (1R,2S,3R,4S)-3-[(6-phenoxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid (5.3 g, 13.0 mmol) in MeOH / water (32 mL / 8 mL) was added 2-amino-2-(hydroxymethyl)propane-1,3-diol (4.6 g, 38 mmol), and the mixture was heated at 70 °C for 15 min. A thick suspension was observed, and DMSO was added until complete solubilization. The mixture was then filtered and cooled to room temperature. In this manner, a precipitate formed, which was filtered, washed with water, and dried to give the title compound as white crystals (2.3 g, 33%). This procedure was repeated to give 1.55 g of the complementary compound. 1H NMR (300 MHz, DMSO-d6) δ = 7.68 (d, J = 8.7 Hz, 1H), 7.60 (d, J = 2.4 Hz, 1H), 7.42 - 7.33 (m, 2H), 7.15 - 7.06 (m, 2H), 7.00 (dd, J = 8.2, 1.1 Hz, 2H), 6.17 (dd, J = 5.5, 2.9 Hz, 1H), 6.13 (dd, J = 5.4, 2.8 Hz, 1H), 3.39 (dd, J = 10.0, 3.0 Hz, 1H), 3.34 (s, 6H), 3.30 (dd, J = 10.0, 3.3Hz, 1H), 3.18 (s, 3H), 3.13 (s, 1H), 3.08 (s, 1H), 1.33 (d, J = 8.4 Hz, 1H), 1.26 (dt, J = 8.4, 1.7 Hz, 1H). LC-MS: Method X, RT = 4.62 min (10 min run), MS (ESI) m / z:407 (M+H) + ; 405 (MH) -

[0158] Example 19: (1R,2S,6R,7S)-4-(6-phenoxy-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione [ka] To a solution of 3-[(6-phenoxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid (108 mg, 0.27 mmol) in AcOEt (1 mL), T3P (50% in AcOEt, 316 μL, 0.53 mmol) was added, and the mixture was stirred at room temperature. After 5 h, the observed precipitate was filtered. EtOAc was added to the filtrate and washed twice with water. The organic layer was dried, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (100% cyclohexane to 50 / 50 cyclohexane / AcOEt) to give the title compound as a white solid (64 mg, 62%). 1H NMR (300 MHz, DMSO-d6) δ = 8.00 (d, J = 9.0 Hz, 1H), 7.77 (d, J = 2.4 Hz, 1H), 7.44 - 7.36 (m, 2H), 7.23 (dd, J = 8.9 Hz, J = 2.5 Hz, 1H), 7.16 (dt, J = 7.5, 1.0 Hz, 1H), 7.08 - 7.02 (m, 2H), 6.21 (t, J = 1.8 Hz, 2H), 3.62 (dd, J = 2.9, 1.6 Hz, 2H), 3.40 - 3.35 (m, 2H) 1.66 - 1.58 (m, 2H). LC-MS: Method X, RT = 5.18 min (10 min run), MS (ESI) m / z: 389 (M+H) + HRMS (ES+) C22H17N2O3S [M+H] + Calculated value: 389.0960 Measured value: 389.0959

[0159] Example 20: 3-[(6-benzyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid

change

[0160] Project 1: 6-ベンジル-1,3-ベンゾチアゾール-2-アミン

change

[0161] Step 2: 3-[(6-benzyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (26 mg, 0.144 mmol) in THF (4 mL) was added 6-benzyl-1,3-benzothiazol-2-amine (34.7 mg, 0.144 mmol). The mixture was stirred under reflux. After 24 h, the observed precipitate was filtered, washed with THF, and dried to give the title compound as a white solid (21.7 mg, 37%). 1H NMR (300 MHz, DMSO-d6) δ = 12.2 (s, 1H), 11.84 (s, 1H), 7.77 (s, 1H), 7.60 (d, J = 8.1 Hz, 1H), 7.34-7.12 (m, 6H), 6.14 (s, 2H), 4.02 (s, 2H), 3.50-3.34 (m, 2H), 3.11 (s, 1H), 3.06 (s, 1H), 1.32 (m, 2H). LC-MS: Method X, RT = 12.13 min (30 min run), MS (ESI) m / z:405 (M+H) + ; 403 (MH) - HRMS (ES+) C23H20N2O3S [M+H] + Calculated value: 405.1195 Measured value: 405.1287

[0162] Example 21: 3-[[6-(4-fluorophenoxy)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka]

[0163] Step 1: 6-(4-fluorophenoxy)-1,3-benzothiazol-2-amine [ka] To a solution of 4-(4-fluorophenoxy)aniline (438 mg, 2.16 mmol) in acetic acid (0.5 M) was added NHSCN (820 mg, 10.8 mmol), and the reaction was stirred for 90 min. The mixture was then cooled to 0 °C, and a solution of bromine (0.166 mL, 3.23 mmol) in acetic acid (1 M) was added. The mixture was allowed to warm to room temperature and stirred for 16 h. The reaction was then quenched by the addition of saturated NaCO solution. The reaction was made alkaline to pH 8. Ethyl acetate was added, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (100% cyclohexane to 20 / 80 cyclohexane / AcOEt) to give the title compound as a slightly yellow solid (297 mg, 53% yield). 1 H NMR (300 MHz, CDCl3) δ = 7.49 (d, J = 8.7 Hz, 1H), 7.21 (d, J = 2.4 Hz, 1H), 7.07-6.91 (m, 5H), 5.38 (brs, 2 H).

[0164] Step 2: 3-[[6-(4-fluorophenoxy)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (63.1 mg, 0.384 mmol) in THF (3 mL) was added 6-(4-fluorophenoxy)-1,3-benzothiazol-2-amine (100 mg, 0.384 mmol), and the mixture was stirred under reflux. After 24 h, the observed precipitate was filtered, washed with THF and ACN, and dried to give the title compound as a white solid (83.8 mg, 50%). 1H NMR (300 MHz, DMSO-d6) δ = 12.22 (s, 1H), 11.84 (s, 1H), 7.68 (d, J = 8.8 Hz, 1H), 7.60 (d, J = 2.5 Hz, 1H), 7.26-7.17 (m, 2H), 7.12-7.02 (m, 3H), 6.15 (s, 2H), 3.49-3.42 (dd, J = 10.2, 3.0 Hz, 1H), 3.39-3.33 (dd, J = 10.2, 3.0 Hz, 1H), 3.12 (s, 1H), 3.07 (s, 1H), 1.39-1.27 (m, 2H). LC-MS: Method X, RT = 12.07 min (30 min run), MS (ESI) m / z:425 (M+H) + ; 423 (MH) - HRMS (ES+) C22H18N2O4SF [M+H] + Calculated value: 425.0971 Measured value: 425.0974

[0165] Example 22: 3-[[6-[4-(trifluoromethyl)phenoxy]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka]

[0166] Step 1: 6-[4-(trifluoromethyl)phenoxy]-1,3-benzothiazol-2-amine [ka] To a solution of 4-[4-trifluoromethyl)phenoxy]aniline (246 mg, 0.971 mmol) in acetic acid (0.5 M) was added NHSCN (370 mg, 4.86 mmol). The mixture was cooled to 0 °C, and a solution of Br (0.05 mL, 1.07 mmol) in acetic acid (1 M) was added. The reaction was allowed to warm to room temperature and stirred overnight. After 16 h, the reaction was quenched by the addition of saturated NaCO solution. The mixture was made alkaline to pH 10. Ethyl acetate was added, and the aqueous phase was extracted twice with ethyl acetate. The organic phase was dried, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (100% cyclohexane to 80 / 20 AcOEt / cyclohexane) to give the title compound as a yellow oil (198 mg, 66%). 1 H NMR (300 MHz, DMSO-d6) δ = 7.70 (d, J = 9.0 Hz, 2H), 7.54 (d, J = 2.4 Hz, 1H), 7.50 (s, 2H), 7.37 (d, J = 8.6 Hz, 1H), 7.09 (d, J = 8.7 Hz, 2H), 7.00 (dd, J = 8.6, 2.5 Hz, 1H). LC-MS: Method X, RT = 2.97 min (5 min run), MS (ESI) m / z:311 (M+H) + ; 309 (MH) -

[0167] 3-[[6-[4-(trifluoromethyl)phenoxy]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (48.1 mg, 0.293 mmol) in THF (3 mL) was added 6-[4-(trifluoromethyl)phenoxy]-1,3-benzothiazol-2-amine (91 mg, 0.293 mmol), and the mixture was stirred under reflux. After 3 h, the observed precipitate was filtered, washed with THF and ACN, and dried to give the title compound as a white solid (13 mg, 9%). 1 H NMR (300 MHz, DMSO-d6) δ = 12.30 (s, 1H), 11.84 (s, 1H), 7.82-7.75 (m, 2H), 7.72 (d, J = 8.6 Hz, 2H), 7.22 (d, J = 8.5 Hz, 1H), 7.14 (d, J = 8.6 Hz, 2H), 6.16 (s, 2H), 3.47-3.42 (m, 2H), 3.14 (s, 1H), 3.09 (s, 1H), 1.34 (m, 2H). LC-MS: Method X, RT = 13.40 min (30 min run), MS (ESI) m / z:475 (M+H) + ; 473 (MH) - HRMS (ES+) C23H18N2O4SF3 [M+H] + Calculated value: 475.0939 Measured value: 475.0914

[0168] Example 23: (1R,2S,6R,7S)-4-[6-[4-(trifluoromethyl)phenoxy]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (52.9 mg, 0.322 mmol) in THF (3 mL) was added 6-[4-(trifluoromethyl)phenoxy]-1,3-benzothiazol-2-amine (compound from step Example 21, 100 mg, 0.322 mmol), and the mixture was stirred under reflux. After 20 h, the observed precipitate was filtered, washed with THF and ACN, and dried to give the title compound as a white solid (91 mg, 62%). 1 H NMR (300 MHz, DMSO-d6) δ = 8.07 (d, J = 8.9 Hz, 1H), 7.95 (d, J = 2.5 Hz, 1H), 7.75 (d, J = 8.7 Hz, 2H), 7.35 (dd, J = 8.9, 2.5 Hz, 1H), 7.20 (d, J = 8.7 Hz, 2H), 6.23 (t, J = 1.9 Hz, 2H), 3.64 (dd, J = 2.93, 1.6 Hz, 2H), 3.40 (m, 2H), 1.64 (m, 2H). LC-MS: Method X, RT = 14.93 min (30 min run), MS (ESI) m / z:457 (M+H) + HRMS (ES+) C23H16N2O3SF3 [M+H] + Calculated value: 457.0834 Measured value: 457.0835

[0169] Example 24: 3-[[6-(4-pyridyloxy)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka]

[0170] Step 1: 6-(4-pyridyloxy)-1,3-benzothiazol-2-amine [ka] To a solution of 2-amino-1,3-benzothiazol-6-ol (200 mg, 1.20 mmol) in DMF (5 mL) was added CsCO (1.180 g, 1.81 mmol) and 4-chloropyridine (205 mg, 1.81 mmol). The reaction mixture was stirred at 100 °C. After 40 h, the reaction was cooled to room temperature. Water was added, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with brine, then dried, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (100% cyclohexane to 100% ethyl acetate) to give the title compound as a white solid (96 mg, 33%). 1 H NMR (300 MHz, DMSO-d6) δ = 8.42 (m, 2H), 7.56 (d, J = 2.4 Hz, 1H), 7.51 (s, 2H), 7.37 (d, J = 8.6 Hz, 1H), 7.03-6.99 (dd, J = 8.6, 2.5 Hz, 1H), 6.88 (m, 2H). LC-MS: Method X, RT = 1.75 min (5 min run), MS (ESI) m / z:244 (M+H) + ; 242 (MH) -

[0171] Step 2: 3-[[6-(4-pyridyloxy)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (58 mg, 0.353 mmol) in THF (4 mL) was added 6-(4-pyridyloxy)-1,3-benzothiazol-2-amine (86 mg, 0.353 mmol). The mixture was heated under reflux. After 5 h, the solvent was evaporated under reduced pressure. The solid was washed with THF and ACN, filtered, and dried to give the title compound as a white solid (51.9 mg, 36%). 1 H NMR (300 MHz, DMSO-d6) δ = 12.31 (brs, 1H), 11.89 (brs, 1H), 8.44 (s,2H), 7.83 (d, J = 2.4 Hz, 1H), 7.76 (d, J = 8.7 Hz, 1H), 7.24-7.20 (dd, J = 8.7, 2.5 Hz, 1H), 6.92 (d, J = 5.9 Hz, 2H), 6.16 (m, 2H), 3.49-3.44 (dd, J = 10.0, 3.0 Hz, 1H), 3.40-3.35 (m, 1H), 3.13 (s, 1H), 3.08 (s, 1H), 1.38-1.29 (m, 2H). LC-MS: Method X, RT = 2.10 min (5 min run), MS (ESI) m / z:408 (M+H) + ; 406 (MH) - HRMS (ES+) C21H17N3O4S [M+H] + Calculated value: 408.1018 Measured value: 408.1034

[0172] Examples 25 and 26: 3-[[6-[[3-(trifluoromethyl)-2-pyridyl]oxy]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid and (1R,2S,6R,7S)-4-[6-[[3-(trifluoromethyl)-2-pyridyl]oxy]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione Step 1: 6-[[3-(trifluoromethyl)-2-pyridyl]oxy]-1,3-benzothiazol-2-amine [ka] To a solution of 2-amino-1,3-benzothiazol-6-ol (500 mg, 3.01 mmol) in DMF (7 mL) was added CsCO (2.94 g, 9.03 mmol) and 2-chloro-3-(trifluoromethyl)pyridine (819 mg, 4.51 mmol). The reaction mixture was stirred at 100 °C. After 48 h, the reaction was cooled to room temperature. Water was added and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with brine, then dried, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (100% cyclohexane to 100% ethyl acetate) to give the title compound as a brown oil (595 mg, 64%). 1 H NMR (300 MHz, DMSO-d6) δ = 8.28 (m, 1H), 7.98 (m, 1H), 7.55 (d, J = 8.7 Hz, 1H), 7.42 (d, J = 2.3 Hz, 1H), 7.15-7.11 (dd, J = 8.7, 2.4 Hz, 1H), 7.07 (m, 1H), 6.12 (brs, 2H). LC-MS: Method X, RT = 2.60 min (5 min run), MS (ESI) m / z:312 (M+H) + ; 310 (MH) -

[0173] Step 2: To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (160 mg, 0.98 mmol) in THF (4 mL) was added 6-[[3-(trifluoromethyl)-2-pyridyl]oxy]-1,3-benzothiazol-2-amine (303 mg, 0.98 mmol). The mixture was heated under reflux. After 24 h, the solvent was evaporated under reduced pressure, and the crude product was purified by column chromatography (100% cyclohexane to 90 / 10 AcOEt / MeOH) to give both title compounds as white solids (Example 25, 16 mg, 3.5%; Example 26, 58 mg, 13%).

[0174] Example 25 3-[[6-[[3-(trifluoromethyl)-2-pyridyl]oxy]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka] 1 H NMR (300 MHz, DMSO-d6) δ = 12.30 (brs, 1H), 11.88 (brs, 1H), 8.37 (d, J = 4.0 Hz, 1H), 8.26 (d, J = 7.7 Hz, 1H), 7.81 (d, J = 2.4 Hz, 1H), 7.73 (d, J = 8.7 Hz, 1H), 7.31 (dd, J = 7.5, 5.2 Hz, 1H), 7.20 (dd, J = 8.7, 2.5 Hz, 1H), 6.16 (m, 2H), 3.49-3.45 (dd, J = 10.0, 3.0 Hz, 1H), 3.40-3.36 (m, 1H), 3.13 (s, 1H), 3.08 (s, 1H), 1.38-1.29 (m, 2H). LC-MS: Method X, RT = 2.78 min (5 min run), MS (ESI) m / z:476 (M+H) + ; 474 (MH) - HRMS (ES+) calculated for C22H17F3N3O4S [M+H]+: 476.0892 Found: 476.0895

[0175] Example 26 (1R,2S,6R,7S)-4-[6-[[3-(trifluoromethyl)-2-pyridyl]oxy]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione [ka] 1H NMR (300 MHz, DMSO-d6) δ = 8.27 (dd, J = 4.9, 1.7 Hz, 1H), 8.12 (d, J = 8.9 Hz, 1H), 8.01 (dd, J = 7.5, 1.7 Hz, 1H), 7.69 (d, J = 2.3 Hz, 1H), 7.32-7.28 (dd, J = 8.9, 2.4 Hz, 1H), 7.14-7.09 (dd, J = 7.6, 5.0, 1H), 6.28 (s, 2H), 3.58-3.53 (m, 4H), 1.82 (d, J = 8.9 Hz, 1H), 1.64 (d, J = 8.9 Hz, 1H). LC-MS: Method X, RT = 3.08 min (5 min run), MS (ESI) m / z: 458 (M+H) + HRMS (ES+) calculated for C22H15F3N3O3S [M+H]+: 458.0786 Found: 458.0780

[0176] Example 27: 3-[[6-[[4-(trifluoromethyl)-2-pyridyl]oxy]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid Step 1: 6-[[4-(trifluoromethyl)-2-pyridyl]oxy]-1,3-benzothiazol-2-amine [ka] To a solution of 2-amino-1,3-benzothiazol-6-ol (2 g, 12.0 mmol) in DMF (15 mL) was added 2-chloro-4-(trifluoromethyl)pyridine (1550 μL, 12.0 mmol) and CsCO (11.8 g, 36.1 mmol). The mixture was heated at 100 °C for 20 h. The reaction was then cooled to room temperature. Water was added, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (100% cyclohexane to 100% AcOEt). The collected fractions were concentrated, and the observed precipitate was washed with cyclohexane to give the title compound as a white solid (933 mg, 25%). 1H NMR (300 MHz, DMSO-d6) δ = 8.38 (d, J = 5.2 Hz, 1H), 7.55 (d, J = 2.2 Hz, 1H), 7.48-7.44 (m, 3H), 7.40 (m, 1H), 7.34 (d, J = 8.8 Hz, 1H), 7.04-7.00 (dd, J = 8.6, 2.5 Hz, 1H). LC-MS: Method X, RT = 2.68 min (5 min run), MS (ESI) m / z:312 (M+H) + ; 310 (MH) -

[0177] Step 2: 3-[[6-[[4-(trifluoromethyl)-2-pyridyl]oxy]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (38 mg, 0.231 mmol) in THF (2 mL) was added 6-[[4-(trifluoromethyl)-2-pyridyl]oxy]-1,3-benzothiazol-2-amine (72.1 mg, 0.231 mmol). The mixture was heated under reflux. After 40 h, the solvent was evaporated and the crude product was purified by column chromatography (100% cyclohexane to 90 / 10 AcOEt / methanol) to give the title compound as a white solid (67.5 mg, 61%). 1H NMR (300 MHz, DMSO-d6) δ = 12.34 (brs, 1H), 11.87 (brs, 1H), 8.40 (d, J = 5.0 Hz, 1H), 7.82 (d, J = 2.4 Hz, 1H), 7.74 (d, J = 8.9 Hz, 1H), 7.51-7.47 (m, 2H), 7.26-7.22 (dd, J = 8.7, 2.4 Hz, 1H), 6.17 (m, 2H), 3.50-3.45 (dd, J = 10.0, 3.2 Hz, 1H), 3.41-3.18 (m, 1H), 3.14 (s, 1H), 3.09 (s, 1H), 1.39-1.30 (m, 2H). LC-MS: Method X, RT = 12.03 min (30 min run), MS (ESI) m / z:476 (M+H) + ; 474 (MH) - HRMS (ES+) C22H17N3O4SF3 [M+H] + Calculated value: 476.0892 Measured value: 476.0892

[0178] Example 28: (1R,2S,6R,7S)-4-[6-[[4-(trifluoromethyl)-2-pyridyl]oxy]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione Step 1: 6-[[4-(trifluoromethyl)-2-pyridyl]oxy]-1,3-benzothiazol-2-amine [ka] To a solution of 2-amino-1,3-benzothiazol-6-ol (2 g, 12.0 mmol) in DMF (15 mL) was added 2-chloro-4-(trifluoromethyl)pyridine (1550 μL, 12.0 mmol) and CsCO (11.8 g, 36.1 mmol). The mixture was heated at 100 °C for 20 h. The reaction was then cooled to room temperature. Water was added, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (100% cyclohexane to 100% AcOEt). The collected fractions were concentrated, and the observed precipitate was washed with cyclohexane to give the title compound as a white solid (933 mg, 25%). 1 H NMR (300 MHz, DMSO-d6) δ = 8.38 (d, J = 5.2 Hz, 1H), 7.55 (d, J = 2.2 Hz, 1H), 7.48-7.44 (m, 3H), 7.40 (m, 1H), 7.34 (d, J = 8.8 Hz, 1H), 7.04-7.00 (dd, J = 8.6, 2.5 Hz, 1H). LC-MS: Method X, RT = 2.68 min (5 min run), MS (ESI) m / z:312 (M+H) + ; 310 (MH) -

[0179] Step 2: (1R,2S,6R,7S)-4-[6-[[4-(trifluoromethyl)-2-pyridyl]oxy]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (492 mg, 3.0 mmol) in THF (4 mL) was added 6-[[4-(trifluoromethyl)-2-pyridyl]oxy]-1,3-benzothiazol-2-amine (933 mg, 3.0 mmol). The mixture was heated under reflux. After 40 h, the solvent was evaporated and the crude product was purified by column chromatography (100% cyclohexane to 90 / 10 AcOEt / methanol) to give the title compound as a white solid (311.2 mg, 23%). 1 H NMR (300 MHz, CDCl3) δ = 8.32 (d, J = 5.2 Hz, 1H), 8.12 (d, J = 8.8 Hz, 1H), 7.67 (d, J = 2.3 Hz, 1H), 7.31-7.27 (dd, J = 8.8, 2.3 Hz, 1H), 7.23 (d, J = 5.2, 1H), 7.21 (s, 1H), 6.28 (s, 2H), 3.58 (s, 2H), 3.56 (d, 2H), 1.83 (d, J = 9.0 Hz, 1H), 1.66 (d, J = 8.8 Hz, 1H). LC-MS: Method X, RT = 13.67 min (30 min run), MS (ESI) m / z:458 (M+H) + HRMS (ES+) calculated for C22H15F3N3O3S [M+H]+: 458.0786 Found: 458.0775

[0180] Examples 29 and 30: 3-[[6-[(4-methyl-2-pyridyl)oxy]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid / (1R,2S,6R,7S)-4-[6-[(4-methyl-2-pyridyl)oxy]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione Step 1: 6-[(4-methyl-2-pyridyl)oxy]-1,3-benzothiazol-2-amine [ka] To a solution of 2-amino-1,3-benzothiazol-6-ol (300 mg, 1.81 mmol) in DMF (5 mL) was added 2-chloro-4-methyl-pyridine (202 μL, 1.81 mmol) and CsCO (1.76 g, 5.42 mmol). The mixture was heated at 100 °C. After 15 days, the reaction was cooled to room temperature. Water was added, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (100% cyclohexane to 100% AcOEt) to give the title compound as a white solid (93.3 mg, 20%). 1 H NMR (300 MHz, DMSO-d6) δ = 7.98-7.96 (dd, J = 5.2, 0.4 Hz, 1H), 7.45-7.44 (dd, J = 2.5, 0.3 Hz, 1H), 7.42 (brs, 2H), 7.33-7.30 (dd, J = 8.6, 0.3 Hz, 1H), 6.95-6.91 (m, 2H), 6.78 (q, J = 0.7 Hz, 1H), 2.30 (s, 3H). LC-MS: Method X, RT = 2.30 min (5 min run), MS (ESI) m / z:258 (M+H) +

[0181] Step 2: 3-[[6-[(4-methyl-2-pyridyl)oxy]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (60 mg, 0.37 mmol) in THF (2 mL) was added 6-[(4-methyl-2-pyridyl)oxy]-1,3-benzothiazol-2-amine (94 mg, 0.37 mmol). The mixture was heated under reflux. After 20 h, the observed precipitate was filtered, washed with THF and ACN, and dried to give the title acid compound as a white solid (Example 29, 36.8 mg, 24%).

[0182] The filtrate was evaporated and the crude product was purified by column chromatography (100% cyclohexane to 90 / 10 AcOEt / methanol) to give the title compound as a white solid (Example 30, 19.3 mg, 13%).

[0183] Example 29 1 H NMR (300 MHz, DMSO-d6) δ = 12.24 (brs, 1H), 11.86 (brs, 1H), 7.98 (d, J = 5.1 Hz, 1H), 7.70 (s, 1H), 7.69 (d, J = 10.4 Hz, 1H), 7.14 (dd, J = 8.7, 2.5 Hz, 1H), 6.95 (d, J = 5.1 Hz, 1H), 6.85 (s, 1H), 6.16 (m, 2H), 3.49-3.44 (dd, J = 10.0, 3.1 Hz, 1H), 3.39-3.34 (m, 1H), 3.13 (s, 1H), 3.08 (s, 1H), 2.07 (s, 3H), 1.37 (d, J = 8.2 Hz, 1H), 1.30 (d, J = 8.3 Hz, 1H). LC-MS: Method X, RT = 2.54 min (5 min run), MS (ESI) m / z:422 (M+H) + ; 420 (MH) - HRMS (ES+) calculated for C22H20N3O4S [M+H]+: 422.1175 Found: 422.1177

[0184] Example 30 (1R,2S,6R,7S)-4-[6-[(4-methyl-2-pyridyl)oxy]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione [ka] 1H NMR (300 MHz, CDCl3) δ = 8.08 (d, J = 8.9 Hz, 1H), 8.06 (d, J = 5.2 Hz, 1H), 7.26 (dd, J = 8.9, 2.3 Hz, 1H), 6.86 (d, J = 5.2 Hz, 1H), 6.74 (s, 1H), 6.28 (brs, 2H), 3.57-3.54 (m, 4H), 2.36 (s, 3H), 1.82 (d, J = 8.9 Hz, 1H), 1.64 (d, J = 8.9 Hz, 1H). LC-MS: Method X, RT = 2.87 min (5 min run), MS (ESI) m / z:404 (M+H) + HRMS (ES+) calculated for C22H18N3O3S [M+H]+: 404.1069 found 404.1046

[0185] Example 31: 2-[[2-[(1R,2S,6R,7S)-3,5-dioxo-4-azatricyclo[5.2.1.02,6]dec-8-en-4-yl]-1,3-benzothiazol-6-yl]oxy]pyridine-4-carbonitrile Step 1: 2-[(2-amino-1,3-benzothiazol-6-yl)oxy]pyridine-4-carbonitrile [ka] To a solution of 2-amino-1,3-benzothiazol-6-ol (400 mg, 2.41 mmol) in DMF (5 mL) was added 2-chloropyridine-4-carbonitrile (500 mg, 3.61 mmol) and CsCO (2.35 g, 7.22 mmol). The mixture was heated at 100 °C. After 48 h, the reaction was cooled to room temperature. Water was added, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (100% cyclohexane to 100% AcOEt) to give the title compound as a white solid (45 mg, 7%). LC-MS: Method X, RT = 2.23 min (5 min run), MS (ESI) m / z:269 (M+H) + ; 267 (MH) -

[0186] Step 2: 2-[[2-[(1R,2S,6R,7S)-3,5-dioxo-4-azatricyclo[5.2.1.02,6]dec-8-en-4-yl]-1,3-benzothiazol-6-yl]oxy]pyridine-4-carbonitrile [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (28 mg, 0.17 mmol) in THF (2 mL) was added 2-[(2-amino-1,3-benzothiazol-6-yl)oxy]pyridine-4-carbonitrile (45.8 mg, 0.17 mmol). The mixture was heated under reflux. After 36 h, the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography (100% cyclohexane to 90 / 10 AcOEt, MeOH) to give the title compound as a white solid (5.2 mg, 7.4%). 1H NMR (300 MHz, DMSO-d6) δ = 8.30 (d, J = 5.8 Hz, 1H), 8.13 (d, J = 8.9 Hz, 1H), 7.66 (d, J = 2.3 Hz, 1H), 7.27 (dd, J = 6.7, 2.1 Hz, 1H), 7.26-7.221 (m, 2H), 6.27 (t, J = 1.6 Hz, 2H), 3.61-3.53 (m, 4H), 1.82 (dt, J = 8.9, 1.4 Hz, 1H), 1.66 (d, J = 8.8 Hz, 1H). LC-MS: Method X, RT = 2.80 min (5 min run), MS (ESI) m / z:415 (M+H) + HRMS (ES+) calculated for C22H15N4O3S [M+H]+: 415.0865 found 415.0865

[0187] Example 32: 3-[[6-[[2-(trifluoromethyl)-4-pyridyl]oxy]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid Step 1: 6-[[2-(trifluoromethyl)-4-pyridyl]oxy]-1,3-benzothiazol-2-amine [ka] To a solution of 2-amino-1,3-benzothiazol-6-ol (500 mg, 3.01 mmol) in DMF (7 mL) was added 4-chloro-2-(trifluoromethyl)pyridine (546 mg, 3.01 mmol) and CsCO (2.94 g, 9.03 mmol). The mixture was heated at 100 °C for 24 h. The reaction was then cooled to room temperature. Water was added, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (100% cyclohexane to 100% AcOEt) to give the title compound as a white solid (129 mg, 14%). 1H NMR (300 MHz, DMSO-d6) δ = 8.60 (d, J = 5.7 Hz, 1H), 7.64 (d, J = 2.5 Hz, 1H), 7.57 (brs, 2H), 7.42-7.39 (m, 2H), 7.13 (dd, J = 5.7, 2.5 Hz, 1H), 7.08 (dd, J = 8.6, 2.5 Hz, 1H). LC-MS: Method X, RT = 2.54 min (5 min run), MS (ESI) m / z:312 (M+H) + ; 310 (MH) -

[0188] Step 2: 3-[[6-[[2-(trifluoromethyl)-4-pyridyl]oxy]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (68 mg, 0.41 mmol) in THF (2 mL) was added 6-[[2-(trifluoromethyl)-4-pyridyl]oxy]-1,3-benzothiazol-2-amine (129 mg, 0.41 mmol). The mixture was heated under reflux. After 24 h, the solvent was evaporated and the crude product was purified by column chromatography (100% cyclohexane to 90 / 10 AcOEt / methanol) to give the title acid compound as a white solid (76.6 mg, 39%). 1H NMR (300 MHz, DMSO-d6) δ = 12.37 (brs, 1H), 11.99 (brs, 1H), 8.61 (d, J = 5.7 Hz, 1H), 7.92 (d, J = 2.4 Hz, 1H), 7.79 (d, J = 8.7 Hz, 1H), 7.44 (d, J = 2.3 Hz, 1H), 7.29 (dd, J = 8.7, 2.5 Hz, 1H), 7.16 (dd, J = 5.7, 2.4 Hz, 1H), 6.16 (m, 2H), 3.46 (dd, J = 9.9, 3.2 Hz, 1H), 3.38 (m, 1H), 3.13 (s, 1H), 3.08 (s, 1H), 1.37 (d, J = 8.2 Hz, 1H), 1.31 (d, J = 8.2 Hz, 1H). LC-MS: Method X, RT = 11.48 min (30 min run), MS (ESI) m / z:476 (M+H) + ; 474 (MH) - HRMS (ES+) calculated for C22H17F3N3O4S [M+H]+: 476.0892 Found: 476.0884

[0189] Example 33: (1R,2S,6R,7S)-4-[6-[(2-chloro-4-pyridyl)oxy]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione Step 1: 6-[(2-chloro-4-pyridyl)oxy]-1,3-benzothiazol-2-amine [ka] To a solution of 2-amino-1,3-benzothiazol-6-ol (500 mg, 3.01 mmol) in DMF (5 mL) was added 4-bromo-2-chloro-pyridine (868 mg, 4.51 mmol) and CsCO (2.94 g, 9.03 mmol). The mixture was heated at 100 °C for 24 h. The reaction was then cooled to room temperature. Water was added, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (100% cyclohexane to 100% AcOEt) to give the title compound as a white solid (206 mg, 25% yield). 1 H NMR (300 MHz, DMSO-d6) δ = 8.26 (d, J = 5.7 Hz, 1H), 7.60 (d, J = 2.5 Hz, 1H), 7.54 (brs, 2H), 7.38 (d, J = 8.6 Hz, 1H), 7.05 (dd, J = 8.6, 2.5 Hz, 1H), 6.96 (d, J = 2.0 Hz, 1H), 6.92 (dd, J = 5.7, 2.3 Hz, 1H). LC-MS: Method X, RT = 2.33 min (5 min run), MS (ESI) m / z:278 (M+H) + ;276 (MH) -

[0190] Step 2: (1R,2S,6R,7S)-4-[6-[(2-chloro-4-pyridyl)oxy]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (121 mg, 0.74 mmol) in THF (3 mL) was added 6-[(2-chloro-4-pyridyl)oxy]-1,3-benzothiazol-2-amine (206 mg, 0.74 mmol). The reaction was heated under reflux. After 16 h, the observed precipitate was filtered, washed with THF and ACN, and dried to give the title compound as a white solid (182 mg, 58%). 1 H NMR (300 MHz, CDCl3): 8.25 (d, J = 5.6 Hz, 1H), 8.14 (d, J = 8.8 Hz, 1H), 7.59 (d, J = 2.3 Hz, 1H), 7.23 (dd, J = 8.8, 2.3 Hz, 1H), 6.86-6.78 (m, 2H), 6.28 (s, 2H), 3.59 (s, 2H), 3.57 (s, 2H), 1.84 (d, J = 8.9 Hz, 1H), 1.67 (d, J = 8.9 Hz, 1H). LC-MS: Method X, RT = 2.90 min (5 min run), MS (ESI) m / z:424 (M+H) + HRMS (ES+) calculated for C21H15ClN3O3S [M+H]+: 424.0523 found 424.0526

[0191] Example 34: (1R,2S,6R,7S)-4-[6-[[6-(trifluoromethyl)-2-pyridyl]oxy]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione Step 1: 6-[[6-(trifluoromethyl)-2-pyridyl]oxy]-1,3-benzothiazol-2-amine [ka] To a solution of 2-amino-1,3-benzothiazol-6-ol (500 mg, 3.01 mmol) in DMF (7 mL) was added 2-chloro-6-(trifluoromethyl)pyridine (819 mg, 4.51 mmol) and CsCO (2.94 g, 9.03 mmol). The reaction was stirred at 100 °C. After 24 h, water and ethyl acetate were added, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (80 / 20 Cyclo / AcOEt to 100% AcOEt) to give the title compound as a yellow oil (427 mg, 45.6%). 1 H NMR (300 MHz, CDCl3) δ = 7.82 (t, J = 11.1 Hz, 1H), 7.52 (d, J = 8.6 Hz, 1H), 7.42 (d, J = 2.1 Hz, 1H), 7.38 (d, J = 7.2 Hz, 1H), 7.10 (dd, J = 8.6, 2.5 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 6.03 (brs, 2H). LC-MS: Method X, RT = 2.63 min (5 min run), MS (ESI) m / z:312 (M+H) + ;310 (MH) -

[0192] Step 2: (1R,2S,6R,7S)-4-[6-[[6-(trifluoromethyl)-2-pyridyl]oxy]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (140 mg, 0.85 mmol) in THF (2 mL) was added 6-[[6-(trifluoromethyl)-2-pyridyl]oxy]-1,3-benzothiazol-2-amine (265 mg, 0.85 mmol). The mixture was heated under reflux. After 24 h, the solvent was evaporated and the crude product was purified by column chromatography (100% cyclohexane to 90 / 10 AcOEt / methanol) to give the title compound as a white solid (309 mg, 80%). 1 H NMR (300 MHz, CDCl3) δ = 8.10 (d, J = 8.9 Hz, 1H), 7.89-7.83 (m, 1H), 7.71 (d, J = 2.2 Hz, 1H), 7.41 (d, J = 7.3 Hz, 1H), 7.31 (dd, J = 8.9, 2.4 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 6.29 (t, J = 1.6 Hz, 2H), 3.62-3.52 (m, 4H), 1.86-1.81 (dt, J = 8.9, 1.5 Hz, 1H), 1.67-1.64 (m, 1H). LC-MS: Method X, RT = 13.43 min (30 min run), MS (ESI) m / z:458 (M+H) + HRMS (ES+) calculated for C22H15F3N3O3S [M+H]+: 458.0786 Found: 458.0773

[0193] Example 35: 3-[[6-[[5-(trifluoromethyl)-2-pyridyl]oxy]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid Step 1: 6-[[5-(trifluoromethyl)-2-pyridyl]oxy]-1,3-benzothiazol-2-amine [ka] To a solution of 2-amino-1,3-benzothiazol-6-ol (500 mg, 3.01 mmol) in DMF (7 mL) was added 2-chloro-5-(trifluoromethyl)pyridine (819 mg, 4.51 mmol) and CsCO (2.94 g, 9.03 mmol). The reaction was stirred at 100 °C. After 24 h, water and ethyl acetate were added, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (80 / 20 Cyclo / AcOEt to 100% AcOEt) to give the title compound as an orange oil (364.5 mg, 39%). 1 H NMR (300 MHz, CDCl3) δ = 8.43 (s, 1H), 7.90 (dd, J = 8.7, 2.5 Hz, 1H), 7.56 (d, J = 8.7 Hz, 1H), 7.40 (d, J = 2.4 Hz, 1H), 7.10 (dd, J = 8.7, 2.4 Hz, 1H), 7.02 (d, J = 8.7 Hz, 1H), 6.00 (brs, 2H). LC-MS: Method X, RT = 2.66 min (5 min run), MS (ESI) m / z:312 (M+H) + ;310 (MH) -

[0194] Step 2: 3-[[6-[[5-(trifluoromethyl)-2-pyridyl]oxy]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (148 mg, 0.90 mmol) in THF (2 mL) was added 6-[[5-(trifluoromethyl)-2-pyridyl]oxy]-1,3-benzothiazol-2-amine (281 mg, 0.90 mmol). The mixture was heated under reflux. After 16 h, the observed precipitate was filtered, washed with THF and ACN, and dried to give the title acid compound as a white solid (155 mg, 36%). The filtrate was evaporated under reduced pressure and purified by column chromatography (100% cyclohexane to 90 / 10 AcOEt / methanol) to give the title succinimide compound as a white solid (146.5 mg, 36%). 1 H NMR (300 MHz, DMSO-d6) δ = 12.29 (brs, 1H), 11.88 (brs, 1H), 8.56 (m, 1H), 8.23 ​​(dd, J = 9.1, 2.3 Hz, 1H), 7.86 (d, J = 2.3 Hz, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.25 (d, J = 8.7 Hz, 1H), 7.24 (dd, J = 8.7, 2.5 Hz, 1H), 6.16 (m, 2H), 3.47 (dd, J = 10.0, 3.1 Hz, 1H), 3.38 (m, 1H), 3.13 (s, 1H), 3.08 (s, 1H), 1.34 (m, 2H). LC-MS: Method X, RT = 12.02 min (30 min run), MS (ESI) m / z:476 (M+H) + ;474 (MH) - HRMS (ES+) calculated for C22H17F3N3O4S [M+H]+: 476.0892 Found: 476.0877

[0195] Example 36: (1R,2S,6R,7S)-4-[6-[[5-(trifluoromethyl)-2-pyridyl]oxy]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (148 mg, 0.90 mmol) in THF (2 mL) was added 6-[[5-(trifluoromethyl)-2-pyridyl]oxy]-1,3-benzothiazol-2-amine (compound from Step 1 of Example 31, 281 mg, 0.90 mmol). The mixture was heated under reflux. After 16 h, the observed precipitate was filtered, washed with THF and ACN, and dried to give the title acid compound as a white solid (155 mg, 36%). The filtrate was evaporated under reduced pressure and purified by column chromatography (100% cyclohexane to 90 / 10 AcOEt / methanol) to give the title succinimide compound as a white solid (146.5 mg, 36%). 1 H NMR (300 MHz, CDCl3) δ = 8.44-8.41 (m, 1H), 8.12 (d, J = 8.9 Hz, 1H), 7.95-7.91 (dd, J = 8.6, 2.6 Hz, 1H), 7.66 (d, J = 2.2 Hz, 1H), 7.30-7.26 (dd, J = 8.9, 2.4 Hz, 1H), 7.05 (d, J = 8.6 Hz, 1H), 6.28 (t, J = 1.5 Hz, 2H), 3.61-3.53 (m, 4H), 1.82 (d, J = 8.9 Hz, 1H), 1.65 (d, J = 8.9 Hz, 1H). LC-MS: Method X, RT = 3.14 min (5 min run), MS (ESI) m / z:458 (M+H) + HRMS (ES+) calculated for C22H15F3N3O3S [M+H]+: 458.0786 Found: 458.0773

[0196] Example 37: 3-[[6-[(5-bromo-2-pyridyl)oxy]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid Step 1: 6-[(5-bromo-2-pyridyl)oxy]-1,3-benzothiazol-2-amine [ka] To a solution of 2-amino-1,3-benzothiazol-6-ol (200 mg, 1.20 mmol) in DMF (5 mL) was added 5-bromo-2-chloro-pyridine (232 mg, 1.20 mmol) and CsCO (1.18 g, 3.61 mmol). The reaction was stirred at 100 °C. After 48 h, water and ethyl acetate were added, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (80 / 20 Cyclo / AcOEt to 100% AcOEt) to give the title compound as a white solid (33.5, 9%). 1 H NMR (300 MHz, CDCl3) δ = 8.20 (dd, J = 2.5, 0.5 Hz, 1H), 7.75 (dd, J = 8.7, 2.5 Hz, 1H), 7.50 (d, J = 8.7 Hz, 1H), 7.35 (d, J = 2.4 Hz, 1H), 7.07-7.03 (dd, J = 8.7, 2.4 Hz, 1H), 6.83 (dd, J = 8.7, 0.5 Hz, 1H). LC-MS: Method X, RT = 2.55 min (5 min run), MS (ESI) m / z:324 (M+2H) + ;320 (M-2H) -

[0197] Step 2: 3-[[6-[(5-bromo-2-pyridyl)oxy]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (14 mg, 0.09 mmol) in THF (2 mL) was added 6-[(5-bromo-2-pyridyl)oxy]-1,3-benzothiazol-2-amine (27.5 mg, 0.09 mmol). The mixture was heated under reflux. After 48 h, the observed precipitate was filtered, washed with THF and ACN, and dried to give the title acid compound as a white solid (7.8 mg, 20%). 1 H NMR (300 MHz, DMSO-d6) δ = 12.26 (brs, 1H), 11.88 (brs, 1H), 8.26 (dd, J = 2.6, 0.6 Hz, 1H), 8.05 (dd, J = 8.7, 2.6 Hz, 1H), 7.76 (d, J = 2.4 Hz, 1H), 7.73-7.70 (d, J = 8.7 Hz, 1H), 7.19 (dd, J = 8.7, 2.5 Hz, 1H), 7.07-7.04 (dd, J = 8.7, 0.6 Hz, 1H), 6.16 (m, 2H), 3.47 (dd, J = 10.0, 3.2 Hz, 1H), 3.38 (dd, J = 10.0, 3.2 Hz, 1H), 3.13 (s, 1H), 3.08 (s, 1H), 1.34 (m, 2H). LC-MS: Method X, RT = 11.42 min (30 min run), MS (ESI) m / z:488 (M+2H) + ;484 (M-2H) - HRMS (ES+) calculated for C21H15BrN3O3S [M+H]+: 486.0123 found 486.0126

[0198] Example 38: 3-[(6-nitro-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (115 mg, 0.7 mmol) in THF (1.5 mL) was added 6-nitro-1,3-benzothiazol-2-amine (115 g, 0.7 mmol). The mixture was stirred under reflux overnight. The observed precipitate was then filtered, washed with ACN and THF, and dried to give the title compound as a beige solid (31 mg, 12%). 1 H NMR (300 MHz, DMSO-d6) δ = 12.67 (brs, 1H), 11.94 (brs, 1H), 9.01 (d, J = 2.3 Hz, 1H), 8.26 (dd, J = 9.0, 2.4 Hz, 1H), 7.84 (d, J = 9.0 Hz, 1H), 6.21 - 6.10 (m, 2H), 3.49 (dd, J = 10.0, 2.8 Hz, 1H), 3.42 (dd, J = 10.0, 2.8 Hz, 1H), 3.15 (s, 1H), 3.10 (s, 1H), 1.36 (m, 2H). LC-MS: Method X, RT = 3.88 min (10 min run), MS (ESI) m / z:360 (M+H) + ;358 (MH) - HRMS (ES+) C16H14N3O5S [M+H] + Calculated value: 360.0654 Measured value: 360.0656

[0199] Example 39: 3-[(6-methylsulfonyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka] Commercially available. Purchased from Vitas-M Laboratory.

[0200] Example 40: 3-[(6-cyano-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (115 mg, 0.7 mmol) in THF (1.5 mL) was added 2-amino-1,3-benzothiazole-5-carbonitrile (123 mg, 0.7 mmol). The mixture was stirred under reflux overnight. The observed precipitate was then filtered, washed with ACN and THF, and dried to give the title compound as a yellow solid (40 mg, 17%). 1 H NMR (300 MHz, DMSO-d6) δ = 12.58 (s, 1), 11.82 (s, 1H), 8.53 (s, 1H), 7.84 - 7.79 (m, 2H), 6.24 - 6.01 (m, 2H), 3.48 (dd, J = 10.0, 3.4 Hz, 1H), 3.41 (dd, J = 10.0, 3.4 Hz, 1H), 3.14 (s, 1H), 3.10 (s, 1H), 1.34 (q, J = 8.6 Hz, 2H). LC-MS: Method X, RT = 4.14 min (10 min run), MS (ESI) m / z:340 (M+H) + ;338 (MH) - HRMS (ES+) C17H14N3O3S [M+H] + Calculated value: 340.0756 Measured value: 340.0746.

[0201] Example 41: 3-[(6-methoxycarbonyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (115 mg, 0.7 mmol) in THF (1.5 mL) was added methyl 2-amino-1,3-benzothiazole-6-carboxylate (146 mg, 0.7 mmol). The mixture was stirred under reflux overnight. The observed precipitate was then filtered, washed with ACN and THF, and dried to give the title compound as a beige solid (162 mg, 62%). 1 H NMR (300 MHz, DMSO-d6) δ = 12.48 (s, 1), 11.87 (s 1H), 8.59 (d, J = 1.5 Hz, 1H), 7.98 (dd, J = 8.5, 2.0 Hz, 1H), 8.45 (d, J = 8.5 Hz, 1H), 6.22 - 6.10 (m, 2H), 3.86 (s, 3H), 3.47 (dd, J = 10.2, 3.2 Hz, 1H), 3.38 (dd, J = 10.3, 3.2 Hz, 1H), 3.13 (s, 1H), 3.08 (s, 1H), 1.41 - 1.26 (m, 2H). LC-MS: Method X, RT = 3.58 min (10 min run), MS (ESI) m / z:373 (M+H) + ;371 (MH) - HRMS (ES+) C18H17N2O5S [M+H] + Calculated value: 373.0858 Measured value: 373.0859

[0202] Example 42: 3-[(6-fluoro-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (115 mg, 0.7 mmol) in THF (1.5 mL) was added 5-fluoro-1,3-benzothiazol-2-amine (118 mg, 0.7 mmol). The mixture was stirred under reflux. After 6 h, the mixture was evaporated under reduced pressure and solubilized with ACN. The observed precipitate was filtered, washed with ACN and THF, and dried to give the title compound as a brown solid (87 mg, 37%). 1H NMR (300 MHz, DMSO-d6) δ = 12.28 (brs, 1H), 11.87 (brs, 1H), 7.84 (dd, J = 8.2, 2.7 Hz, 1H), 7.70 (dd, J = 8.8, 4.8 Hz, 1H), 7.25 (td, J = 9.2, 2.7 Hz, 1H), 6.19-6.12 (m, 2H), 3.46 (dd, J = 10.2, 3.2 Hz, 1H), 3.38 (dd, J = 10.1, 3.3 Hz, 1H), 3.13 (s, 1H), 3.08 (s, 1H), 1.33 (dd, J = 17.2, 8.2 Hz, 2H). LC-MS: Method X, RT = 3.77 min (5 min run), MS (ESI) m / z:333 (M+H) + ;331 (MH) - HRMS (ES+) C16H14N2O3SF [M+H] + Calculated value: 333.0709 Measured value: 333.0729

[0203] Example 43: 3-[[6-(trifluoromethyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (115 mg, 0.7 mmol) in THF (1.5 mL) was added 6-(trifluoromethyl)-1,3-benzothiazol-2-amine (153 mg, 0.7 mmol). The mixture was stirred under reflux overnight. The observed precipitate was filtered, washed with ACN and THF, and dried to give the title compound as a white solid (127 mg, 48%). 1H NMR (300 MHz, DMSO-d6) δ = 12.51 (s, 1H), 11.92 (s, 1H), 8.44 (s, 1H), 7.8 (d, J = 8.5 Hz, 1H), 7.71 (dd, J = 8.5, 1.5 Hz, 1H), 6.20 (dd, J = 5.6, 2.9 Hz, 1H), 6.14 (dd, J = 5.7, 2.9 Hz, 1H), 3.5 (dd, J = 10.2, 3.2 Hz, 1H), 3.40 (dd, J = 10.2, 3.2 Hz, 1H), 3.14 (s, 1H), 3.09 (s, 1H), 1.41 - 1.28 (m, 2H). LC-MS: Method X, RT = 4.84 min (10 min run), MS (ESI) m / z:383 (M+H) + ;381 (MH) - HRMS (ES+) C17H14N2O3F3S [M+H] + Calculated value: 383.0677 Measured value: 383.0657

[0204] Example 44: 3-[[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (115 mg, 0.7 mmol) in THF (1.5 mL) was added 6-(trifluoromethoxy)-1,3-benzothiazol-2-amine (164 mg, 0.7 mmol). The mixture was stirred under reflux. After 4 h, the observed precipitate was filtered, washed with ACN and THF, and dried to give the title compound as a white solid (140 mg, 50%). 1H NMR (300 MHz, DMSO-d6) δ = 12.38 (s, 1H), 11.89 (s, 1H), 8.07 (d, J = 2.2 Hz, 1H), 7.77 (d, J = 8.6 Hz, 1H), 7.38 (ddd, J = 8.7, 2.3, 0.9 Hz, 1H), 6.22 - 6.13 (m, 2H), 3.47 (dd, J = 10.2, 3.4 Hz, 1H), 3.39 (dd, J = 10.2, 3.3 Hz, 1H), 3.13 (s, 1H), 3.09 (s, 1H), 1.41 - 1.28 (m, 2H). LC-MS: Method X, RT = 4.90 min (10 min run), MS (ESI) m / z:399 (M+H) + ;397 (MH) - HRMS (ES+) C17H14N2O4F3S [M+H] + Calculated value: 399.0626 Measured value: 399.0630.

[0205] Example 45: (1R,2S,6R,7S)-4-[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione [ka] To a solution of 3-[[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid (140 mg, 0.35 mmol) in AcOEt (2 mL), T3P (50% in AcOEt, 416 μL, 0.70 mmol) was added, and the mixture was stirred at room temperature. After 5 h, EtOAc was added, and the organic phase was washed twice with water. The organic layer was dried, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (100% cyclohexane to 50 / 50 cyclohexane / AcOEt) to give the title compound as a white solid (95 mg, 71%). 1H NMR (300 MHz, DMSO-d6) δ = 8.26 (dd, J = 2.2, 0.8 Hz, 1H), 8.09 (d, J = 8.9 Hz, 1H), 7.52 (ddd, J = 8.9, 2.2, 0.8 Hz, 1H), 6.21 (t, J = 1.8 Hz, 2H), 3.64 (dd, J = 2.8, 1.8 Hz, 2H), 3.42 - 3.36 (m, 2H), 1.69 - 1.54 (m,2H). LC-MS: Method X, RT = 5.07 min (10 min run), MS (ESI) m / z:381 (M+H) +

[0206] Example 46: 3-[(6-chloro-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka] Commercially available. Purchased from Vitas-M Laboratory.

[0207] Example 47: 3-[(6-bromo-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka] Commercially available. Purchased from Vitas-M Laboratory.

[0208] Example 48: 3-[(5-bromo-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (115 mg, 0.7 mmol) in THF (1.5 mL) was added 5-bromo-1,3-benzothiazol-2-amine (160 mg, 0.7 mmol). The mixture was stirred under reflux. After 3 h, the observed precipitate was filtered, washed with ACN and THF, and dried to give the title compound as a white solid (120 mg, 44%). 1H NMR (300 MHz, DMSO-d6) δ = 12.34 (brs, 1H), 11.88 (brs, 1H), 8.20 (s, 1H), 8.61 (d, J = 8.6 Hz, 1H), 7.53 (d, J = 8.5 Hz, 1H), 6.15 (br s, 2H), 3.46 (dd, J = 10.0, 2.9 Hz, 1H), 3.37 (dd, J = 10.0, 2.9 Hz, 1H), 3.12 (s, 1H), 3.07 (s, 1H), 1.33 (dd, J = 17.1, 8.2 Hz, 2H). LC-MS: Method X, RT = 4.20 min (10 min run), MS (ESI) m / z:395 (M+H) + ;393 (MH) - HRMS (ES+) C16H14N2O3SBr [M+H] + Calculated value: 392.9909 Measured value: 392.9906

[0209] Example 49: 3-[(6-iodo-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid Step 1: 3-[(6-iodo-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (101 mg, 0.6 mmol) in THF (3 mL) was added 6-iodo-1,3-benzothiazol-2-amine (170 mg, 0.6 mmol). The mixture was stirred under reflux. After 50 h, the observed precipitate was filtered, washed with THF, and dried to give the title compound as a gray solid (197 mg, 73%). 1H NMR (300 MHz, DMSO-d6) δ = 12.33 (brs, 1H), 11.97 (brs, 1H), 8.33 (d, J = 1.6 Hz, 1H), 7.69 (dd, J = 8.4 Hz, J = 1.7 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 6.20 - 6.11 (m, 2H), 3.47 (dd, J = 10.1 Hz, J = 3.1 Hz, 1H), 3.37 (dd, J = 10.1 Hz, J = 3.1 Hz, 1H ), 3.12 (s, 1H), 3.08 (s, 1H), 1.34 (q, J = 8.5 Hz, 2H). LC-MS: Method X, RT = 2.70 min (5 min run), MS (ESI) m / z:441 (M+H) + ;439 (MH) - HRMS (ES+) C16H14N2O3SI [M+H] + Calculated value: 440.9770 Measured value: 440.9785

[0210] Example 50: 3-[(6-hydroxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (150 mg, 0.91 mmol) in THF (1 mL) was added 2-amino-1,3-benzothiazol-6-ol (152 mg, 0.91 mmol). The mixture was stirred under reflux overnight. The observed precipitate was then filtered, washed with ACN and THF, and dried to give the title compound as a gray solid (85 mg, 28%). 1H NMR (300 MHz, DMSO-d6) δ = 12.03 (s, 1H), 11.84 (s, 1H), 9.47 (s, 1H), 7.50 (d, J = 8.5 Hz, 1H), 7.22 (d, J = 2.2 Hz, 1H), 6.86 (dd, J = 8.6, 2.3 Hz, 1H), 6.22 - 6.09 (m, 2H), 3.52 - 3.27 (m, 2H), 3.12 (s, 1H), 3.07 (s, 1H), 1.36 (d, J = 8.0 Hz, 1H), 1.30 (d, J = 8.1 Hz, 1H) LC-MS: Method X, RT = 1.98 min (5 min run), MS (ESI) m / z:331 (M+H) + ;329 (MH) - HRMS (ES+) C16H15N2O4S [M+H] + Calculated value: 331.0753 Measured value: 331.0773

[0211] Example 51: 3-[(6-phenyl-1,3-benzothiazol-2-yl)carbamoyl]-7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid Step 1: 6-phenyl-1,3-benzothiazol-2-amine [ka] In a sealed tube, phenylboronic acid (274 mg, 2.25 mmol), 6-bromo-1,3-benzothiazol-2-amine (344 mg, 1.5 mmol), Pd(dppf)Cl (220 mg, 0.3 mmol), and KCO (138 mg, 1 mmol) were introduced. The mixture was purged with argon for 15 minutes before adding a dioxane / water mixture (2 mL, 3:1). The solution was heated at 100 °C for 30 minutes under microwave irradiation. The reaction mixture was filtered through cotton, and the filtrate was evaporated under reduced pressure. The crude product was purified by reverse flash chromatography (C18, 90 / 10 water / MeOH to 100% MeOH). The collected fractions were evaporated and resolubilized with ACN. The observed precipitate was filtered and dried to give the title compound as a beige solid (213 mg, 62%). 1 H NMR (300 MHz, DMSO-d6) δ = 7.97 (d, J = 1.7 Hz, 1H), 7.64 (d, J = 7.6 Hz, 2H), 7.52 (m, 3H), 7.45 -7.35 (m, 3H), 7.3 (t, J = 7.6 Hz, 1H). LC-MS: Method X, RT = 3.00 min (5 min run), MS (ESI) m / z:227 (M+H) +

[0212] Step 2: 3-[(6-phenyl-1,3-benzothiazol-2-yl)carbamoyl]-7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (116 mg, 0.7 mmol) in THF (1 mL) was added 6-phenyl-1,3-benzothiazol-2-amine (158 mg, 0.7 mmol). The mixture was stirred under reflux. After 4 h, the observed precipitate was filtered, washed with ACN and THF, and dried to give the title compound as a white solid (184 mg, 67%). 1 H NMR (300 MHz, DMSO-d6) δ = 12.30 (brs, 1H), 11.88 (brs, 1H), 8.25 (s, 1H), 7.72 (br s, 4H), 7.47 (t, J = 8.3 Hz, 2H), 7.35 (t, J = 6.8 Hz, 1H), 6.18 (brs, 2H), 3.49 (d, J = 9.3 Hz, 1H), 3.38 (d, J = 9.4 Hz, 1H), 3.14 (s, 1H), 3.09 (s, 1H), 1.34 (m, 2H). LC-MS: Method X, RT = 2.82 min (5 min run), MS (ESI) m / z:391 (M+H)+ ;389 (MH) - HRMS (ES+) C22H19N2O3S [M+H] + Calculated value: 391.1116 Measured value: 391.1076

[0213] Example 52: 3-[(6-cyclohexyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid Step 1: 6-Cyclohexyl-1,3-benzothiazol-2-amine [ka] To a solution of 4-cyclohexylaniline (162 mg, 0.92 mmol) in AcOH (0.5 M) was added ammonium thiocyanate (352 mg, 4.62 mmol). The reaction was stirred at room temperature for 90 min. The mixture was then cooled to 0 °C, and a solution of bromine (52.1 μL, 1.02 mmol) in AcOH (1 M) was added. The reaction was stirred at 0 °C for 1 h, then allowed to warm to room temperature and stirred overnight. After 16 h, the reaction was poured into cold water and made alkaline (to pH 10) by the addition of saturated Na2CO3 solution. Ethyl acetate was added, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (100% cyclohexane to 50 / 50 cyclohexane / AcOEt) to give the title compound as a white solid (154 mg, 72%). 1 H NMR (300 MHz, DMSO-d6) δ = 7.49 (d, J = 1.6 Hz, 1H), 7.32 (s, 2H), 7.23 (d, J = 8.2 Hz, 1H), 7.06 (dd, J = 8.3, 1.8 Hz, 1H), 1.79-1.71 (m, 5H), 1.39-1.22 (m, 5H). LC-MS: Method X, RT = 3.07 min (5 min run), MS (ESI) m / z:233 (M+H) +

[0214] Step 2: 3-[(6-cyclohexyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (98.9 mg, 0.603 mmol) in THF (3 mL) was added 6-cyclohexyl-1,3-benzothiazol-2-amine (140 mg, 0.603 mmol). The mixture was stirred under reflux overnight. The observed precipitate was then filtered, washed with ACN and THF, and dried to give the title compound as a white solid (74 mg, 31%). 1 H NMR (300 MHz, DMSO-d6) δ = 12.16 (s, 1H), 11.85 (s, 1H), 7.76 (d, J = 1.6 Hz, 1H), 7.60 (d, J = 8.3 Hz, 1H), 7.27 (dd, J = 8.4, 1.8 Hz, 1H), 6.17 (t, J = 1.6 Hz, 2H), 3.47 (dd, J = 10.1, 3.1 Hz, 1H), 3.37 (dd, J = 10.2, 3.3 Hz, 1H), 3.12 (s, 1H), 3.09 (s, 1H), 2.59 (m, 1H), 1.82-1.73 (m, 5H), 1.46-1.34 (m, 7H). LC-MS: Method X, RT = 13.35 min (30 min run), MS (ESI) m / z:397 (M+H) + ;395 (MH) - HRMS (ES+) C22H25N2O3S [M+H] + Calculated value: 397.1586 Measured value: 397.1595

[0215] Example 53: 3-[[6-(p-tolyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid Step 1: 6-(p-Tolyl)-1,3-benzothiazol-2-amine [ka] In a sealed tube, p-tolylboronic acid (102 mg, 0.75 mmol), 6-bromo-1,3-benzothiazol-2-amine (115 mg, 0.5 mmol), Pd(dppf)Cl (73.2 mg, 0.1 mmol), and KCO (138 mg, 1 mmol) were introduced. The mixture was purged with argon for 15 minutes before adding a dioxane / water mixture (4 mL, 3:1). The solution was heated at 100 °C for 30 minutes under microwave irradiation. The reaction mixture was filtered through cotton, and the filtrate was evaporated under reduced pressure. The crude product was dissolved in EtOAc and washed twice with water. The organic layer was dried, filtered, and concentrated under reduced pressure. The crude product was resolubilized with ACN. The observed precipitate was filtered and dried to give the title compound as a beige solid (32 mg, 27%). 1 H NMR (300 MHz, DMSO-d6) δ = 7.93 (d, J = 1.7 Hz, 1H), 7.54 (d, J = 8.2 Hz, 2H), 7.51 - 7.45 (m, 3H), 7.36 (d, J = 8.3 Hz, 1H), 7.23 (d, J = 8.2 Hz, 2H), 2.32 (s, 3H). LC-MS: Method X, RT = 2.88 min (5 min run), MS (ESI) m / z:241 (M+H) + ;239 (MH) -

[0216] Step 2: 3-[[6-(p-Tolyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (20.5 mg, 0.125 mmol) in THF (3 mL) was added 6-(p-tolyl)-1,3-benzothiazol-2-amine (30 mg, 0.125 mmol). The mixture was stirred under reflux. After 3 h, the observed precipitate was filtered, washed with ACN and THF, and dried to give the title compound as a beige solid (21 mg, 42%). 1 H NMR (300 MHz, DMSO-d6) δ = 12.29 (s, 1H), 11.90 (s, 1H), 8.22 (d, J = 1.3 Hz, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.69 (dd, J = 8.4, 1.7 Hz, 1H), 7.62 (d, J = 8.1 Hz, 2H), 7.27 (d, J = 8.1 Hz, 2H), 6.17 (brs, 2H), 3.49 (dd, J = 10.2, 3.2 Hz, 1H), 3.38 (dd, J = 10.1, 3.1 Hz, 1H), 3.14 (s, 1H), 3.09 (s, 1H), 2.35 (s, 3H), 1.35 (q, J = 8.2 Hz, 2H). LC-MS: Method X, RT = 3.00 min (5 min run), MS (ESI) m / z:405 (M+H) + ;403 (MH) - HRMS (ES+) C23H21N2O3S [M+H] + Calculated value: 405.1273 Measured value: 405.1273

[0217] Example 54: 3-[[6-(4-methoxyphenyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid Step 1: 6-(4-Methoxyphenyl)-1,3-benzothiazol-2-amine [ka] In a sealed tube, (4-methoxyphenyl)boronic acid (160 mg, 1.05 mmol), 6-bromo-1,3-benzothiazol-2-amine (160 mg, 0.7 mmol), Pd(dppf)Cl (51.2 mg, 0.07 mmol), and KCO (193 mg, 1.4 mmol) were introduced. The mixture was purged with argon for 15 minutes before a dioxane / water mixture (4 mL, 3:1) was added. The solution was heated at 100 °C for 30 minutes under microwave irradiation. The reaction mixture was filtered through a cotton and Celite pad, and the filtrate was evaporated under reduced pressure. The crude product was dissolved in EtOAc and washed twice with water. The organic layer was dried, filtered, and concentrated under reduced pressure. The crude product was resolubilized with ACN. The observed precipitate was filtered and dried to give the title compound as a light brown solid (110 mg, 61%). 1 H NMR (300 MHz, DMSO-d6) δ = 7.90 (d, J = 1.83 Hz, 1H), 7.57 (d, J = 8.9 Hz, 2H), 7.47 (s, 2H), 7.45 (dd, J = 8.4, 1.9 Hz, 1H), 7.34 (d, J = 8.5 Hz, 1H), 7.0 (d, J = 8.9 Hz, 2H), 3.78 (s, 3H). LC-MS: Method X, RT = 2.63 min (5 min run), MS (ESI) m / z:257 (M+H) +

[0218] Step 2: 3-[[6-(4-methoxyphenyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (70.4 mg, 0.43 mmol) in THF (3 mL) was added 6-(4-methoxyphenyl)-1,3-benzothiazol-2-amine (110 mg, 0.43 mmol). The mixture was stirred under reflux. After 3 h, the observed precipitate was filtered, washed with ACN and THF, and dried to give the title compound as a pale beige solid (30 mg, 17%). 1 H NMR (300 MHz, DMSO-d6) δ = 12.27 (s, 1H), 11.85 (s, 1H), 8.17 (s, 1H), 7.75 - 7.61 (m, 4H), 7.03 (d, J = 8.7 Hz, 2H), 6.16 (brs, 2H), 3.79 (s, 3H), 3.47 (dd, J = 10.0, 3.1 Hz, 1H), 3.37 (dd, J = 10.2, 3.1 Hz, 1H), 3.13 (s, 1H), 3.07 (s, 1H), 1.33 (dd, J = 17.7, 8.2 Hz, 2H). LC-MS: Method X, RT = 2.78 min (5 min run), MS (ESI) m / z:421 (M+H) + ;419 (MH) - HRMS (ES+) C23H21N2O4S [M+H] + Calculated value: 421.1222 Measured value: 421.1244

[0219] Example 55: 3-[[6-(4-chlorophenyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid Step 1: 6-(4-chlorophenyl)-1,3-benzothiazol-2-amine [ka] In a sealed tube, (4-chlorophenyl)boronic acid (164 mg, 1.05 mmol), 6-bromo-1,3-benzothiazol-2-amine (160 mg, 0.7 mmol), Pd(dppf)Cl (51.2 mg, 0.07 mmol), and KCO (193 mg, 1.4 mmol) were introduced. The mixture was purged with argon for 15 minutes before adding a dioxane / water mixture (4 mL, 3:1). The solution was heated at 100 °C for 30 minutes under microwave irradiation. The reaction mixture was filtered through cotton, and the filtrate was evaporated under reduced pressure. The crude product was dissolved in EtOAc and washed twice with water. The organic layer was dried, filtered, and concentrated under reduced pressure. The crude product was resolubilized with ACN, and the precipitate was filtered. The filtrate was evaporated and resolubilized with DCM. The observed precipitate was filtered and dried to give the title compound as a pale beige solid (130 mg, 71%). 1 H NMR (300 MHz, DMSO-d6) δ = 7.99 (d, J = 1.8 Hz, 1H), 7.67 (dd, J = 8.7, 1.9 Hz, 2H), 7.60 (s, 2H), 7.50 (dd, J = 8.5, 2.0 Hz, 1 H), 7.47 (dd, J = 8.7, 1.9 Hz, 2H), 7.37 (d, J = 8.4 Hz, 1H). LC-MS: Method X, RT = 2.77 min (5 min run), MS (ESI) m / z:261 (M+H) + ;259 (MH) -

[0220] Step 2: 3-[[6-(4-chlorophenyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (81.8 mg, 0.5 mmol) in THF (3 mL) was added 6-(4-chlorophenyl)-1,3-benzothiazol-2-amine (130 mg, 0.5 mmol). The mixture was stirred under reflux. After 3 h, the observed precipitate was filtered, washed with ACN and THF, and dried to give the title compound as a pale beige solid (140 mg, 66%). 1 H NMR (300 MHz, DMSO-d6) δ = 12.39 (s, 1H), 11.91 (s, 1H), 8.28 (d, J = 1.3 Hz, 1H), 7.80 - 7.67 (m, 4H), 7.51 (dt, J = 9.4, 2.7 Hz, 2H), 6.19 - 6.11 (m, 2H), 3.52 (dd, J = 10.2, 3.2 Hz, 1H), 3.40 (dd, J = 10.0, 3.4 Hz, 1H), 3.14(s, 1H), 3.09 (s, 1H), 1.34 (m, 2H). LC-MS: Method X, RT = 3.03 min (5 min run), MS (ESI) m / z:425 (M+H) + ;423 (MH) - HRMS (ES+) C22H18N2O3ScL [M+H] + Calculated value: 425.0727 Measured value: 425.0736

[0221] Example 56: 3-[[6-(3,4-dichlorophenyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid Step 1: 6-(3,4-dichlorophenyl)-1,3-benzothiazol-2-amine [ka] In a sealed tube, (3,4-dichlorophenyl)boronic acid (200 mg, 1.05 mmol), 6-bromo-1,3-benzothiazol-2-amine (160 mg, 0.7 mmol), Pd(dppf)Cl (51.2 mg, 0.07 mmol), and KCO (193 mg, 1.4 mmol) were introduced. The mixture was purged with argon for 15 minutes before a dioxane / water mixture (4 mL, 3:1) was added. The solution was heated at 100 °C for 30 minutes under microwave irradiation. The reaction mixture was filtered through a cotton and Celite pad, and the filtrate was evaporated under reduced pressure. The crude product was dissolved in EtOAc and washed twice with water. The organic layer was dried, filtered, and concentrated under reduced pressure. The crude product was resolubilized with ACN. The observed precipitate was filtered, washed with ACN and MeOH and dried to afford the title compound as a beige solid (87 mg, 42%). 1 H NMR (300 MHz, DMSO-d6) δ = 8.06 (d, J = 1.9 Hz, 1H), 7.92 (s, 1H), 7.66 (m, 2H), 7.61 (brs, 2H), 7.56 (dd, J = 8.4, 2.2 Hz, 1H), 7.38 (d, J = 8.2 Hz, 1H). LC-MS: Method X, RT = 3.15 min (5 min run), MS (ESI) m / z:295 (M+H) + ;293 (MH) -

[0222] Step 2: 3-[[6-(3,4-dichlorophenyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (50.1 mg, 0.31 mmol) in THF (1.5 mL) was added 6-(3,4-dichlorophenyl)-1,3-benzothiazol-2-amine (90 mg, 0.31 mmol). The mixture was stirred under reflux overnight. The observed precipitate was then filtered, washed with ACN and THF, and dried to give the title compound as a white solid (82 mg, 58%). 1 H NMR (300 MHz, DMSO-d6) δ = 12.35 (s, 1H), 11.87 (s, 1H), 8.34 (s, 1H), 8.01 (d, J = 1.8 Hz, 1H), 7.65 (s, 2H), 7.74 - 7.68 (m, 2H), 6.16 (brs, 2H), 3.47 (dd, J = 10.1, 3.9 Hz, 1H), 3.37 (dd, J = 10.2, 3.2 Hz, 1H), 3.13 (s, 1H), 3.08 (s, 1H), 1.33 (dd, J = 17.4, 8.2 Hz, 2H). LC-MS: Method X, RT = 3.20 min (5 min run), MS (ESI) m / z:459 (M+H) + ;457 (MH) - HRMS (ES+) C22H17N2O3SCl2 [M+H] + Calculated value: 459.0337 Measured value: 459.0323

[0223] Examples 57 and 58: 3-[[6-[2-(trifluoromethyl)phenyl]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid / (1R,2S,6R,7S)-4-[6-[2-(trifluoromethyl)phenyl]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione Step 1: 6-[2-(trifluoromethyl)phenyl]-1,3-benzothiazol-2-amine [ka] In a sealed tube, [2-(trifluoromethyl)phenyl]boronic acid (200 mg, 1.05 mmol), 6-bromo-1,3-benzothiazol-2-amine (160 mg, 0.7 mmol), Pd(dppf)Cl (51.2 mg, 0.07 mmol), and KCO (193 mg, 1.4 mmol) were introduced. The mixture was purged with argon for 15 minutes before a mixture of dioxane / water (4 mL, 3:1) was added. The solution was heated at 100 °C for 30 minutes under microwave irradiation. The reaction mixture was evaporated under reduced pressure and purified by column chromatography (100% cyclohexane to 50 / 50 cyclohexane / AcOEt). A mixture of two products was obtained, which was purified by reverse column chromatography (90 / 10 water / MeOH to 100% MeOH) to give the title compound as a white solid (55 mg, 27%). LC-MS: Method X, RT = 4.63 min (10 min run), MS (ESI) m / z:295 (M+H) + ;293 (MH) -

[0224] Step 2: Example 57 3-[[6-[2-(trifluoromethyl)phenyl]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka]

[0225] Example 58 (1R,2S,6R,7S)-4-[6-[2-(trifluoromethyl)phenyl]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (30.7 mg, 0.19 mmol) in THF (1 mL) was added 6-[2-(trifluoromethyl)phenyl]-1,3-benzothiazol-2-amine (55.0 mg, 0.19 mmol). The mixture was stirred under reflux. After 6 h, the reaction mixture was evaporated and resolubilized with ACN. The observed precipitate was filtered, washed with ACN and THF, and dried. The precipitate was purified by reverse column chromatography (70 / 30 water / ACN to 100% ACN) to give both title compounds as white solids (Example 57, 54 mg, 63%; Example 58, 14.0 mg, 17%).

[0226] Example 57 1 H NMR (300 MHz, DMSO-d6) δ = 12.33 (s, 1H), 11.88 (s, 1H), 7.89 (s, 1H), 7.84 (d, J = 7.9 Hz, 1H), 7.77 - 7.67 (m, 2H), 7.61 (t, J = 7.5 Hz, 1H), 7.46 (d, J = 7.5 Hz, 1H), 7.33 (d, J = 7.9 Hz, 1H), 6.16 (brs, 2H), 3.48 (dd, J = 10.0, 2.9 Hz, 1H), 3.38 (dd, J = 10.0, 2.9 Hz, 1H), 3.13 (s, 1H), 3.08 (s, 1H), 1.40 - 1.25 (m, 2H). LC-MS: Method X, RT = 4.90 min (10 min run), MS (ESI) m / z:459 (M+H) + ;457 (MH) - HRMS (ES+) C23H18N2O3F3S [M+H] + Calculated value: 459.0990 Measured value: 459.0989

[0227] Example 58 1H NMR (300 MHz, DMSO-d6) δ = 8.10 (d, J = 1.7 Hz, 1H) 8.04 (dd, J = 8.4, 0.5 Hz, 1H), 7.86 (dd, J = 7.6, 0.7 Hz, 1H), 7.75 (t, J = 7.7 Hz, 1H), 7.65 (t, J = 7.5 Hz, 1H), 7.51 - 7.43 (m, 2H), 6.22 (t, J = 1.8 Hz, 2H), 3.65 (dd, J = 2.8, 1.5 Hz, 2H), 3.45 - 3.38 (m, 2H), 1.68 - 1.59 (m, 2H). LC-MS: Method X, RT = 5.52 min (10 min run), MS (ESI) m / z:441 (M+H) + HRMS (ES+) C23H16N2O2F3S [M+H] + Calculated value: 441.0888 Measured value: 441.0864

[0228] Example 59: 3-[[6-[3-(trifluoromethyl)phenyl]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid Step 1: 6-[3-(trifluoromethyl)phenyl]-1,3-benzothiazol-2-amine [ka] In a sealed tube, [3-(trifluoromethyl)phenyl]boronic acid (200 mg, 1.05 mmol), 6-bromo-1,3-benzothiazol-2-amine (160 mg, 0.7 mmol), Pd(dppf)Cl2 (51.2 mg, 0.07 mmol), and K2CO3 (193 mg, 1.4 mmol) were introduced. The mixture was purged with argon for 15 min before adding a mixture of dioxane / water (4 mL, 3:1). The solution was heated at 100 °C for 30 min under microwave irradiation. The reaction mixture was evaporated under reduced pressure and purified by column chromatography (100% cyclohexane to 50 / 50 cyclohexane / AcOEt). A mixture of two products was obtained, solubilized with DCM. The observed precipitate was filtered to give the title compound as a white solid (55 mg, 27%). 1 H NMR (300 MHz, DMSO-d6) δ = 8.10 (d, J = 1.9 Hz, 1H), 8.00 - 7.92 (m, 2H), 7.68 - 7.63 (m, 2H), 7.62 - 7.56 (m, 3H), 7.41 (d, J = 8.4 Hz, 1H). LC-MS: Method X, RT = 2.90 min (5 min run), MS (ESI) m / z:295 (M+H) + ;293 (MH) -

[0229] Step 2: 3-[[6-[3-(trifluoromethyl)phenyl]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (30.7 mg, 0.19 mmol) in THF (1 mL) was added 6-[3-(trifluoromethyl)phenyl]-1,3-benzothiazol-2-amine (55.0 mg, 0.19 mmol). The mixture was stirred under reflux overnight. The observed precipitate was then washed with THF and ACN and dried to give both title compounds as white solids (54 mg, 63%). 1 H NMR (300 MHz, DMSO-d6) δ = 12.36 (s, 1H), 11.89 (s, 1H), 8.38 (s, 1H), 8.09 - 7.93 (m, 2H), 7.89 - 7.76 (m, 2H), 7.64 - 7.63 (m, 2H), 6.16 (brs, 2H), 3.48 (dd, J = 10.1, 3.2 Hz, 1H), 3.38 (dd, J = 10.2, 3.2 Hz, 1H), 3.13 (s, 1H), 3.08 (s, 1H), 1.41 - 1.24 (m, 2H). LC-MS: Method X, RT = 5.08 min (10 min run), MS (ESI) m / z:459 (M+H) + ;457 (MH) - HRMS (ES+) C23H18N2O3SF3 [M+H] + Calculated value: 459.0990 Measured value: 459.1003

[0230] Example 60: 3-[[6-[4-(trifluoromethyl)phenyl]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid Step 1: 6-[4-(trifluoromethyl)phenyl]-1,3-benzothiazol-2-amine [ka] In a sealed tube, [4-(trifluoromethyl)phenyl]boronic acid (200 mg, 1.05 mmol), 6-bromo-1,3-benzothiazol-2-amine (160 mg, 0.7 mmol), Pd(dppf)Cl (51.2 mg, 0.07 mmol), and KCO (193 mg, 1.4 mmol) were introduced. The mixture was purged with argon for 15 minutes before adding a mixture of dioxane / water (4 mL, 3:1). The solution was heated at 100 °C for 30 minutes under microwave irradiation. The reaction mixture was filtered through cotton and evaporated under reduced pressure. The crude product was purified by column chromatography (100% cyclohexane to 50 / 50 cyclohexane / AcOEt). The combined fractions were evaporated and resolubilized with DCM. The observed precipitate was filtered to give the title compound as a white solid (132 mg, 64%). 1 H NMR (300 MHz, DMSO-d6) δ = 8.09 (d, J = 1.8 Hz, 1H), 7.88 (d, J = 8.1 Hz, 2H), 7.77 (d, J = 8.4 Hz, 2H), 7.64 (s, 2H), 7.59 (dd, J = 8.4, 1.8 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H). LC-MS: Method X, RT = 2.97 min (5 min run), MS (ESI) m / z:295 (M+H) + ;293 (MH) -

[0231] Step 2: 3-[[6-[4-(trifluoromethyl)phenyl]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (45.7 mg, 0.28 mmol) in THF (3 mL) was added 6-[4-(trifluoromethyl)phenyl]-1,3-benzothiazol-2-amine (82.0 mg, 0.28 mmol). The mixture was stirred under reflux overnight. The observed precipitate was then washed with THF and ACN and dried to give the title compound as a beige solid (82 mg, 64%). 1 H NMR (300 MHz, DMSO-d6) δ = 12.35 (brs, 1H), 11.89 (brs, 1H), 8.36 (s 1H), 7.95 (d, J = 8.2 Hz, 2H), 7.86-7.78 (m, 4H), 6.17 (m, 2H), 3.61 (dd, J = 10.0, 3.1 Hz, 1H), 3.48 (dd, J = 10.0, 3.2 Hz, 1H), 3.13 (s, 1H), 3.09 (s, 1H), 1.34 (dd, J = 17.4, 8.4 Hz, 2H). LC-MS: Method X, RT = 3.08 min (5 min run), MS (ESI) m / z:459 (M+H) + ;457 (MH) - HRMS (ES+) C23H18N2O3SF3 [M+H] + Calculated value: 459.0990 Measured value: 459.0992

[0232] Example 61: (1R,2S,6R,7S)-4-[6-[4-(trifluoromethyl)phenyl]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione [ka] To a solution of 3-[[6-[4-(trifluoromethyl)phenyl]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid (Example 55, 80 mg, 0.17 mmol) in AcOEt (1 mL), T3P (50% in AcOEt, 208 μL, 0.35 mmol) was added, and the mixture was stirred at room temperature. After 5 h, the observed precipitate was removed by filtration. AcOEt was added, and the organic phase was washed twice with water. The organic layer was dried, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (100% cyclohexane to 50 / 50 cyclohexane / AcOEt) to give the title compound as a white solid (42 mg, 55%). 1 H NMR (300 MHz, DMSO-d6) δ = 8.54 (d, J = 1.6 Hz, 1H), 8.10 (d, J = 8.6 Hz, 1H), 7.99 (d, J = 8.0 Hz, 2H), 7.91 (dd, J = 8.9, 1.9 Hz, 1H), 7.86 (d, J = 8.3 Hz, 2H), 6.23 (t, J = 1.8 Hz, 2H), 3.65 (dd, J = 2.8, 1.5 Hz, 2H), 3.44 - 3.37 (m, 2H), 1.69 - 1.58 (m, 2H). LC-MS: Method X, RT = 5.72 min (10 min run), MS (ESI) m / z:441 (M+H) + HRMS (ES+) C23H16N2O2S [M+H] + Calculated value: 441.0885 Measured value: 441.0883

[0233] Example 62: 3-[[6-[4-(trifluoromethoxy)phenyl]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid Step 1: 6-[4-(trifluoromethoxy)phenyl]-1,3-benzothiazol-2-amine [ka] In a sealed tube, [4-(trifluoromethoxy)phenyl]boronic acid (200 mg, 0.48 mmol), 6-bromo-1,3-benzothiazol-2-amine (91.6 mg, 0.4 mmol), Pd(dppf)Cl (23.9 mg, 0.04 mmol), and KCO (111 mg, 0.8 mmol) were introduced. The mixture was purged with argon for 15 minutes before adding a mixture of dioxane / water (4 mL, 3:1). The solution was heated at 100 °C for 30 minutes under microwave irradiation. The reaction mixture was filtered through cotton and evaporated under reduced pressure. The crude product was purified by column chromatography (100% cyclohexane to 50 / 50 cyclohexane / AcOEt) to give the title compound as a beige solid (77 mg, 62%). LC-MS: Method X, RT = 3.03 min (5 min run), MS (ESI) m / z:311 (M+H) + ;309 (MH) -

[0234] Step 2: 3-[[6-[4-(trifluoromethoxy)phenyl]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (7.40 mg, 0.045 mmol) in THF (3 mL) was added 6-[4-(trifluoromethoxy)phenyl]-1,3-benzothiazol-2-amine (14.0 mg, 0.045 mmol). The mixture was stirred under reflux. After 5 h, the observed precipitate was washed with THF and ACN and dried. The precipitate was further purified by reverse column chromatography (C18, 90 / 10 water / ACN to 100 ACN) to give the title compound as a white solid (11 mg, 54%). 1H NMR (300 MHz, DMSO-d6) δ = 8.24 (d, J = 1.3 Hz, 1H), 7.83 (d, J = 8.6 Hz, 2H), 7.74 (d, J = 8.2 Hz, 1H), 7.69 (dd, J = 8.3, 1.5 Hz, 1H), 7.44 (d, J = 8.6 Hz, 2H), 6.15 (s, 2H), 3.41 (dd, J = 10.0, 3.0 Hz, 1H), 3.31 (dd, J = 10.1, 3.1 Hz, 1H), 3.14 (s, 1H), 3.09 (s, 1H), 1.37 - 1.21 (m, 2H). LC-MS: Method X, RT = 3.12 min (5 min run), MS (ESI) m / z: 475 (M+H) + ;473 (MH) - HRMS (ES+) C23H18N2O4F3S [M+H] + Calculated value: 475.0939 Measured value 475.0947

[0235] Example 63: (1R,2S,6R,7S)-4-[6-(4-hydroxyphenyl)-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione Project 1: 4-(2-アミノ-1,3-ベンゾチアゾール-6-イル)フェノール

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[0236] Step 2: (1R,2S,6R,7S)-4-[6-(4-hydroxyphenyl)-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (5.42 mg, 0.033 mmol) in THF (1 mL) was added 4-(2-amino-1,3-benzothiazol-6-yl)phenol (8.0 mg, 0.033 mmol). The mixture was stirred under reflux overnight. The reaction mixture was then evaporated under reduced pressure, and ACN was added. The observed precipitate was washed with THF and ACN and dried to give the title compound as a white solid (10 mg, 78%). 1H NMR (300 MHz, DMSO-d6) δ = 9.62 (s, 1H), 8.32 (dd, J = 2.0, 0.5 Hz, 1H), 8.00 (dd, J = 8.7, 0.5 Hz, 1H), 7.76 (dd, J = 8.7, 1.9 Hz, 1H), 7.63 - 7.54 (m, 2H), 6.91 - 6.84 (m, 2H), 6.24 (t, J = 1.7 Hz, 2H), 3.64 (dd, J = 2.9, 1.6 Hz, 2H), 3.43 - 3.37 (m, 2H), 1.64 (d, J = 1.8 Hz, 2H). LC-MS: Method X, RT = 2.65 min (5 min run), MS (ESI) m / z: 389 (M+H) + ;387 (MH) - HRMS (ES+) C22H17N2O3S [M+H] + Calculated value: 389.0960 Measured value: 389.0970

[0237] Example 64: 3-[[6-(4-pyridyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid Project 1: 6-(4-ピリジル)-1,3-ベンゾチアゾール-2-アミン

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[0238] Step 2: 3-[[6-(4-pyridyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (10.8 mg, 0.066 mmol) in THF (1.5 mL) was added 6-(4-pyridyl)-1,3-benzothiazol-2-amine (15.0 mg, 0.066 mmol). The mixture was stirred under reflux overnight. The observed precipitate was then washed with THF and ACN and dried to give the title compound as a beige solid (23 mg, 89%). 1 H NMR (300 MHz, DMSO-d6) δ = 12.38 (s, 1H), 11.91 (s, 1H), 8.62 (dd, J = 4.5, 1.6 Hz, 2H), 8.45 (d, J = 1.4 Hz, 1H), 7.86 (dd, J = 8.6, 2.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.77 (dd, J = 4.7, 1.7 Hz, 2H), 6.21 - 6.12 (m, 2H), 3.48 (dd, J = 10.0, 3.0 Hz, 1H), 3.39 (dd, J = 10.0, 3.1 Hz, 1H), 3.13 s, 1H), 3.08 (s, 1H), 1.34 (dd, J = 17.7, 8.4 Hz, 2H). LC-MS: Method X, RT = 2.10 min (5 min run), MS (ESI) m / z:392 (M+H) + ;390 (MH) - HRMS (ES+) C21H18N3O3S [M+H] + Calculated value: 392.1069 Measured value: 392.1059

[0239] Example 65: (1R,2S,6R,7S)-4-[6-(6-fluoro-3-pyridyl)-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione Step 1: 6-(6-fluoro-3-pyridyl)-1,3-benzothiazol-2-amine [ka] In a sealed vial, 6-bromo-1,3-benzothiazol-2-amine (100 mg, 0.436 mmol), 2-fluoropyridine-5-boronic acid (80.0 mg, 0.567 mmol), bis-(triphenylphosphine)palladium(II) chloride (15.9 mg, 0.0218 mmol), and CsF (199 mg, 1.31 mmol) were introduced in a mixture of 1,4-dioxane (3.60 mL) and water (1.80 mL). The reaction mixture was purged under argon for 15 minutes and heated at 90 °C. After 4 days, the reaction was cooled to room temperature and filtered through a pad of Celite. DCM and water were added, and the aqueous phase was extracted twice with DCM. The combined organic layers were washed with saturated NaHCO solution and then with brine. The organic layers were dried, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (100% cyclohexane to 100% AcOEt) to afford the title compound as an orange solid (55 mg, 51%). 1 H NMR (300 MHz, DMSO-d6) δ = 8.53 (d, J = 2.5 Hz, 1H), 8.26 (td, J = 8.3, 2.7 Hz, 1H), 8.05 (d, J = 1.9 Hz, 1H), 7.62 (s, 2H), 7.56 (dd, J = 8.4, 2.0 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.26 (dd, J = 8.6, 2.9 Hz, 1H). LC-MS: Method X, RT = 2.20 min (5 min run), MS (ESI) m / z:246 (M+H) + ;244 (MH) -

[0240] Step 2: (1R,2S,6R,7S)-4-[6-(6-fluoro-3-pyridyl)-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (34.8 mg, 0.21 mmol) in THF (1.5 mL) was added 6-(6-fluoro-3-pyridyl)-1,3-benzothiazol-2-amine (52.0 mg, 0.21 mmol). The mixture was stirred under reflux. After 7 days, the mixture was evaporated under reduced pressure. The crude product was purified by column chromatography (100% cyclohexane to 90 / 10 AcOEt, MeOH) to give the title compound as a white solid (15 mg, 18%). 1 H NMR (300 MHz, DMSO-d6) δ = 8.65 (d, J = 2.6 Hz, 1H), 8.52 (d, J = 1.5 Hz, 1H), 8.38 (td, J = 8.2, 2.7 Hz, 1H), 8.11 (d, J = 8.6 Hz, 1H), 7.90 (dd, J = 8.6, 2.0 Hz, 1H), 7.34 (dd, J = 8.6, 2.9 Hz, 1H), 6.24 (t, 2H), 3.66 (q, J = 1.5 Hz, 2H), 3.41 (m, 2H), 1.65 (m, 2H). LC-MS: Method X, RT = 11.38 min (30 min run), MS (ESI) m / z:392 (M+H) + HRMS (ES+) C21H15N3O2FS [M+H] + Calculated value: 392.0869 Measured value: 392.0872

[0241] Examples 66 and 67: 3-[[6-[6-(trifluoromethyl)-3-pyridyl]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid / (1R,2S,6R,7S)-4-[6-[6-(trifluoromethyl)-3-pyridyl]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione Step 1: 6-[6-(trifluoromethyl)-3-pyridyl]-1,3-benzothiazol-2-amine [ka] In a sealed vial, 6-bromo-1,3-benzothiazol-2-amine (100 mg, 0.436 mmol), [6-(trifluoromethyl)-3-pyridyl]boronic acid (108 mg, 0.567 mmol), bis(triphenylphosphine)palladium(II) chloride (15.9 mg, 0.0218 mmol), and CsF (199 mg, 1.31 mmol) were introduced in a mixture of 1,4-dioxane (3.60 mL) and water (1.80 mL). The reaction mixture was purged under argon for 15 minutes and heated at 90 °C. After 7 days, the reaction was cooled to room temperature and filtered through a pad of Celite. DCM and water were added, and the aqueous phase was extracted twice with DCM. The combined organic layers were washed with saturated NaHCO solution and then with brine. The organic layers were dried, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (100% cyclohexane to 100% AcOEt) to afford the title compound as a brown solid (78 mg, 61%). 1 H NMR (300 MHz, DMSO-d6) δ = 9.09 (d, J = 2.3 Hz, 1H), 8.35 (dd, J = 8.3, 2.2 Hz, 1H), 8.19 (d, J = 1.8 Hz, 1H), 7.95 (d, J = 8.3 Hz, 1H), 7.70 (s, 2H), 7.69 (dd, J = 8.5, 2.0 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H). LC-MS: Method X, RT = 2.55 min (5 min run), MS (ESI) m / z:294 (MH) -

[0242] Step 2: Example 66 3-[[6-[6-(trifluoromethyl)-3-pyridyl]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka]

[0243] Example 67 (1R,2S,6R,7S)-4-[6-[6-(trifluoromethyl)-3-pyridyl]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (37.2 mg, 0.23 mmol) in THF (1 mL) was added 6-[6-(trifluoromethyl)-3-pyridyl]-1,3-benzothiazol-2-amine (67.0 mg, 0.23 mmol). The mixture was stirred under reflux. After 48 h, the mixture was cooled to room temperature, and a mixture of ACN and THF was added. The observed precipitate was filtered and washed with ACN and THF to give the title acid compound as a white solid (Example 66, 11 mg, 11%). The filtrate was evaporated and purified by column chromatography (80 / 20 cyclohexane / AcOEt to 90 / 10 AcOEt / MeOH) to give the title succinimide compound as a white solid (Example 67, 14 mg, 14%).

[0244] Example 66 1 H NMR (300 MHz, DMSO-d6) δ = 12.40 (s, 1H), 11.90 (s, 1H), 9.17 (d, J = 1.9 Hz, 1H), 8.48 (d, J = 1.5 Hz, 1H), 8.43 (dd, J = 8.2, 2.1 Hz, 1H), 8.00 (d, J = 8.3 Hz, 1H), 7.89 (dd, J = 8.5, 1.8 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 6.18 (m, 2H), 3.50 (dd, J = 10.1, 3.1 Hz, 1H), 3.40 (dd, J = 10.3, 3.5 Hz, 1H), 3.13 (d, J = 15.8 Hz, 2H), 1.36 (m, 2H). LC-MS: Method X, RT = 11.55 min (30 min run), MS (ESI) m / z: 460 (M+H) + ;458 (MH) - HRMS (ES+) C22H17N3O3F3S [M+H] + Calculated value: 460.0943 Measured value 460.0934

[0245] Example 67 1 H NMR (300 MHz, DMSO-d6) δ = 9.20 (d, J = 2.4 Hz, 1H), 8.65 (d, J = 1.6 Hz, 1H), 8.47 (dd, J = 8.3, 2.2 Hz, 1H), 8.16 (d, J = 8.6 Hz, 1H), 8.05 (d, J = 8.4 Hz, 1H), 8.01 (dd, J = 8.6, 1.9 Hz, 1H), 6.25 (t, 2H), 3.67 (q, J = 1.4 Hz, 2H), 3.42 (m, 2H), 1.66 (m, 2H). LC-MS: Method X, RT = 12.93 min (30 min run), MS (ESI) m / z: 442 (M+H) + HRMS (ES+) C22H15N3O2F3S [M+H] + Calculated value: 442.0837 Measured value 442.0845

[0246] Example 68: (1R,2S,6R,7S)-4-[6-(3-thienyl)-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione Project 1: tert-ブチルN-(6-ブロモ-1,3-ベンゾチアゾール-2-イル)カルバマート

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[0247] Step 2: tert-Butyl N-[6-(3-thienyl)-1,3-benzothiazol-2-yl]carbamate [ka] Into a sealed vial, tert-butyl N-(6-bromo-1,3-benzothiazol-2-yl)carbamate (150 mg, 0.46 mmol), 3-thienylboronic acid (70.0 mg, 0.55 mmol), bis(triphenylphosphine)palladium(II) chloride (16.6 mg, 0.0228 mmol), and CsF (208 mg, 1.37 mmol) were introduced in a mixture of 1,4-dioxane (3.60 mL) and water (1.80 mL). The reaction mixture was purged under argon for 15 minutes and heated at 90 °C. After 16 hours, the reaction was cooled to room temperature and filtered through a pad of Celite. DCM and water were added, and the aqueous phase was extracted twice with DCM. The combined organic layers were washed with saturated NaHCO solution and then with brine. The organic layers were dried, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (100% cyclohexane to 50 / 50 cyclohexane / AcOEt) to afford the title compound as a yellow solid (74 mg, 49%). 1 H NMR (300 MHz, CDCl3) δ = 7.99 (d, J = 1.4 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.66 (dd, J = 8.4, 1.8 Hz, 1H), 7.49 (m, 1H), 7.45-7.42 (m, 2H), 1.62 (s, 9H). LC-MS: Method X, RT = 3.32 min (5 min run), MS (ESI) m / z:277 (MC(CH3)3) + ;331 (MH) -

[0248] Step 3: 6-(3-thienyl)-1,3-benzothiazol-2-amine [ka] To a solution of TFA (43.9 mg, 0.385 mmol) in DCM (5 mL) was added dropwise a solution of tert-butyl N-[6-(3-thienyl)-1,3-benzothiazol-2-yl]carbamate (64 mg, 0.193 mmol) in DCM (5 mL) at 0 °C. After 8 days, the solution was made alkaline by adding saturated NaHCO solution. The aqueous phase was extracted three times with DCM. The combined organic phases were dried, filtered, and concentrated under reduced pressure. The crude product was used in the next step without further purification. 1 H NMR (300 MHz, CDCl3) δ = 8.02 (d, J = 1.7 Hz, 1H), 7.60 (dd, J = 2.9, 1.3 Hz, 1H), 7.63-7.51 (m, 5H), 7.34 (d, J = 8.4 Hz, 1H). LC-MS: Method X, RT = 3.5 min (5 min run), MS (ESI) m / z:233 (M+H) +

[0249] Step 4: (1R,2S,6R,7S)-4-[6-(3-thienyl)-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (45.2 mg, 0.25 mmol) in THF (2 mL) was added 6-(3-thienyl)-1,3-benzothiazol-2-amine (58.3 mg, 0.25 mmol). The mixture was stirred under reflux. After 5 days, the reaction mixture was evaporated under reduced pressure. The crude product was purified by column chromatography (100% cyclohexane to 100% AcOEt) to give the title compound as a white solid (39 mg, 41%). 1H NMR (300 MHz, DMSO-d6) δ = 8.48 (d, J = 1.8 Hz, 1H), 8.20-8.0 (d, J = 8.5 Hz, 1H), 7.99-7.98 (dd, J = 2.9, 1.4 Hz, 1H), 7.93-7.89 (dd, J= 8.5, 1.8 Hz, 1H), 7.70-7.67 (dd, J= 5.0, 2.9 Hz, 1H), 7.66-7.63 (dd, J= 5.0, 1.4 Hz, 1H), 6.23 (d, J= 1.8 Hz, 2H), 3.64-3.62 (dd, J= 2.9, 1.6 Hz, 2H), 3.39 (m, 2H), 1.63 (m, 2H). LC-MS: Method X, RT = 12.90 min (30 min run), MS (ESI) m / z: 379 (M+H) + HRMS (ES+) C20H15N2O2S2 [M+H] + Calculated value: 379.0575 Measured value: 379.0580

[0250] Examples 69 and 70: 3-[[6-(3-furyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid and (1R,2S,6R,7S)-4-[6-(3-furyl)-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione Project 1: 6-(3-フリル)-1,3-ベンゾチアゾール-2-アミン

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[0251] Step 2: Example 69 3-[[6-(3-furyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka]

[0252] Example 70 (1R,2S,6R,7S)-4-[6-(3-furyl)-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (72.1 mg, 0.44 mmol) in THF (2 mL) was added 6-(3-furyl)-1,3-benzothiazol-2-amine (95.0 mg, 0.44 mmol). The mixture was stirred under reflux. After 9 h, the observed precipitate was filtered, washed with ACN and THF, and dried to give the title acid compound as a white solid (Example 69, 31 mg, 19%). The filtrate was evaporated, and the crude product was purified by column chromatography (100% cyclohexane to 90 / 10 AcOEt / MeOH) to give the title compound as a white solid (Example 70, 31 mg, 20%).

[0253] Example 69 1 H NMR (300 MHz, DMSO-d6) δ = 12.27 (s, 1H), 11.87 (s, 1H), 8.22 (t, J = 1.2 Hz, 1H), 8.19 (d, J = 1.3 Hz, 1H), 7.75 (t, J = 1.7 Hz, 1H), 7.70 (d, J = 7.7 Hz, 1H), 7.67 (d, 1H), 7.03 (dd, J = 1.9, 0.8 Hz, 1H), 6.20 (m, 2H), 3.48 (dd, J = 10.2, 3.1 Hz, 1H), 3.38 (dd, J = 10.3, 3.5 Hz, 1H), 3.11 (d, J = 14.9 Hz, 2H), 1.34 (q, 2H). LC-MS: Method X, RT = 10.60 min (30 min run), MS (ESI) m / z:381 (M+H) + ;379 (MH) - HRMS (ES+) C20H17N2O4S [M+H] + Calculated value: 381.0909 Measured value: 381.0907

[0254] Example 70 1 H NMR (300 MHz, DMSO-d6) δ = 8.37 (d, J = 1.6 Hz, 1H), 8.29 (dd, J = 1.4, 0.9 Hz, 1H), 8.00 (d, J = 8.5 Hz, 1H), 7.82 (dd, J = 8.6, 1.8 Hz, 1H), 7.79 (t, J = 1.7 Hz, 1H), 7.05 (dd, J = 1.9, 0.9 Hz, 1H), 6.23 (t, 2H), 3.64 (q, 2H), 3.40 (m, 2H), 1.64 (m, 2H). LC-MS: Method X, RT = 12.10 min (30 min run), MS (ESI) m / z:363 (M+H) + HRMS (ES+) C20H15N2O3S [M+H] + Calculated value: 363.0803 Measured value: 363.0809

[0255] Example 71: (1R,2S,6R,7S)-4-[6-(4-prop-2-ynoxyphenyl)-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione Step 1: 4-(2-amino-1,3-benzothiazol-6-yl)phenol [ka] Into a sealed tube, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (54.8 mg, 0.25 mmol), 6-bromo-1,3-benzothiazol-2-amine (57.0 mg, 0.25 mmol), Pd(dppf)Cl (36.4 mg, 0.05 mmol), and KCO (68.8 mg, 0.5 mmol) were introduced. The mixture was purged with argon for 15 minutes before adding a mixture of 1,4-dioxane / water (4 mL, 3:1). The solution was heated at 100 °C under microwave irradiation for 1 hour. The reaction mixture was filtered through cotton, and the filtrate was evaporated under reduced pressure. The crude product was purified by column chromatography (100% cyclohexane to 50 / 50 cyclohexane / AcOEt) to give the title compound as a beige solid (30 mg, 50%). LC-MS: Method X, RT = 2.02 min (5 min run), MS (ESI) m / z:243 (M+H) + ;241 (MH) -

[0256] Step 2: (1R,2S,6R,7S)-4-[6-(4-hydroxyphenyl)-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (5.42 mg, 0.03 mmol) in THF (1 mL) was added 4-(2-amino-1,3-benzothiazol-6-yl)phenol (8.0 mg, 0.03 mmol). The mixture was stirred under reflux overnight. The reaction mixture was evaporated, and ACN was added. The observed precipitate was filtered, washed with ACN and THF, and dried to give the title compound as a white solid (10 mg, 78%). 1H NMR (300 MHz, DMSO-d6) δ = 9.62 (s, 1H), 8.32 (dd, J = 2.0, 0.5 Hz, 1H), 8.00 (dd, J = 8.7, 0.5 Hz, 1H), 7.76 (dd, J = 8.7, 1.9 Hz, 1H), 7.63 - 7.54 (m, 2H), 6.91 - 6.84 (m, 2H), 6.24 (t, J = 1.7 Hz, 2H), 3.64 (dd, J = 2.9, 1.6 Hz, 2H), 3.43 - 3.37 (m, 2H), 1.64 (d, J = 1.8Hz, 2H). LC-MS: Method X, RT = 2.65 min (5 min run), MS (ESI) m / z:389 (M+H) + ;387 (MH) - HRMS (ES+) C22H17N2O3S [M+H] + Calculated value: 389.0960 Measured value: 389.0970

[0257] Step 3: (1R,2S,6R,7S)-4-[6-(4-prop-2-ynoxyphenyl)-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione [ka] To a solution of 4-[6-(4-hydroxyphenyl)-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (15 mg, 0.039 mmol) in acetone (1.5 mL) was added K2CO3 (18.7 mg, 0.077 mmol). The reaction mixture was stirred at room temperature for 1.5 h before propargyl bromide (5.85 μL, 0.077 mmol) was added dropwise. The reaction was then stirred at 50 °C overnight. The crude product was evaporated under reduced pressure and purified by column chromatography (100% cyclohexane to 70 / 30 cyclohexane / AcOEt) to give the title compound as a white solid (4 mg, 24%). 1 H NMR (300 MHz, DMSO-d6) δ = 8.12 (d, J = 8.9 Hz, 1H), 8.01 (brs, 1H), 7.68 (dd, J = 8.5, 2.4 Hz, 1H), 7.59 (d, J = 8.6 Hz, 2H), 7.09 (d, J = 8.9 Hz, 2H), 6.30 (t, J = 1.6 Hz, 2H), 4.76 (d, J = 2.4 Hz, 2H), 3.63 - 3.53 (m, 4H), 2.56 (t, J = 2.5 Hz, 1H), 1.72 - 1.64 (m, 2H). LC-MS: Method X, RT = 3.10 min (5 min run), MS (ESI) m / z:427 (M+H) +

[0258] Example 72: (1R,2S,6R,7S)-4-(6-ethynyl-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione Step 1: 6-Iodo-1,3-benzothiazol-2-amine [ka] To a solution of 6-bromo-1,3-benzothiazol-2-amine (500 mg, 2.18 mmol) in 1,4-dioxane (5.0 mL) was added CuI (21 mg, 0.11 mmol, 5.0 mol%), sodium iodide (650 mg, 4.4 mmol), and (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (35 μL, 0.218 mmol). The reaction mixture was heated at 110 °C for 1 week. The reaction was then evaporated and purified by reverse column chromatography (90 / 10 water / MeOH to 100% MeOH) to give the title compound as a white solid (430 mg). LC-MS: Method X, RT = 2.50 min (5 min run), MS (ESI) m / z:277 (M+H) + ;275 (MH) -

[0259] Step 2: 6-(2-trimethylsilylethynyl)-1,3-benzothiazol-2-amine [ka] In a sealed tube, 6-iodo-1,3-benzothiazol-2-amine (150 mg, 0.54 mmol), PdCl(PPh) (23 mg, 0.033 mmol), and CuI (20.6 mg, 0.108 mmol) were introduced. The mixture was purged with argon for 15 minutes before adding ACN (1 mL), TEA (1.28 mL, 9.20 mmol), and ethynyl(trimethyl)silane (0.101 mL, 0.806 mmol). The solution was heated at 100 °C for 45 minutes under microwave irradiation. EtOAc and water were then added, and the aqueous layer was extracted twice with AcOEt. The combined organic layers were washed with brine, dried, filtered, and concentrated under reduced pressure. The title compound was used without further purification; the yield was assumed to be quantitative (white solid, 134 mg, 100%). LC-MS: Method X, RT = 3.08 min (5 min run), MS (ESI) m / z:247 (M+H) + ;245 (MH) -

[0260] Step 3: (1R,2S,6R,7S)-4-[6-(2-trimethylsilylethynyl)-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (89.3 mg, 0.54 mmol) in THF (1 mL) was added 6-(2-trimethylsilylethynyl)-1,3-benzothiazol-2-amine (134 mg, 0.54 mmol). The mixture was stirred under reflux. After 48 h, the reaction mixture was evaporated and THF was added. The observed precipitate was filtered, washed with ACN and THF, and dried to give the title compound as a white solid (110 mg, 51%). 1 H NMR (300 MHz, DMSO-d6) δ = 8.29 (dd, J = 1.7, 0.5 Hz, 1H), 7.95, (dd, J = 8.5, 0.5 Hz, 1H), 7.557 (dd, J = 8.5, 1.8 Hz, 1H), 6.21 (t, J = 1.8 Hz, 2H), 3.64 (dd, J = 2.9, 1.6 Hz, 2H), 3.43 - 3.37 (m, 2H), 1.68 - 1.58 (m, 2H), 0.26 (s, 9H). LC-MS: Method X, RT = 6.02 min (10 min run), MS (ESI) m / z:393 (M+H) +

[0261] Step 4: (1R,2S,6R,7S)-4-(6-ethynyl-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione [ka] To a solution of (1R,2S,6R,7S)-4-[6-(2-trimethylsilylethynyl)-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (80 mg, 0.20 mmol) in THF (2 mL) was added TBAF (64.3 mg, 0.20 mmol), and the reaction mixture was stirred at room temperature overnight. Next, AcOEt was added and washed twice with water and brine. The organic layer was dried, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (100% cyclohexane to 60 / 40 cyclohexane / AcOEt) to give the title compound as a white solid (20 mg, 31%). 1 H NMR (300 MHz, CDCl3) δ = 8.04 (d, J = 8.6 Hz, 1H), 8.02 (d, J = 1.8 Hz, 1H), 7.60 (dd, J =8.5, 1.7 Hz, 1H), 6.30 (t, J = 1.7 Hz, 2H), 3.66 - 3.54 (m, 4H), 3.16 (s, 1H), 1.84 (dt, J = 9.0, 4.6 Hz, 1H), 1.67 (d, J = 9.0 Hz, 1H). LC-MS: Method X, RT = 2.82 min (5 min run), MS (ESI) m / z:321 (M+H) + HRMS (ES+) C18H13N2O2S [M+H] + Calculated value: 321.0698 Measured value: 321.0702

[0262] Example 73: (1R,2S,6R,7S)-4-(6-prop-2-ynoxy-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione Step 1: (1R,2S,6R,7S)-4-(6-hydroxy-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (500 mg, 3.05 mmol) in THF (1 mL) was added 2-amino-1,3-benzothiazol-6-ol (506 mg, 3.05 mmol), and the mixture was stirred under reflux for 4 hours. Next, T3P (50% in AcOEt, 3.05 mmol) was added, and the reaction was stirred under reflux overnight. The mixture was evaporated under reduced pressure, and THF was added. The observed precipitate was filtered, washed with THF, and dried to give the title compound as a white solid (750 mg, 79%). 1 H NMR (300 MHz, DMSO-d6) δ = 9.91 (s, 1H), 7.80 (d, J = 8.9 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 6.99 (dd, J = 8.9, 2.5 Hz, 1H), 6.21 (t, J = 1.9 Hz, 2H), 3.60 (dd, J = 2.8, 1.5 Hz, 2H), 3.37 (m, 2H), 1.62 (s, 2H). LC-MS: Method X, RT = 3.47 min (10 min run), MS (ESI) m / z:313 (M+H) + ;311 (MH) -

[0263] Step 2: (1R,2S,6R,7S)-4-(6-prop-2-ynoxy-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione [ka] To a solution of (1R,2S,6R,7S)-4-(6-hydroxy-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (50 mg, 0.16 mmol) in acetone (1.5 mL) was added K2CO3 (77.4 mg, 0.56 mmol), and the mixture was stirred at room temperature for 1.5 hours. Next, a solution of propargyl bromide (24.3 μL, 0.32 mmol) in acetone (0.5 mL) was added, and the reaction was stirred at 50 °C overnight. The mixture was then evaporated under reduced pressure, and AcOEt was added. The organic layer was washed twice with water, dried, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (100% cyclohexane to 60 / 40 cyclohexane / AcOEt) to afford the title compound as a white solid (12 mg, 43%). 1 H NMR (300 MHz, CDCl3) δ = 8.00 (d, J = 9.1 Hz, 1H), 7.41 (d, J = 2.5 Hz, 1H), 7.16 (dd, J = 9.0, 2.6 Hz, 1H), 6.28 (t, J = 1.8 Hz, 2H), 4.76 (d, J = 2.4 Hz 2H), 3.61 - 3.51 (m, 4H), 2.55 (t, J = 2.4 Hz, 1H), 1.82 (dt, J = 9.0, 1.8 Hz, 1H), 1.64 (d, J = 9.0 Hz, 1H). LC-MS: Method X, RT = 4.35 min (10 min run), MS (ESI) m / z:351 (M+H) + HRMS (ES+) C19H15N2O3S [M+H] + Calculated value: 351.0803 Measured value: 351.0806

[0264] Example 74: (1R,2S,3R,4S)-3-[(4-hydroxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (200 mg, 1.22 mmol) in THF (2 mL) was added 2-amino-1,3-benzothiazol-4-ol (202 mg, 1.22 mmol). The mixture was stirred under reflux overnight. The reaction mixture was then evaporated, and the crude product was purified by reverse column chromatography (90 / 10 water / ACN to 100% ACN) to give the title compound as a beige solid (126 mg, 33%). 1 H NMR (300 MHz, DMSO-d6) δ = 10.30 (s, 1H), 7.49 (dd, J = 8.1, 1.0 Hz, 1H), 7.29 (t, J = 8.1 Hz, 1H), 6.92 (dd, J = 7.9, 1.0 Hz, 1H), 6.24 (t, J = 1.9 Hz, 2H), 3.64 (dd, J = 2.9, 1.6 Hz, 2H), 3.41 - 3.38 (m, 2H), 1.64 (s, 2H). LC-MS: Method X, RT = 4.18 min (10 min run), MS (ESI) m / z:313 (M+H) + ;311 (MH) - HRMS (ES+) C16H13N2O3S [M+H] + Calculated value: 313.0647 Measured value: 313.0648

[0265] Example 75: 3-[(4-prop-2-ynoxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka] To a solution of (1R,2S,6R,7S)-4-(4-hydroxy-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (100 mg, 0.32 mmol) in acetone (1.5 mL) was added KCO (155 mg, 1.12 mmol), and the mixture was stirred at room temperature for 1.5 h. Next, a solution of propargyl bromide (50 μL, 0.64 mmol) in acetone (0.5 mL) was added, and the reaction was stirred at 50 °C overnight. The mixture was then evaporated under reduced pressure, and DCM was added. The organic layer was washed twice with 1 N aqueous HCl and brine. The organic layer was dried, filtered, and concentrated under reduced pressure. The crude product was purified by reverse column chromatography (90 / 10 water / ACN to 100% ACN) to give the title compound as a white solid (12 mg, 11%). 1 H NMR (300 MHz, DMSO-d6) δ = 12.43 (s, 1H), 11.83 (brs, 1H), 7.54 (dd, J = 8.0, 0.9 Hz, 1H), 7.22 (t, J = 8.0 Hz, 1H), 7.04 (dd, J = 8.0, 0.9 Hz, 1H), 6.16 (brs, 2H), 4.96 (d, J = 2.4 Hz, 2H), 3.58 (t, J = 2.5 Hz, 1H), 3.44 (dd, J = 10.0, 3.1 Hz, 1H), 3.37 (dd, J = 10.0, 3.2 Hz, 1H), 3.13 (brs, 1H), 3.08 (brs, 1H), 1.42 - 1.28 (m, 2H) LC-MS: Method X, RT = 4.40 min (10 min run), MS (ESI) m / z:369 (M+H) + ;367 (MH) - HRMS (ES+) C19H17N2O4S [M+H] + Calculated value: 369.0909 Measured value: 369.0929

[0266] Example 76: (1R,2S,6R,7S)-4-(4-prop-2-ynoxy-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione [ka] To a solution of (1R,2S,6R,7S)-4-(4-hydroxy-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (100 mg, 0.32 mmol) in acetone (1.5 mL) was added KCO (155 mg, 1.12 mmol), and the mixture was stirred at room temperature for 1.5 h. Next, a solution of propargyl bromide (50 μL, 0.64 mmol) in acetone (0.5 mL) was added, and the reaction was stirred at 50 °C overnight. The mixture was then evaporated under reduced pressure, and DCM was added. The organic layer was washed twice with 1 N aqueous HCl and brine. The organic layer was dried, filtered, and concentrated under reduced pressure. The crude product was purified by reverse column chromatography (90 / 10 water / ACN to 100% ACN) to give the title compound as a white solid (12 mg, 11%). 1 H NMR (300 MHz, DMSO-d6) δ = 7.49 (dd, J = 8.1, 1.0 Hz, 1H), 7.38 (t, J = 8.1 Hz, 1H), 7.12 (dd, J = 8.0, 1.0 Hz, 1H), 6.29 (brs, 2H), 5.00 (d, J = 2.3 Hz, 2H), 3.62 - 3.52 (m, 4H), 2.53 (t, J = 2.3 Hz, 1H), 1.82 (d, J = 8.9 Hz, 1H), 1.65 (d, J = 8.8 Hz, 1H) LC-MS: Method X, RT = 2.48 min (5 min run), MS (ESI) m / z:351 (M+H) + HRMS (ES+) C19H15N2O3S [M+H] + Calculated value: 351.0803 Measured value: 351.0817

[0267] Example 77: 3-[[6-(2-phenylethynyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid Step 1: 6-Iodo-1,3-benzothiazol-2-amine [ka] To a solution of 6-bromo-1,3-benzothiazol-2-amine (500 mg, 2.18 mmol) in 1,4-dioxane (5.0 mL) was added CuI (21 mg, 0.11 mmol, 5.0 mol%), sodium iodide (650 mg, 4.4 mmol), and (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (35 μL, 0.218 mmol). The reaction mixture was heated at 110 °C for 1 week. The reaction was then evaporated and purified by reverse column chromatography (90 / 10 water / MeOH to 100% MeOH) to give the title compound as a white solid (430 mg). LC-MS: Method X, RT = 2.50 min (5 min run), MS (ESI) m / z:277 (M+H) + ;275 (MH) -

[0268] Step 2: 6-(2-phenylethynyl)-1,3-benzothiazol-2-amine [ka] In a sealed tube, 6-iodo-1,3-benzothiazol-2-amine (100 mg, 0.36 mmol), PdCl(PPh) (15.3 mg, 0.022 mmol), and CuI (13.8 mg, 0.07 mmol) were introduced. The mixture was purged with argon for 15 min before adding ACN (1 mL), TEA (0.858 mL, 6.16 mmol), and ethynylbenzene (0.060 mL, 0.54 mmol). The solution was heated at 100 °C for 30 min under microwave irradiation. The organic layer was then washed twice with EtOAc and water. The aqueous phase was extracted with EtOAc, and the organic layers were combined, dried, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (100% DCM to 90 / 10 DCM / MeOH). A second purification by reverse column chromatography (90 / 10 water / ACN to 100% ACN) gave the title compound as a light brown solid (73 mg, 81%). 1H NMR (300 MHz, DMSO-d6) δ = 7.88 (d, J = 1.30 Hz, 1H), 7.71 (s, 2H), 7.53 (m, 2H), 7.39 (m, 5H). LC-MS: Method X, RT = 2.92 min (5 min run), MS (ESI) m / z:251 (M+H) + ;249 (MH) -

[0269] Step 3: 3-[[6-(2-phenylethynyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (47.9 mg, 0.29 mmol) in THF (3 mL) was added 6-(2-phenylethynyl)-1,3-benzothiazol-2-amine (73 mg, 0.29 mmol). The mixture was stirred under reflux overnight. The observed precipitate was filtered, washed with ACN, and dried. The precipitate was then solubilized with AcOEt and washed twice with 1N HCl and once with brine. The organic layer was evaporated under reduced pressure. ACN was added, and the observed precipitate was filtered, washed with ACN, and dried to give the title compound as a white solid (17.8 mg, 14%). 1 H NMR (300 MHz, DMSO-d6) δ = 12.42 (brs, 1H), 11.95 (brs, 1H), 8.18 (brs, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.58 (m, 3H), 7.44 (m, 3H), 6.17 (m, 2H), 3.48 (dd, J = 9.7, 2.4 Hz, 1H), 3.40 (dd, J = 9.6, 2.4 Hz, 1H), 3.14 (s, 1H), 3.10 (s, 1H), 1.35 (q, 2H). LC-MS: Method X, RT = 3.03 min (5 min run), MS (ESI) m / z:415 (M+H) + ;413 (MH) - HRMS (ES+) C24H19N2O3S [M+H] + Calculated value: 415.1116 Measured value: 415.1129

[0270] Example 78: 3-[[6-(3,3-dimethylbut-1-ynyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid Process 1: (HL3312) 6-(3,3-dimethylbut-1-ynyl)-1,3-benzothiazol-2-amine [ka] In a sealed tube, 6-iodo-1,3-benzothiazol-2-amine (compound from Step 1 of Example 73, 100 mg, 0.36 mmol), PdCl(PPh) (15.3 mg, 0.022 mmol), and CuI (13.8 mg, 0.07 mmol) were introduced. The mixture was purged with argon for 15 minutes before adding ACN (1 mL), TEA (0.858 mL, 6.16 mmol), and 3,3-dimethylbut-1-yne (0.070 mL, 0.54 mmol). The solution was heated under microwave irradiation at 100 °C for 30 minutes. The organic layer was then washed twice with EtOAc and water. The aqueous phase was extracted with EtOAc, and the organic layers were combined, dried, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (100% DCM to 90 / 10 DCM / MeOH) to afford the title compound as a light brown solid (36.6 mg, 44%). 1H NMR (300 MHz, DMSO-d6) δ = 7.64 (d, J = 1.74, 0.4 Hz, 1H), 7.42 (d, J = 8.47, 0.5 Hz, 1H), 7.35 (dd, J = 8.31, 1.7 Hz, 1H), 1.35 (s, 9H). LC-MS: Method X, RT = 2.97 min (5 min run), MS (ESI) m / z:229 (M+H)+ ;227 (MH) -

[0271] Step 2: 3-[[6-(3,3-dimethylbut-1-ynyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (26.1 mg, 0.16 mmol) in THF (3 mL) was added 6-(3,3-dimethylbut-1-ynyl)-1,3-benzothiazol-2-amine (37 mg, 0.16 mmol). The mixture was stirred under reflux overnight. ACN was then added, and the observed precipitate was filtered, washed with ACN, and dried to give the title compound as a white solid (22.3 mg, 36%). 1 H NMR (300 MHz, DMSO-d6) δ = 12.35 (brs, 1H), 11.87 (brs, 1H), 7.95 (d, J = 1.2 Hz, 1H), 7.62 (d, J = 8.5 Hz, 1H), 7.36 (dd, J = 8.4, 1.6 Hz, 1H), 6.16 (s, 2H), 3.47 (dd, J = 10.1, 2.7 Hz, 1H), 3.38 (dd, J = 10.1, 2.7 Hz, 1H), 3.13 (s, 1H), 3.08 (s, 1H), 1.30 (m, 11H). LC-MS: Method X, RT = 3.08 min (5 min run), MS (ESI) m / z:395 (M+H) + ;393 (MH) - HRMS (ES+) C22H23N2O3S [M+H] + Calculated value: 395.1429 Measured value: 395.1451

[0272] Example 79: 3-[[6-(2-cyclopropylethynyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid Step 1: 6-(2-cyclopropylethynyl)-1,3-benzothiazol-2-amine [ka] In a sealed tube, 6-iodo-1,3-benzothiazol-2-amine (compound from Step 1 of Example 73, 160 mg, 0.58 mmol), PdCl(PPh) (24.4 mg, 0.035 mmol), and CuI (22.1 mg, 0.12 mmol) were added. The mixture was purged with argon for 15 min before adding ACN (1 mL), TEA (1.7 mL, 12.2 mmol), and ethynylcyclopropane (0.142 mL, 1.68 mmol). The solution was heated at 100 °C for 30 min under microwave irradiation. The organic layer was then washed twice with EtOAc and water. The aqueous phase was extracted with EtOAc, and the organic layers were combined, dried, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (100% DCM to 90 / 10 DCM / MeOH). A second purification by reverse column chromatography (90 / 10 water / ACN to 100% ACN) gave the title compound as a light brown solid (33.2 mg, 26%). LC-MS: Method X, RT = 2.62 min (5 min run), MS (ESI) m / z:229 (M+H) + ;227 (MH) -

[0273] Step 2: 3-[[6-(2-cyclopropylethynyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (25.4 mg, 0.16 mmol) in THF (3 mL) was added 6-(2-cyclopropylethynyl)-1,3-benzothiazol-2-amine (33.2 mg, 0.16 mmol). The mixture was stirred under reflux overnight. ACN was then added, and the observed precipitate was filtered, washed with ACN, and dried to give the title compound as a white solid (30 mg, 51%). 1 H NMR (300 MHz, DMSO-d6) δ = 12.34 (brs, 1H), 11.86 (brs, 1H), 7.96 (s, 1H), 7.62 (d, J = 8.3 Hz, 1H), 7.37 (dd, J = 8.3, 1.2 Hz, 1H), 6.16 (s, 2H), 3.47 (dd, J = 10.2, 2.8 Hz, 1H), 3.39 (dd, J = 10.2, 3.2 Hz, 1H), 3.13 (s, 1H), 3.08 (s, 1H), 1.55 (m, 1H), 1.34 (q, J = 7.8 Hz, 2H), 0.93 (m, 2H), 0.89 (m, 2H). LC-MS: Method X, RT = 2.80 min (5 min run), MS (ESI) m / z:379 (M+H) + ;377 (MH) - HRMS (ES+) C21H19N2O3S [M+H] + Calculated value: 379.1116 Measured value: 379.1129

[0274] Example 80: 3-[(6-pyrimidin-5-yl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid Step 1: 6-(3-pyridyl)-1,3-benzothiazol-2-amine [ka] In a sealed vial, 6-bromo-1,3-benzothiazol-2-amine (300 mg, 1.31 mmol), 5-pyrimidinylboronic acid (243 mg, 1.96 mmol), bis(triphenylphosphine)palladium(II) chloride (47.9 mg, 0.066 mmol), and K2CO3 (362 mg, 2.62 mmol) were introduced. The reaction mixture was purged under argon for 15 min before a mixture of 1,4-dioxane (6.90 mL) and water (1.80 mL) was added. The mixture was irradiated at 100 °C for 60 min. The mixture was then filtered through a Celite pad, and the filtrate was evaporated under reduced pressure. The crude product was purified by column chromatography (100% cyclohexane to 70 / 30 AcOEt / MeOH) to give the title compound as a brown solid (152.8 mg, 51%). 1 H NMR (300 MHz, DMSO-d6) δ = 9.12 (m, 3H), 8.16 (d, J = 1.7 Hz, 1H), 7.66 (m, 3H), 7.45 (d, J = 8.4 Hz, 1H). LC-MS: Method X, RT = 1.66 min (5 min run), MS (ESI) m / z:229 (M+H) + ;227 (MH) -

[0275] Step 2: 3-[(6-pyrimidin-5-yl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (105 mg, 0.64 mmol) in THF (3.5 mL) was added 6-pyrimidin-5-yl-1,3-benzothiazol-2-amine (146.0 mg, 0.64 mmol). The mixture was stirred under reflux. After 4 days, the reaction mixture was evaporated and purified by column chromatography (80 / 20 cyclohexane / AcOEt to 90 / 10 AcOEt / MeOH) to give the title compound as a white solid (17.2 mg, 7%). 1 H NMR (300 MHz, DMSO-d6) δ = 12.37 (brs, 1H), 11.98 (brs, 1H), 9.21 (s, 2H), 9.17 (s, 1H), 8.44 (dd, J = 1.8, 0.6 Hz, 1H), 7.89-7.85 (dd, J = 8.5, 1.8 Hz, 1H), 7.84-7.81 (dd, J = 8.5, 0.6 Hz, 1H), 6.17 (m, 2H), 3.51-3.46 (dd, J = 10.0, 3.1 Hz, 1H), 3.41-3.37 (dd, J = 10.0, 3.2 Hz, 1H), 3.15 (s, 1H), 3.09 (s, 1H), 3.34 (m, 2H). LC-MS: Method X, RT = 9.00 min (30 min run), MS (ESI) m / z:375 (M+H) + HRMS (ES+) C20H17N4O3S [M+H] + Calculated value: 393.1021 Measured value: 393.1032

[0276] Example 81: 3-[[6-(6-quinolyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid Step 1: 6-(6-quinolyl)-1,3-benzothiazol-2-amine [ka] In a sealed vial, 6-bromo-1,3-benzothiazol-2-amine (100 mg, 0.436 mmol), 6-quinolylboronic acid (98.2 mg, 0.567 mmol), bis(triphenylphosphine)palladium(II) chloride (15.9 mg, 0.0218 mmol), and CsF (199 mg, 1.31 mmol) were introduced in a mixture of 1,4-dioxane (3.60 mL) and water (1.80 mL). The reaction mixture was purged under argon for 15 minutes and heated at 90 °C. After 6 days, the reaction was cooled to room temperature and filtered through a Celite pad. DCM and water were added, and the aqueous phase was extracted twice with DCM. The combined organic layers were washed with saturated NaHCO solution and then with brine. The organic layers were dried, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (100% cyclohexane to 100% AcOEt) to afford the title compound as a brown solid (29 mg, 24%). 1 H NMR (300 MHz, DMSO-d6) δ = 8.89 (dd, J = 4.1, 1.7 Hz, 1H), 8.41 (dd, J = 8.5, 1.6 Hz, 1H), 8.28 (d, J = 2.0 Hz, 1H), 8.18 (d, J = 2.0 Hz, 1H), 8.13 (dd, J = 8.9, 2.1 Hz, 1H), 8.07 (d, J = 8.9 Hz, 1H), 7.71 (dd, J = 8.5, 2.0 Hz, 1H), 7.60 (s, 2H), 7.56 (q, J = 4.1 Hz, 1H), 7.46 (d, J = 8.3 Hz, 1H). LC-MS: Method X, RT = 2.18 min (5 min run), MS (ESI) m / z:278 (M+H) +

[0277] Step 2: 3-[[6-(6-quinolyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (38.5 mg, 0.24 mmol) in THF (3.5 mL) was added 6-(6-quinolyl)-1,3-benzothiazol-2-amine (65.0 mg, 0.24 mmol). The mixture was stirred under reflux. After 36 h, the observed precipitate was filtered and washed with ACN and THF to give the title acid compound as a white solid (42.2 mg, 41%). 1 H NMR (300 MHz, DMSO-d6) δ = 12.37 (brs, 1H), 11.95 (brs, 1H), 8.91 (dd, J = 4.2, 1.7 Hz, 1H), 8.47-8.36 (m, 3H), 8.21-8.17 (dd, J = 8.9, 2.0Hz, 1H), 8.10 (d, J = 8.9 Hz, 1H), 7.91 (dd, J = 8.5, 1.8 Hz, 1H), 7.84 (d, J = 8.5 Hz, 1H), 7.57 (dd, J = 8.3, 4.2 Hz, 1H), 6.19 (m, 2H), 3.50 (dd, J = 10.0, 3.0 Hz, 1H), 3.40 (dd, J = 10.0, 3.1 Hz, 1H), 3.16 (s, 1H), 3.10 (s, 1H), 1.36 (m, 2H). LC-MS: Method X, RT = 2.43 min (5 min run), MS (ESI) m / z:442 (M+H) + ;440 (MH) - HRMS (ES+) C25H20N3O3S [M+H] + Calculated value: 442.1225 Measured value: 442.1246

[0278] Example 82: (1R,2S,6R,7S)-4-(6-anilino-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione Step 1: N6-phenyl-1,3-benzothiazole-2,6-diamine [ka] To a solution of N1-phenylbenzene-1,4-diamine (458 mg, 2.49 mmol) in acetic acid (5 mL) was added ammonium thiocyanate (946 mg, 12.4 mmol), and the reaction was stirred for 90 min. The mixture was cooled to 0 °C, and a solution of Br2 (140 μL, 2.73 mmol) in acetic acid (2.5 mL) was added dropwise. The reaction was stirred at 0 °C for 1 h, then allowed to reach room temperature and stirred overnight. The mixture was then poured into cold water, and saturated Na2CO3 solution was added until the pH was approximately 10. The aqueous phase was extracted with ethyl acetate (3 times). The combined organic phases were dried, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (100% cyclohexane to 20 / 80 cyclohexane / ethyl acetate) to give the desired product as a brown solid (179 mg, 30%). 1 H NMR (300 MHz, CDl3OD) δ = 7.38 (m, 2H), 6.98 (m, 2H), 6.88 (m, 2H), 6.76 (m, 2H). LC-MS: Method X, RT = 2.48 min (5 min run), MS (ESI) m / z:242 (M+1H) + ;240 (M-1H) -

[0279] Step 2: (1R,2S,6R,7S)-4-(6-anilino-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (68 mg, 0.41 mmol) in THF (2 mL) was added N6-phenyl-1,3-benzothiazole-2,6-diamine (100 mg, 0.41 mmol). The mixture was heated under reflux. After 6 h, the observed precipitate was filtered, washed with THF and ACN, and dried to give the title acid compound as a white solid ( The filtrate was purified by column chromatography (50 / 50 cyclohexane / ethyl acetate to 90 / 10 ethyl acetate / methanol) to give the desired product as a white solid (25.3 mg, 16%). 1 H NMR (300 MHz, CDCl3) δ = 7.45 (m, 2H), 7.16-7.04 (m, 6H), 6.26 (t, J = 1.8 Hz, 2H), 6.01 (brs, 1H), 3.51 (m, 2H), 3.43 (m, 2H), 1.80 (dt, J = 8.8, 1.6 Hz, 1H), 1.63 (d, J = 8.8 Hz, 1H). LC-MS: Method X, RT = 2.87 min (5 min run), MS (ESI) m / z:388 (M+1H) + ;386 (M-1H) - HRMS (ES+) calculated for C22H18N3O2S [M+H]+: 388.1120 Found: 388.1123

[0280] Example 83: (1R,2S,6R,7S)-4-[6-(2-pyridylamino)-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione Step 1: tert-Butyl N-(6-bromo-1,3-benzothiazol-2-yl)carbamate [ka] To a solution of 6-bromo-1,3-benzothiazol-2-amine (500 mg, 2.18 mmol) in DCM (20 mL) at 0 °C, DMAP (8 mg, 0.066 mmol) and BOC anhydride (714 mg, 3.27 mmol) were added. The reaction was allowed to warm to room temperature and stirred overnight. After 16 h, water was added to the reaction mixture, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with water and brine, then dried, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (100% cyclohexane to 70 / 30 cyclohexane / AcOEt) to give the title compound as a white solid (486.2 mg, 67.7% yield). 1 H NMR (300 MHz, CDCl3) δ = 7.91 (d, J= 1.9 Hz, 1H), 7.70 (d, J = 8.6 Hz, 1H), 7.54-7.49 (dd, J = 8.6, 1.9 Hz, 1H), 1.6 (s, 9H). LC-MS: Method X, RT = 3.27 min (5 min run), MS (ESI) m / z:275 (MC(CH3)3) + ;329 (MH) -

[0281] Step 2: tert-Butyl N-[6-(2-pyridylamino)-1,3-benzothiazol-2-yl]carbamate [ka] The vial was charged with 1,4-dioxane, which had been degassed for 10 min, before the addition of Pd(OAc) (40.9 mg, 0.18 mmol) and X-Phos (237 mg, 0.56 mmol). The mixture was stirred at 110 °C for 2 min, followed by the addition of pyridin-2-amine (206 mg, 2.19 mmol) and tBuOK (614 mg, 5.47 mmol). The reaction mixture was stirred at 110 °C. After 48 h, the reaction was cooled to room temperature and the solvent was evaporated. The crude product was purified by column chromatography (80 / 20 cyclohexane / ethyl acetate to 90 / 10 ethyl acetate / methanol) to give the desired product as a white solid (244.1 mg, 39%). LC-MS: Method X, RT = 2.78 min (5 min run), MS (ESI) m / z:343 (M+H) + ;341 (MH) -

[0282] Step 3: N6-(2-pyridyl)-1,3-benzothiazole-2,6-diamine [ka] To a solution of DCM / TFA (5 mL / 0.5 mL), tert-butyl N-[6-(2-pyridylamino)-1,3-benzothiazol-2-yl]carbamate (220 mg, 0.64 mmol) was added, and the mixture was stirred at room temperature. The solution was then neutralized with saturated NaHCO3 solution. The aqueous phase was extracted with DCM (3 times). The combined organic phases were dried, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (100% cyclohexane to 100% ethyl acetate). The desired product was obtained as a white solid (90 mg, 58%). 1H NMR (300 MHz, CDCl3) δ = 8.88 (s, 1H), 8.14 (d, J = 1.8 Hz, 1H), 8.10 (m, 1H), 7.50 (m, 1H), 7.29-7.21 (m, 4H), 6.76 (d, J = 8.4 Hz, 1H), 6.67 (ddd, J = 6.0, 5.0, 0.8 Hz, 1H).

[0283] Step 4: 4-[6-(2-pyridylamino)-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (61.1 mg, 0.37 mmol) in THF (2 mL), N6-(2-pyridyl)-1,3-benzothiazole-2,6-diamine (90.2 mg, 0.37 mmol) was added, and the mixture was heated under reflux overnight. The solvent was then evaporated under reduced pressure. The crude product was purified by column chromatography (50 / 50 cyclohexane / ethyl acetate to 90 / 10 ethyl acetate / methanol) to give the title compound as a white solid (8.4 mg, 6%). 1H NMR (300 MHz, DMSO-d6) δ = 12.12 (brs, 1H), 11.85 (brs, 1H), 9.12 (s, 1H), 8.42 (d, J = 2.0 Hz, 1H), 8.17 (m, 1H), 7.60-7.46 (m, 3H), 6.83 (d, J = 8.4 Hz, 1H), 6.73 (m, 1H), 6.15 (m, 2H), 3.45 (dd, J = 10.0, 3.3 Hz, 1H), 3.33 (m, 1H), 3.12 (s, 1H), 3.07 (s, 1H), 1.33 (m, 2H). LC-MS: Method X, RT = 2.20 min (5 min run), MS (ESI) m / z:407 (M+H) + ;405 (MH) - HRMS (ES+) calculated for C21H19N4O3S [M+H]+: 407.1178 Found: 407.1171

[0284] Example 84 3-[[6-[(4-methyl-2-pyridyl)amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid Step 2: N6-(4-methyl-2-pyridyl)-1,3-benzothiazole-2,6-diamine [ka] The vial was charged with 1,4-dioxane, which had been degassed for 10 min, before the addition of Pd(OAc) (40.9 mg, 0.18 mmol) and X-Phos (237 mg, 0.56 mmol). The mixture was stirred at 110 °C for 2 min, followed by the addition of 4-methylpyridin-2-amine (237 mg, 2.19 mmol) and tBuOK (614 mg, 5.47 mmol). The reaction mixture was stirred at 110 °C. After 48 h, the reaction was cooled to room temperature and the solvent was evaporated. The crude product was purified by column chromatography (50 / 50 cyclohexane / ethyl acetate to 90 / 10 ethyl acetate / methanol) to give the desired product as a white solid (136.9 mg, 21%). LC-MS: Method X, RT = 2.73 min (5 min run), MS (ESI) m / z:357(M+H) + ;355(MH) -

[0285] Step 3: N6-(4-methyl-2-pyridyl)-1,3-benzothiazole-2,6-diamine [ka] To a solution of DCM / TFA (5 mL / 0.5 mL) was added tert-butyl N-[6-[(4-methyl-2-pyridyl)amino]-1,3-benzothiazol-2-yl]carbamate (120 mg, 0.34 mmol), and the mixture was stirred at room temperature. The solution was then neutralized with saturated NaHCO3 solution. The aqueous phase was extracted with DCM (3 times). The combined organic phases were dried, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (100% cyclohexane to 100% ethyl acetate). The desired product was obtained as a white solid (43.8 mg, 51%). 1H NMR (300 MHz, CDCl3) δ = 8.78 (s, 1H), 8.13 (d, J = 1.8 Hz, 1H), 7.98 (d, J = 5.2 Hz, 1H), 7.27 (dd, J = 8.6, 2.0 Hz, 1H), 7.24 (s, 1H), 7.21 (s, 2H), 6.58 (s, 1H), 6.54 (d, J = 5.2 Hz, 1H), 2.21 (s, 3H).

[0286] Step 4: 3-[[6-[(4-methyl-2-pyridyl)amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (26.1 mg, 0.16 mmol) in THF (3 mL) was added N6-(4-methyl-2-pyridyl)-1,3-benzothiazole-2,6-diamine (40.8 mg, 0.16 mmol), and the mixture was heated under reflux overnight. The observed precipitate was then filtered, washed with a mixture of ACN / THF, and dried to give the title acid compound as a white solid (Example 84, 20.3 mg, 30%). 1 H NMR (300 MHz, DMSO-d6) δ = 12.10 (brs, 1H), 11.84 (brs, 1H), 9.01 (s, 1H), 8.41 (d, J = 2.0 Hz, 1H), 8.03 (d, J = 5.2 Hz, 1H), 7.58 (d, J = 8.7 Hz, 1H), 7.47 (dd, J = 8.8, 2.2 Hz, 1H), 6.64 (s, 1H), 6.59 (d, J = 5.2 Hz, 1H), 6.15 (m, 2H), 3.46 (dd, J = 10.2, 3.2 Hz, 1H), 3.35 (m, 1H), 3.12 (s, 1H), 3.06 (s, 1H), 2.29 (s, 3H), 1.36 (d, J = 8.4 Hz, 1H), 1.29 (d, J = 8.4 Hz, 1H). LC-MS: Method X, RT = 8.33 min (30 min run), MS (ESI) m / z:421 (M+H) + ;419 (MH) - HRMS (ES+) calculated for C22H21N4O3S [M+H]+: 421.1334 found: 421.1342

[0287] Example 85: 3-[[6-[(4-fluoro-2-pyridyl)amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid Process 1 6-[(4-fluoro-2-pyridyl)amino]-1,3-benzothiazole-2,6-diamine [ka] tert-Butyl-N-[6-bromo-1,3-benzothiazole-2-amino]carbamate (300.0 mg, 0.911 mmol), 4-fluoropyridin-2-amine (123.0 mg, 1.09 mmol), Pd2dba3 (26.2 mg, 0.0911 mmol), tBuONa (131.0 mg, 1.37 mmol), and tBuBrettPhos (44.2 mg, 0.0911 mmol) were slurried in argon-flushed, pre-degassed dioxane (2 mL, dry) and then heated to 110 °C. After 1 h, the reaction mixture was cooled to room temperature, treated with 5% aqueous NaHCO3, then extracted with EA, and the organic phase was washed several times with water and brine and then dried over MgSO4. The product was purified by flash chromatography (10 / 0 to 3 / 7 DCM / EA) to yield an off-white solid (159 mg, 67%). 1 H NMR (300MHz, CD3CN) δ = 8.14 (dd, 1H, J= 5.8 Hz, 9.4 Hz), 7.98 (d, 1H, J= 2.2 Hz), 7.51 (s, 1H), 7.39 (d, 1H, J= 8.6 Hz), 7.27 (dd, 1H, J= 2.2 Hz, 8.6 Hz), 6.55 (dt, 1H, J= 2.2 Hz, 8.0 Hz), 6.47 (dd, 1H, J= 2.1 Hz, 11.8 Hz), 5.86 (s, 2H). 19 F NMR (300MHz, CD3CN) δ = -105.93. LC-MS:1.63 min (5 min) MS (ESI) m / z:(M+H)+ 261.13;(MH)- 259.13

[0288] Process 2 3-[[6-[(4-fluoro-2-pyridyl)amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (95 mg, 0.365 mmol) in dry THF (0.6 mL) was added N6-(4-pyridyl)-1,3-benzothiazole-2,6-diamine (59.9 mg, 0.365 mmol). The mixture was stirred under reflux for 4 hours and then cooled to room temperature, after which a white precipitate was observed. The precipitate was filtered, washed thoroughly with THF and ACN, and then dried to give the title compound as a white solid (42 mg, 28% yield). 1 H NMR (300MHz, DMSO-d6) δ =12.13 (s, 1H), 11.86 (s, 1H), 9.33 (s, 1H), 8.37 (d, 1H, J= 2.0 Hz), 8.21 (dd, 1H, J= 5.8 Hz, 9.7 Hz), 7.62 (d, 1H, J= 8.7 Hz), 7.47 (dd, 1H, J= 2.1 Hz, 8.7 Hz), 6.67 (dt, 1H, J= 2.2 Hz, 8.5 Hz), 6.59 (dd, 1H, J= 2.1 Hz, 11.9 Hz), 6.17 (m, 2H), 3.48 (dd, 1H, J= 3.1 Hz, 10.0 Hz), 3.36 (m, 1H), 3.11 (d, 2H, J= 15.2 Hz), 1.35 (m, 2H). 19 F NMR (300MHz, DMSO-d6) δ = -104.56. LC-MS: Method X, RT = 9.01 min (30 min run), MS (ESI) m / z:(M+H)+ 425.29;(MH)- 423.24 HRMS (ES+) C 21 H 18 Calculated for N4O3SF [M+H]+: 425.1084, found 425.1073.

[0289] Examples 86 and 87: 3-[[6-[(5-fluoro-2-pyridyl)amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid and 4-[6-[(5-fluoro-2-pyridyl)amino]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione Process 1 tert-Butyl N-[6-[[5-fluoro-2-pyridyl]amino]-1,3-benzothiazol-2-yl]carbamate [ka] tert-Butyl-N-[6-bromo-1,3-benzothiazole-2-amino]carbamate (200.0 mg, 0.612 mmol), 5-fluoropyridin-2-amine (68.0 mg, 0.612 mmol), Pd2dba3 (27.9 mg, 0.0306 mmol), tBuONa (88.2 mg, 0.918 mmol), and tBuBrettPhos (29.7 mg, 0.0612 mmol) were slurried in argon-flushed, pre-degassed dioxane (2 mL, dry) and then heated to 110 °C. After 1 h, the reaction mixture was cooled to room temperature, treated with 5% aqueous NaHCO3, then extracted with EA, and the organic phase was washed several times with water and brine and then dried over MgSO4. The product was purified by flash chromatography (10 / 0 to 3 / 7 DCM / EA) to yield the title compound as an off-white solid (108 mg, 68%). 1 H NMR (300MHz, MeOD) δ = 8.27 (d, 1H, J= 2.1 Hz), 8.03 (d, 1H, J= 3.0 Hz), 7.57 (d, 1H, J= 8.7 Hz), 7.45-7.35 (m, 2H), 6.84 (dd, 1H, J= 3.5 Hz, 9.1 Hz). 19 F NMR (300MHz, MeOD) δ = -144.03. LC-MS: 2.16 min (5 min run) MS (ESI) m / z:(M+H)+ 361.19; (MH)- 359.14

[0290] Process 2 N6-(5-fluoro-2-pyridyl)-1,3-benzothiazole-2,6-diamine [ka] tert-Butyl-N-[6-[(5-fluoro-2-pyridyl)amino]-1,3-benzothiazol-2-yl]carbamate (108 mg, 0.415 mmol) was slurried in DCM (0.7 mL), to which TFA (0.3 mL) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 3 hours, after which saturated aqueous Na2CO3 solution was added, and the product was extracted with EA. The collected organic layer was washed several times with water and brine, and then dried over MgSO4. The product was obtained as a yellow oil (93 mg, 86% yield). LC-MS: 1.07 min (5 min run), MS (ESI) m / z:(M+H)+ 261.15.

[0291] Process 3 Example 86: 3-[[6-[(5-fluoro-2-pyridyl)amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka]

[0292] Example 87: 4-[6-[(5-fluoro-2-pyridyl)amino]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (70.6 mg, 0.430 mmol) in dry THF (1.0 mL) was added N6-(5-fluoro-2-pyridyl)-1,3-benzothiazole-2,6-diamine (112 mg, 0.430 mmol). The mixture was stirred under reflux for 4 hours and then cooled to room temperature, after which a white precipitate was observed. The precipitate was filtered, washed thoroughly with THF and ACN, and then dried to give the title compound as a white solid (Example 86, 113 mg, 61% yield). The filtrate was then purified by flash chromatography (10 / 0 to 5 / 5 Cy / EA) to produce the compound as an off-white solid (Example 87, 7 mg, 4% yield).

[0293] Example 86 1 H NMR (300MHz, DMSO-d6) δ = 12.10 (s, 1H), 11.98 (s, 1H), 9.21 (s, 1H), 8.38 (d, 1H, J= 2.1 Hz), 8.15 (d, 1H, J= 3.03 Hz), 9.61-9.51 (m, 2H), 7.45 (dd, 1H, J= 2.1 Hz, 8.8 Hz), 6.88 (dd, 1H, J= 3.6 Hz, 9.2 Hz), 6.18-6.14 (m, 2H), 3.46-3.40 (m, 2H), 3.10 (d, 2H, J= 15.8 Hz), 1.34 (q, 2H, J= 8.3 Hz). 19 F NMR (300MHz, DMSO-d6) δ = -141.8. LC-MS: Method X, RT = 9.19 min (30 min run), MS (ESI) m / z:(M+H)+ 423.24;(MH)- 425.19 HRMS (ES+) C 21 H 18 Calculated value for N4O3SF [M+H]+: 425.1084, Found value: 425.1084

[0294] Example 87 1 H NMR (300MHz, CDCl3) δ = 8.08 (dd, 2H, J= 2.8 Hz, 8.9 Hz), 8.02 (d, 1H, J= 8.8 Hz), 7.41-7.30 (m, 2H), 7.05 (s, 1H), 6.87 (dd, 1H, J= 3.1 Hz, 9.1 Hz), 6.31-6.29 (m, 2H), 3.62-3.54 (m, 4H), 1.83 (d, 1H, J= 8.9 Hz), 1.67 (d, 1H, J= 9.0 Hz). 19 F NMR (300MHz, CDCl3) δ = -139.40. LC-MS: Method X, RT = 11.07 min (30 min run), MS (ESI) m / z:(M+H)+ 407.35 HRMS (ES+) C 21 H 16 Calculated for N4O2FS [M+H]+: 407.0978, found 407.0953.

[0295] Examples 88 and 89: 3-[[6-[(6-fluoro-2-pyridyl)amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid and 4-[6-[(6-fluoro-2-pyridyl)amino]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione Process 1 tert-Butyl N-[6-[[6-fluoro-2-pyridyl]amino]-1,3-benzothiazol-2-yl]carbamate [ka] tert-Butyl-N-[6-bromo-1,3-benzothiazole-2-amino]carbamate (200.0 mg, 0.608 mmol), 6-fluoropyridin-2-amine (68.1 mg, 0.608 mmol), Pd2dba3 (17.5 mg, 0.0304 mmol), tBuONa (87.6 mg, 0.911 mmol), and tBuBrettPhos (29.4 mg, 0.0608 mmol) were slurried in argon-flushed, pre-degassed dioxane (2 mL, dry) and then heated to 110 °C. After 1 h, the reaction mixture was cooled to room temperature, treated with 5% aqueous NaHCO3, then extracted with EA, and the organic phase was washed several times with water and brine and then dried over MgSO4. The crude product was triturated with a minimal amount of DCM to give a pale yellow precipitate which was filtered (119 mg, 54%). 1 H NMR (300MHz, MeOD) δ = 7.99 (d, 1H, J= 1.7 Hz), 7.65-7.56 (m, 1H), 7.34-7.25 (m, 2H), 6.60 (dd, 1H, J= 2.0 Hz, 7.9 Hz), 6.26 (dd, 1H, J= 2.3 Hz, 7.6 Hz). 19 F NMR (300MHz, MeOD) δ = -72.52. LC-MS:2.23 min (5 min run), MS (ESI) m / z:(M+H)+ 361.19; (MH)- 359.09.

[0296] Process 2 N6-(6-fluoro-2-pyridyl)-1,3-benzothiazole-2,6-diamine [ka] tert-Butyl-N-[6-[(6-fluoro-2-pyridyl)amino]-1,3-benzothiazol-2-yl]carbamate (119 mg, 0.330 mmol) was slurried in DCM (0.7 mL), to which TFA (0.3 mL) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 3 hours, after which saturated aqueous Na2CO3 was added, and the product was extracted with EA. The collected organic layer was washed several times with water and brine, and then dried over MgSO4. The product was obtained as a colorless oil (81 mg, 94% yield). LC-MS:1.73 min (5 min run), MS (ESI) m / z:(M+H)+ 261.18; (MH)- 259.13.

[0297] Process 3 Example 88: 3-[[6-[(6-fluoro-2-pyridyl)amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka] Example 89: 4-[6-[(6-fluoro-2-pyridyl)amino]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione [ka] N6-[6-Fluoro-2-pyridyl]-1,3-benzothiazole-2,6-diamine (81 mg, 0.311 mmol) and (1S,2R,6S,7R)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (56.1 mg, 0.311 mmol) were flushed with argon and then slurried in dry THF (1 mL), after which the mixture was heated to 70 °C. After 4 h, the reaction was cooled to room temperature and a precipitate was observed. An initial filtration was performed and the precipitate was washed with THF and acetonitrile. The title compound was obtained as a white solid (Example 88, 11 mg, 8% yield). The filtrate was dried, and the title compound was isolated as a white solid (Example 89, 25 mg, 19% yield) by flash chromatography (9 / 1 to 5 / 5 Cy / EA).

[0298] Example 88 1 H NMR (300MHz, DMSO-d6) δ = 12.27 (s, 1H), 11.73 (s, 1H), 9.44 (s, 1H), 8.22 (d, 1H, J= 2.1 Hz), 7.71 (q, 1H, J= 8.8 Hz), 7.63 (d, 1H, J= 8.7 Hz), 7.48 (dd, 1H, J= 2.2 Hz, 8.8 Hz), 6.72 (dd, 1H, J= 2.1 Hz, 8.0 Hz), 6.40 (dd, 1H, J= 2.4 Hz, 7.7 Hz), 6.19-6.14 (m, 2H), 3.46 (dd, 2H, J= 3.1 Hz, 10.0 Hz), 3.11 (d, 2H, J= 16.3 Hz), 1.34 (q, 2H, J= 9.4 Hz). 19 F NMR (300MHz, DMSO-d6) δ = -69.91. LC-MS: Method X, RT = 9.60 min (30 min run), MS (ESI) m / z:(M+H)+ 425.14;(MH)- 423.04 HRMS (ES+) C 21 H 18Calculated value for N4O3SF [M+H]+: 425.1084, Found: 425.1086

[0299] Example 89 1 H NMR (300MHz, CDCl3) δ = 8.09 (d, 1H, J= 2.0 Hz), 8.03 (d, 1H, J= 8.8 Hz), 7.61 (dd, 1H, J= 8.1 Hz, 16.1 Hz), 7.35 (dd, 1H, J= 1.9 Hz, 8.7 Hz), 6.80 (s, 1H), 6.68 (dd, 1H, J= 1.8 Hz, 8.0 Hz), 6.39 (dd, 1H, J= 2.2 Hz, 7.8 Hz), 6.30 (t, 2H, J= 1.6 Hz), 3.61-3.55 (m, 4H), 1.84 (d, 1H, J= 8.7 Hz), 1.67 (d, 1H, J= 8.8 Hz). LC-MS: Method X, RT = 9.64 min (30 min run), MS (ESI) m / z:407.15 (M+H)+ HRMS (ES+) C 21 H 16 N4O2SF [M+H] + Calculated value: 407.0978, Measured value: 407.0908.

[0300] Example 90: 4-[6-[[2-(trifluoromethyl)-4-pyridyl]amino]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione Process 1 tert-Butyl N-[6-[[2-(trifluoromethyl)-4-pyridyl]amino]-1,3-benzothiazol-2-yl]carbamate [ka] tert-Butyl-N-[6-bromo-1,3-benzothiazole-2-amino]carbamate (200.0 mg, 0.873 mmol), 5-(trifluoromethyl)pyridin-4-amine (142.0 mg, 0.873 mmol), Pd2dba3 (25.1 mg, 0.043 mmol), tBuONa (126.0 mg, 1.31 mmol), and tBuBrettPhos (42.3 mg, 0.0873 mmol) were slurried in argon-flushed, pre-degassed dioxane (2 mL, dry) and then heated to 110 °C. After 1 h, the reaction mixture was cooled to room temperature, treated with 5% aqueous NaHCO3, then extracted with EA, and the organic phase was washed several times with water and brine and then dried over MgSO4. The crude product was triturated with a minimal amount of DCM to give a pale yellow precipitate which was filtered (220 mg, 61%). 1 H NMR (300MHz, MeOD) δ = 8.23 ​​(d, 1H, J= 5.8 Hz), 7.75 (d, 1H, J= 2.1 Hz), 7.71 (d, 1H, J= 8.7 Hz), 7.31 (dd, 1H, J= 2.2 Hz, 8.6 Hz), 7.19 (d, 1H, J= 2.3 Hz), 7.05 (dd, 1H, J= 2.3 Hz, 5.9 Hz). 19 F NMR (300MHz, MeOD) δ = -70.47. LC-MS:2.15 min (5 min run), MS (ESI) m / z:411.20 (M+H)+; 409.20 (MH)-

[0301] Process 2 N6-[2-(trifluoromethyl)-4-pyridyl]-1,3-benzothiazole-2,6-diamine [ka] tert-Butyl N-[6-[(2-trifluoromethyl-4-pyridyl)amino]-1,3-benzothiazol-2-yl]carbamate (160 mg, 0.390 mmol) was slurried in DCM (0.7 mL), to which TFA (0.3 mL) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 3 hours, after which saturated aqueous Na2CO3 was added, and the product was extracted with EA. The collected organic layer was washed several times with water and brine, and then dried over MgSO4. The product was obtained as a yellow oil (112 mg, 92% yield). LC-MS:1.66 min (5 min run), MS (ESI) m / z:311.08 (M+H)+; 309.03 (MH)-

[0302] Process 3 Example 90: 4-[6-[[2-(trifluoromethyl)-4-pyridyl]amino]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione [ka] N6-[2-trifluoromethyl-4-pyridyl]-1,3-benzothiazole-2,6-diamine (112 mg, 0.361 mmol) and (1S,2R,6S,7R)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (59.3 mg, 0.361 mmol) were flushed with argon and then slurried in dry THF (1 mL), after which the mixture was heated to 70 °C. After 4 h, the reaction was cooled to room temperature and a precipitate was observed. An initial filtration was performed and the precipitate was washed with THF and acetonitrile. The title compound was obtained as a white solid (11 mg, 8% yield). The filtrate was dried, and the title compound was isolated as a white solid (25 mg, 19% yield) by flash chromatography (9 / 1 to 5 / 5 Cy / EA). 1H NMR (300MHz, CDCl3) δ = 8.39 (d, 1H, J= 5.7 Hz), 8.09 (d, 1H, J= 8.7 Hz), 7.72 (d, 1H, J= 1.9 Hz), 7.33 (dd, 1H, J= 2.1 Hz, 8.7 Hz), 7.19 (d, 1H, J= 2.1 Hz), 6.98 (dd, 1H, J= 2.1 Hz, 5.7 Hz), 6.79 (s, 1H), 6.31-6.29 (m, 2H), 3.63-3.57 (m, 4H), 1.86 (d, 1H, J= 9.0 Hz), 1.68 (d, 1H, J= 8.9 Hz). 19 F NMR (300MHz, CDCl3) δ = -68.74. LC-MS: Method X, RT = 10.89 min (30 min run), MS (ESI) m / z:457.14 (M+H)+ HRMS (ES+) C 22 H 16 Calculated value for N4O2F3S [M+H]+: 457.0946, Found value: 457.0945

[0303] Example 91: 3-[[6-[[5-(trifluoromethyl)-3-pyridyl]amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid Process 1 tert-Butyl N-[6-[[5-(trifluoromethyl)-3-pyridyl]amino]-1,3-benzothiazol-2-yl]carbamate [ka] tert-Butyl-N-[6-bromo-1,3-benzothiazole-2-amino]carbamate (300.0 mg, 0.911 mmol), 5-(trifluoromethyl)pyridin-3-amine (177.0 mg, 1.09 mmol), Pd2dba3 (26.2 mg, 0.0456 mmol), tBuONa (131.0 mg, 1.37 mmol), and tBuBrettPhos (44.2 mg, 0.0911 mmol) were flushed with argon and slurried in pre-degassed dioxane (2 mL, dry) and then heated to 110 °C. After 1 h, the reaction mixture was cooled to room temperature, treated with 5% aqueous NaHCO3, then extracted with EA, and the organic phase was washed several times with water and brine and then dried over MgSO4. The crude product was triturated with a minimal amount of DCM to give a pale yellow precipitate which was filtered (251 mg, 67%). 1 H NMR (300MHz, MeOD) δ = 8.47 (s, 1H), 8.22 (s, 1H), 7.69 (m, 1H), 7.67 (d, 1H, J=4.9 Hz), 7.58 (m, 1H), 7.27 (dd, 1H, J=2.2 Hz, 8.7 Hz), 4.63 (s, 1H), 1.59 (s, 9H). 19 F NMR (300MHz, MeOD) δ = -64.85. LC-MS:2.21 min (5 min), MS (ESI) m / z:411.54 (M+H)+; 409.20 (MH)-

[0304] Process 2 Example 91: 3-[[6-[[5-(trifluoromethyl)-3-pyridyl]amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka] tert-Butyl-N-[6-[(5-trifluoromethyl-3-pyridyl)amino]-1,3-benzothiazol-2-yl]carbamate (200 mg, 0.365 mmol) was slurried in DCM (0.7 mL), to which TFA (0.3 mL) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 3 hours, after which saturated aqueous Na2CO3 was added, and the product was extracted with EA. The collected organic layer was washed several times with water and brine, and then dried over MgSO4. The product was obtained as a yellow oil (117 mg, 76% yield). Without further purification, N-6-[[5-(trifluoromethyl)-3-pyridyl]amino]-1,3-benzothiazol-2,6-amine (117 mg, 0.361 mmol) and (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (59.3 mg, 0.361 mmol) were dissolved in dry THF (1 mL) and heated at 70 °C. After 5 h, the reaction mixture was cooled, and the resulting precipitate was filtered and washed several times with THF and ACN. The title product was obtained as a white solid (39 mg, 22% yield). 1 H NMR (300MHz, DMSO-d6) δ = 12.20 (s, 1H), 11.94 (s, 1H), 8.82 (s, 1H), 8.58 (d, 1H, J= 2.2 Hz), 8.31 (s, 1H), 7.78 (d, 1H, J= 2.1 Hz), 7.68 (d, 1H, J= 8.6 Hz), 7.55 (t, 1H, J= 2.2 Hz), 7.24 (dd, 1H, J= 2.2 Hz, 8.7 Hz), 6.17 (t, 2H, J= 1.5 Hz), 3.51-3.36 (m, 2H), 3.11 (d, 2H, J= 14.7 Hz), 1.35 (q, 2H, J = 8.1 Hz). 19 F NMR (300MHz, DMSO-d6) δ = -61.70. LC-MS: Method X, RT = 9.94 min (30 min run), MS (ESI) m / z:(M+H)+ 473.30;(MH)- 475.15 HRMS (ES+) C22 H 18 Calculated value for N4O3SF3[M+H]+: 475.1062, Found value: 475.1052

[0305] Example 92: 4-[6-[(2-methoxy-4-pyridyl)amino]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione Process 1 tert-Butyl N-[6-[[2-methoxy-4-pyridyl]amino]-1,3-benzothiazol-2-yl]carbamate [ka] tert-Butyl-N-[6-bromo-1,3-benzothiazole-2-amino]carbamate (300.0 mg, 0.911 mmol), 2-methoxypyridin-4-amine (113.0 mg, 0.911 mmol), Pd2dba3 (26.2 mg, 0.045 mmol), tBuONa (131.0 mg, 1.37 mmol), and tBuBrettPhos (44.2 mg, 0.0911 mmol) were flushed with argon and slurried in pre-degassed dioxane (2 mL, dry) and then heated to 110 °C. After 1 h, the reaction mixture was cooled to room temperature, treated with 5% aqueous NaHCO3, then extracted with EA, and the organic phase was washed several times with water and brine and then dried over MgSO4. The crude product was triturated with a minimum amount of DCM to give the title compound as a pale yellow precipitate which was filtered (247 mg, 72%). 1 H NMR (MeOD, 300MHz) δ = 7.77 (d, 1H, J= 6.0 Hz), 7.68-7.61 (m, 2H), 7.26 (dd, 1H, J= 2.1 Hz, 8.6 Hz), 6.57 (dd, 1H, J= 1.9 Hz, 5.9 Hz), 6.28 (d, 1H, J= 1.8 Hz), 3.84 (s, 3H), 1.59 (s, 9H). LC-MS:2.75 min (5 min run), MS (ESI) m / z:373.21 (M+H)+; 371.25 (MH)-

[0306] Process 2 N6-(2-Methoxy-4-pyridyl)-1,3-benzothiazole-2,6-diamine [ka] tert-Butyl N-[6-[(2-methoxy-4-pyridyl)amino]-1,3-benzothiazol-2-yl]carbamate (200 mg, 0.516 mmol) was slurried in DCM (0.7 mL), to which TFA (0.3 mL) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 3 hours, after which saturated aqueous Na2CO3 was added, and the product was extracted with EA. The collected organic layer was washed several times with water and brine, and then dried over MgSO4. The title product was obtained as a yellow oil (145 mg, 99% yield). LC-MS:1.94 min (5 min run), MS (ESI) m / z:272.87 (M+H)+; 271.13 (MH)-

[0307] Process 3 4-[6-[(2-methoxy-4-pyridyl)amino]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione [ka] To a solution of (1R,2S,6R,7S)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (33 mg, 0.202 mmol) in dry THF (1 mL) was added N6-(2-methoxy-4-pyridyl)-1,3-benzothiazole-2,6-diamine (55 mg, 0.202 mmol). The mixture was stirred under reflux overnight and then cooled to room temperature. DCM was then added, and the resulting precipitate was filtered off. The filtrate was then purified by flash chromatography (100 / 0 to 2 / 8 Cy / EA) to produce the title compound as an off-white solid (7 mg, 8% yield). 1H NMR (300MHz, CDCl3) δ = 8.03 (d, 1H, J= 8.7 Hz), 7.91 (d, 1H, J= 4.8 Hz), 7.71 (s, 1H), 7.33 (s, 1H), 7.03 (s, 1H), 6.58 (s, 1H), 6.34 (s, 1H), 6.31-6.26 (m, 2H), 3.92 (s, 3H), 3.58 (d, 2H, J= 6.4 Hz), 3.35 (s, 1H), 3.22 (s, 1H), 1.83 (d, 1H, J= 9.0 Hz), 1.67 (d, 1H, J= 9.0 Hz). LC-MS: Method X, RT = 11.31 min (30 min run), MS (ESI) m / z:419.24 (M+H)+ HRMS (ES+) C 22 H 19 Calculated value for N4O3S [M+H]+: 419.1178, found 419.1169.

[0308] Examples 93 and 94: 3-[[6-[[5-(trifluoromethoxy)-2-pyridyl]amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid and 4-[6-[[5-(trifluoromethoxy)-2-pyridyl]amino]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione Process 1 tert-Butyl N-[6-[[5-(trifluoromethoxy)-2-pyridyl]amino]-1,3-benzothiazol-2-yl]carbamate [ka] tert-Butyl-N-[6-bromo-1,3-benzothiazole-2-amino]carbamate (300.0 mg, 0.911 mmol), 5-trifluoromethoxypyridin-2-amine (102.0 mg, 0.911 mmol), Pd2dba3 (26.2 mg, 0.045 mmol), tBuONa (131.0 mg, 1.37 mmol), and tBuBrettPhos (44.2 mg, 0.0911 mmol) were slurried in argon-flushed, pre-degassed dioxane (2 mL, dry) and then heated to 110 °C. After 1 h, the reaction mixture was cooled to room temperature, treated with 5% aqueous NaHCO3, then extracted with EA, and the organic phase was washed several times with water and brine and then dried over MgSO4. The crude product was triturated with a minimal amount of DCM to give a pale yellow precipitate which was filtered to yield the title compound as a pale yellow solid (230 mg, 59%). 1 H NMR (300MHz, DMSO-d6) δ = 8.15 (d, 1H, J= 2.0 Hz), 7.88 (d, 1H, J= 1.9 Hz), 7.74 (d, 1H, J= 8.6 Hz), 7.57 (s, 1H), 7.46 (d, 1H, J=10.6 Hz), 7.32-7.29 (m, 1H), 6.86 (d, 1H, J= 9.1 Hz), 1.61 (s, 9H). 19 F NMR (300MHz, DMSO-d6) δ = -59.47. LC-MS:2.41 min (5 min run), MS (ESI) m / z:(M+H)+ 427.23; (MH)- 425.19

[0309] Process 2 N6-[5-(trifluoromethoxy)-2-pyridyl]-1,3-benzothiazole-2,6-diamine [ka] tert-Butyl N-[6-[(5-trifluoromethoxy-2-pyridyl)amino]-1,3-benzothiazol-2-yl]carbamate (220 mg, 0.516 mmol) was slurried in DCM (0.7 mL), to which TFA (0.3 mL) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 3 hours, after which saturated aqueous Na2CO3 was added, and the product was extracted with EA. The collected organic layer was washed several times with water and brine, then dried over MgSO4. The title compound was obtained as a white solid (164 mg, 97% yield). LC-MS:1.94 min (5 min run), MS(ESI)m / z:(M+H)+ 327.07; (MH)- 325.07

[0310] Process 3 Example 93: 3-[[6-[[5-(trifluoromethoxy)-2-pyridyl]amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka]

[0311] Example 94: 4-[6-[[5-(trifluoromethoxy)-2-pyridyl]amino]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione [ka] N6-[5-(trifluoromethoxy)-2-pyridyl]-1,3-benzothiazole-2,6-diamine (164 mg, 0.503 mmol) and (1S,2R,6S,7R)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (82.5 mg, 0.503 mmol) were flushed with argon and then slurried with dry THF (1 mL). The mixture was then heated to 70 °C, and the reaction was monitored by LC-MS. After 2.5 h, the reaction was cooled to room temperature and excess THF was added. An initial filtration was performed, and the precipitate was washed with THF and acetonitrile. The filtrate was concentrated, and a second precipitate was observed and filtered. The title compound was obtained as a white solid (Example 93, 157 mg, 63% yield). The filtrate was dried and the title compound was isolated by flash chromatography purification (9 / 1 to 5 / 5 Cy / EA) as a white solid (Example 94, 8 mg, 3% yield).

[0312] Example 93 1 H NMR (300MHz, DMSO-d6) δ = 12.12 (s, 1H), 11.88 (s, 1H), 9.44 (1H), 8.40-8.24 (m, 2H), 7.64-7.50 (m, 2H), 6.93 (d, 1H), 6.17 (s, 2H), 3.46-3.09 (m, 4H), 1.35 (m, 2H). 19 F NMR (300MHz, DMSO-d6) δ = -58.31. LC-MS: Method X, RT = 11.45 min (30 min run), MS (ESI) m / z:(M+H)+ 491.09; (MH)- 488.99 HRMS: (ES+) C 22 H 18 Calculated for F3N4O4S [M+H]+: 491.1001 Found: 491.0996.

[0313] Example 94 1H NMR (300MHz, DMSO-d6) δ = 9.66 (s, 1H), 8.62 (d, 1H, J= 2.1 Hz), 8.27 (d, 1H, J= 2.8 Hz), 7.91 (d, 1H, J= 8.9 Hz), 7.71 (dd, 1H, J= 2.0 Hz, 9.1 Hz), 7.62 (dd, 1H, J= 2.2 Hz, 8.9 Hz), 6.99 (d, 1H, J= 9.1 Hz), 6.23 (t, 2H, J= 1.8 Hz), 3.63 (dd, 2H, J= 1.5 Hz, 2.8 Hz), 3.39 (m, 1H), 1.64 (m, 2H). 19 F NMR (300MHz, DMSO-d6) δ = -58.26. LC-MS: Method X, RT = 13.28 min (30 min run), MS (ESI) m / z:473.20 (M+H)+; 471.20 (MH)- HRMS: (ES+) C 22 H 16 Calculated value for F3N4O3S [M+H]+: 473.0895 Found: 473.0900.

[0314] Examples 95 and 96: 4-[6-[[5-(trifluoromethyl)-2-pyridyl]amino]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione and 3-[[6-[[5-(trifluoromethyl)-2-pyridyl]amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid Process 1 tert-Butyl-N-[6-[[5-(trifluoromethyl)-2-pyridyl]amino]-1,3-benzothiazol-2-yl]carbamate [ka] tert-Butyl-N-[6-bromo-1,3-benzothiazole-2-amino]carbamate (200.0 mg, 0.873 mmol), 5-trifluoromethylpyridin-2-amine (141.0 mg, 0.873 mmol), Pd2dba3 (25.0 mg, 0.0435 mmol), tBuONa (125.0 mg, 1.30 mmol), and tBuBrettPhos (42.3 mg, 0.0873 mmol) were slurried in argon-flushed, pre-degassed dioxane (2 mL, dry) and then heated to 110 °C. After 1 h, the reaction mixture was cooled to room temperature, treated with 5% aqueous NaHCO3, then extracted with EA, and the organic phase was washed several times with water and brine and then dried over MgSO4. The crude product was purified by flash chromatography (100 / 0 to 80 / 20 Cy / EA), then the isolated fraction was triturated with a minimum amount of DCM and the corresponding precipitate was filtered and washed with DCM and EtO to give the title compound as an off-white solid (171 mg, 63% yield). 1 H NMR (300MHz, CDCl3) δ = 8.60 (d, 1H, J= 2.4 Hz), 8.36 (s, 1H), 7.84 (d, 1H, J= 8.6 Hz), 7.61 (d, 1H, J= 2.1 Hz), 7.53 (s, 1H), 7.24 (dd, 1H, J= 2.0 Hz, 8.7 Hz), 6.38 (s, 1H), 1.61 (s, 9H). 19 F NMR (300MHz, CDCl3) δ = -63.21. LC-MS:2.18 min (5 min run), MS (ESI) m / z:(M+H)+ 411.24; (MH)- 409.24.

[0315] Process 2 N-[6-[[5-(trifluoromethyl)-2-pyridyl]amino]-1,3-benzothiazole-2,6-diamine [ka] tert-Butyl N-[6-[(5-trifluoromethyl-2-pyridyl)amino]-1,3-benzothiazol-2-yl]carbamate (171 mg, 0.417 mmol) was slurried in DCM (0.7 mL), to which TFA (0.3 mL) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 3 hours, after which saturated aqueous Na2CO3 solution was added, and the product was extracted with EA. The collected organic layer was washed several times with water and brine, and then dried over MgSO4. The product was obtained as a white solid (114 mg, 88% yield). LC-MS: 1.73 min (5 min run), MS (ESI) m / z: (M+H)+ 311.13; (MH)- 308.93.

[0316] Process 3 Example 95: 4-[6-[[5-(trifluoromethyl)-2-pyridyl]amino]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione [ka]

[0317] Example 96: 3-[[6-[[5-(trifluoromethyl)-2-pyridyl]amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka] N6-[6-(trifluoromethyl)-2-pyridyl]-1,3-benzothiazole-2,6-diamine (114 mg, 0.367 mmol) and (1S,2R,6S,7R)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (60.3 mg, 0.367 mmol) were flushed with argon and then slurried in dry THF (1 mL), after which the system was heated to 70 °C. After 6 h, the reaction was cooled to room temperature, and a small amount of ACN was added to induce precipitation. The precipitate was filtered and washed with THF and ACN to yield the title compound as a white solid (Example 96, 41 mg, 23%). The filtrate was concentrated, followed by flash chromatography purification (100 / 0 to 3 / 7 Cy / EA) to afford the title compound as an off-white solid (Example 95, 14 mg, 8%).

[0318] Example 95: 1 H NMR (300MHz, CDCl3) δ = 9.26 (d, 1H, J= 2.0 Hz), 8.50 (dd, 1H, J= 2.4 Hz, 8.3 Hz), 7.98 (d, 1H, J= 8.7 Hz), 7.66 (dd, 1H, J= 1.9 Hz, 8.7 Hz), 7.33 (d, 1H, J= 8.7 Hz), 6.36 (t, 2H, J= 1.7 Hz), 3.58-3.51 (m, 4H), 1.84 (d, 1H, J= 8.8 Hz), 1.66 (d, 1H, J= 8.8 Hz). LC-MS: Method X, RT = 12.49 min (30 min run), MS (ESI) m / z:452.02 (M+H)+ HRMS: (ES+) C 22 H 16 Calculated value for F3N4O2S [M+H]+: 457.0953 Found: 457.0946.

[0319] Example 96: 1H NMR (300MHz, DMSO-d6) δ = 12.20 (s, 2H), 9.71 (s, 1H), 8.52 (s, 1H), 8.41 (d, 1H, J= 1.9 Hz), 7.86 (dd, 1H, J= 2.3 Hz, 8.8 Hz), 7.66 (d, 1H, J= 8.7 Hz), 7.53 (dd, 1H, J= 2.0 Hz, 8.8 Hz), 6.95 (d, 1H, J= 8.9 Hz), 6.19-6.16 (m, 2H), 3.50-3.35 (m, 2H), 3.11 (d, 2H, J= 16.0 Hz), 1.34 (q, 2H, J= 8.3 Hz). 19 F NMR (300MHz, DMSO-d6) δ = -60.11. LC-MS: Method X, RT = 11.18 min (30 min run), MS (ESI) m / z:473.10 (MH)- HRMS: (ES+) C 22 H 18 Calculated value for F3N4O3S [M+H]+: 475.1052 Found: 475.1024.

[0320] Example 97: 4-[6-[[6-(trifluoromethyl)-2-pyridyl]amino]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione Process 1 tert-Butyl N-[6-[[6-(trifluoromethyl)-2-pyridyl]amino]-1,3-benzothiazol-2-yl]carbamate [ka] tert-Butyl-N-[6-bromo-1,3-benzothiazole-2-amino]carbamate (200.0 mg, 0.608 mmol), 6-trifluoromethylpyridin-2-amine (98.5 mg, 0.608 mmol), Pd2dba3 (27.8 mg, 0.0304 mmol), tBuONa (87.6 mg, 0.911 mmol), and tBuBrettPhos (29.4 mg, 0.0608 mmol) were slurried in argon-flushed, pre-degassed dioxane (2 mL, dry) and then heated to 110 °C. After 1 h, the reaction mixture was cooled to room temperature, treated with 5% aqueous NaHCO3, then extracted with EA, and the organic phase was washed several times with water and brine and then dried over MgSO4. The crude product was purified by flash chromatography (100 / 0 to 80 / 20 Cy / EA) to give the title compound as an off-white solid (128 mg, 51% yield). 1 H NMR (300MHz, CDCl3) δ = 8.10 (s, 1H), 7.68-7.57 (m, 2H), 7.34 (dd, 1H, J= 2.2 Hz, 8.7 Hz), 7.07 (d, 1H, J= 7.3 Hz), 6.94-6.89 (m, 1H), 1.56 (s, 9H). 19 F NMR (300MHz, CDCl3) δ = -69.27. LC-MS: 2.32 min (5 min run) MS (ESI) m / z:(M+H)+ 411.25 (MH)- 409.20.

[0321] Process 2 N-[6-[[6-(trifluoromethyl)-2-pyridyl]amino]-1,3-benzothiazol-2,6-amine [ka] tert-Butyl N-[6-[(6-trifluoromethyl-2-pyridyl)amino]-1,3-benzothiazol-2-yl]carbamate (100 mg, 0.312 mmol) was slurried in DCM (0.7 mL), to which TFA (0.3 mL) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 3 hours, after which saturated aqueous Na2CO3 solution was added, and the product was extracted with EA. The collected organic layer was washed several times with water and brine, and then dried over MgSO4. The product was obtained as a white solid (90 mg, 93% yield). LC-MS: 1.93 min (5 min run) MS (ESI) m / z:(M+H)+ 311.13 (MH)- 309.03.

[0322] Process 3 4-[6-[[6-(trifluoromethyl)-2-pyridyl]amino]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione [ka] N6-[6-(trifluoromethyl)-2-pyridyl]-1,3-benzothiazole-2,6-diamine (90 mg, 0.290 mmol) and (1S,2R,6S,7R)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (47.6 mg, 0.290 mmol) were flushed with argon and then slurried in dry THF (1 mL), after which the system was heated to 70 °C. After 2.5 h, the reaction was cooled to room temperature and excess THF was added. An initial filtration was performed, washing the precipitate with THF and acetonitrile, and the filtrate was concentrated. Flash chromatography (9 / 1 to 5 / 5 Cy / EA) then afforded the title compound as a white solid (19 mg, 14%). 1H NMR (300MHz, CDCl3) δ = 8.19 (d, 1H, J= 2.1 Hz), 8.00 (d, 1H, J= 8.8 Hz), 7.65 (t, 1H, J= 7.9 Hz), 7.34 (dd, 1H, J= 2.2 Hz, 8.8 Hz), 7.14 (d, 1H, J= 7.4 Hz), 7.07 (s, 1H), 6.98 (d, 1H, J= 8.5 Hz), 6.30-6.29 (m, 2H), 3.60-3.54 (m, 4H), 1.84 (d, 1H, J= 8.9 Hz), 1.66 (d, 1H, J= 8.9 Hz). 19 F NMR (300MHz, CDCl3) δ = -69.09. LC-MS: Method X, RT = 12.98 min (30 min run), MS (ESI) m / z:(M+H)+ 457.06; (MH)- 455.06 HRMS: (ES+) C 22 H 16 Calculated value for F3N4O2S [M+H]+: 457.0946 Found: 457.0958.

[0323] Examples 98 and 99: 4-[6-[(2-fluoro-4-pyridyl)amino]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione and 3-[[6-[(2-fluoro-4-pyridyl)amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid Process 1 tert-Butyl N-[6-[(2-fluoro-4-pyridyl)amino]-1,3-benzothiazol-2-yl]carbamate [ka] tert-Butyl-N-[6-bromo-1,3-benzothiazole-2-amino]carbamate (300.0 mg, 0.911 mmol), 2-fluoropyridin-4-amine (102.0 mg, 0.911 mmol), Pd2dba3 (26.2 mg, 0.045 mmol), tBuONa (131.0 mg, 1.37 mmol), and tBuBrettPhos (44.2 mg, 0.0911 mmol) were slurried in argon-flushed, pre-degassed dioxane (2 mL, dry) and then heated to 110 °C. After 1 h, the reaction mixture was cooled to room temperature, treated with 5% aqueous NaHCO3, then extracted with EA, and the organic phase was washed several times with water and brine and then dried over MgSO4. The crude product was triturated with a minimum amount of DCM to give a white precipitate which was filtered (117 mg, 35%). 1 H NMR (300MHz, CDCl3) δ = 7.79 (d, 1H, J= 6.0 Hz), 7.73 (d, 1H, J= 2.0 Hz), 7.69 (d, 1H, J= 8.6 Hz), 7.29 (dd, 1H, J= 2.2 Hz, 8.6 Hz), 6.77 (dt, 1H, J= 1.7 Hz, 4.2 Hz), 6.42 (d, 1H, J= 1.2 Hz). 19 F NMR (300MHz, CDCl3) δ = -73.86. LC-MS: 2.01 min (5 min run) MS (ESI) m / z:(M+H)+ 361.24 (MH)- 359.09.

[0324] Process 2 N6-(2-fluoro-4-pyridyl)-1,3-benzothiazole-2,6-diamine [ka] tert-Butyl N-[6-[(5-fluoro-3-pyridyl)amino]-1,3-benzothiazol-2-yl]carbamate (200 mg, 0.555 mmol) was slurried in DCM (0.7 mL), to which TFA (0.3 mL) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 3 hours, after which saturated aqueous Na2CO3 solution was added, and the product was extracted with EA. The collected organic layer was washed several times with water and brine, and then dried over MgSO4. The product was obtained as a white solid (72 mg, 85%). LC-MS: 1.49 min (5 min run) MS (ESI) m / z:(M+H)+ 261.13 (MH)- 259.18.

[0325] Process 3 Example 98: 4-[6-[(2-fluoro-4-pyridyl)amino]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione [ka]

[0326] Example 99: 3-[[6-[(2-fluoro-4-pyridyl)amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka] N6-(2-fluoro-4-pyridyl)-1,3-benzothiazole-2,6-diamine (75.5 mg, 0.290 mmol) and (1S,2R,6S,7R)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (47.6 mg, 0.290 mmol) were flushed with argon in a two-neck flask equipped with a condenser and then slurried with dry THF (1 mL). The system was then heated to 70 °C, and the reaction was monitored by LC-MS. After 2.5 h, the reaction was cooled to room temperature and excess THF was added. An initial filtration was performed, and the precipitate was washed with THF and acetonitrile. The title compound was recovered as a white solid (Example 99, 45.0 mg, 38% yield). The filtrate was concentrated, followed by flash chromatography purification (10 / 0 to 5 / 5 Cy / EA) leading to the title compound as a white solid (Example 98, 21 mg, 17% yield).

[0327] Example 98 1 H NMR (300MHz, CDCl3) δ = 8.02 (d, 1H, J= 8.7 Hz), 7.92 (d, 1H, J= 5.8 Hz), 7.67 (d, 1H, J= 2.1 Hz), 7.30 (d, 1H, J= 1.3 Hz), 6.70 (s, 1H), 6.68 (t, 1H, J= 1.8 Hz), 6.40 (d, 1H, J= 1.9 Hz), 6.29 (t, 2H, J= 1.5 Hz), 3.62-3.56 (m, 4H), 1.84 (d, 1H, J= 8.9 Hz), 1.67 (d, 1H, J= 8.9 Hz). 19 F NMR (300MHz, CDCl3) δ = -68.99. LC-MS: Method X, RT = 9.52 min (30 min run), MS (ESI) m / z:(M+H)+ 405.15;(MH)- 407.20 HRMS: (ES+) C 21 H 16 Calculated for FN4O2S [M+H]+: 407.0968 Found: 407.0978.

[0328] Example 99 1 H NMR (300MHz, DMSO-d6) δ = 12.22 (s, 1H), 12.01 (s, 1H), 9.19 (s, 1H), 7.83 (s, 2H), 7.69 (d, 1H, J= 8.2 Hz), 7.26 (d, 1H, J= 7.7 Hz), 6.78 (s, 1H), 6.43 (s, 1H), 6.17 (s, 2H), 3.46-3.42 (m, 2H), 3.11 (d, 2H, J= 13.4 Hz), 1.35 (d, 2H, J= 8.5 Hz). 19 F NMR (300MHz, DMSO-d6) δ = -69.99. LC-MS: Method X, RT = 8.19 min (30 min run), MS (ESI) m / z:(M+H)+ 425.19; (MH)- 423.24. HRMS: (ES+) C 21 H 18 Calculated for FN4O3S [M+H]+: 425.1084 Found: 425.1096.

[0329] Example 100: 3-[[6-[4-(1-piperidyl)anilino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid Process 1 tert-Butyl N-[6-[4-(1-piperidyl)phenyl]-1,3-benzothiazol-2-yl]carbamate [ka] tert-Butyl-N-[6-bromo-1,3-benzothiazole-2-amino]carbamate (200.0 mg, 0.607 mmol), 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine (209.2 mg, 0.728 mmol), Pd(dppf)Cl (88.7 mg, 0.121 mmol), and KPO (193.3 mg, 0.910 mmol) were slurried in a mixture of 1,4-dioxane and water (4 mL, 4 / 1 vol / vol mixture) that had been flushed with argon and previously degassed, and then heated to 110 °C. After 7 h, the reaction mixture was cooled to room temperature, treated with 5% aqueous NaHCO, and then extracted with EA. The organic phase was washed several times with water and brine and then dried over MgSO. The product was purified by flash chromatography (100 / 0 to 9 / 1 Cy / EA) and then the isolated fraction was precipitated from a DCM / pentane solvent mixture (50 mg, 20% yield). 1 H NMR (300MHz, CDCl3) δ = 10.79 (s, 1H), 7.96 (d, 1H, J= 1.7 Hz), 7.92 (dd, 1H, J= 3.4 Hz, 8.4 Hz), 7.62 (dd, 1H, J= 1.7 Hz, 8.4 Hz), 7.58 (d, 2H, J= 9.1 Hz), 7.10 (m, 2H), 3.27 (t, 4H, J= 4.8 Hz), 1.80 (m, 4H), 1.63 (m, 11H). LC-MS: 2.74 min (5 min run) MS (ESI) m / z:(M+H)+ 410.30.

[0330] Process 2 N-[6-[4-(1-piperidyl)phenyl]-1,3-benzothiazole-2,6-diamine [ka] tert-Butyl N-[6-[4-(1-piperidyl)phenyl]-1,3-benzothiazol-2-yl]carbamate (72 mg, 0.176 mmol) was dissolved in DCM (1.0 mL), then TFA was slowly added (0.5 mL), and the reaction was stirred at room temperature. The compound was then treated with saturated Na2CO3 solution and extracted with EA. The organic layer was washed with water and brine, then dried over MgSO4. Trituration with DCM led to the clean product as a white solid (51 mg, 93%). LC-MS: 2.22 min (5 min run) MS (ESI )m / z:(M+H)+ 310.18.

[0331] Process 3 3-[[6-[4-(1-piperidyl)anilino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid [ka] N-[6-[4-(1-piperidyl)phenyl]-1,3-benzothiazole-2,6-diamine (51 mg, 0.165 mmol) and (1S,2R,6S,7R)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (27.1 mg, 0.165 mmol) were flushed with argon and then slurried in dry THF (1 mL), after which the system was heated to 70 °C. After overnight, the reaction was cooled to room temperature and a white precipitate began to form. An initial filtration and washing of the precipitate with THF and acetonitrile afforded the title compound as a white solid (37 mg, 47% yield). 1H NMR (300MHz, DMSO-d6) δ = 12.24 (s, 1H), 11.94 (s, 1H), 8.15 (d, 1H, J= 1.4 Hz), 7.73-7.63 (m, 2H), 7.58 (d, 1H, J= 8.8 Hz), 7.01 (d, 2H, J= 8.9 Hz), 6.17 (s, 2H), 3.22-3.08 (m, 6H), 1.69-1.53 ​​(m, 6H), 1.35 (q, 2H, J= 9.1 Hz). LC-MS: Method X, RT = 13.02 min (30 min run), MS (ESI) m / z:(M+H)+ 474.20;(MH)- 472.20 HRMS: (ES+) C 27 H 28 Calculated value for N3O3S [M +H]+: 474.1851 Found value: 474.1834.

[0332] Example 101: tert-butyl 4-[4-[2-[(1R,2S,6R,7S)-3,5-dioxo-4-azatricyclo[5.2.1.02,6]dec-8-en-4-yl]-1,3-benzothiazol-6-yl]phenyl]piperazine-1-carboxylate Process 1 tert-Butyl 4-[4-(2-amino-1,3-benzothiazol-6-yl)phenyl]piperazine-1-carboxylate [ka] 6-Bromo-1,3-benzothiazol-2-amine (200.0 mg, 0.873 mmol), tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine-1-carboxylate (407.2 mg, 1.05 mmol), Pd(dppf)Cl (128.0 mg, 0.175 mmol), and KPO (278.0 mg, 1.31 mmol) were slurried in a mixture of argon-flushed, pre-degassed 1,4-dioxane and water (4 mL, 4 / 1 vol / vol mixture) and heated to 110 °C. After 7 h, the reaction mixture was cooled to room temperature, treated with 5% aqueous NaHCO, extracted with EA, and the organic phase was washed several times with water and brine and then dried over MgSO. The product was purified by flash chromatography (100 / 0 to 3 / 7 DCM / EA) to afford the title compound as a white solid (86 mg, 24% yield). 1 H NMR (300MHz, CDCl3) δ = 7.76 (s, 1H), 7.63-7.54 (m, 2H), 7.51 (d, 2H, J= 8.7 Hz), 7.01 (d, 2H, J= 8.8 Hz), 3.63 (t, 4H, J= 4.9 Hz), 3.22 (t, 4H, J= 5.2 Hz), 1.51 (s, 9H). LC-MS: 2.21 min (5 min run) MS (ESI) m / z: (M+H)+ 411.25, (MH)- 409.35.

[0333] tert-Butyl 4-[4-[2-[(1R,2S,6R,7S)-3,5-dioxo-4-azatricyclo[5.2.1.02,6]dec-8-en-4-yl]-1,3-benzothiazol-6-yl]phenyl]piperazine-1-carboxylate [ka] tert-Butyl 4-[4-(2-amino-1,3-benzothiazol-6-yl)phenyl]piperazine-1-carboxylate (60 mg, 0.146 mmol) and (1S,2R,6S,7R)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (24.0 mg, 0.146 mmol) were flushed with argon and then slurried in dry THF (1 mL), after which the system was heated to 70 °C. After overnight, the reaction was cooled to room temperature and a white precipitate began to form. An initial filtration and washing of the precipitate with THF and acetonitrile afforded the title compound as a white solid (31 mg, 38% yield). 1 H NMR (300MHz, CDCl3) δ = 8.12 (d, 1H, J= 8.5 Hz), 8.02 (d, 1H, J= 1.6 Hz), 7.71 (dd, 1H, J= 1.8 Hz, 8.5 Hz), 7.60 (d, 2H, J= 8.7 Hz), 7.13-7.04 (m, 2H), 6.31 (t, 2H, J= 1.6 Hz), 3.70-3.55 (m, 8H), 3.24 (t, 4H, J= 4.8 Hz), 1.84 (d, 1H, J= 9.0 Hz), 1.67 (d, 1H, J= 9.0 Hz), 1.52 (s, 9H). LC-MS: Method X, RT = 15.42 min (30 min run), MS (ESI) m / z:(M+H)+ 557.15. HRMS: (ES+) C 31 H 32 Calculated value for N4O4S [M +H]+: 557.2223, found 557.2261.

[0334] Example 102: 4-[6-(4-morpholinophenyl)-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione Process 1 tert-Butyl N-[6-(4-morpholinophenyl)-1,3-benzothiazol-2-yl]carbamate [ka] tert-Butyl-N-[6-bromo-1,3-benzothiazole-2-amino]carbamate (100.0 mg, 0.365 mmol), 1-[4-(4,4,5,5-tetramethyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]morpholine (105 mg, 0.365 mmol), Pd(dppf)Cl (44.5 mg, 0.0608 mmol), and KPO (96.8 mg, 0.456 mmol) were slurried in a mixture of 1,4-dioxane and water (4 mL, 4 / 1 vol / vol mixture) that had been flushed with argon and previously degassed, and then heated at 110 °C. After 7 h, the reaction mixture was cooled to room temperature and 5% COOH was obtained. The organic phase was washed several times with water and brine and then dried over MgSO. The product was purified by flash chromatography (100 / 0 to 9 / 1 Cy / EA) to give the title compound as an off-white solid (91 mg, 72% yield). 1 H NMR (300MHz, CDCl3) δ = 7.96 (d, 1H, J= 1.6 Hz), 7.82 (d, 1H, J= 8.4 Hz), 7.65-7.59 (m, 3H), 7.12 (d, 2H, J= 8.8 Hz), 3.97 (t, 4H, J= 4.5 Hz), 3.28 (t, 4H, J= 4.7 Hz), 1.61 (s, 9H). LC-MS: 2.33 min (5 min run) MS (ESI) m / z:(M+H)+ 412.15.

[0335] Process 2 6-(4-morpholinophenyl)-1,3-benzothiazol-2-amine [ka] tert-Butyl N-[6-(4-morpholinophenyl)-1,3-benzothiazol-2-yl]carbamate (91 mg, 0.221 mmol) was dissolved in DCM (1.0 mL), then TFA was slowly added (0.5 mL), and the reaction was stirred at room temperature. This compound was then treated with saturated Na2CO3 solution and extracted with EA. The organic layer was washed with water and brine, then dried over MgSO4. The product was obtained as a white solid (66 mg, 95%). LC-MS: 1.81 min (5 min run) MS (ESI) m / z:(M+H)+ 311.98.

[0336] Process 3 4-[6-(4-morpholinophenyl)-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione [ka] 6-(4-Morpholinophenyl)-1,3-benzothiazol-2-amine (55 mg, 0.177 mmol) and (1S,2R,6S,7R)-4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (29.0 mg, 0.177 mmol) were flushed with argon and then slurried in dry THF (1 mL), after which the system was heated to 70 °C. After overnight, the reaction was cooled to room temperature and a white precipitate began to form. An initial filtration and washing of the precipitate with THF and acetonitrile afforded the title compound as a white solid (19 mg, 23% yield). 1H NMR (300MHz, CDCl3) δ = 8.12 (d, 1H, J= 8.5 Hz), 8.02 (d, 1H, J= 1.5 Hz), 7.71 (dd, 1H, J= 1.7 Hz, 8.5 Hz), 7.60 (d, 2H, J= 8.3 Hz), 6.31 (t, 2H, J= 1.7 Hz), 3.92 (t, 4H, J= 4.7 Hz), 3.60-3.56 (m, 4H), 3.26 (t, 4H, J= 4.9 Hz), 1.85 (d, 1H, J= 8.9 Hz), 1.67 (d, 1H, J= 8.9 Hz). LC-MS: Method X, RT = 12.34 min (30 min run), MS (ESI) m / z:(M+H)+ 458.16. HRMS: (ES+) C 26 H 24 Calculated value for N3O3S [M+H]+: 458.1538, found 458.1530.

[0337] Part B: Activity of the compounds of the present invention material and method 1. Construction of Mycobacterial Recombinant Strains M. tuberculosis H37Rv_gfp strain. The M. tuberculosis H37Rv recombinant strain (H37Rv_GFP) expressing green fluorescent protein was obtained by transformation of the integrative plasmid pNIP48 (Abadie et al., 2005; Cremer et al., 2002). In this plasmid, derived from the Ms6 mycobacteriophage, the GFP gene was cloned under the strong mycobacterial promoter pBlaF, and GFP was constitutively expressed. This plasmid also contained a hygromycin resistance gene.

[0338] M. tuberculosis H37Rv_DdnL49P_gfp strain. The M. tuberculosis H37Rv_DdnL49P_gfp strain is a derivative of the H37Rv_gfp strain selected on agar plates containing pretomanid (2 μg / ml). This strain carries the Leu49Pro mutation in Ddn.

[0339] 2. Growth and Preparation of Fluorescent Mycobacteria The bacterial stock solution (1 ml) kept at -80°C was used to culture 50 mg.mL in a 125 ml culture flask (Dutscher 29674). -1 The cells were inoculated into 25 ml of Middlebrook 7H9 medium supplemented with oleic acid-albumin-dextrose-catalase (OADC, Difco, Sparks MD, USA) along with 100 mg of hygromycin (Invitrogen, Carlsbad, CA, USA). The flasks were incubated at 37°C for 7 days without shaking. The cultures were then diluted with fresh culture medium until the OD600 reached 0.2 and incubated at 37°C for 3 days without shaking.

[0340] 3. Microplate Preparation Pretomanid and delamanid in DMSO at 10 mg.mL -1 The compounds were dissolved in DMSO and stored frozen in aliquots at -20°C. Test compounds were resuspended in DMSO to a final concentration of 10 mM and stored at -20°C. Pretomanid, delamanid, and test compounds were transferred to a 384-well low-dead-volume polypropylene plate (Corning, no. 3672) and used to prepare the assay plate. Ten 3-fold serial dilutions of compounds (50 to 0.02 μM) were performed in a black Greiner 384-well clear-bottom polystyrene plate (Greiner, no. 781091) using an Echo 550 liquid Handler (Labcyte). The amount of DMSO was corrected to ensure uniform concentrations (0.5%) in all wells. Controls in the assay plate included 0.5% DMSO (negative control) and 0.1 μg mL -1 of Rif (positive control).

[0341] Pretomanid, delamanid, or DMSO was then transferred to a 384-well plate using an Echo. Final concentrations of pretomanid and delamanid were 20 ng / mL for assays containing H37Rv_gfp. -1 or 4ng.mL -1and for assays containing H37Rv_DdnL49P_gfp, pretomanid was at 5 μg.mL-1. The final amount of DMSO in the assay plate was 0.6 and 0.55% (v / v) for assays containing H37Rv_gfp and H37Rv_DdnL49P_gfp, respectively.

[0342] The culture was diluted to an OD600 (nm) of 0.02 (using fresh culture medium without hygromycin), and 50 μL was transferred to each assay plate. The assay plate was incubated at 37°C for 5 days. Fluorescence signals were acquired using an excitation = 485 nm / emission = 535 nm in a Victor 3 multilabel plate reader (Perkin Elmer).

[0343] The assay yielded an EC50 H37Rv_gfp and an EC50 H37Rv_DdnL49P_gfp.

[0344] result Biological activity in combination with pretomanid: The results are shown in Table 1 below:

[0345] [Table 1] TIFF2025502036000214.tif237161 TIFF2025502036000215.tif237161 TIFF2025502036000216.tif242161 TIFF2025502036000217.tif246161 TIFF2025502036000218.tif179161

[0346] In particular, each of Examples 1a, 7, 12, 20, 21, 27, 28, 30, 32, 36, 53, 54, 55, 60, 61, 62, 69, 71, 73, 77, 78, 79 was found to have an average EC50 H37Rv_gfp of <500 nM and an average EC50 H37Rv_DdnL49P_gfp of <1 μM.

[0347] Certain exemplary compounds are described below.

[0348] Example 1a was found to have an average EC50 H37Rv_gfp of 0.25 and an average EC50 H37Rv_DdnL49P_gfp of 0.72.

[0349] Example 7 was found to have an average EC50 H37Rv_gfp of 0.15 and an average EC50 H37Rv_DdnL49P_gfp of 1.0.

[0350] Example 21 was found to have an average EC50 H37Rv_gfp of 0.27, and an average EC50 H37Rv_DdnL49P_gfp of 0.4.

[0351] Example 27 was found to have an average EC50 H37Rv_gfp of 0.11 and an average EC50 H37Rv_DdnL49P_gfp of 0.23.

[0352] Example 28 was found to have an average EC50 H37Rv_gfp of 0.13 and an average EC50 H37Rv_DdnL49P_gfp of 0.21.

[0353] Example 32 was found to have an average EC50 H37Rv_gfp of 0.32 and an average EC50 H37Rv_DdnL49P_gfp of 0.32.

[0354] Example 36 was found to have an average EC50 H37Rv_gfp of 0.22 and an average EC50 H37Rv_DdnL49P_gfp of 0.49.

[0355] Example 54 was found to have an average EC50 H37Rv_gfp of 0.11 and an average EC50 H37Rv_DdnL49P_gfp of 0.69.

[0356] Example 60 was found to have an average EC50 H37Rv_gfp of 0.05 and an average EC50 H37Rv_DdnL49P_gfp of 0.48.

[0357] Example 78 was found to have an average EC50 H37Rv_gfp of 0.13 and an average EC50 H37Rv_DdnL49P_gfp of 0.22.

[0358] Biological activity in combination with delamanid: The results are shown in Table 2 below:

[0359] [Table 2]

Claims

1. Formula (I): 【Chemistry 212】 [In the formula: R １ teeth, -H; -OH; Linear or branched chain - (C １ -C ６ ) alkyl; and Linear or branched chain - (C １ -C ６ ) Alkoxy (C ２ -C ６ ) alkynyl; is selected from R ２ teeth, -H; Linear or branched chain - (C １ -C ６ ) alkyl; Linear or branched chain - (C １ -C ６ ) alkoxy; and halogen atoms; is selected from R ３ teeth, -H; halogen atoms; - Straight or branched chain -(C １ -C ６ ) alkyl; - Straight or branched chain -(C １ -C ６ ) alkoxy; Linear or branched chain - (C ２ -C ８ ) alkynyl; Linear or branched chain - (C １ -C ６ ) alkoxy-(C ２ -C ６ ) alkynyl; -OR; -NHR; - (C ２ -C ８ ) cycloalkyl; Linear or branched chain - (C ２ -C ６ ) alkynyl-(C ６ -C １０ ) aryl; Linear or branched chain - (C １ -C ６ ) alkyl-(C ６ -C １０ ) aryl; one or more -OH, halogen atoms, linear or branched -(C １ -C ６ ) alkyl, linear or branched chain optionally substituted with one or more halogen atoms -(C １ -C ６ ) alkoxy, optionally substituted by -NRaRb, -(C ６ -C １０ ) aryl; Heteroaryl containing 3 to 10 ring members and having at least one heteroatom selected from O, N or S; linear or branched, optionally substituted with one or more halogen atoms, one or more halogen atoms -(C １ -C ６ ) alkyl; straight or branched chain -(C ２ -C ６ ) alkynyl-(C ２ -C ６ ) the heteroaryl optionally substituted by cycloalkyl; Linear or branched chain - (C ６ -C １０ ) aryl-(C １ -C ６ ) alkoxy-(C ２ -C ６ ) alkynyl; ・-NO ２ ; Linear or branched chain -SO ２ (C １ -C ３ ) alkyl; -CN; -COO-(C １ -C ３ ) alkyl; is selected from R is -H; - Straight or branched chain -(C １ -C ６ ) alkyl; - (C ６ -C １０ ) aryl, optionally substituted with one or more halogen atoms, —OH, linear or branched —(C １ -C ６ ) alkyl, optionally substituted with one or more halogen atoms -(C １ -C ６ ) alkoxy, ６ -C １０ ) aryl; Heteroaryl containing 3 to 10 ring members and having at least one heteroatom selected from O, N or S; linear or branched, optionally substituted with one or more halogen atoms, one or more halogen atoms -(C １ -C ６ ) alkyl; straight or branched chain -(C １ -C ６ ) alkoxy; said heteroaryl optionally substituted by -CN; is selected from Ra and Rb are the same or different, -H; - Straight or branched chain -(C １ -C ６ ) alkyl; or Ra and Rb are linked together to represent a heterocycloalkyl containing 3 to 10 ring members; one or more linear or branched -(C １ -C ６ ) alkyl, —COO—(C １ -C ３ ) alkyl, -NRcRd; forming said heterocycloalkyl optionally substituted by oxo; Rc and Rd are the same or different; -H; and Linear or branched chain - (C １ -C ６ ) alkyl; or R ２ and R ３ are linked together to form -O-(C １ -C ６ ) forming an alkyl-O- group; R ４ is H, R ５ teeth, 【Chemistry 213】 or R ４ and R ５ together with the nitrogen atom to which they are attached, 【Chemistry 214】 Form or a pharma- ceutically acceptable salt or optical isomer, racemate, diastereoisomer, enantiomer or tautomer thereof; However, the following compounds: 3-[(1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-methyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(4-methyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(5,6-dimethyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 3-[(6-bromo-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-chloro-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(4,6-dimethyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 3-[(6-ethoxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-nitro-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 3-[(6-methylsulfonyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 4-(6-methyl-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; 2-[(6-ethyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-3-carboxylic acid; 2-[(6-fluoro-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-3-carboxylic acid; 2-[(5-ethoxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-3-carboxylic acid; - (2-(benzo[d]thiazol-2-yl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindole-1,3(2H)-dione 2-(5-chloro-6-methylbenzo[d]thiazol-2-yl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindole-1,3(2H)-dione 2-(4-methylbenzo[d]thiazol-2-yl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindole-1,3(2H)-dione 2-(6-bromobenzo[d]thiazol-2-yl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindole-1,3(2H)-dione 2-(6-methoxybenzo[d]thiazol-2-yl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindole-1,3(2H)-dione; - Compose decrit dans D3= ChemCats 2008; 3-[(6-methoxy-1,3-benzothiazol-2-yl)carbamoyl]norbornane-2-carboxylic acid - 4-(6-methoxy-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 4-(5-chloro-6-methyl-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 4-(4-methyl-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 4-(6-bromo-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 4-(4-methyl-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]decane-3,5-dione The above compounds, salts or isomers, excluding:

2. The following: - 3-[(6-methyl-1,3-benzothiazol-2-yl)carbamoyl]norbornane-2-carboxylic acid; - (1S,2S,6R,7R)-4-(6-methyl-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]decane-3,5-dione; - 3-[(5-methoxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-methoxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 3-[(5,6-dimethoxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 3-(6,7-dihydro-[1,4]dioxino[2,3-f][1,3]benzothiazol-2-ylcarbamoyl)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 3-[(6-ethyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-tert-butyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(4,5-dimethyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-phenoxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-(6-phenoxy-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; 3-[(6-benzyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 3-[[6-(4-fluorophenoxy)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 3-[[6-[4-(trifluoromethyl)phenoxy]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-[6-[4-(trifluoromethyl)phenoxy]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; 3-[[6-(4-pyridyloxy)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 3-[[6-[[3-(trifluoromethyl)-2-pyridyl]oxy]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-[6-[[3-(trifluoromethyl)-2-pyridyl]oxy]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; 3-[[6-[[4-(trifluoromethyl)-2-pyridyl]oxy]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-[6-[[4-(trifluoromethyl)-2-pyridyl]oxy]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; 3-[[6-[(4-methyl-2-pyridyl)oxy]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 2-[[2-[(1R,2S,6R,7S)-3,5-dioxo-4-azatricyclo[5.2.1.02,6]dec-8-en-4-yl]-1,3-benzothiazol-6-yl]oxy]pyridine-4-carbonitrile; 3-[[6-[[2-(trifluoromethyl)-4-pyridyl]oxy]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-[6-[[6-(trifluoromethyl)-2-pyridyl]oxy]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; 3-[[6-[[5-(trifluoromethyl)-2-pyridyl]oxy]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-[6-[[5-(trifluoromethyl)-2-pyridyl]oxy]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; 3-[[6-[(5-bromo-2-pyridyl)oxy]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 3-[(6-cyano-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-methoxycarbonyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-fluoro-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 3-[[6-(trifluoromethyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 3-[[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; 3-[(5-bromo-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 3-[(6-iodo-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-hydroxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-phenyl-1,3-benzothiazol-2-yl)carbamoyl]-7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-cyclohexyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 3-[[6-(p-tolyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 3-[[6-(4-methoxyphenyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 3-[[6-(4-chlorophenyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 3-[[6-(3,4-dichlorophenyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 3-[[6-[2-(trifluoromethyl)phenyl]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-[6-[2-(trifluoromethyl)phenyl]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; 3-[[6-[3-(trifluoromethyl)phenyl]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 3-[[6-[4-(trifluoromethyl)phenyl]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-[6-[4-(trifluoromethyl)phenyl]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; 3-[[6-[4-(trifluoromethoxy)phenyl]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-[6-(4-hydroxyphenyl)-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; 3-[[6-(4-pyridyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-[6-(6-fluoro-3-pyridyl)-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; 3-[[6-[6-(trifluoromethyl)-3-pyridyl]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-[6-[6-(trifluoromethyl)-3-pyridyl]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 3-[(6-pyrimidin-5-yl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid - 3-[[6-(6-quinolyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid - 4-[6-(3-thienyl)-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione 3-[[6-(3-furyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-[6-(3-furyl)-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 4-[6-(4-prop-2-ynoxyphenyl)-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - (1R,2S,6R,7S)-4-(6-ethynyl-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - (1R,2S,6R,7S)-4-(6-prop-2-ynoxy-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - (1R,2S,3R,4S)-3-[(4-hydroxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(4-prop-2-ynoxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-(4-prop-2-ynoxy-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; 3-[[6-(2-phenylethynyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 3-[[6-(3,3-dimethylbut-1-ynyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 3-[[6-(2-cyclopropylethynyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - [2-hydroxy-1,1-bis(hydroxymethyl)ethyl]ammonium; - (1R,2S,3R,4S)-3-[(6-phenoxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylate; - (1R,2S,6R,7S)-4-[6-[(4-methyl-2-pyridyl)oxy]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - (1R,2S,6R,7S)-4-[6-[(2-chloro-4-pyridyl)oxy]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; 3-[[6-[6-(trifluoromethyl)-3-pyridyl]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-(6-anilino-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; 4-[6-(2-pyridylamino)-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; and 3-[[6-[(4-methyl-2-pyridyl)amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 3-[[6-[(4-fluoro-2-pyridyl)amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 3-[[6-[(5-fluoro-2-pyridyl)amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 4-[6-[(5-fluoro-2-pyridyl)amino]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; 3-[[6-[(6-fluoro-2-pyridyl)amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 4-[6-[(6-fluoro-2-pyridyl)amino]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 4-[6-[[2-(trifluoromethyl)-4-pyridyl]amino]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; 3-[[6-[[5-(trifluoromethyl)-3-pyridyl]amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 4-[6-[(2-methoxy-4-pyridyl)amino]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; 3-[[6-[[5-(trifluoromethoxy)-2-pyridyl]amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 4-[6-[[5-(trifluoromethoxy)-2-pyridyl]amino]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 4-[6-[[5-(trifluoromethyl)-2-pyridyl]amino]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; 3-[[6-[[5-(trifluoromethyl)-2-pyridyl]amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 4-[6-[[6-(trifluoromethyl)-2-pyridyl]amino]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 4-[6-[(2-fluoro-4-pyridyl)amino]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; 3-[[6-[(2-fluoro-4-pyridyl)amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 3-[[6-[4-(1-piperidyl)anilino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - tert-butyl 4-[4-[2-[(1R,2S,6R,7S)-3,5-dioxo-4-azatricyclo[5.2.1.02,6]dec-8-en-4-yl]-1,3-benzothiazol-6-yl]phenyl]piperazine-1-carboxylate; - 4-[6-(4-morpholinophenyl)-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; 2. A compound of formula (I) according to claim 1, selected from: or a pharma- ceutically acceptable salt or optical isomer, racemate, diastereoisomer, enantiomer or tautomer thereof.

3. R １ is H; R ２ is H; R ３ but, Linear or branched chain - (C ２ -C ６ ) alkynyl; - Straight or branched chain -(C １ -C ６ ) alkoxy; -OR; -NHR; one or more linear or branched chains, optionally substituted by one or more halogen atoms -(C １ -C ６ ) alkyl, linear or branched chain optionally substituted with one or more halogen atoms -(C １ -C ６ ) alkoxy, optionally substituted by NRaRb; ６ -C １０ ) aryl; is selected from, and R is, - Straight or branched chain -(C １ -C ６ ) alkyl; one or more linear or branched chains, optionally substituted by one or more halogen atoms -(C １ -C ６ Optionally substituted by alkyl, —(C ６ -C １０ ) aryl; Heteroaryl containing 3 to 10 ring members, having at least one heteroatom selected from O, N or S; linear or branched -(C １ -C ６ ) the heteroaryl optionally substituted by alkyl; is selected from Ra and Rb are linked together to form a heterocycloalkyl containing 3 to 10 ring members; one or more linear or branched -(C １ -C ６ ) alkyl, —COO—(C １ -C ３ ) alkyl, -NRcRd; forming said heterocycloalkyl optionally substituted by oxo; and Rc and Rd are the same or different; -H; and Linear or branched chain - (C １ -C ６ ) Alkyl 2. The compound of formula (I) according to claim 1, selected from:

4. R １ is H; R ２ is H; R ３ but, Trifluoromethoxy; 3,3-dimethylbut-1-ynyl; -OR; -NHR; phenyl optionally substituted by one or more trifluoromethyl, methoxy, trifluoromethoxy and / or piperidyl; is selected from, and R is, - linear or branched (C １ -C ３ ) alkyl; phenyl optionally substituted by one or more methyl and / or trifluoromethyl; Heteroaryl containing 6 ring members and having at least one nitrogen atom; said heteroaryl being optionally substituted by one or more trifluoromethyl, trifluoromethoxy and / or fluorine; for example pyridyl substituted by one or more trifluoromethyl, trifluoromethoxy and / or fluorine.

4. A compound of formula (I) according to claim 1, selected from:

5. The following: 3-[[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; 3-[[6-(3,3-dimethylbut-1-ynyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 3-[[6-(4-methoxyphenyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 3-[[6-[4-(trifluoromethoxy)phenyl]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 3-[[6-[4-(trifluoromethyl)phenyl]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-[6-[4-(trifluoromethyl)phenyl]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 3-[(6-phenoxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-(6-phenoxy-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - [2-hydroxy-1,1-bis(hydroxymethyl)ethyl]ammonium; (1R,2S,3R,4S)-3-[(6-phenoxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylate; 3-[[6-[[4-(trifluoromethyl)-2-pyridyl]oxy]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 3-[[6-[(4-fluoro-2-pyridyl)amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 3-[[6-[(5-fluoro-2-pyridyl)amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 3-[[6-[(6-fluoro-2-pyridyl)amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 4-[6-[[2-(trifluoromethyl)-4-pyridyl]amino]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; 3-[[6-[[5-(trifluoromethoxy)-2-pyridyl]amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 4-[6-[[5-(trifluoromethyl)-2-pyridyl]amino]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 4-[6-[[6-(trifluoromethyl)-2-pyridyl]amino]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; 3-[[6-[4-(1-piperidyl)anilino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 10. A compound of formula (I) according to any one of the preceding claims, or a pharma- ceutically acceptable salt or optical isomer, racemate, diastereoisomer, enantiomer or tautomer thereof, selected from:

6. A pharmaceutical composition comprising a compound of formula (I) as defined in any one of claims 1 to 5 and a pharma- ceutically acceptable excipient.

7. 6. The pharmaceutical composition of claim 5, further comprising at least one other antimycobacterial agent.

8. A compound of formula (I): 【Chemistry 215】 [In the formula: R １ teeth, -H; -OH; Linear or branched chain - (C １ -C ６ ) alkyl; and Linear or branched chain - (C １ -C ６ ) Alkoxy (C ２ -C ６ ) alkynyl; is selected from R ２ teeth, -H; Linear or branched chain - (C １ -C ６ ) alkyl; Linear or branched chain - (C １ -C ６ ) alkoxy; and halogen atoms; is selected from R ３ teeth, -H; halogen atoms; - Straight or branched chain -(C １ -C ６ ) alkyl; - Straight or branched chain -(C １ -C ６ ) alkoxy; Linear or branched chain - (C ２ -C ８ ) alkynyl; Linear or branched chain - (C １ -C ６ ) alkoxy-(C ２ -C ６ ) alkynyl; -OR; -NHR; - (C ２ -C ８ ) cycloalkyl; Linear or branched chain - (C ２ -C ６ ) alkynyl-(C ６ -C １０ ) aryl; Linear or branched chain - (C １ -C ６ ) alkyl-(C ６ -C １０ ) aryl; one or more -OH, halogen atoms, linear or branched -(C １ -C ６ ) alkyl, one or more linear or branched chain -(C １ -C ６ ) alkoxy, optionally substituted by NRaRb; ６ -C １０ ) aryl; Heteroaryl containing 3 to 10 ring members and having at least one heteroatom selected from O, N or S; linear or branched, optionally substituted with one or more halogen atoms, one or more halogen atoms -(C １ -C ６ ) alkyl; straight or branched chain -(C ２ -C ６ ) alkynyl-(C ２ -C ６ ) the heteroaryl optionally substituted by cycloalkyl; Linear or branched chain - (C ６ -C １０ ) aryl-(C １ -C ６ ) alkoxy-(C ２ -C ６ ) alkynyl; ・-NO ２ ; Linear or branched chain -SO ２ (C １ -C ３ ) alkyl; -CN; -COO-(C １ -C ３ ) alkyl; is selected from R is -H; - Straight or branched chain -(C １ -C ６ ) alkyl; - (C ６ -C １０ ) aryl, optionally substituted with one or more halogen atoms, —OH, linear or branched —(C １ -C ６ ) alkyl, optionally substituted with one or more halogen atoms -(C １ -C ６ ) alkoxy optionally substituted with ６ -C １０ ) aryl; Heteroaryl containing 3 to 10 ring members and having at least one heteroatom selected from O, N or S; linear or branched, optionally substituted with one or more halogen atoms, one or more halogen atoms -(C １ -C ６ ) alkyl; straight or branched chain -(C １ -C ６ ) the heteroaryl optionally substituted by alkoxy, -CN; is selected from Ra and Rb are the same or different, -H; - Straight or branched chain -(C １ -C ６ ) alkyl; or Ra and Rb are linked together to represent a heterocycloalkyl containing 3 to 10 ring members; one or more linear or branched -(C １ -C ６ ) alkyl, —COO—(C １ -C ３ ) alkyl, -NRcRd; forming said heterocycloalkyl optionally substituted by oxo; Rc and Rd are the same or different; -H; and Linear or branched chain - (C １ -C ６ ) alkyl; or R ２ and R ３ are linked together to form -O-(C １ -C ６ ) forming an alkyl-O- group; R ４ is H, R ５ teeth, 【Chemistry 216】 or R ４ and R ５ together with the nitrogen atom to which they are attached, 【Chemistry 217】 Form or a pharma- ceutically acceptable salt or optical isomer, racemate, diastereoisomer, enantiomer or tautomer thereof; However, the following compounds: 3-[(6-methylsulfonyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; The above compounds, salts or isomers, excluding:

9. The compound of formula (I) is 3-[(1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-methyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 4-(6-methyl-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 3-[(6-methyl-1,3-benzothiazol-2-yl)carbamoyl]norbornane-2-carboxylic acid; - (1S,2S,6R,7R)-4-(6-methyl-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]decane-3,5-dione; - 3-[(5-methoxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-methoxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 3-[(6-ethoxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-(6-ethoxy-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; 3-[(5,6-dimethoxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 3-(6,7-dihydro-[1,4]dioxino[2,3-f][1,3]benzothiazol-2-ylcarbamoyl)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 3-[(6-ethyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-tert-butyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(4,6-dimethyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(5,6-dimethyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(4,5-dimethyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(4-methyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-phenoxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-(6-phenoxy-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; 3-[(6-benzyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 3-[[6-(4-fluorophenoxy)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 3-[[6-[4-(trifluoromethyl)phenoxy]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-[6-[4-(trifluoromethyl)phenoxy]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; 3-[[6-(4-pyridyloxy)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 3-[[6-[[3-(trifluoromethyl)-2-pyridyl]oxy]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-[6-[[3-(trifluoromethyl)-2-pyridyl]oxy]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; 3-[[6-[[4-(trifluoromethyl)-2-pyridyl]oxy]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-[6-[[4-(trifluoromethyl)-2-pyridyl]oxy]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; 3-[[6-[(4-methyl-2-pyridyl)oxy]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 2-[[2-[(1R,2S,6R,7S)-3,5-dioxo-4-azatricyclo[5.2.1.02,6]dec-8-en-4-yl]-1,3-benzothiazol-6-yl]oxy]pyridine-4-carbonitrile; 3-[[6-[[2-(trifluoromethyl)-4-pyridyl]oxy]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-[6-[[6-(trifluoromethyl)-2-pyridyl]oxy]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; 3-[[6-[[5-(trifluoromethyl)-2-pyridyl]oxy]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-[6-[[5-(trifluoromethyl)-2-pyridyl]oxy]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; 3-[[6-[(5-bromo-2-pyridyl)oxy]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-nitro-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 3-[(6-methylsulfonyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 3-[(6-cyano-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-methoxycarbonyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-fluoro-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 3-[[6-(trifluoromethyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 3-[[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 3-[(6-chloro-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 3-[(6-bromo-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 3-[(5-bromo-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 3-[(6-iodo-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-hydroxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-phenyl-1,3-benzothiazol-2-yl)carbamoyl]-7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(6-cyclohexyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 3-[[6-(p-tolyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 3-[[6-(4-methoxyphenyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 3-[[6-(4-chlorophenyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 3-[[6-(3,4-dichlorophenyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 3-[[6-[2-(trifluoromethyl)phenyl]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-[6-[2-(trifluoromethyl)phenyl]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; 3-[[6-[3-(trifluoromethyl)phenyl]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 3-[[6-[4-(trifluoromethyl)phenyl]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-[6-[4-(trifluoromethyl)phenyl]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; 3-[[6-[4-(trifluoromethoxy)phenyl]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-[6-(4-hydroxyphenyl)-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; 3-[[6-(4-pyridyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-[6-(6-fluoro-3-pyridyl)-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; 3-[[6-[6-(trifluoromethyl)-3-pyridyl]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-[6-[6-(trifluoromethyl)-3-pyridyl]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 3-[(6-pyrimidin-5-yl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 3-[[6-(6-quinolyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 4-[6-(3-thienyl)-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; 3-[[6-(3-furyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-[6-(3-furyl)-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 4-[6-(4-prop-2-ynoxyphenyl)-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - (1R,2S,6R,7S)-4-(6-ethynyl-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - (1R,2S,6R,7S)-4-(6-prop-2-ynoxy-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - (1R,2S,3R,4S)-3-[(4-hydroxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 3-[(4-prop-2-ynoxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-(4-prop-2-ynoxy-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; 3-[[6-(2-phenylethynyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 3-[[6-(3,3-dimethylbut-1-ynyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 3-[[6-(2-cyclopropylethynyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - [2-hydroxy-1,1-bis(hydroxymethyl)ethyl]ammonium; (1R,2S,3R,4S)-3-[(6-phenoxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylate; - (1R,2S,6R,7S)-4-[6-[(4-methyl-2-pyridyl)oxy]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - (1R,2S,6R,7S)-4-[6-[(2-chloro-4-pyridyl)oxy]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; 3-[[6-[6-(trifluoromethyl)-3-pyridyl]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-(6-anilino-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; 4-[6-(2-pyridylamino)-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; and 3-[[6-[(4-methyl-2-pyridyl)amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 3-[[6-[(4-fluoro-2-pyridyl)amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 3-[[6-[(5-fluoro-2-pyridyl)amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 4-[6-[(5-fluoro-2-pyridyl)amino]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; 3-[[6-[(6-fluoro-2-pyridyl)amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 4-[6-[(6-fluoro-2-pyridyl)amino]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 4-[6-[[2-(trifluoromethyl)-4-pyridyl]amino]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; 3-[[6-[[5-(trifluoromethyl)-3-pyridyl]amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 4-[6-[(2-methoxy-4-pyridyl)amino]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; 3-[[6-[[5-(trifluoromethoxy)-2-pyridyl]amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 4-[6-[[5-(trifluoromethoxy)-2-pyridyl]amino]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 4-[6-[[5-(trifluoromethyl)-2-pyridyl]amino]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; 3-[[6-[[5-(trifluoromethyl)-2-pyridyl]amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 4-[6-[[6-(trifluoromethyl)-2-pyridyl]amino]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 4-[6-[(2-fluoro-4-pyridyl)amino]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; 3-[[6-[(2-fluoro-4-pyridyl)amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 3-[[6-[4-(1-piperidyl)anilino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - tert-butyl 4-[4-[2-[(1R,2S,6R,7S)-3,5-dioxo-4-azatricyclo[5.2.1.02,6]dec-8-en-4-yl]-1,3-benzothiazol-6-yl]phenyl]piperazine-1-carboxylate; - 4-[6-(4-morpholinophenyl)-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; 9. The compound for use according to claim 8, selected from: or a pharma- ceutically acceptable salt or optical isomer, racemate, diastereoisomer, enantiomer or tautomer thereof.

10. The compound of formula (I) R １ is H; R ２ is H; R ３ but, - Straight or branched chain -(C １ -C ６ ) alkyl; - Straight or branched chain -(C １ -C ６ ) alkoxy; Linear or branched chain (C ２ -C ６ ) alkynyl; -OR; -NHR; one or more linear or branched chains, optionally substituted by one or more halogen atoms -(C １ -C ６ ) alkyl, linear or branched chain optionally substituted with one or more halogen atoms -(C １ -C ６ ) alkoxy, optionally substituted by NRaRb; ６ -C １０ ) aryl; is selected from, and R is, - Straight or branched chain -(C １ -C ６ ) alkyl; one or more linear or branched chains, optionally substituted by one or more halogen atoms -(C １ -C ６ Optionally substituted by alkyl, —(C ６ -C １０ ) aryl; Heteroaryl containing 3 to 10 ring members, having at least one heteroatom selected from O, N or S; linear or branched -(C １ -C ６ ) the heteroaryl optionally substituted by alkyl; is selected from Ra and Rb are linked together to form a heterocycloalkyl containing 3 to 10 ring members; one or more linear or branched -(C １ -C ６ ) alkyl, —COO—(C １ -C ３ ) alkyl, -NRcRd; forming said heterocycloalkyl optionally substituted by oxo; and Rc and Rd are the same or different; -H; and Linear or branched chain - (C １ -C ６ ) Alkyl Selected from A compound for use according to claim 8.

11. The compound of formula (I) R １ is H; R ２ is H; R ３ but, Linear or branched chain - (C １ -C ３ ) alkyl, preferably methyl; Trifluoromethoxy; ethoxy; 3,3-dimethylbut-1-ynyl; -OR, -NHR; phenyl optionally substituted by one or more trifluoromethyl, methoxy, trifluoromethoxy and / or piperidyl; is selected from, and R is, - linear or branched -(C １ -C ３ ) alkyl; phenyl optionally substituted by one or more methyl and / or trifluoromethyl; Heteroaryl containing 6 ring members and having at least one nitrogen atom; said heteroaryl being optionally substituted by one or more trifluoromethyl, trifluoromethoxy and / or fluorine; for example pyridyl substituted by one or more trifluoromethyl, trifluoromethoxy and / or fluorine. Selected from A compound for use according to any one of claims 8 or 10, characterized in that it is

12. The compound of formula (I) is 3-[(6-ethoxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-(6-ethoxy-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; 3-[[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; 3-[[6-(3,3-dimethylbut-1-ynyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 3-[[6-(4-methoxyphenyl)-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 3-[[6-[4-(trifluoromethoxy)phenyl]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 3-[[6-[4-(trifluoromethyl)phenyl]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-[6-[4-(trifluoromethyl)phenyl]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 3-[(6-methyl-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 4-(6-methyl-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 3-[(6-phenoxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - (1R,2S,6R,7S)-4-(6-phenoxy-1,3-benzothiazol-2-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - [2-hydroxy-1,1-bis(hydroxymethyl)ethyl]ammonium; (1R,2S,3R,4S)-3-[(6-phenoxy-1,3-benzothiazol-2-yl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylate; 3-[[6-[[4-(trifluoromethyl)-2-pyridyl]oxy]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 3-[[6-[(4-fluoro-2-pyridyl)amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 3-[[6-[(5-fluoro-2-pyridyl)amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 3-[[6-[(6-fluoro-2-pyridyl)amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 4-[6-[[2-(trifluoromethyl)-4-pyridyl]amino]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; 3-[[6-[[5-(trifluoromethoxy)-2-pyridyl]amino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; - 4-[6-[[5-(trifluoromethyl)-2-pyridyl]amino]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; - 4-[6-[[6-(trifluoromethyl)-2-pyridyl]amino]-1,3-benzothiazol-2-yl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione; 3-[[6-[4-(1-piperidyl)anilino]-1,3-benzothiazol-2-yl]carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; 12. The compound for use according to any one of claims 8 to 11, selected from: or a pharma- ceutically acceptable salt or optical isomer, racemate, diastereoisomer, enantiomer or tautomer thereof.

13. A compound for use according to any one of claims 8 to 12 in the prevention and / or treatment of mycobacterial infections or in the treatment of a disease caused by infection with mycobacteria.

14. 14. The compound for use according to claim 13, wherein the mycobacterial infection is a Mycobacterium tuberculosis infection.

15. A compound for use according to any one of claims 8 to 14 for the prevention and / or treatment of tuberculosis.

16. A compound for use according to any one of claims 8 to 15 in combination with at least one other antimycobacterial agent.

17. A combination of (a) a compound of formula (I) as defined in any one of claims 8 to 12, and (b) at least one other antimycobacterial agent.

18. The pharmaceutical composition according to claim 7, the compound for use according to claim 16 or the combination according to claim 17, wherein the at least one other anti-mycobacterial agent is an anti-tuberculosis agent.

19. 19. The pharmaceutical composition according to claim 18, the compound for use according to claim 18 or the combination according to claim 18, wherein the antituberculous agent is selected from nitroimidazole compounds, such as pretomanid and delamanid.

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