HK1245253B - Parg inhibitory compounds - Google Patents

Description

PARG inhibitory compounds

Technical Field

The present invention relates to certain compounds that are useful as inhibitors of PARG (poly ADP-ribose glycohydrolase) enzyme activity. The present invention also relates to processes for preparing these compounds, to pharmaceutical compositions containing them, and to their use in the treatment of proliferative diseases such as cancer and other diseases or conditions in which PARG activity is implicated.

Background Art

Cancer is caused by uncontrolled and unregulated cell proliferation. This often rapid proliferation results in high levels of oxidative stress within tumors, which damages DNA and leads to a substantial increase in mutation rates. Consequently, tumor cells engage and rely heavily on DNA damage repair mechanisms.

Single-strand breaks (SSBs) are the most common type of lesion generated in cells, and PARG (poly ADP-ribose glycohydrolase) and PARP, along with many other proteins, are involved in single-strand break repair (SSBR) as well as in another repair mechanism called base excision repair (BER).

One of the earliest events during single-strand DNA repair is the break to which PARP (poly ADP-ribose polymerase) is bound and the rapid synthesis of poly ADP-ribose (PAR) from PARP itself. This molecular structure acts as a signal to recruit other DNA repair proteins, primarily XRCC1, which then repair the break (Mortusewicz, Fouquerel et al. 2011). The signal initiated by these PAR chains is short-lived because they are rapidly degraded by PAR glycohydrolase (PARG). When PARP is bound to PAR, its catalytic activity is reduced, and therefore PARG activity helps restore PARP to its catalytically active form (Curtin and Szabo 2013).

PARG exists as a single gene with isoforms present in the nucleus, mitochondria, and cytosol. The only other known protein with glycohydrolase activity is ARH3, which is localized to the mitochondria (Mashimo, Kato et al. 2014). Although known primarily for its direct role in DNA repair, PARG affects PAR signaling in splicing, transcription, and epigenetic pathways (Ji and Tulin 2009) (Le May, Iltis et al. 2012) (Dahl, Maturi et al. 2014) (Guastafierro, Catizone et al. 2013) (Caiafa, Guastafierro et al. 2009).

Cancer cells may become reliant on specific DNA repair pathways when other mechanisms of DNA repair are ineffective. Tumors harboring mutations in proteins involved in double-strand break repair are often more sensitive to PARP inhibitors of SSBR. There is some evidence that PARG depletion inhibits SSBR and reduces the survival of BRCA2-deficient cells (Fathers, Drayton et al. 2012). However, other tumor mutations may cause defects in double-strand DNA repair mechanisms (so-called "BRCAization"), thereby sensitizing tumor cells to PARG inhibition.

PARG depletion has been studied in many mouse and human model systems. Mouse cells that are null or deficient in PARG have increased sensitivity to experimental and clinical DNA damaging agents. However, due to the lack of PARG, all drugs (e.g., gemcitabine, camptothecin) are insensitive, indicating that PARG function is specific for certain DNA damage repair and chemotherapy and radiotherapy pathways (Fujihara, Ogino et al. 2009) (Shirai, Fujimori et al. 2013) (Zhou, Feng et al. 2010) (Zhou, Feng et al. 2011).

In humans, PARG depletion sensitizes lung, cervical, and pancreatic cancer cells to γ-irradiation or experimental DNA damaging agents (e.g., hydrogen peroxide, methyl methanesulfonate) (Ame, Fouquerel et al. 2009) (Nakadate, Kodera et al. 2013) (Shirai, Poetsch et al. 2013).

PARP inhibitors are currently undergoing a series of clinical trials in which the concepts of synthetic lethality or chemosensitization are being explored. Clinical resistance to PARP inhibitors has been described (Drost and Jonkers 2014) (Barber, Sandhu et al. 2013), and there is therefore a demand for alternative inhibitors that target DNA damage repair mechanisms. Since PARG depletion results in a reduction in the rate of SSBR to the same extent as depletion of PARP1, PARG inhibition may provide a therapeutic advantage in PARP inhibitor-resistant cells (Fisher, Hochegger et al. 2007). Furthermore, depletion of PARG has been reported to result in a gene expression pattern that is significantly different from that of PARP depletion in breast cancer cells (Frizzell, Gamble et al. 2009).

Although current models suggest that PARG depletion leads to PARP-dependent effects on DNA repair, recent studies have shown mechanistic differences from PARP inhibition. Following genotoxic stimulation of PARG, in contrast to PARP depletion, PARG depletion leads to a decrease in NAD levels. This results in lung cancer cell death, which may be a result of energy failure (Erdelyi, Bai et al. 2009).

Cell permeable PARG inhibitors are limited to compounds such as tannic acid or gallotannin, which have questionable specificity for PARG and limited bioavailability (Sun, Zhang et al. 2012) (Fathers, Drayton et al. 2012) (Blenn, Wyrsch et al. 2011).

The object of the present invention is to provide specific cell-permeable inhibitors of PARG.

Summary of the Invention

In one aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof.

In another aspect, the present invention provides a pharmaceutical composition as defined herein, comprising a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable excipients.

In another aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in therapy.

In another aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in treating a proliferative disorder.

In another aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in treating cancer. In specific embodiments, the cancer is a human cancer.

In another aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in producing a PARG inhibitory effect.

In another aspect, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of a proliferative disorder.

In another aspect, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer. Suitably, the medicament is for the treatment of cancer in a human.

In another aspect, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for producing a PARG inhibitory effect.

In another aspect, the present invention provides a method of inhibiting PARG in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof.

In another aspect, the present invention provides a method of inhibiting cell proliferation in vitro or in vivo, the method comprising contacting the cell with an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof.

In another aspect, the present invention provides a method of treating a proliferative disease in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein.

In another aspect, the present invention provides a method of treating cancer in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein.

The present invention also provides a method for synthesizing a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof.

In another aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, obtainable by, or by, or directly by a synthetic method as defined herein.

In another aspect, the invention provides novel intermediates as defined herein suitable for use in any of the synthetic methods set out herein.

Preferred, suitable and optional features of any particular aspect of the invention are also preferred, suitable and optional features of any other aspect.

Detailed Description of the Invention

definition

Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below.

It should be understood that references to "treating" or "treatment" include preventing as well as alleviating established symptoms of a condition. Thus, "treating" or "treatment" of a condition, disorder, or condition includes: (1) preventing or delaying the appearance of clinical symptoms of the condition, disorder, or condition that develops in a human being who is suffering from or susceptible to the condition, disorder, or condition but who does not yet experience or display clinical or subclinical symptoms of the condition, disorder, or condition; (2) inhibiting the condition, disorder, or condition, i.e., arresting, reducing, or delaying the development of the condition or its recurrence (in the case of maintenance therapy) or the development of at least one clinical or subclinical symptom thereof; or (3) alleviating or slowing the condition, i.e., causing regression of the condition, disorder, or condition or at least one clinical or subclinical symptom thereof.

"Therapeutically effective amount" means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to affect such treatment of the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal to be treated.

In this specification, the term "alkyl" includes both straight-chain and branched-chain alkyl groups. References to individual alkyl groups such as "propyl" are specific only to the straight-chain version, and references to individual branched-chain alkyl groups such as "isopropyl" are specific only to the branched version. For example, "(1-6C)alkyl" includes (1-4C)alkyl, (1-3C)alkyl, propyl, isopropyl, and tert-butyl. Similar conventions apply to other groups, for example, "phenyl(1-6C)alkyl" includes phenyl(1-4C)alkyl, benzyl, 1-phenylethyl, and 2-phenylethyl.

The term "(m-nC)" or "(m-nC) group" used alone or as a prefix refers to any group having from m to n carbon atoms.

An "alkylene," "alkenylene," or "alkynylene" group is an alkyl, alkenyl, or alkynyl group that is positioned between and serves to link two other chemical groups. Thus, "(1-6C)alkylene" refers to a straight-chain, saturated divalent hydrocarbon radical having from one to six carbon atoms or a branched, saturated divalent hydrocarbon radical having from three to six carbon atoms, for example, methylene, ethylene, propylene, 2-methylpropylene, pentylene, and the like.

"(2-6C)alkenylene" refers to a straight-chain divalent hydrocarbon group having two to six carbon atoms or a branched-chain divalent hydrocarbon group having three to six carbon atoms containing at least one double bond, for example, vinylene, 2,4-pentadienylene, and the like.

"(2-6C)alkynylene" refers to a straight-chain divalent hydrocarbon group having two to six carbon atoms or a branched-chain divalent hydrocarbon group having three to six carbon atoms, containing at least one triple bond, for example, ethynylene, propynylene, butynylene, and the like.

"(3-8C)cycloalkyl" means a hydrocarbon ring containing from 3 to 8 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or bicyclo[2.2.1]heptyl.

"(3-8C)cycloalkenyl" means a hydrocarbon ring containing at least one double bond, for example cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl, for example 3-cyclohexen-1-yl or cyclooctenyl.

"(3-8C)cycloalkyl-(1-6C)alkylene" means a (3-8C)cycloalkyl group covalently attached to a (1-6C)alkylene group, both as defined herein.

The term "halo" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

The term "heterocyclyl,""heterocyclic," or "heterocycle" means one or more non-aromatic, saturated or partially saturated monocyclic, fused, bridged, or spirobicyclic heterocyclic ring systems. The term heterocyclyl includes both monovalent and divalent species. Monocyclic heterocycles contain from about 3 to 12 (suitably from 3 to 7) ring atoms, having from 1 to 5 (suitably 1, 2, or 3) heteroatoms selected from nitrogen, oxygen, or sulfur in the ring. Bicyclic heterocycles contain from 7 to 17 member atoms, suitably 7 to 12 member atoms, in the ring. Bicyclic heterocycles contain from about 7 to about 17 (suitably from 7 to 12) ring atoms. One or more bicyclic heterocycles may be fused, spiro, or bridged ring systems. Examples of heterocyclic groups include cyclic ethers such as oxiranyl, oxetane, tetrahydrofuranyl, dioxanyl, and substituted cyclic ethers. Nitrogen-containing heterocycles include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, tetrahydropyrazolyl, etc. Typical sulfur-containing heterocycles include tetrahydrothiophene, dihydro-1,3-dithiol, tetrahydro-2H-thiopyran and hexahydrothiazolyl. Other heterocycles include dihydro-oxathiolyl, tetrahydro-oxazolyl, tetrahydrooxadiazolyl, tetrahydrodioxazolyl, tetrahydro-oxathiazolyl, hexahydrotriazinyl, tetrahydro-oxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl and octahydrobenzothiazolyl. For sulfur-containing heterocycles, oxidized sulfur heterocycles containing SO or _SO groups are also included. Examples include tetrahydrothiophene and thiomorpholinyl in their sulfoxide and sulfone forms, such as tetrahydrothiophene 1,1-dioxide and thiomorpholinyl 1,1-dioxide. Suitable values for heterocyclyl groups carrying one or two oxo (=O) or thio (=S) substituents are, for example, 2-oxopyrrolidinyl, 2-thiopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl. Specific heterocyclic radical group is the saturated monocyclic 3 to 7 membered heterocyclic radicals comprising 1,2 or 3 heteroatoms selected from nitrogen, oxygen or sulphur, such as azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothiophenyl, tetrahydrothiophenyl 1,1-dioxide, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, piperidyl, homopiperidyl, piperazinyl or homopiperazinyl. As will be appreciated by the skilled artisan, any heterocycle can be connected to another group via any suitable atom, such as via carbon or nitrogen-atoms. However, mentioning piperidyl or morpholinyl herein refers to piperidin-1-yl or morpholine-4-yl rings connected by ring nitrogen.

"Bridged ring system" means a ring system in which two rings share more than two atoms, see, e.g., Advanced Organic Chemistry, Jerry March, ^4th Edition, Wiley Interscience, pages 131-133, 1992. Examples of bridged heterocyclic ring systems include aza-bicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, aza-bicyclo[2.2.2]octane, aza-bicyclo[3.2.1]octane, and quinuclidine.

"Heterocyclyl(1-6C)alkyl" means a heterocyclyl group covalently attached to a (1-6C)alkylene group, both as defined herein.

The term "heteroaryl" or "heteroaromatic" refers to an aromatic monocyclic, bicyclic or polycyclic ring having one or more (e.g., 1-4, particularly 1, 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur. The term heteroaryl includes both monovalent and divalent species. Examples of heteroaryl groups are monocyclic and bicyclic groups containing from five to twelve ring members, and more typically from 5 to 10 ring members. A heteroaryl group can be, for example, a 5- or 6-membered monocyclic or a 9- or 10-membered bicyclic ring, such as a bicyclic structure formed by a fused five-membered and six-membered ring or two fused six-membered rings. Each ring can contain up to about four heteroatoms typically selected from nitrogen, sulfur and oxygen. Typically, the heteroaryl ring will contain up to 3 heteroatoms, more typically up to 2, such as a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl ring can be basic, as in the case of imidazole or pyridine, or substantially non-basic, as in the case of indole or pyrrole nitrogen. Generally, the number of basic nitrogen atoms present in a heteroaryl group (including any amino group substituent of the ring) will be less than five.

Examples of heteroaryl groups include furanyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, benzofuranyl, indolyl, isoindolyl, benzothiophenyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, Cinnolinyl, pteridinyl, naphthyridinyl, carbazolyl, phenazinyl, benzoisoquinolinyl, pyridopyrazinyl, thieno[2,3-b]furanyl, 2H-furo[3,2-b]-pyranyl, 5H-pyrido[2,3-d]-oxazinyl, 1H-pyrazolo[4,3-d]-oxazinyl, 4H-imidazo[4,5-d]thiazolyl, pyrazino[2,3-d]pyridazinyl, imidazo[2,1-b]thiazolyl, imidazo[1,2-b][1,2,4]triazinyl. "Heteroaryl" also encompasses partially aromatic bicyclic or polycyclic ring systems in which at least one ring is aromatic and one or more other rings are non-aromatic, saturated or partially saturated, provided that at least one ring contains one or more heteroatoms selected from nitrogen, oxygen or sulfur. Examples of some aromatic heteroaryl groups include, for example, tetrahydroisoquinolyl, tetrahydroquinolyl, 2-oxo-1,2,3,4-tetrahydroquinolyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,3]dioxolyl, 2,2-dioxo-1,3-dihydro-2-benzothiophenyl, 4,5,6,7-tetrahydrobenzofuranyl, dihydroindole, 1,2,3,4-tetrahydro-1,8-naphthyridinyl, 1,2,3,4-tetrahydropyrido[2,3b]pyrazinyl, and 3,4-dihydro-2Hpyrido[3,2b][1,4]oxazinyl.

Examples of five-membered heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, and tetrazolyl groups.

Examples of six-membered heteroaryl groups include, but are not limited to, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazinyl.

The bicyclic heteroaryl group may be, for example, a group selected from:

a benzene ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms;

a pyridine ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms;

a pyrimidine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

a pyrrole ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms;

a pyrazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

a pyrazine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

an imidazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

an oxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

an isoxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

a thiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

an isothiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

a thiophene ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms;

a furan ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms;

a cyclohexyl ring fused to a 5- or 6-membered heteroaromatic ring containing 1, 2, or 3 ring heteroatoms; and

A cyclopentyl ring fused to a 5- or 6-membered heteroaromatic ring containing 1, 2 or 3 ring heteroatoms.

Specific examples of bicyclic heteroaryl groups comprising a six-membered ring fused to a five-membered ring include, but are not limited to, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl (e.g., adeninyl, guaninyl), indazolyl, benzodioxolyl, and pyrazolopyridinyl groups.

Specific examples of bicyclic heteroaryl groups comprising two fused six-membered rings include, but are not limited to, quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochromenyl, chromanyl, isochromanyl, benzodioxanyl, quinolizinyl, benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, and pteridinyl groups.

"Heteroaryl(1-6C)alkyl" means a heteroaryl group covalently attached to a (1-6C)alkylene group, both as defined herein. Examples of heteroarylalkyl include pyridin-3-ylmethyl, 3-(benzofuran-2-yl)propyl, and the like.

The term "aryl" means a cyclic or polycyclic aromatic ring having from 5 to 12 carbon atoms. The term aryl includes both monovalent and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, and the like. In a specific embodiment, aryl is phenyl.

The term "aryl(1-6C)alkyl" means an aryl group covalently attached to a (1-6C)alkylene group, both as defined herein. Examples of aryl-(1-6C)alkyl groups include benzyl, phenylethyl, and the like.

This specification also uses several composite terms to describe groups that include more than one functionality. These terms will be understood by those skilled in the art. For example, heterocyclyl (m-nC) alkyl includes (m-nC) alkyl substituted with a heterocyclyl.

The term "optionally substituted" refers to substituted groups, structures or molecules as well as unsubstituted groups, structures or molecules. The term "wherein one/any CH, CH ₂ , CH ₃ group or heteroatom (i.e., NH) in the R ¹ group is optionally substituted" means that (any) one hydrogen radical of the R ¹ group is replaced by the relevant specified group.

When optional substituents are selected from "one or more" groups, it is to be understood that this definition includes all substituents selected from one of the specified groups or substituents selected from two or more of the specified groups.

The phrase "compounds of the invention" refers to those compounds disclosed both generally and specifically herein.

Compounds of the present invention

In one aspect, the present invention relates to compounds of formula (I) shown below:

in:

Bond c does not exist or is a single bond;

R _1a is selected from hydrogen, fluorine, chlorine, cyano, formyl, (1-2C)alkyl, (1-2C)haloalkyl, (2C)alkenyl or (2C)alkynyl;

R _1b , R _1c , R _1d and R _1e are each independently selected from H, fluoro or methyl;

W is selected from -NH-S(O) _y- , -S(O) _y -NH-, -C(O)NH-, -NHC(O)-, -NH-S(O)(NH)-, -S(O)(NH)-NH-, wherein y is 0, 1 or 2;

X ₁ is selected from CR ₂ or N; wherein R ₂ is H or fluorine;

X ₂ is selected from CR ₃ or N; wherein R ₃ is H or fluorine;

X ₃ is selected from CR ₄ or N; wherein R ₄ is H, halogen, cyano, (1-2C) alkyl, (1-2C) haloalkyl, (1-2C) alkoxy, (1-2C) haloalkoxy or (2C) alkynyl; or

_R4 is selected from the group having the following chemical formula:

-L ₄ -L _4C -Q _4C

in

L ₄ is absent or is (1-3C)alkylene optionally substituted with (1-2C)alkyl or oxo;

L _4C is absent or selected from O, S, SO, SO ₂ , N(R _4b ), C(O), C(O)O, OC(O), C(O)N(R _4b ), N(R _4b )C(O), N(R _4b )C(O)N(R _4c ), S(O) ₂ N(R _4b ), or N(R _4b )SO ₂ , wherein R _4b and R _4c are each independently selected from hydrogen or (1-2C)alkyl; and

_Q4C is hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein _Q6C is optionally replaced by one or more groups selected from halogen, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, amino, carboxyl, carbamoyl, sulfamoyl, (1-4C)alkyl, _NR4dR4e , _OR4d , C(O) _R4d , C(O) _OR4d , OC(O) _R4d , C(O)N( _R4e ) _R4d , N( _R4e )C(O) _{R4d , S(O)yR4d ( wherein y} is 0, 1 or 2 ₎ , _SO2N ( _R4e ) _R4d , _N ( _R4e ) _SO2R4d or ( _CH2 ) _zNR4eR4d (wherein z is 1, 2 or 3), wherein R _4d and R _4e are each independently selected from H or (1-4C)alkyl;

HET is a fused 5-membered saturated, partially saturated or unsaturated heterocyclic ring having the formula:

in

Bond a is optionally a double bond;

R ₅ is H, (1-4C) alkyl or a group having the following chemical formula:

-L ₁ -L ₅ -Q ₅

in

L ₁ is absent or selected from (1-3C)alkylene optionally substituted with (1-2C)alkyl or oxo, or (2-3C)alkenylene or (2-3C)alkynylene linkers optionally substituted with (1-2C)alkyl;

_L5 is absent or selected from C(O), C(O)O, OC(O), C(O)N(R _a ), N(R _a )C(O), N(R _a )C(O)N(R _b ), S(O) ₂ N(R _a ), N(R _a )SO ₂ , wherein R _a and R _b are each independently selected from hydrogen or (1-2C)alkyl; and

_Q5 is selected from hydrogen, (1-4C)alkyl, aryl, 5-6 membered heteroaryl, (4-6C)cycloalkyl, (4-6C)cycloalkenyl, (2C)alkenyl or 5-6 membered heterocyclyl;

and wherein _Q5 is optionally substituted by one or more substituents selected from (1-4C)alkyl, halogen, amino, cyano, amino, carboxyl, carbamoyl, sulfamoyl, trifluoromethoxy, haloalkyl, _NRcRd , _ORc , C(O) _Rc , C(O) _ORc , OC(O) _Rc , _C (O)N( _Rc ) _Rd , N( _Rc )C(O) _Rd , S(O) _{yRc (} wherein y is 0, 1 or 2), _SO2N ( _Rc ) _Rd , N(Rc) _SO2Rd , or ( _{CH2 ) zNRcRd} (wherein z is 1, 2 or 3), wherein _{Rc and Rd are} each independently selected from H _or (1-4C)alkyl _;

Or Q ₅ is optionally substituted with a group having the following formula:

-W ₅ -Y ₅ -Z ₅

in

_W5 is absent or selected from (1-3C)alkylene optionally substituted with (1-2C)alkyl or oxo, or (2-3C)alkenylene or (2-3C)alkynylene linkers optionally substituted with (1-2C)alkyl;

_Y5 is absent or selected from C(O), C(O)O, OC(O), C(O)N( _Re ), N( _Re )C(O), N( _Re )C(O)N( _Rf ), S(O) _2N ( _Re ), N( _Re ) _SO2 , wherein _Re and _Rf are each independently selected from hydrogen or (1-2C)alkyl; and

_Z is selected from hydrogen, (1-4C)alkyl, phenyl, 5- or 6-membered heterocyclyl, or 5-6-membered heteroaryl; and wherein _Z is optionally substituted with one or more substituents selected from (1-4C)alkyl, halogen, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxy, carboxyl, carbamoyl, or sulfamoyl;

When bond a is a single bond, X ₄ is selected from C(═O), C(═NH), C(═S), CHR _6c or NR _6N , or when bond a is a double bond, X ₄ is selected from CR _6c or N;

in

R _6c is selected from hydrogen, cyano, halogen or a group having the following chemical formula:

-L ₆ -L _6C -Q _6C

in

L ₆ is absent or is (1-3C)alkylene optionally substituted by (1-2C)alkyl or oxo;

L _6C is absent or selected from O, S, SO, SO ₂ , N(R _g ), C(O), C(O)O, OC(O), C(O)N(R _g ), N(R _g )C(O), N(R _g )C(O)N(R _h ), S(O) ₂ N(R _g ) or N(R _g )SO ₂ , wherein R _g and R _h are each independently selected from hydrogen or (1-2C)alkyl; and

_Q6C is hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl, or heteroaryl, each of which is optionally substituted with one or more substituents selected from (1-4C)alkyl, halogen, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, amino, carboxyl, carbamoyl, sulfamoyl, NR1Rj, _OR1 , C(O) _R1 , _C (O) _OR1 , OC(O) _R1 , C(O) _N ( _R1 ) _Rj , N( _R1 )C(O) _Rj , S(O) _yR1 (wherein y is 0, 1, or 2), _SO2N ( _R1 ) _Rj , N( _R1 ) _{SO2Rj ,} or ( _CH2 ) _zNR1Rj (wherein z is 1 _, 2, or 3), wherein _R1 and _Rj are each independently selected from _{H or} (1-4C)alkyl;

R _6N is selected from hydrogen or a group having the following chemical formula:

-L ₆ -L _6N -Q _6N

in

L ₆ is absent or is (1-3C)alkylene optionally substituted by (1-2C)alkyl or oxo;

L _6N is absent or selected from O, S, SO, SO ₂ , N(R _k ), C(O), C(O)O, OC(O), C(O)N(R _k ), N(R _k )C(O), N(R _k )C(O)N(R _l ), S(O) ₂ N(R _k ) or N(R _k )SO ₂ , wherein R _k and R _l are each independently selected from hydrogen or (1-2C)alkyl; and

_Q6N is hydrogen, cyano, (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl, or heteroaryl, each of which is optionally substituted with one or more substituents selected from (1-4C)alkyl, halogen, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, amino, carboxyl, carbamoyl, sulfamoyl, _NRmRn , _ORm , C(O) _Rm , C(O) _ORm , OC(O) _Rm , C(O)N( _Rm ) _Rn , N( _Rm )C(O _{) Rn} , S(O) _yRm (wherein y is 0, 1, or 2), _SO2N ( _Rm ) _Rn , N( _Rm ) _SO2Rn , or ( _CH2 ) _zNRmRn (wherein _z is 1, ₂ , or 3), wherein _Rm and _Rn are each independently selected _from H or (1-4C)alkyl _;

When bond a is a single bond, X ₅ is selected from C(═O), C(═NH), C(═S), CHR _7c or NR _7N , or when bond a is a double bond, X ₄ is selected from CR _7c or N;

in

R _7c is selected from hydrogen, cyano, halogen or a group having the following chemical formula:

-L ₇ -L _7C -Q _7C

in

L ₇ is absent or is (1-3C)alkylene optionally substituted by (1-2C)alkyl or oxo;

L _7C is absent or selected from O, S, SO, SO ₂ , N(R ₀ ), C(O), C(O)O, OC(O), C(O)N(R ₀ ), N(R ₀ )C(O), N(R ₀ )C(O)N(R _p ), S(O) ₂ N(R ₀ ) or N(R ₀ )SO ₂ , wherein R ₀ and R _p are each independently selected from hydrogen or (1-2C)alkyl; and

_Q7C is hydrogen, cyano, (1-6C)alkyl, (2C)alkynyl, (2-3C)alkenyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein _Q8C is optionally replaced by one or more groups selected from (1-4C)alkyl, halogen, trifluoromethyl, trifluoromethoxy, amino, cyano, nitro, hydroxy, _{amino, carboxyl, carbamoyl, sulfamoyl, NRqRr, ORq, C(O)Rq, C(O)ORq, OC(O)Rq , C ( O )} N( _Rq ) _Rr , N( _Rq )C(O) _{Rr , S(O)yRq ( wherein} y is 0, 1 or 2), _SO2N ( _Rq ) _Rr , _N ( _Rq ) _SO2Rr or ( _{CH2 ) zNRqRr} (wherein z is 1, 2 or 3), wherein _Rq and _Rr are each independently selected from H or (1-4C)alkyl; or

Q _7C is optionally substituted with a group having the following formula:

-W _7C -L _7' -Z _7C

in

W _7C is absent or is a (1-3C)alkylene group substituted by a (1-2C)alkyl group or an oxo group;

L _7′ is absent or selected from C(O), C(O)O, OC(O), C(O)N(R _s ), N(R _s )C(O), N(R _s )C(O)N(R _t ), S(O) ₂ N(R _s ), N(R _s )SO ₂ , wherein R _s and R _t are each independently selected from hydrogen or (1-2C)alkyl; and

Z _7C is phenyl or 5-6 membered heteroaryl; each of which is optionally substituted with one or more substituents selected from (1-4C)alkyl, halogen, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxy, carboxyl, carbamoyl or sulfamoyl;

R _7N is selected from hydrogen or a group having the following chemical formula:

-L ₇ -L _7N -Q _7N

in

L ₇ is absent or is (1-3C)alkylene optionally substituted by (1-2C)alkyl;

L _7N is absent or selected from O, S, SO, SO ₂ , N(R _u ), C(O), C(O)O, OC(O), C(O)N(R _u ), N(R _u )C(O), N(R _u )C(O)N(R _v ), S(O) ₂ N(R _u ) or N(R _u )SO ₂ , wherein R _u and R _v are each independently selected from hydrogen or (1-2C)alkyl; and

_Q7N is hydrogen, cyano, (1-6C)alkyl, (2C)alkynyl, (2-3C)alkenyl, (3-6C)cycloalkyl, aryl, heterocyclyl, or heteroaryl, each of which is optionally substituted with one or more substituents selected from (1-4C)alkyl, halogen, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, amino, carboxyl, carbamoyl, sulfamoyl, _NRwRx , _ORw , _C (O)Rw, C(O) _{ORw ,} OC(O) _Rw , C(O)N( _Rw ) _Rx , N( _Rw )C(O) _Rx , S(O) _{yRw (} wherein y is 0, 1, or 2), _SO2N ( _Rw ) _{Rx ,} N( _Rw ) _SO2Rx , or ( _CH2 ) _zNRwRx (wherein _{z is} 1, 2, or 3), wherein _Rw and R Each _x is independently selected from H or (1-4C)alkyl; or

Q _7N is optionally substituted with a group having the following formula:

-W _7N -L _7' -Z _7N

in

W _7N is absent or is (1-3C)alkylene optionally substituted by (1-3C)alkyl;

L _7′ is absent or selected from C(O), C(O)O, OC(O), C(O)N(R _y ), N(R _y )C(O), N(R _y )C(O)N(R _z ), S(O) ₂ N(R _y ), N(R _y )SO ₂ , wherein R _y and R _z are each independently selected from hydrogen or (1-2C)alkyl; and

Z _7N is phenyl or 5-6 membered heteroaryl; each of which is optionally substituted with one or more substituents selected from (1-4C)alkyl, halogen, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxy, carboxyl, carbamoyl or sulfamoyl;

The premise is:

(i) only one or two of R _1b-e may be selected from any substituent other than H;

(ii) only one or two of X ₁ , X ₂ or X ₃ may be N;

(iii) Het may contain up to 2 ring nitrogen atoms only; and

(iv) Only one of X ₄ or X ₅ may be selected from C(═O), C(═NH) or C(═S).

Specific compounds of the present invention include, for example, compounds of Formula I or pharmaceutically acceptable salts and/or solvates thereof, wherein, unless otherwise indicated, c, R _1a , R _1b , R _1c , R _1d , R _1e , W, X ₁ , X ₂ , X ₃ , X ₄ , X ₅ , R ₅ and any associated substituents have any of the meanings defined above or in any of paragraphs (1) to (55) below:

(1) c is a single bond;

(2) R _1a is selected from hydrogen, fluorine, cyano, formyl, (1-2C)alkyl, (1-2C)haloalkyl, or (2C)alkynyl;

(3) R _1a is selected from hydrogen, cyano, formyl, (1-2C)alkyl, or (1-2C)haloalkyl;

(4) R _1a is selected from hydrogen, cyano, methyl, or CF ₃ ;

(5) R _1a is selected from hydrogen, cyano, methyl, or fluoromethyl;

(6) R _1a is selected from cyano, methyl, or fluoromethyl;

(7) R _1a is selected from methyl or fluoromethyl;

(8) R _1a is methyl;

(9) R _1b , R _1c , R _1d and R _1e are independently selected from H and fluorine;

(10) R _1b , R _1c , R _1d and R _1e are H;

(11) W is selected from -NH-S(O) _y- , -S(O) _y- NH-, -C(O)NH- or -NHC(O)-, wherein y is 0, 1 or 2;

(12) W is selected from -NH-S(O) ₂ -, -S(O) ₂ -NH-, -C(O)NH- or -NHC(O)-;

(13) W is selected from -NH-S(O) ₂ - or -S(O) ₂ -NH-;

(14) W is -NH-S(O) ₂ -;

(15) X ₁ is N or CR ₂ , wherein R ₂ is H or fluorine;

(16) _X1 is N or CH;

(17) X ₁ is CH;

(18) X ₂ is N or CR ₃ , wherein R ₃ is H or fluorine;

(19) X ₂ is N or CH;

(20) X ₂ is CH or CF;

(21) X ₂ is CH;

(22) X ₃ is selected from CR ₄ or N; wherein R ₄ is H, halogen, cyano, (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)alkoxy, (1-2C)haloalkoxy or (2C)alkynyl; or

_R4 is selected from the group having the following chemical formula:

-L ₄ -L _4C -Q _4C

in

L ₄ is absent or is (1-3C)alkylene optionally substituted with (1-2C)alkyl or oxo;

L _4C is absent or selected from O, S, SO, SO ₂ , N(R _4b ), C(O), C(O)O, OC(O), C(O)N(R _4b ), N(R _4b )C(O), N(R _4b )C(O)N(R _4c ), S(O) ₂ N(R _4b ), or N(R _4b )SO ₂ , wherein R _4b and R _4c are each independently selected from hydrogen or (1-2C)alkyl; and

_Q4C is hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein _Q6C is optionally replaced by one or more groups selected from halogen, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, amino, carboxyl, carbamoyl, sulfamoyl, (1-4C)alkyl, _NR4dR4e , _OR4d , C(O) _R4d , C(O) _OR4d , OC(O) _R4d , C(O)N( _R4e ) _R4d , N( _R4e )C(O) _{R4d , S(O)yR4d ( wherein y} is 0, 1 or 2 ₎ , _SO2N ( _R4e ) _R4d , _N ( _R4e ) _SO2R4d or ( _CH2 ) _zNR4eR4d (wherein z is 1, 2 or 3), wherein R _4d and R _4e are each independently selected from H or (1-4C)alkyl;

(23) X ₃ is selected from CR ₄ or N; wherein R ₄ is H, halogen, cyano, (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)alkoxy, (1-2C)haloalkoxy or (2C)alkynyl; or

_R4 is selected from the group having the following chemical formula:

-L ₄ -L _4C -Q _4C

in

L ₄ is absent or is (1-3C)alkylene optionally substituted with (1-2C)alkyl or oxo;

L _4C is absent or selected from O, S, SO, SO ₂ , N(R _4b ), C(O), C(O)O, OC(O), C(O)N(R _4b ), N(R _4b )C(O), N(R _4b )C(O)N(R _4c ), S(O) ₂ N(R _4b ), or N(R _4b )SO ₂ , wherein R _4b and R _4c are each independently selected from hydrogen or (1-2C)alkyl; and

Q _4C is hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Q _6C is optionally substituted with one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, amino, carboxyl, carbamoyl or sulfamoyl;

(24) X ₃ is selected from CR ₄ or N; wherein R ₄ is H, halogen, cyano, (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)alkoxy, (1-2C)haloalkoxy or (2C)alkynyl; or

_R4 is selected from the group having the following chemical formula:

-L ₄ -L _4C -Q _4C

in

L ₄ is absent or is (1-3C)alkylene optionally substituted with (1-2C)alkyl or oxo;

L _4C is absent or selected from SO ₂ , N(R _4b ), C(O), C(O)O, OC(O), C(O)N(R _4b ), N(R _4b )C(O), wherein R _4b is selected from hydrogen or (1-2C)alkyl; and

_Q4C is hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein _Q6C is optionally replaced by one or more groups selected from halogen, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, amino, carboxyl, carbamoyl, sulfamoyl, (1-4C)alkyl, _NR4dR4e , _OR4d , C(O) _R4d , C(O) _OR4d , OC(O) _R4d , C(O)N( _R4e ) _R4d , N( _R4e )C(O) _{R4d , S(O)yR4d ( wherein y} is 0, 1 or 2 ₎ , _SO2N ( _R4e ) _R4d , _N ( _R4e ) _SO2R4d or ( _CH2 ) _zNR4eR4d (wherein z is 1, 2 or 3), wherein R _4d and R _4e are each independently selected from H or (1-4C)alkyl;

(25) X ₃ is selected from CR ₄ or N; wherein R ₄ is H, halogen, cyano, (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)alkoxy, (1-2C)haloalkoxy or (2C)alkynyl; or

_R4 is selected from the group having the following chemical formula:

-L ₄ -L _4C -Q _4C

in

L ₄ is absent or is (1-3C)alkylene optionally substituted with (1-2C)alkyl or oxo;

L _4C is absent or selected from SO ₂ , N(R _4b ), C(O), C(O)O, OC(O), C(O)N(R _4b ), N(R _4b )C(O), wherein R _4b is selected from hydrogen or (1-2C)alkyl; and

Q _4C is hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Q _6C is optionally substituted with one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, amino, carboxyl, carbamoyl or sulfamoyl;

(26) X ₃ is selected from CR ₄ or N; wherein R ₄ is H, halogen, cyano, (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)alkoxy, (1-2C)haloalkoxy or (2C)alkynyl; or

_R4 is selected from the group having the following chemical formula:

-L ₄ -L _4C -Q _4C

in

L ₄ is absent or is (1-2C)alkylene optionally substituted with (1-2C)alkyl or oxo;

L _4C is absent or selected from C(O)O, OC(O), C(O)N(R _4b ), N(R _4b )C(O), wherein R _4b is selected from hydrogen or (1-2C)alkyl; and

Q _4C is hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Q _6C is optionally substituted with one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, amino, carboxyl, carbamoyl or sulfamoyl;

(27) X ₃ is selected from CR ₄ or N; wherein R ₄ is H, halogen, cyano, (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)alkoxy, (1-2C)haloalkoxy or (2C)alkynyl; or

_R4 is selected from the group having the following chemical formula:

-L _4C -Q _4C

in

L _4C is absent or selected from C(O)N(R _4b ), wherein R _4b is selected from hydrogen or (1-2C)alkyl; and

Q _4C is hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Q _6C is optionally substituted with one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, amino, carboxyl, carbamoyl or sulfamoyl;

(28) X ₃ is selected from CR ₄ or N; wherein R ₄ is H, halogen, cyano, (1-2C)alkyl, (1-2C)haloalkyl, or (2C)alkynyl;

(29) X ₃ is selected from CR ₄ or N; wherein R ₄ is H, halogen, (1-2C)alkyl or (1-2C)haloalkyl;

(30) X ₃ is selected from CR ₄ or N; wherein R ₄ is H, fluorine, methyl or CF ₃ ;

(31) X ₃ is selected from CR ₄ or N; wherein R ₄ is H or fluorine;

(32) X ₃ is CH or CF;

(33) when bond a is a single bond, X ₄ is selected from C(═O), C(═NH), C(═S), CHR _6c or NR _6N , or when bond a is a double bond, X ₄ is selected from CHR _6c or N;

in

R _6c is selected from hydrogen, cyano, halogen or a group having the following chemical formula:

-L ₆ -L _6C -Q _6C

in

L ₆ is absent or is (1-3C)alkylene optionally substituted by (1-2C)alkyl or oxo;

L _6C is absent or selected from O, S, SO, SO2, N( _Rg ), C(O), C(O)O, OC(O), C(O)N( _Rg ), N(Rg) _C (O), N( _Rg )C(O)N( _Rh ), S(O)2N( _Rg ) or N( _Rg )SO2, wherein _Rg and _Rh are each independently selected from hydrogen or (1-2C)alkyl; and

Q _6C is hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl, or heteroaryl, each of which is optionally substituted with one or more substituents selected from (1-4C)alkyl, halogen, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, amino, carboxyl, carbamoyl, sulfamoyl, or NR _i R _j (wherein R _i and R _j are each independently selected from H or (1-4C)alkyl);

R _6N is selected from hydrogen or a group having the following chemical formula:

-L ₆ -L _6N -Q _6N

in

L ₆ is absent or is (1-3C)alkylene optionally substituted by (1-2C)alkyl or oxo;

_L6N is absent or selected from O, S, SO, SO2, N( _Rk ), C(O), C(O)O, OC(O), C(O)N( _Rk ), N(Rk)C ₍ O), N( _Rk )C(O)N( _Rl ), S(O)2N( _Rk ) or N( _Rk )SO2, wherein _Rk and _Rl are each independently selected from hydrogen or (1-2C)alkyl; and

Q _6N is hydrogen, cyano, (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted with one or more substituents selected from (1-4C)alkyl, halogen, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, amino, carboxyl, carbamoyl, sulfamoyl or NR _m R _n (wherein R _m and R _n are each independently selected from H or (1-4C)alkyl);

(34) when bond a is a single bond, X ₄ is selected from C(═O), C(═NH), C(═S), CHR _6c or NR _6N , or when bond a is a double bond, X ₄ is selected from CHR _6c or N;

in

R _6c is selected from hydrogen, cyano, halogen or a group having the following chemical formula:

-L ₆ -L _6C -Q _6C

in

L ₆ is absent or is (1-3C)alkylene optionally substituted by (1-2C)alkyl or oxo;

L _6C is absent or selected from O, S, SO, SO ₂ , N(R _g ), C(O), C(O)O, OC(O), C(O)N(R _g ), N(R _g )C(O), N(R _g )C(O)N(R _h ), S(O) 2 N(R _g ) or N(R _g )SO ₂ , wherein R _g and R _h are each independently selected from hydrogen or (1-2C)alkyl; and

Q _6C is hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted with one or more substituents selected from (1-4C)alkyl, halogen, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, carboxyl, carbamoyl, sulfamoyl or NR _i R _j (wherein R _i and R _j are each independently selected from H or (1-4C)alkyl);

R _6N is selected from hydrogen or a group having the following chemical formula:

-L ₆ -Q _6N

in

L ₆ is absent or is (1-3C)alkylene optionally substituted by (1-2C)alkyl or oxo;

Q _6N is hydrogen, cyano, (1-4C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl, or 5- or 6-membered heteroaryl, each of which is optionally substituted with one or more substituents selected from (1-4C)alkyl, halogen, trifluoromethyl, amino, or cyano;

(35) when bond a is a single bond, X ₄ is selected from C(═O), C(═NH), C(═S), CHR _6c or NR _6N , or when bond a is a double bond, X ₄ is selected from CHR _6c or N;

in

R _6c is selected from hydrogen, cyano, halogen or a group having the following chemical formula:

-L ₆ -L _6C -Q _6C

in

L ₆ is absent or is (1-3C)alkylene optionally substituted by (1-2C)alkyl or oxo;

L _6C is absent or selected from O, S, SO, SO ₂ , N(R _g ), C(O), C(O)O, OC(O), C(O)N(R _g ), N(R _g )C(O), N(R _g )C(O)N(R _h ), S(O) ₂ N(R _g ) or N(R _g )SO ₂ , wherein R _g and R _h are each independently selected from hydrogen or (1-2C)alkyl; and

Q _6C is hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted with one or more substituents selected from (1-4C)alkyl, halogen, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, carboxyl, carbamoyl, sulfamoyl or NR _i R _j (wherein R _i and R _j are each independently selected from H or (1-4C)alkyl);

(36) when bond a is a single bond, X ₄ is selected from C(═O), C(═NH), C(═S), CHR _6c or NR _6N , or when bond a is a double bond, X ₄ is selected from CHR _6c or N;

in

R _6c is selected from hydrogen or a group having the following chemical formula:

-L ₆ -L _6C -Q _6C

in

L ₆ is absent or is (1-3C)alkylene optionally substituted with (1-2C)alkyl or oxo;

L _6C is absent or selected from O, S, SO, SO ₂ , N(R _g ), C(O), C(O)O, OC(O), C(O)N(R _g ) or N(R _g )C(O), wherein R _g is selected from hydrogen or (1-2C)alkyl; and

Q _6C is hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, aryl, (3-6C)heterocyclyl, or 5- or 6-membered heteroaryl, each of which is optionally substituted with one or more substituents selected from (1-4C)alkyl, halogen, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, carboxyl, carbamoyl, sulfamoyl, or NR _i R _j (wherein R _i and R _j are each independently selected from H or (1-2C)alkyl);

(37) when bond a is a single bond, X ₄ is selected from C(═O), C(═NH), CHR _6c or NR _6N , or when bond a is a double bond, X ₄ is selected from CR _6c or N;

in

R _6c is selected from hydrogen or a group having the following chemical formula:

-L ₆ -L _6C -Q _6C

in

L ₆ is absent or is (1-3C)alkylene optionally substituted by (1-2C)alkyl or oxo;

L _6C is absent or selected from O, S, SO ₂ , N(R _g ), C(O), C(O)O, C(O)N(R _g ) or N(R _g )C(O), wherein R _g is selected from hydrogen or (1-2C)alkyl; and

Q _6C is hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, aryl, (3-6C)heterocyclyl, or 5- or 6-membered heteroaryl, each of which is optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, trifluoromethyl, amino, or cyano;

(38) When bond a is a single bond, X ₄ is selected from C(═O) or CHR _6c , or when bond a is a double bond, X ₄ is selected from CR _6c ;

in

R _6c is selected from hydrogen or a group having the following chemical formula:

-L ₆ -L _6C -Q _6C

in

L ₆ is absent or is (1-2C)alkylene optionally substituted with (1-2C)alkyl;

L _6C is absent or selected from C(O)O or C(O)N(R _g ), wherein R _g is selected from hydrogen or (1-2C)alkyl; and

Q _6C is hydrogen, (1-4C)alkyl, phenyl, or 5- or 6-membered heteroaryl, each of which is optionally substituted with one or more substituents selected from (1-4C)alkyl, halogen, trifluoromethyl, amino, or cyano;

(39) When a is a single bond, X ₄ is selected from C(=O), or when bond a is a double bond, X ₄ is selected from CR _6c ;

in

R _6c is selected from hydrogen or a group having the following chemical formula:

-L ₆ -L _6C -Q _6C

in

L ₆ is absent or is (1-2C)alkylene;

L _6C is absent or selected from C(O)O or C(O)N(R _g ), wherein R _g is selected from hydrogen or methyl; and

Q _6C is hydrogen, (1-4C)alkyl, phenyl, or 5- or 6-membered heteroaryl, each of which is optionally substituted with one or more substituents selected from (1-2C)alkyl, halogen, trifluoromethyl, amino, or cyano;

(40) when bond a is a single bond, X ₅ is selected from C(═O), C(═NH), C(═S), CHR _7c or NR _7N , or when bond a is a double bond, X ₅ is selected from CR _7c or N;

in

R _7c is selected from hydrogen, cyano, halogen or a group having the following chemical formula:

-L ₇ -L _7C -Q _7C

in

L ₇ is absent or is (1-3C)alkylene optionally substituted by (1-2C)alkyl or oxo;

L _7C is absent or selected from O, S, SO, SO ₂ , N(R ₀ ), C(O), C(O)O, OC(O), C(O)N(R ₀ ) or N(R ₀ )C(O), wherein R ₀ is selected from hydrogen or (1-2C)alkyl; and

Q _7C is hydrogen, cyano, (1-6C)alkyl, (2C)alkynyl, (2-3C)alkenyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Q _8C is optionally substituted with one or more substituents selected from (1-4C)alkyl, halogen, trifluoromethyl, trifluoromethoxy, amino, cyano, nitro, hydroxy, amino, carboxyl, carbamoyl, sulfamoyl, NR _q R _r , OR _q , wherein R _q and R _r are each independently selected from H or (1-4C)alkyl; or

Q _7C is optionally substituted with a group having the following formula:

-W _7C -L _7' -Z _7C

in

W _7C is absent or is a (1-3C)alkylene group substituted by a (1-2C)alkyl group or an oxo group;

L _7′ is absent or selected from C(O), C(O)O, OC(O), C(O)N(R _s ), N(R _s )C(O), wherein R _s is selected from hydrogen or (1-2C)alkyl; and

Z _7C is phenyl or 5-6 membered heteroaryl; each of which is optionally substituted with one or more substituents selected from (1-4C)alkyl or halogen;

R _7N is selected from hydrogen or a group having the following chemical formula:

-L ₇ -L _7N -Q _7N

in

L ₇ is absent or is (1-3C)alkylene optionally substituted by (1-2C)alkyl;

L _7N is absent or selected from O, S, SO, SO ₂ , N(R _u ), C(O), C(O)O, OC(O), C(O)N(R _u ) or N(R _u )C(O), wherein R _u is selected from hydrogen or (1-2C)alkyl; and

_Q7N is hydrogen, cyano, (1-6C)alkyl, (2C)alkynyl, (2-3C)alkenyl, (3-6C)cycloalkyl, aryl, heterocyclyl, or heteroaryl, each of which is optionally substituted with one or more substituents selected from (1-4C)alkyl, halogen, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, amino, carboxyl, carbamoyl, sulfamoyl, _NRwRx , _ORw , _C (O)Rw, C(O) _{ORw ,} OC(O) _Rw , C(O)N( _Rw ) _Rx , N( _Rw )C(O) _Rx , S(O) _{yRw (} wherein y is 0, 1, or 2), _SO2N ( _Rw ) _{Rx ,} N( _Rw ) _SO2Rx , or ( _CH2 ) _zNRwRx (wherein _{z is} 1, 2, or 3), wherein _Rw and R Each _x is independently selected from H or (1-4C)alkyl; or

Q _7N is optionally substituted with a group having the following formula:

-W _7N -L _7' -Z _7N

in

W _7N is absent or is (1-3C)alkylene optionally substituted by (1-3C)alkyl;

L _7′ is absent or selected from C(O), C(O)O, OC(O), C(O)N(R _y ), N(R _y )C(O), wherein R _y is selected from hydrogen or (1-2C)alkyl; and

Z _7N is phenyl or 5-6 membered heteroaryl; each of which is optionally substituted with one or more substituents selected from (1-4C)alkyl, halogen, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxy, carboxyl, carbamoyl or sulfamoyl;

(41) when bond a is a single bond, X ₅ is selected from C(═O), C(═NH), C(═S), CHR _7c or NR _7N , or when bond a is a double bond, X ₅ is selected from CR _7c or N;

in

R _7c is selected from hydrogen, cyano, halogen or a group having the following chemical formula:

-L ₇ -L _7C -Q _7C

in

L ₇ is absent or is (1-3C)alkylene optionally substituted by (1-2C)alkyl or oxo;

L _7C is absent or selected from O, S, SO, SO ₂ , N(R ₀ ), C(O), C(O)O, OC(O), C(O)N(R ₀ ) or N(R ₀ )C(O), wherein R ₀ is selected from hydrogen or (1-2C)alkyl; and

Q _7C is hydrogen, cyano, (1-6C)alkyl, (2C)alkynyl, (2-3C)alkenyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Q _8C is optionally substituted with one or more substituents selected from (1-4C)alkyl, halogen, trifluoromethyl, trifluoromethoxy, amino or cyano; or

Q _7C is optionally substituted with a group having the following formula:

-W _7C' -Z _7C

in

W _7C is absent or is a (1-3C)alkylene group substituted by a (1-2C)alkyl group or an oxo group;

Z _7C is phenyl or 5-6 membered heteroaryl; each of which is optionally substituted with one or more substituents selected from (1-4C)alkyl or halogen;

R _7N is selected from hydrogen or a group having the following chemical formula:

-L ₇ -L _7N -Q _7N

in

L ₇ is absent or is (1-3C)alkylene optionally substituted by (1-2C)alkyl;

L _7N is absent or selected from O, S, SO, SO ₂ , N(R _u ), C(O), C(O)O, OC(O), C(O)N(R _u ) or N(R _u )C(O), wherein R _u is selected from hydrogen or (1-2C)alkyl; and

_Q7N is hydrogen, cyano, (1-6C)alkyl, (2C)alkynyl, (2-3C)alkenyl, (3-6C)cycloalkyl, aryl, heterocyclyl, or heteroaryl, each of which is optionally substituted with one or more substituents selected from (1-4C)alkyl, halogen, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, amino, carboxyl, carbamoyl, sulfamoyl, _NRwRx , _ORw , _C (O)Rw, C(O) _{ORw ,} OC(O) _Rw , C(O)N( _Rw ) _Rx , N( _Rw )C(O) _Rx , wherein _Rw and _Rx are each independently selected from H or (1-4C)alkyl; or

Q _7N is optionally substituted with a group having the following formula:

-W _7N' -Z _7N

in

W _7N is absent or is (1-3C)alkylene optionally substituted by (1-3C)alkyl;

Z _7N is phenyl or 5-6 membered heteroaryl; each of which is optionally substituted with one or more substituents selected from (1-4C)alkyl, halogen, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxy, carboxyl, carbamoyl or sulfamoyl;

(42) when bond a is a single bond, X ₅ is selected from C(═O), C(═NH), CHR _7c or NR _7N , or when bond a is a double bond, X ₅ is selected from CR _7c or N;

in

R _7c is selected from hydrogen, halogen or a group having the following chemical formula:

-L ₇ -L _7C -Q _7C

in

L ₇ is absent or is (1-3C)alkylene optionally substituted by (1-2C)alkyl or oxo;

L _7C is absent or selected from O, S, N(R ₀ ), C(O), C(O)O, C(O)N(R ₀ ), N(R ₀ )C(O), wherein R ₀ is selected from hydrogen or (1-2C)alkyl; and

Q _7C is hydrogen, cyano, (1-6C)alkyl, (2C)alkynyl, (2-3C)alkenyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Q _8C is optionally substituted with one or more substituents selected from (1-4C)alkyl, halogen, trifluoromethyl, amino or cyano;

R _7N is selected from hydrogen or a group having the following chemical formula:

-L ₇ -L _7N -Q _7N

in

L ₇ is absent or is (1-3C)alkylene optionally substituted by (1-2C)alkyl;

L _7N is absent or selected from O, S, N(R _u ), C(O), C(O)O, C(O)N(R _u ) or N(R _u )C(O), wherein R _u is selected from hydrogen or (1-2C)alkyl; and

_Q7N is hydrogen, cyano, (1-6C)alkyl, (2C)alkynyl, (2-3C)alkenyl, (3-6C)cycloalkyl, aryl, heterocyclyl, or heteroaryl, each of which is optionally substituted with one or more substituents selected from (1-4C)alkyl, halogen, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, amino, carboxyl, carbamoyl, sulfamoyl, _NRwRx , _ORw , _C (O)Rw, C(O) _{ORw ,} OC(O) _Rw , C(O)N( _Rw ) _Rx , N( _Rw )C(O) _Rx , wherein _Rw and _Rx are each independently selected from H or (1-4C)alkyl;

(43) when bond a is a single bond, X ₅ is selected from C(=O), CHR _7c or NR _7N , or when bond a is a double bond, X ₅ is selected from CR _7c or N;

in

R _7c is selected from hydrogen, halogen or a group having the following chemical formula:

-L ₇ -L _7C -Q _7C

in

L ₇ is absent or is (1-3C)alkylene optionally substituted by (1-2C)alkyl or oxo;

L _7C is absent or selected from O, N(R ₀ ), C(O), C(O)O, C(O)N(R ₀ ), N(R ₀ )C(O), wherein R ₀ is selected from hydrogen or (1-2C)alkyl; and

Q _7C is hydrogen, cyano, (1-4C)alkyl, (2C)alkynyl, (2-3C)alkenyl, (3-6C)cycloalkyl, aryl, (3-6C)heterocyclyl, or 5- or 6-membered heteroaryl; and wherein Q _8C is optionally substituted with one or more substituents selected from (1-2C)alkyl, halogen, trifluoromethyl, amino, or cyano;

R _7N is selected from hydrogen or a group having the following chemical formula:

-L ₇ -Q _7N

in

L ₇ is absent or is (1-3C)alkylene optionally substituted by (1-2C)alkyl;

_Q7N is hydrogen, cyano, (1-6C)alkyl, (2C)alkynyl, (2-3C)alkenyl, (3-6C)cycloalkyl, aryl, heterocyclyl, or heteroaryl, each of which is optionally substituted with one or more substituents selected from (1-4C)alkyl, halogen, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, amino, carboxyl, carbamoyl, sulfamoyl, _NRwRx , _ORw , _C (O)Rw, C(O) _{ORw ,} OC(O) _Rw , C(O)N( _Rw ) _Rx , N( _Rw )C(O) _Rx , wherein _Rw and _Rx are each independently selected from H or (1-2C)alkyl;

(44) when bond a is a single bond, X ₅ is selected from C(=O), CHR _7c or NR _7N , or when bond a is a double bond, X ₅ is selected from CR _7c or N;

in

R _7c is selected from hydrogen or a group having the following chemical formula:

-L ₇ -L _7C -Q _7C

in

L ₇ is absent or is (1-3C)alkylene optionally substituted by methyl or oxo;

L _7C is absent or selected from C(O), C(O)O, C(O)N(R ₀ ), N(R ₀ )C(O), wherein R ₀ is selected from hydrogen or (1-2C)alkyl; and

Q _7C is hydrogen, cyano, (1-4C)alkyl, (2C)alkynyl, (2-3C)alkenyl, (3-6C)cycloalkyl, aryl, (3-6C)heterocyclyl, or 5- or 6-membered heteroaryl; and wherein Q _8C is optionally substituted with one or more substituents selected from (1-2C)alkyl, halogen, trifluoromethyl, amino, or cyano;

R _7N is selected from hydrogen or a group having the following chemical formula:

-L ₇ -Q _7N

in

L ₇ is absent or is (1-3C)alkylene optionally substituted by (1-2C)alkyl;

_Q7N is hydrogen, cyano, (1-6C)alkyl, (2C)alkynyl, (2-3C)alkenyl, (3-6C)cycloalkyl, aryl, heterocyclyl, or heteroaryl, each of which is optionally substituted with one or more substituents selected from (1-2C)alkyl, halogen, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, amino, carboxyl, carbamoyl, sulfamoyl, _NRwRx , _ORw , C(O) _Rw , _C (O) _ORw , C(O)N( _Rw )Rx, N( _Rw )C(O) _Rx , wherein _Rw and _Rx are each independently selected from H or (1-2C)alkyl;

(45) When bond a is a single bond, X5 is NR _7N , or when bond a is a double bond, X5 is CR _7c or N;

in

R _7c is selected from hydrogen or a group having the following chemical formula:

-L ₇ -L _7C -Q _7C

in

L ₇ is absent or is (1-2C)alkylene optionally substituted by methyl or oxo;

L _7C is absent or selected from C(O), C(O)O, C(O)N(R ₀ ), N(R ₀ )C(O), wherein R ₀ is selected from hydrogen or (1-2C)alkyl; and

Q _7C is hydrogen, (1-4C)alkyl, (2C)alkynyl, (3-6C)cycloalkyl, phenyl, (3-6C)heterocyclyl, or 5- or 6-membered heteroaryl; and wherein Q _8C is optionally substituted with one or more substituents selected from (1-2C)alkyl, halogen, trifluoromethyl, amino, or cyano;

R _7N is selected from hydrogen or a group having the following chemical formula:

-L ₇ -Q _7N

in

L ₇ is absent or is (1-2C)alkylene optionally substituted by (1-2C)alkyl;

Q _7N is hydrogen, (1-6C)alkyl, (2C)alkynyl, (3-6C)cycloalkyl, phenyl, or 5- or 6-membered heteroaryl, each of which is optionally substituted with one or more substituents selected from (1-2C)alkyl, halogen, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, NR _w R _x or OR _w , wherein R _w and R _x are each independently selected from H or (1-2C)alkyl;

(46) When bond a is a single bond, X5 is NR _7N , or when bond a is a double bond, X5 is CR _7c or N;

in

R _7c is selected from hydrogen or a group having the following chemical formula:

-L ₇ -L _7C -Q _7C

in

L ₇ is absent or is (1-2C)alkylene optionally substituted by methyl or oxo;

L _7C is absent or selected from C(O), C(O)O, C(O)N(R ₀ ), N(R ₀ )C(O), wherein R ₀ is selected from hydrogen or (1-2C)alkyl; and

Q _7C is hydrogen, (1-4C)alkyl, (2C)alkynyl, (3-6C)cycloalkyl, phenyl, (4-6C)heterocyclyl, or 5- or 6-membered heteroaryl; and wherein Q _8C is optionally substituted with one or more substituents selected from (1-2C)alkyl, halogen, trifluoromethyl, amino, or cyano;

R _7N is selected from hydrogen or a group having the following chemical formula:

-L ₇ -Q _7N

in

L ₇ is absent or is (1-2C)alkylene;

Q _7N is (1-4C)alkyl, (2C)alkynyl, (3-6C)cycloalkyl, phenyl, or 5- or 6-membered heteroaryl, each of which is optionally substituted with one or more substituents selected from (1-2C)alkyl, (1-2C)alkoxy, halogen, trifluoromethyl, trifluoromethoxy, or amino;

(47) When bond a is a single bond, X5 is NR _7N , or when bond a is a double bond, X5 is CR _7c or N;

in

R _7c is selected from hydrogen or a group having the following chemical formula:

-L ₇ -L _7C -Q _7C

in

L ₇ is absent or is (1-2C)alkylene optionally substituted by methyl or oxo;

L _7C is absent or selected from C(O), C(O)O or C(O)N(R ₀ ), wherein R ₀ is selected from hydrogen or (1-2C)alkyl; and

Q _7C is hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, phenyl, (4-6C)heterocyclyl, or 5- or 6-membered heteroaryl; and wherein Q _8C is optionally substituted with one or more substituents selected from (1-2C)alkyl, halogen, trifluoromethyl, amino, or cyano;

R _7N is selected from hydrogen or a group having the following chemical formula:

-L ₇ -Q _7N

in

L ₇ is absent or is (1-2C)alkylene;

Q _7N is (1-4C)alkyl, (2C)alkynyl, (3-6C)cycloalkyl, phenyl, or 5- or 6-membered heteroaryl, each of which is optionally substituted with one or more substituents selected from (1-2C)alkyl, halogen, trifluoromethyl, trifluoromethoxy, or amino;

(48) R ₅ is H, (1-4C) alkyl, or a group having the following chemical formula:

-L ₁ -L ₅ -Q ₅

in

L ₁ is absent or selected from (1-3C)alkylene optionally substituted with (1-2C)alkyl or oxo;

_L5 is absent or selected from C(O), C(O)O, OC(O), C(O)N( _Ra ), N( _Ra )C(O), wherein _Ra and _Rb are each independently selected from hydrogen or (1-2C)alkyl; and

_Q5 is selected from hydrogen, (1-4C)alkyl, aryl, 5-6 membered heteroaryl, (4-6C)cycloalkyl, (4-6C)cycloalkenyl, (2C)alkenyl or 5-6 membered heterocyclyl;

and wherein Q ₅ is optionally substituted by one or more substituents selected from (1-4C)alkyl, halogen, amino, cyano, carboxyl, carbamoyl, sulfamoyl, trifluoromethoxy, haloalkyl, NR _c R _d , OR _c , C(O)R _c , C(O)OR _c , OC(O)R _c , C(O)N(R _c )R _d , N(R _c )C(O)R _d , wherein R _c and R _d are each independently selected from H or (1-4C)alkyl;

Or Q ₅ is optionally substituted with a group having the following chemical formula;

-W ₅ -Y ₅ -Z ₅

in

W ₅ is absent or selected from (1-3C)alkylene optionally substituted with (1-2C)alkyl or oxo;

_Y5 is absent or selected from C(O), C(O)O, OC(O), C(O)N( _Re ), N( _Re )C(O), wherein _Re is selected from hydrogen or (1-2C)alkyl; and

_Z is selected from hydrogen, (1-4C)alkyl, phenyl, 5- or 6-membered heterocyclyl, or 5-6-membered heteroaryl; and wherein _Z is optionally substituted with one or more substituents selected from (1-4C)alkyl, halogen, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxy, carboxyl, carbamoyl, or sulfamoyl;

(49) R ₅ is H, (1-4C) alkyl, or a group having the following chemical formula:

-L ₁ -L ₅ -Q ₅

in

L ₁ is absent or selected from (1-3C)alkylene optionally substituted by (1-2C)alkyl or oxo;

_L5 is absent or selected from C(O), C(O)O, OC(O), C(O)N( _Ra ), N( _Ra )C(O), wherein _Ra and _Rb are each independently selected from hydrogen or (1-2C)alkyl; and

_Q5 is selected from hydrogen, (1-4C)alkyl, aryl, 5-6 membered heteroaryl, (4-6C)cycloalkyl, (4-6C)cycloalkenyl, (2C)alkenyl or 5-6 membered heterocyclyl;

and wherein Q ₅ is optionally substituted with one or more substituents selected from (1-4C)alkyl, halogen, amino, cyano, carboxyl, carbamoyl, sulfamoyl, trifluoromethoxy, haloalkyl, NR _c R _d , OR _c or C(O)R _c , wherein R _c and R _d are each independently selected from H or (1-2C)alkyl;

Or Q ₅ is optionally substituted with a group having the following chemical formula;

-W ₅ -Y ₅ -Z ₅

in

W ₅ is absent or selected from (1-3C)alkylene optionally substituted with (1-2C)alkyl or oxo;

_Y5 is absent or selected from C(O), C(O)O, OC(O), C(O)N( _Re ), N( _Re )C(O), wherein _Re is selected from hydrogen or (1-2C)alkyl; and

_Z is selected from hydrogen, (1-4C)alkyl, phenyl, 5- or 6-membered heterocyclyl, or 5-6-membered heteroaryl; and wherein _Z is optionally substituted with one or more substituents selected from (1-2C)alkyl, halogen, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)alkoxy, (1-2C)alkylamino, amino, cyano, hydroxy, carboxyl, carbamoyl, or sulfamoyl;

(50) R ₅ is H, (1-4C) alkyl, or a group having the following chemical formula:

-L ₁ -L ₅ -Q ₅

in

L ₁ is absent or selected from (1-3C)alkylene optionally substituted with (1-2C)alkyl or oxo;

_L5 is absent or selected from C(O), C(O)O, OC(O), C(O)N( _Ra ), N( _Ra )C(O), wherein _Ra and _Rb are each independently selected from hydrogen or (1-2C)alkyl; and

_Q5 is selected from hydrogen, (1-4C)alkyl, aryl, 5-6 membered heteroaryl, (4-6C)cycloalkyl, (2C)alkenyl or 5-6 membered heterocyclyl;

and wherein Q ₅ is optionally substituted with one or more substituents selected from (1-2C)alkyl, halogen, amino, cyano, carboxyl, carbamoyl, sulfamoyl, trifluoromethoxy, haloalkyl, NR _c R _d , OR _c or C(O)R _c , wherein R _c and R _d are each independently selected from H or (1-2C)alkyl;

Or Q ₅ is optionally substituted with a group having the following chemical formula;

-W ₅ -Y ₅ -Z ₅

in

W ₅ is absent or selected from (1-3C)alkylene optionally substituted with (1-2C)alkyl or oxo;

_Y5 is absent or selected from C(O), C(O)O, C(O)N( _Re ), N( _Re )C(O), wherein _Re is selected from hydrogen or (1-2C)alkyl; and

Z ₅ is selected from hydrogen, (1-4C)alkyl, phenyl, 5- or 6-membered heterocyclyl, or 5-6-membered heteroaryl; and wherein Z ₅ is optionally substituted with one or more substituents selected from (1-2C)alkyl, halogen, CF ₃ (1-2C)alkoxy, amino, cyano, hydroxy, carboxyl, carbamoyl, or sulfamoyl;

(51) R ₅ is H, (1-4C) alkyl, or a group having the following chemical formula:

-L ₁ -L ₅ -Q ₅

in

L ₁ is absent or selected from (1-3C)alkylene optionally substituted with (1-2C)alkyl or oxo;

_L5 is absent or selected from C(O), C(O)O, C(O)N( _Ra ), N( _Ra )C(O), wherein _Ra and _Rb are each independently selected from hydrogen or methyl; and

_Q5 is selected from hydrogen, (1-4C)alkyl, aryl, 5-6 membered heteroaryl, (4-6C)cycloalkyl, (2C)alkenyl or 5-6 membered heterocyclyl;

and wherein Q ₅ is optionally substituted with one or more substituents selected from (1-2C)alkyl, halogen, haloalkyl, amino, cyano, carboxyl, carbamoyl, CF ₃ , NR _c R _d , OR _c or C(O)R _c , wherein R _c and R _d are each independently selected from H or (1-2C)alkyl;

Or Q ₅ is optionally substituted with a group having the following chemical formula;

-W ₅ -Y ₅ -Z ₅

in

W ₅ is absent or selected from (1-3C)alkylene optionally substituted with (1-2C)alkyl or oxo;

_Y5 is absent or selected from C(O), C(O)O, C(O)N( _Re ), N( _Re )C(O), wherein _Re is selected from hydrogen or (1-2C)alkyl; and

Z ₅ is selected from hydrogen, (1-4C)alkyl, phenyl, 5- or 6-membered heterocyclyl, or 5-6-membered heteroaryl; and wherein Z ₅ is optionally substituted with one or more substituents selected from (1-2C)alkyl, halogen, or CF ₃ .

(52) R ₅ is H, (1-4C) alkyl, or a group having the following chemical formula:

-L ₁ -L ₅ -Q ₅

in

L ₁ is absent or selected from (1-2C)alkylene optionally substituted with (1-2C)alkyl or oxo;

_L5 is absent or selected from C(O), C(O)O, C(O)N( _Ra ), N( _Ra )C(O), wherein _Ra and _Rb are each independently selected from hydrogen or methyl; and

_Q5 is selected from hydrogen, (1-4C)alkyl, phenyl, 5-6 membered heteroaryl, (4-6C)cycloalkyl, (2C)alkenyl or 5-6 membered heterocyclyl;

and wherein Q ₅ is optionally substituted with one or more substituents selected from (1-2C)alkyl, halogen, amino, cyano, carboxyl, carbamoyl, CF ₃ , NR _c R _d , OR _c or C(O)R _c , wherein R _c and R _d are each independently selected from H or (1-2C)alkyl;

(53) R ₅ is a 5-6 membered heteroaryl group, optionally substituted with one or more substituents selected from (1-2C)alkyl, halogen, haloalkyl, amino, cyano, carboxyl, carbamoyl, CF ₃ , NR _c R _d , OR _c or C(O)R _c , wherein R _c and R _d are each independently selected from H or (1-2C)alkyl;

Or the heteroaryl group is optionally substituted with a group having the following chemical formula:

-W ₅ -Y ₅ -Z ₅

in

W ₅ is absent or selected from (1-2C)alkylene optionally substituted with (1-2C)alkyl or oxo;

_Y5 is absent or selected from C(O), C(O)O, C(O)N( _Re ), N( _Re )C(O), wherein _Re is selected from hydrogen or (1-2C)alkyl; and

Z ₅ is selected from hydrogen, (1-4C)alkyl, phenyl, 5- or 6-membered heterocyclyl, or 5-6-membered heteroaryl; and wherein Z ₅ is optionally substituted with one or more substituents selected from (1-2C)alkyl, halogen, or CF ₃ ;

(54) R ₅ is a 5- or 6-membered heteroaryl group, optionally substituted with one or more substituents selected from (1-2C)alkyl, halogen, amino, cyano, carboxyl, carbamoyl, CF ₃ , CHF ₂ , NR _c R _d , OR _c or C(O)R _c , wherein R _c and R _d are each independently selected from H or (1-2C)alkyl;

(55) R ₅ is thiadiazole or oxadiazole, optionally substituted with one or more substituents selected from (1-2C)alkyl, halogen, amino, cyano, carboxyl, carbamoyl, CF ₃ , CHF ₂ , NR _c R _d , OR _c or C(O)R _c , wherein R _c and R _d are each independently selected from H or (1-2C)alkyl.

Suitably, a heteroaryl or heterocyclyl group as defined herein is a monocyclic heteroaryl or heterocyclyl group comprising one, two or three heteroatoms selected from N, O or S.

Suitably, the heteroaryl group is a 5- or 6-membered heteroaryl ring comprising one, two or three heteroatoms selected from N, O or S.

Suitably, the heterocyclyl group is a 4-, 5- or 6-membered heterocyclyl group comprising one, two or three heteroatoms selected from N, O or S. Most suitably, the heterocyclyl group is a 5- or 6-membered ring comprising one, two or three heteroatoms selected from N, O or S [e.g. morpholinyl (e.g. 4-morpholinyl), oxetane, methyloxetane (e.g. 3-methyloxetane), pyrrolidone (e.g. pyrrolidin-2-one)].

The aryl group is suitably phenyl.

Suitably, R _1a is as defined in any one of paragraphs (2) to (8) above. Most suitably, R _1a is methyl.

Suitably, R _1b , R _1c , R _1d and R _1e are as defined above in paragraphs (9) and (10). Most preferably, R _1b , R _1c , R _1d and R _1e are H.

Suitably, W is as defined in any one of paragraphs (11) to (14) above. Most preferably, W is as defined in paragraph (14).

Suitably, _Xi is as defined in any one of paragraphs (15) to (17) above. Most preferably, _Xi is as defined in paragraph (17).

Suitably, _X2 is as defined in any one of paragraphs (18) to (21) above. Most preferably, _X2 is as defined in paragraph (21).

Suitably, _X3 is as defined in any one of paragraphs (22) to (32) above. Most preferably, _X3 is as defined in paragraph (32).

Suitably, _X4 is as defined in any one of paragraphs (33) to (39) above. Most preferably, _X4 is as defined in paragraph (39).

Suitably, _X5 is as defined in any one of paragraphs (40) to (47) above. Most preferably, _X5 is as defined in paragraph (47).

Suitably, _X6 is as defined in any one of paragraphs (48) to (55) above. Most preferably, _X6 is as defined in paragraph (55).

In embodiments, the compound of the invention is not one of the following:

6-[(Cyclopropylamino)sulfonyl]-2,3-dihydro-2-methyl-N-[4-(1-pyrrolidinyl)phenyl]-1H-indole-1-carboxamide;

6-[(Cyclopropylamino)sulfonyl]-2,3-dihydro-N-(4-methoxyphenol)-2-methyl-1H-indole-1-carboxamide;

N-[1,1'-biphenyl]-4-yl-6-[(cyclopropylamino)sulfonyl]-2,3-dihydro-2-methyl-1H-indole-1-carboxamide;

6-[(Cyclopropylamino)sulfonyl]-2,3-dihydro-2-methyl-N-[4-(4-morpholinyl)phenyl]-1H-indole-1-carboxamide;

6-[(Cyclopropylamino)sulfonyl]-2,3-dihydro-N-(4-ethoxyphenol)-2-methyl-1H-indole-1-carboxamide;

N-(1,1-dimethylethyl)-1H-indole-6-sulfonamide;

3-(1-cyclohexen-1-yl)-N-(1,1-dimethylethyl)-1H-indole-6-sulfonamide;

3-cyclohexyl-N-(1,1-dimethylethyl)-1H-indole-6-sulfonamide;

2-Bromo-3-cyclohexyl-N-(1,1-dimethylethyl)-1H-indole-6-sulfonamide;

2-(2-amino-4-methylphenyl)-3-cyclohexyl-N-(1,1-dimethylethyl)-1H-indole-6-sulfonamide;

6-[(cyclopropylamino)sulfonyl]-1-(1-methylethyl)-1H-indazole-4-carboxylic acid methyl ester; or

6-[(Cyclopropylamino)sulfonyl]-1-(1-methylethyl)-1H-indazole-4-carboxylic acid.

In a specific group of compounds of the present invention, c is a single bond and W is -NH-S(O) ₂ -, ie the compound has the structural formula IIa shown below (subdefinition of formula I):

wherein a, X ₁ , X ₂ , X ₃ , X ₄ , X ₅ , R ₅ , R _1a , R _1b , R _1c , R _1d and R _1e each have any meaning as defined herein; or a pharmaceutically acceptable salt, hydrate and/or solvate thereof.

In an embodiment of a compound of Formula IIa:

R _1a is as defined in any of paragraphs (2) to (8);

R _1b , R _1c , R _1d and R _1e are as defined in any of paragraphs (9) and (10);

_X1 is as defined in any of paragraphs (15) to (17) above;

_X2 is as defined in any of paragraphs (18) to (21) above;

_X3 is as defined in any of paragraphs (22) to (32) above;

_X4 is as defined in any of paragraphs (33) to (39) above;

_X5 is as defined in any of paragraphs (40) to (47) above; and

_R5 is as defined in any of paragraphs (48) to (55).

In an embodiment of a compound of Formula IIa:

R _1a is as defined in paragraph (8) above;

R _1b , R _1c , R _1d and R _1e are as defined in paragraph (10) above;

_X1 is as defined in paragraph (17) above;

_X2 is as defined in paragraph (21) above;

_X3 is as defined in paragraph (32) above;

_X4 is as defined in paragraph (39) above;

_X5 is as defined in paragraph (47) above; and

_R5 is as defined in paragraph (55).

In a specific group of compounds of the present invention, c is a single bond, W is -NH-S(O) ₂ -, R _1b , R _1c , R _1d and R _1e are H, and X ₁ is H, i.e., the compound has the structural formula IIb shown below (subdefinition of formula I):

wherein a, X ₂ , X ₃ , X ₄ , X ₅ , R ₅ and R _1a each have any one meaning defined herein; or a pharmaceutically acceptable salt, hydrate and/or solvate thereof.

In an embodiment of a compound of Formula IIa:

R _1a is as defined in any of paragraphs (2) to (8);

_X2 is as defined in any of paragraphs (18) to (21) above;

_X3 is as defined in any of paragraphs (22) to (32) above;

_X4 is as defined in any of paragraphs (33) to (39) above;

_X5 is as defined in any of paragraphs (40) to (47) above; and

_R5 is as defined in any of paragraphs (48) to (55).

In an embodiment of a compound of Formula IIa:

R _1a is as defined in paragraph (8) above;

_X2 is as defined in paragraph (21) above;

_X3 is as defined in paragraph (32) above;

_X4 is as defined in paragraph (39) above;

_X5 is as defined in paragraph (47) above; and

_R5 is as defined in paragraph (55).

In a specific group of compounds of the present invention, c is a single bond, W is -NH-S(O) ₂ -, R _1b , R _1c , R _1d and R _1e are H, and X ₁ , X ₂ and X ₃ are H, i.e., the compound has the structural formula IIc shown below (subdefinition of formula I):

wherein a, X ₄ , X ₅ , R ₅ and R _1a each have any one of the meanings defined herein; or a pharmaceutically acceptable salt, hydrate and/or solvate thereof.

In an embodiment of a compound of Formula IIa:

R _1a is as defined in any of paragraphs (2) to (8);

_X4 is as defined in any of paragraphs (33) to (39) above;

_X5 is as defined in any of paragraphs (40) to (47) above; and

_R5 is as defined in any of paragraphs (48) to (55).

In an embodiment of a compound of Formula IIa:

R _1a is as defined in paragraph (8) above;

_X4 is as defined in paragraph (39) above;

_X5 is as defined in paragraph (47) above; and

_R5 is as defined in paragraph (55).

In another specific group of compounds of the present invention, HET is a compound of formula (III), (IV) or (V):

In another specific group of compounds of the present invention, HET is a compound of formula (III):

In a specific group of compounds of the present invention, c is a single bond, W is -NH-S(O) _2- , _R1b , _R1c , _R1d and _R1e are H, _X1 , _X2 and _X3 are H, a is a single bond, _X4 is C=O and _X5 is _NR7N , that is, the compound has the structural formula IId shown below (subdefinition of formula I):

wherein R ₅ , R _7N and R _1a each have any one meaning defined herein; or a pharmaceutically acceptable salt, hydrate and/or solvate thereof.

In an embodiment of a compound of Formula IIa:

R _1a is as defined in any of paragraphs (2) to (8);

R _7N is as defined in any of paragraphs (40) to (47) above; and

_R5 is as defined in any of paragraphs (48) to (55).

In an embodiment of a compound of Formula IIa:

R _1a is as defined in paragraph (8) above;

R _7N is as defined in paragraph (47) above; and

_R5 is as defined in paragraph (55).

Specific compounds of the present invention include any compound exemplified in this application, or a pharmaceutically acceptable salt or solvate thereof, and in particular any of the following:

1-[(2,6-dichlorophenyl)methyl]-3-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide;

1-(Cyclopropylmethyl)-3-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide;

1-Benzyl-3-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide;

1-(Cyclopropylmethyl)-N-(1-methylcyclopropyl)-2-oxo-3-phenyl-benzimidazole-5-sulfonamide;

3-Methyl-N-(1-methylcyclopropyl)-2-oxo-1-(3-pyridylmethyl)benzimidazole-5-sulfonamide;

1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide;

1-Isobutyl-3-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide;

3-Methyl-N-(1-methylcyclopropyl)-1-[(2-methylcyclopropyl)methyl]-2-oxo-benzimidazole-5-sulfonamide;

3-Methyl-N-(1-methylcyclopropyl)-1-[(1-methylcyclopropyl)methyl]-2-oxo-benzimidazole-5-sulfonamide;

3-Methyl-N-(1-methylcyclopropyl)-1-[(3-methyloxetan-3-yl)methyl]-2-oxo-benzimidazole-5-sulfonamide;

1-(Cyclobutylmethyl)-3-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide;

1-(Cyclohexylmethyl)-3-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide;

3-Methyl-N-(1-methylcyclopropyl)-2-oxo-1-(4-pyridylmethyl)benzimidazole-5-sulfonamide;

N-(1-methylcyclopropyl)-1-[2-(2-oxooxazolidin-3-yl)acetyl]indoline-6-sulfonamide;

1-(2,2-dimethylpropyl)-3-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide;

1-(Cyclopentylmethyl)-3-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide;

3-Methyl-N-(1-methylcyclopropyl)-2-oxo-1-prop-2-ynyl-benzimidazole-5-sulfonamide;

1-allyl-3-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide;

1-(2-Cyclopropylethyl)-3-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide;

3-Methyl-N-(1-methylcyclopropyl)-1-[(5-methyl-2-furyl)methyl]-2-oxo-benzimidazole-5-sulfonamide;

N-(1-methylcyclopropyl)-1-[2-(2-oxoimidazolidin-1-yl)acetyl]indoline-6-sulfonamide;

Ethyl 2-[3-methyl-5-[(1-methylcyclopropyl)sulfamoyl]-2-oxo-benzimidazol-1-yl]acetate;

3-Methyl-N-(1-methylcyclopropyl)-1-[(1-methylpyrazol-3-yl)methyl]-2-oxo-benzimidazole-5-sulfonamide;

3-Acetyl-1-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide;

N-(1-methylcyclopropyl)-1-[2-(3-methyl-2-oxoimidazolidin-1-yl)acetyl]indoline-6-sulfonamide;

1-methyl-N-(1-methylcyclopropyl)-2-oxo-3-(3-thienyl)benzimidazole-5-sulfonamide;

3-Benzoyl-1-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide;

3-(Cyclohexanecarbonyl)-1-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide;

1-Methyl-3-(4-methylbenzoyl)-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide;

1-Methyl-3-(3-methylbenzoyl)-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide;

1-Methyl-3-(2-methylbenzoyl)-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide;

N-ethyl-3-methyl-6-[(1-methylcyclopropyl)sulfamoyl]-2-oxo-benzimidazole-1-carboxamide;

3-Methyl-N-(1-methylcyclopropyl)-1-(m-tolylmethyl)-2-oxo-benzimidazole-5-sulfonamide;

3-Methyl-N-(1-methylcyclopropyl)-2-oxo-1-(p-tolylmethyl)benzimidazole-5-sulfonamide;

1-[(2-methoxyphenyl)methyl]-3-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide;

1-[(3-methoxyphenyl)methyl]-3-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide;

1-[(4-methoxyphenyl)methyl]-3-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide;

1-[(3-chlorophenyl)methyl]-3-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide;

1-[(4-chlorophenyl)methyl]-3-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide;

1-[(2-Fluorophenyl)methyl]-3-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide;

1-[(3-Fluorophenyl)methyl]-3-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide;

1-[(4-Fluorophenyl)methyl]-3-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide;

1-[(2-cyanophenyl)methyl]-3-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide;

1-[(3-cyanophenyl)methyl]-3-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide;

1-[(4-cyanophenyl)methyl]-3-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide;

3-Methyl-N-(1-methylcyclopropyl)-2-oxo-1-[[2-(trifluoromethyl)phenyl]methyl]benzimidazole-5-sulfonamide;

1-[(2,6-difluorophenyl)methyl]-3-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide;

1-[(3,5-dichlorophenyl)methyl]-3-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide;

1-[(3,5-dimethylphenyl)methyl]-3-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide;

1-[(3,5-dimethoxyphenyl)methyl]-3-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide;

1-[(3,5-difluorophenyl)methyl]-3-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide;

3-(2-Furyl)-1-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide;

1-Methyl-N-(1-methylcyclopropyl)-2-oxo-3-thiazol-2-yl-benzimidazole-5-sulfonamide;

3-(5-Formyl-2-thienyl)-1-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide;

N,3-Dimethyl-6-[(1-methylcyclopropyl)sulfamoyl]-2-oxo-benzimidazole-1-carboxamide;

6-Fluoro-1,3-dimethyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide;

3-Methyl-N-(1-methylcyclopropyl)-2-oxo-1-phenyl-benzimidazole-5-sulfonamide;

1-[(4-cyano-3-fluoro-phenyl)methyl]-3-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide;

4-[[3-Methyl-5-[(1-methylcyclopropyl)sulfamoyl]-2-oxo-benzimidazol-1-yl]methyl]benzamide;

N-methyl-5-[[3-methyl-5-[(1-methylcyclopropyl)sulfamoyl]-2-oxo-benzimidazol-1-yl]methyl]-1,2,4-oxadiazole-3-carboxamide;

3-[[3-Methyl-5-[(1-methylcyclopropyl)sulfamoyl]-2-oxo-benzimidazol-1-yl]methyl]benzamide;

3-Methyl-N-(1-methylcyclopropyl)-1-[(5-nitro-2-furyl)methyl]-2-oxo-benzimidazole-5-sulfonamide;

N-[4-[[3-Methyl-5-[(1-methylcyclopropyl)sulfamoyl]-2-oxo-benzimidazol-1-yl]methyl]phenyl]acetamide;

3-Methyl-N-(1-methylcyclopropyl)-1-[(2-methylpyrazol-3-yl)methyl]-2-oxo-benzimidazole-5-sulfonamide;

3-Methyl-N-(1-methylcyclopropyl)-1-[(2-methylthiazol-5-yl)methyl]-2-oxo-benzimidazole-5-sulfonamide;

3-Methyl-6-[(1-methylcyclopropyl)sulfamoyl]-2-oxo-benzimidazole-1-carboxylic acid ethyl ester;

(E)-3-[5-[3-methyl-6-[(1-methylcyclopropyl)sulfamoyl]-2-oxo-benzimidazol-1-yl]-2-furyl]prop-2-enoic acid;

1-methyl-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide;

(E)-3-[2-[3-methyl-6-[(1-methylcyclopropyl)sulfamoyl]-2-oxo-benzimidazol-1-yl]thiazol-5-yl]prop-2-enoic acid;

3-[2-[3-methyl-6-[(1-methylcyclopropyl)sulfamoyl]-2-oxo-benzimidazol-1-yl]thiazol-5-yl]propanoic acid;

N,N-Dimethyl-3-[2-[3-methyl-6-[(1-methylcyclopropyl)sulfamoyl]-2-oxo-benzimidazol-1-yl]thiazol-5-yl]propionamide;

1-[(4-Fluorophenyl)methyl]-N-(1-methylcyclopropyl)-2-oxo-3H-benzimidazole-5-sulfonamide;

1-[(4-Fluorophenyl)methyl]-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide;

N-methyl-3-[2-[3-methyl-6-[(1-methylcyclopropyl)sulfamoyl]-2-oxo-benzimidazol-1-yl]thiazol-5-yl]propionamide;

3-[(4-Fluorophenyl)methyl]-6-[(1-methylcyclopropyl)sulfamoyl]-2-oxo-benzimidazole-1-carboxylic acid ethyl ester;

1-[(4-Fluorophenyl)methyl]-N-(1-methylcyclopropyl)-2-oxo-3-thiazol-2-yl-benzimidazole-5-sulfonamide;

1-methyl-N-(1-methylcyclopropyl)-2-oxo-3-(1,3,4-thiadiazol-2-yl)benzimidazole-5-sulfonamide;

1-methyl-N-(1-methylcyclopropyl)-2-oxo-3-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]benzimidazole-5-sulfonamide;

3-[5-(Difluoromethyl)-1,3,4-thiadiazol-2-yl]-1-methyl-N-(1-methylcyclopropyl)-2-oxobenzimidazole-5-sulfonamide;

N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-1H-benzimidazole-5-sulfonamide;

3-(5-amino-1,3,4-thiadiazol-2-yl)-1-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide;

1-(Cyclopropylmethyl)-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide;

N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-1-[(2-methylthiazol-5-yl)methyl]-2-oxo-benzimidazole-5-sulfonamide;

1-[(2,5-dimethylpyrazol-3-yl)methyl]-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide;

1-[2-(Dimethylamino)ethyl]-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide;

1-[(4-methoxyphenyl)methyl]-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide;

1-[(2,4-dimethylthiazol-5-yl)methyl]-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide;

3-[5-(Difluoromethyl)-1,3,4-thiadiazol-2-yl]-1-[(2,4-dimethylthiazol-5-yl)methyl]-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide;

1-[(2,4-dimethylthiazol-5-yl)methyl]-N-(1-methylcyclopropyl)-2-oxo-3H-benzimidazole-5-sulfonamide;

1-[(2,4-dimethylthiazol-5-yl)methyl]-N-(1-methylcyclopropyl)-2-oxo-3-(1,2,4-thiadiazol-5-yl)benzimidazole-5-sulfonamide;

1-[(2,4-dimethylthiazol-5-yl)methyl]-3-(1H-imidazol-5-yl)-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide;

1-[(2,4-dimethylthiazol-5-yl)methyl]-N-(1-methylcyclopropyl)-2-oxo-3-(1H-pyrazol-4-yl)benzimidazole-5-sulfonamide;

1-[(2,4-dimethylthiazol-5-yl)methyl]-3-isothiazol-4-yl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide;

N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxo-1H-benzimidazole-5-sulfonamide;

1-[(2,4-Dimethylthiazol-5-yl)methyl]-N-(1-methylcyclopropyl)-2-oxo-3-thiazol-4-yl-benzimidazole-5-sulfonamide;

1-[(2,4-dimethylthiazol-5-yl)methyl]-N-(1-methylcyclopropyl)-3-(1-methylpyrazol-3-yl)-2-oxo-benzimidazole-5-sulfonamide;

1-[(2,4-Dimethylthiazol-5-yl)methyl]-N-(1-methylcyclopropyl)-2-oxo-3-thiazol-5-yl-benzimidazole-5-sulfonamide;

1-methyl-N-(1-methylcyclopropyl)-2-oxo-3-(1,2,4-thiadiazol-5-yl)benzimidazole-5-sulfonamide;

1-[(2,4-dimethylthiazol-5-yl)methyl]-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide;

N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-1-prop-2-ynyl-benzimidazole-5-sulfonamide;

N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-1-(oxazol-2-ylmethyl)-2-oxo-benzimidazole-5-sulfonamide;

N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-1-(1H-pyrazol-4-ylmethyl)benzimidazole-5-sulfonamide;

N-(1-methylcyclopropyl)-1-[(5-methyl-2-furyl)methyl]-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide;

N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-1-[(5-methyl-2-thienyl)methyl]-2-oxo-benzimidazole-5-sulfonamide;

1-[(2,4-dimethylthiazol-5-yl)methyl]-3-(3-methoxy-1,2,4-thiadiazol-5-yl)-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide;

1-[(2,4-dimethylthiazol-5-yl)methyl]-N-(1-methylcyclopropyl)-3-(4-methylthiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide;

1-[(2,4-dimethylthiazol-5-yl)methyl]-N-(1-methylcyclopropyl)-3-(5-methylthiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide;

3-(3-Bromo-1,2,4-thiadiazol-5-yl)-1-[(2,4-dimethylthiazol-5-yl)methyl]-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide;

1-[(2,4-dimethylthiazol-5-yl)methyl]-N-(1-methylcyclopropyl)-2-oxo-3-pyridazin-3-yl-benzimidazole-5-sulfonamide;

1-[(2,4-dimethylthiazol-5-yl)methyl]-N-(1-methylcyclopropyl)-2-oxo-3-(1,3,4-thiadiazol-2-yl)benzimidazole-5-sulfonamide;

1-[(2,4-dimethylthiazol-5-yl)methyl]-N-(1-methylcyclopropyl)-2-oxo-3-thiazol-2-yl-benzimidazole-5-sulfonamide;

3-[(2,4-Dimethylthiazol-5-yl)methyl]-6-[(1-methylcyclopropyl)sulfamoyl]-2-oxo-benzimidazole-1-carboxylic acid ethyl ester;

3-(Cyclopenten-1-yl)-1-[(2,4-dimethylthiazol-5-yl)methyl]-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide;

7-Fluoro-1-methyl-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide;

N-(1-methylcyclopropyl)-1-(5-methyl-1,3,4-thiadiazol-2-yl)indole-6-sulfonamide;

6-Fluoro-1-methyl-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide;

N-methyl-5-[[5-[(1-methylcyclopropyl)sulfamoyl]-3-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxo-benzimidazol-1-yl]methyl]-1,2,4-oxadiazole-3-carboxamide;

N-(1-methylcyclopropyl)-2-[(3-methylisoxazol-5-yl)methyl]-3-(5-methyl-1,3,4-thiadiazol-2-yl)benzimidazole-5-sulfonamide;

N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)benzimidazole-5-sulfonamide;

N-(1-methylcyclopropyl)-2-[(1-methylpyrazol-4-yl)methyl]-3-(5-methyl-1,3,4-thiadiazol-2-yl)benzimidazole-5-sulfonamide;

N-(1-methylcyclopropyl)-2-[2-(1-methylpyrazol-4-yl)ethyl]-3-(5-methyl-1,3,4-thiadiazol-2-yl)benzimidazole-5-sulfonamide;

2-methyl-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)benzimidazole-5-sulfonamide;

1-methyl-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-7-(trifluoromethyl)benzimidazole-5-sulfonamide;

N-[[6-[(1-methylcyclopropyl)sulfamoyl]-1-(5-methyl-1,3,4-thiadiazol-2-yl)benzimidazol-2-yl]methyl]acetamide;

2-(2-aminoethyl)-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)benzimidazole-5-sulfonamide;

3-Benzyl-N-(1-methylcyclopropyl)-1-(5-methyl-1,3,4-thiadiazol-2-yl)indole-6-sulfonamide;

3-[(4-Fluorophenyl)methyl]-N-(1-methylcyclopropyl)-1-(5-methyl-1,3,4-thiadiazol-2-yl)indole-6-sulfonamide;

3-(Cyclopropylmethyl)-N-(1-methylcyclopropyl)-1-(5-methyl-1,3,4-thiadiazol-2-yl)indole-6-sulfonamide;

3-[(2,4-dimethylthiazol-5-yl)methyl]-N-(1-methylcyclopropyl)-1-(5-methyl-1,3,4-thiadiazol-2-yl)indole-6-sulfonamide;

3-(Cyclopropanecarbonyl)-N-(1-methylcyclopropyl)-1-(5-methyl-1,3,4-thiadiazol-2-yl)indole-6-sulfonamide;

3-(4-Fluorobenzoyl)-N-(1-methylcyclopropyl)-1-(5-methyl-1,3,4-thiadiazol-2-yl)indole-6-sulfonamide;

Ethyl 3-[(2,4-dimethylthiazol-5-yl)methyl]-6-[(1-methylcyclopropyl)sulfamoyl]indole-1-carboxylate;

1-[3-(Dimethylamino)propyl]-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide;

1-(2-methoxyethyl)-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide;

1-[3-(Dimethylamino)propyl]-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide;

N-(1-methylcyclopropyl)-1-[(1-methyl-3-piperidinyl)methyl]-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide;

1-[2-(Dimethylamino)ethyl]-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide;

N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[(1-methyl-2-piperidinyl)methyl]-2-oxo-benzimidazole-5-sulfonamide;

N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[(1-methyl-3-piperidinyl)methyl]-2-oxo-benzimidazole-5-sulfonamide;

N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxo-1-[2-(1-piperidinyl)ethyl]benzimidazole-5-sulfonamide;

N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-oxadiazol-2-yl)-1-(2-morpholinoethyl)-2-oxo-benzimidazole-5-sulfonamide;

N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxo-1-(2-pyrrolidin-1-ylethyl)benzimidazole-5-sulfonamide;

N-(1-methylcyclopropyl)-1-[(1-methyl-2-piperidinyl)methyl]-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide;

3-Acetyl-N-(1-methylcyclopropyl)-1-(5-methyl-1,3,4-thiadiazol-2-yl)indole-6-sulfonamide;

3-(Cyclopropanecarbonyl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-(1-methylcyclopropyl)indole-6-sulfonamide;

3-[(4-Fluorophenyl)methyl]-N-(1-methylcyclopropyl)-1-(5-methyl-1,3,4-thiadiazol-2-yl)indazole-6-sulfonamide;

1-(2-methoxyethyl)-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide;

1-(3-methoxypropyl)-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide;

N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-1-[2-(1-piperidinyl)ethyl]benzimidazole-5-sulfonamide;

1-(3-methoxypropyl)-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide;

3-[5-[(1-methylcyclopropyl)sulfamoyl]-3-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxo-benzimidazol-1-yl]propionamide;

N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-1-(2-morpholinoethyl)-2-oxo-benzimidazole-5-sulfonamide;

N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-1-(2-pyrrolidin-1-ylethyl)benzimidazole-5-sulfonamide;

3-[5-[(1-methylcyclopropyl)sulfamoyl]-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazol-1-yl]propionamide;

N-(1-methylcyclopropyl)-1-[(1-methylpyrrolidin-2-yl)methyl]-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide;

N-[1-(Fluoromethyl)cyclopropyl]-1-methyl-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide;

N-(1-cyanocyclopropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-1H-benzimidazole-5-sulfonamide;

N-(1-cyanocyclopropyl)-1-ethyl-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide;

1-Ethyl-N-[1-(fluoromethyl)cyclopropyl]-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide;

N-[1-(Fluoromethyl)cyclopropyl]-1-(2-methoxyethyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide;

N-(1-cyanocyclopropyl)-1-(2-methoxyethyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide;

N-(1-cyanocyclopropyl)-3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1-(2-methoxyethyl)-2-oxo-benzimidazole-5-sulfonamide;

3-[5-(Difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-[1-(fluoromethyl)cyclopropyl]-1-(2-methoxyethyl)-2-oxo-benzimidazole-5-sulfonamide;

3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1-[(2,5-dimethylpyrazol-3-yl)methyl]-N-[1-(fluoromethyl)cyclopropyl]-2-oxo-benzimidazole-5-sulfonamide;

N-(1-cyanocyclopropyl)-3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1-[(2,5-dimethylpyrazol-3-yl)methyl]-2-oxo-benzimidazole-5-sulfonamide;

1-(Cyanomethyl)-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide;

3-[5-(Difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-fluoro-N-[1-(fluoromethyl)cyclopropyl]-1-(2-methoxyethyl)-2-oxo-benzimidazole-5-sulfonamide;

3-[5-(Difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-fluoro-1-(2-methoxyethyl)-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide;

3-[5-(Difluoromethyl)-1,3,4-thiadiazol-2-yl]-1-(2-methoxyethyl)-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide;

3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1-[3-(dimethylamino)propyl]-N-[1-(fluoromethyl)cyclopropyl]-2-oxo-benzimidazole-5-sulfonamide;

6-Fluoro-1-methyl-N-(1-methylcyclopropyl)-3-(3-methyl-1,2,4-thiadiazol-5-yl)-2-oxo-benzimidazole-5-sulfonamide;

6-Fluoro-N-[1-(fluoromethyl)cyclopropyl]-1-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-2-oxo-benzimidazole-5-sulfonamide;

3-[5-(Difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-fluoro-1-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide;

3-[5-(Difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-fluoro-N-[1-(fluoromethyl)cyclopropyl]-1-methyl-2-oxo-benzimidazole-5-sulfonamide;

N-[1-(Fluoromethyl)cyclopropyl]-1-methyl-2-oxo-3-(1,2,4-thiadiazol-5-yl)benzimidazole-5-sulfonamide;

1-methyl-N-(1-methylcyclopropyl)-3-(3-methyl-1,2,4-thiadiazol-5-yl)-2-oxo-benzimidazole-5-sulfonamide;

N-[1-(Fluoromethyl)cyclopropyl]-1-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-2-oxo-benzimidazole-5-sulfonamide;

1-(Cyanomethyl)-N-[1-(fluoromethyl)cyclopropyl]-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide;

1-(Cyanomethyl)-N-(1-methylcyclopropyl)-3-(3-methyl-1,2,4-thiadiazol-5-yl)-2-oxo-benzimidazole-5-sulfonamide;

1-(Cyanomethyl)-N-[1-(fluoromethyl)cyclopropyl]-3-(3-methyl-1,2,4-thiadiazol-5-yl)-2-oxo-benzimidazole-5-sulfonamide;

3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-[1-(fluoromethyl)cyclopropyl]-1-methyl-2-oxo-benzimidazole-5-sulfonamide;

1-(2-methoxyethyl)-N-(1-methylcyclopropyl)-3-(3-methyl-1,2,4-thiadiazol-5-yl)-2-oxo-benzimidazole-5-sulfonamide;

N-[1-(Fluoromethyl)cyclopropyl]-1-(2-methoxyethyl)-2-oxo-3-(1,2,4-thiadiazol-5-yl)benzimidazole-5-sulfonamide;

N-[1-(Fluoromethyl)cyclopropyl]-1-(2-methoxyethyl)-3-(3-methyl-1,2,4-thiadiazol-5-yl)-2-oxo-benzimidazole-5-sulfonamide;

N-[1-(Fluoromethyl)cyclopropyl]-1-(3-methoxypropyl)-3-(3-methyl-1,2,4-thiadiazol-5-yl)-2-oxo-benzimidazole-5-sulfonamide;

1-[2-(Dimethylamino)ethyl]-N-[1-(fluoromethyl)cyclopropyl]-3-(3-methyl-1,2,4-thiadiazol-5-yl)-2-oxo-benzimidazole-5-sulfonamide;

N-[1-(Fluoromethyl)cyclopropyl]-1-(3-methoxypropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide;

1-[2-(Dimethylamino)ethyl]-N-[1-(fluoromethyl)cyclopropyl]-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide;

1-Methyl-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide;

1-Ethyl-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide;

1-(2-Fluoroethyl)-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide;

6-Fluoro-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxo-1H-benzimidazole-5-sulfonamide;

3-[5-(Difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-[1-(fluoromethyl)cyclopropyl]-2-oxo-1-prop-2-ynyl-benzimidazole-5-sulfonamide;

6-Fluoro-N-[1-(fluoromethyl)cyclopropyl]-3-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxo-1H-benzimidazole-5-sulfonamide;

3-[5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl]-1-methyl-N-(1-methylcyclopropyl)-2-oxobenzimidazole-5-sulfonamide;

3-[5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl]-N-[1-(fluoromethyl)cyclopropyl]-1-methyl-2-oxo-benzimidazole-5-sulfonamide;

6-Fluoro-1-methyl-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide;

6-Fluoro-1-(2-fluoroethyl)-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide;

3-[5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl]-1-ethyl-6-fluoro-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide;

3-[5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl]-1-ethyl-6-fluoro-N-[1-(fluoromethyl)cyclopropyl]-2-oxo-benzimidazole-5-sulfonamide;

3-[5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl]-1-ethyl-N-(1-methylcyclopropyl)-2-oxobenzimidazole-5-sulfonamide;

3-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1-ethyl-N-[1-(fluoromethyl)cyclopropyl]-2-oxo-benzimidazole-5-sulfonamide;

6-Fluoro-N-[1-(fluoromethyl)cyclopropyl]-1-(2-methoxyethyl)-3-(6-methylpyridazin-3-yl)-2-oxo-benzimidazole-5-sulfonamide;

6-Fluoro-N-[1-(fluoromethyl)cyclopropyl]-1-methyl-3-(6-methylpyridazin-3-yl)-2-oxo-benzimidazole-5-sulfonamide;

6-Fluoro-1-methyl-N-(1-methylcyclopropyl)-3-(6-methylpyridazin-3-yl)-2-oxo-benzimidazole-5-sulfonamide;

6-Fluoro-N-[1-(fluoromethyl)cyclopropyl]-1-methyl-2-oxo-3-[6-(trifluoromethyl)pyridazin-3-yl]benzimidazole-5-sulfonamide;

3-[5-(Difluoromethyl)-1,3,4-thiadiazol-2-yl]-1-ethyl-6-fluoro-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide;

3-[5-(Difluoromethyl)-1,3,4-thiadiazol-2-yl]-1-ethyl-6-fluoro-N-[1-(fluoromethyl)cyclopropyl]-2-oxo-benzimidazole-5-sulfonamide;

3-[5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl]-6-fluoro-1-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide;

3-[5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl]-6-fluoro-N-[1-(fluoromethyl)cyclopropyl]-1-methyl-2-oxo-benzimidazole-5-sulfonamide;

3-[5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl]-6-fluoro-1-(2-fluoroethyl)-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide;

3-[5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl]-6-fluoro-1-(2-fluoroethyl)-N-[1-(fluoromethyl)cyclopropyl]-2-oxo-benzimidazole-5-sulfonamide;

3-[5-(Difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-fluoro-N-[1-(fluoromethyl)cyclopropyl]-2-oxo-1-prop-2-ynyl-benzimidazole-5-sulfonamide;

2-[3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-fluoro-5-[[1-(fluoromethyl)cyclopropyl]sulfamoyl]-2-oxo-benzimidazol-1-yl]acetamide;

1-(Cyanomethyl)-3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-fluoro-N-[1-(fluoromethyl)cyclopropyl]-2-oxo-benzimidazole-5-sulfonamide;

3-[5-(Difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-fluoro-1-(2-fluoroethyl)-N-[1-(fluoromethyl)cyclopropyl]-2-oxo-benzimidazole-5-sulfonamide;

3-[5-(Difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-fluoro-1-(2-fluoroethyl)-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide;

Ethyl 3-methyl-5-[(1-methylcyclopropyl)sulfamoyl]benzofuran-2-carboxylate;

or a pharmaceutically acceptable salt or solvate thereof.

The various functional groups and substituents comprising the compounds of Formula I are typically selected so that the molecular weight of the compounds of Formula I does not exceed 1000. More typically, the molecular weight of the compound will be less than 900, e.g., less than 800, or less than 750, or less than 700, or less than 650. More preferably, the molecular weight is less than 600, and for example, is 550 or less.

Suitable pharmaceutically acceptable salts of the compounds of the present invention are, for example, acid addition salts of sufficiently basic compounds of the present invention, for example, acid addition salts with, for example, inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid or maleic acid. In addition, suitable pharmaceutically acceptable salts of sufficiently acidic compounds of the present invention are alkali metal salts, such as sodium or potassium salts, alkaline earth metal salts, such as calcium or magnesium salts, ammonium salts or salts formed with organic bases providing pharmaceutically acceptable cations, such as salts formed with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

Compounds with the same molecular formula but different properties or sequences of their atomic bonding or the arrangement of their atoms in space are referred to as "isomers". The term "stereoisomer" refers to isomers whose atoms are arranged differently in space. Stereoisomers that are not mirror images of each other are referred to as "diastereomers" and stereoisomers that are non-superimposable mirror images of each other are referred to as "enantiomers". When a compound has an asymmetric center, for example, when it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers are characterized by the absolute configuration of their asymmetric center and are described and designated as right-handed or left-handed (i.e., as (+) or (-)-isomers, respectively) by the R- and S-sequencing rules of Cahn and Prelog, or by the method of rotating the plane of polarized light by molecules. Chiral compounds can exist as single enantiomers or mixtures thereof. A mixture comprising equal proportions of enantiomers is referred to as a "racemic mixture".

The compounds of the present invention may have one or more asymmetric centers; therefore, such compounds may be produced as separate (R)- or (S)-stereoisomers or mixtures thereof. Unless otherwise indicated, the description or naming of a specific compound in the specification and claims is intended to include two separate enantiomers and racemic mixtures or other mixtures thereof. Methods for stereochemical determination and separation of stereoisomers are well known in the art (see discussion in Chapter 4 of "Advanced Organic Chemistry", 4th edition J. March, John Wiley and Sons, New York, 2001 [discussion in Chapter 4 of "Advanced Organic Chemistry", 4th edition, J. March, John Wiley and Sons, New York, 2001]) such as by synthesis from optically active starting materials or by resolution of racemic forms. Some compounds of the present invention may have geometric isomerization centers (E- and Z-isomers). It should be understood that the present invention encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof having activity against malignant cell proliferation.

The present invention also encompasses compounds of the present invention as defined herein that include one or more isotopic substitutions. For example, H can be in any isotopic form, including ¹ H, ² H (D), and ³ H (T); C can be in any isotopic form, including ¹² C, ¹³ C, and ¹⁴ C; and O can be in any isotopic form, including ¹⁶ O and ¹⁸ O; and the like.

It will also be understood that certain compounds of Formula I can exist in solvated as well as unsolvated forms, such as, for example, hydrated forms. It will be understood that the present invention encompasses all such solvated forms that possess activity against the proliferation of malignant cells.

It will also be understood that certain compounds of Formula I may exhibit polymorphism and that the present invention encompasses all such forms which possess activity against the proliferation of malignant cells.

Compounds of formula (I) can exist in a number of different tautomeric forms, and reference to compounds of formula (I) includes all such forms. For the avoidance of doubt, where a compound can exist in one of several tautomeric forms, and only one is specifically described or shown, reference to compounds of formula (I) encompasses all such forms. Examples of tautomeric forms include keto, enol and enolate forms, as in, for example, the following tautomeric pairs: keto/enol (shown below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol and nitro/acid nitro.

The compounds of formula I comprising amine functional groups can also form N-oxides. The compounds of formula I comprising amine functional groups mentioned herein also include N-oxides. When the compound comprises several amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxides. Specific examples of N-oxides are tertiary amines of nitrogen-containing heterocycles or N-oxides of nitrogen atoms. N-oxides can be formed by treating the corresponding amine with an oxidant such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid), see, for example, Advanced Organic Chemistry, Jerry March, ^4th Edition, Wiley Interscience, pages [Advanced Organic Chemistry, edited by Jerry March, 4th Edition, Wiley International Science, pages]. More specifically, N-oxides can be prepared by the procedure of LW Deady (Syn. Comm. 1977, 7, 509-514) wherein the amine compound is reacted with meta-chloroperbenzoic acid (mCPBA) in an inert solvent such as dichloromethane.

The compounds of formula I can be administered in the form of prodrugs that decompose in the human or animal body to release the compounds of the invention. Prodrugs can be used to modify the physical properties and/or pharmacokinetic properties of the compounds of the invention. Prodrugs can be formed when the compounds of the invention contain a suitable group or substituent to which a property-modifying group can be attached. Examples of prodrugs include ester derivatives that can be formed in vivo at carboxyl groups or hydroxyl groups in the compounds of formula I and amide derivatives that can be formed in vivo at carboxyl groups or amino groups in the compounds of formula I.

The present invention therefore includes those compounds of formula I as defined above when obtainable by organic synthesis and when obtainable in the human or animal body by cleavage of their prodrugs. The present invention therefore includes those compounds of formula I produced by organic synthesis and also those compounds produced in the human or animal body by metabolism of precursor compounds, i.e. compounds of formula I which may be synthetically produced compounds or metabolically produced compounds.

Suitable pharmaceutically acceptable prodrugs of the compounds of Formula I are those that are, based on sound medical judgment, suitable for administration to the human or animal body without undesirable pharmacological activity and without undue toxicity.

For example, in the following documents various forms of prodrugs have been described:-

a) Methods in Enzymology, Vol. 42 , p. 309-396, edited by K. Widder, et al. (Academic Press, 1985);

b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985);

c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H.Bundgaard, Chapter 5 “Design and Application of Prodrugs”, by H.Bundgaard p.113-191 (1991);

d) H. Bundgaard, Advanced Drug Delivery Reviews , 8 , 1-38 (1992); [H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38, 1992]

e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77 , 285 (1988);

f) N. Kakeya, et al., Chem. Pharm. Bull. , 32 , 692 (1984); [N. Kakeya et al., Chemistry and Pharmacy Bull., 32, 692, 1984]

g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, A.C.S. Symposium Series, Volume 14; and

h) E. Roche (editor), "Bioreversible Carriers in Drug Design", Pergamon Press, 1987.

Suitable pharmaceutically acceptable prodrugs of compounds of formula I (which prodrugs have a carboxyl group) are, for example, in vivo cleavable esters thereof. An in vivo cleavable ester of a compound of formula I comprising a carboxyl group is, for example, a pharmaceutically acceptable ester that is cleaved in the human or animal body to produce the parent acid. Suitable pharmaceutically acceptable esters of carboxyl groups include C _1-6 alkyl esters such as methyl, ethyl and tert-butyl, C _1-6 alkoxymethyl esters such as methoxymethyl ester, C _1-6 alkanoyloxymethyl esters such as pivaloyloxymethyl ester, 3-phthalyl ester, C _3-8 cycloalkylcarbonyloxy-C _1-6 alkyl esters such as cyclopentylcarbonyloxymethyl ester and 1-cyclohexylcarbonyloxyethyl ester, 2-oxo-1,3-dioxolenylmethyl ester such as 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl ester and C _1-6 alkoxycarbonyloxy-C _1-6 alkyl esters such as methoxycarbonyloxymethyl ester and 1-methoxycarbonyloxyethyl ester.

Suitable pharmaceutically acceptable prodrugs (the prodrugs have hydroxyl groups) of compounds of formula I are, for example, esters or ethers thereof that can be cleaved in vivo. Esters or ethers that can be cleaved in vivo of compounds of formula I comprising hydroxyl groups are, for example, pharmaceutically acceptable esters or ethers that are cleaved in the human or animal body to produce the parent hydroxyl compound. Suitable pharmaceutically acceptable ester-forming groups of hydroxyl groups include inorganic esters such as phosphates (including phosphoramidite cyclic esters). Other suitable pharmaceutically acceptable ester-forming groups of hydroxyl groups include: C _1-10 alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, C _1-10 alkoxycarbonyl groups such as ethoxycarbonyl, N,N-(C _1-6 ) 2carbamoyl, ₂ -dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ring substituents on phenylacetyl and benzoyl include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(C _1-4 alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether-forming groups for hydroxy groups include α-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

Suitable pharmaceutically acceptable prodrugs of compounds of formula I (which prodrugs have a carboxyl group) are, for example, amides thereof which can be cleaved in vivo, for example amides formed from amines such as ammonia, C _1-4 alkylamines such as methylamine, (C _1-4 alkyl) ₂ amines such as dimethylamine, N-ethyl-N-methylamine or diethylamine, C _1-4 alkoxy-C _2-4 alkylamines such as 2-methoxyethylamine, phenyl-C _1-4 alkylamines such as benzylamine and amino acids such as glycine or an ester thereof.

Suitable pharmaceutically acceptable prodrugs of compounds of Formula I (which have an amino group) are, for example, amide derivatives thereof that can be cleaved in vivo. Suitable pharmaceutically acceptable amides derived from amino groups include, for example, amides formed with C _1-10 alkanoyl groups, such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C _1-4 alkyl)piperazin-1-ylmethyl.

The in vivo effects of the compounds of formula I may be effected in part by one or more metabolites formed in the human or animal body following administration of the compounds of formula I. As described above, the in vivo effects of the compounds of formula I may also be effected by means of the metabolism of precursor compounds (prodrugs).

Although the present invention may be directed to any compound or group of compounds defined by an optional, preferred or suitable feature or otherwise with respect to a particular embodiment, the present invention may also be directed to any compound or group of compounds that specifically excludes that optional, preferred or suitable feature or particular embodiment.

Suitably, the present invention excludes any individual compound that does not possess the biological activity defined herein.

synthesis

The compounds of the present invention can be prepared by any suitable technique known in the art. Specific methods for preparing these compounds are further described in the accompanying examples.

In the descriptions of synthetic methods described herein, and in any referenced synthetic methods for the preparation of starting materials, it is understood that all proposed reaction conditions, including the choice of solvents, reaction atmospheres, reaction temperatures, duration of experiments, and work-up procedures, can be selected by one skilled in the art.

Those skilled in the art of organic synthesis will understand that the functionality present on the various portions of the molecule must be compatible with the reagents and reaction conditions employed.

It will be appreciated that during the synthesis of the compounds of the invention in the processes defined herein, or during the synthesis of certain starting materials, it may be necessary to protect certain substituent groups to prevent their undesirable reactions. A skilled chemist will understand when such protection is necessary and how these protecting groups can be placed in place and subsequently removed.

For examples of protecting groups, see one of the many general texts on the subject, such as "Protective Groups in Organic Synthesis" by Theodora Green (publisher: John Wiley & Sons). Protecting groups may be removed by any convenient method described in the literature or known to the skilled chemist, suitable for the removal of the protecting group in question, the method being selected so as to effect removal of the protecting group with minimal perturbation of groups elsewhere in the molecule.

Thus, if reactants include, for example, groups such as amino, carboxyl or hydroxy groups, it may be necessary to protect this group in some of the reactions mentioned herein.

For example, the suitable protecting group of amino or alkylamino group is such as acyl group, for example alkanoyl group such as acetyl, alkoxycarbonyl group, for example methoxycarbonyl, ethoxycarbonyl or tert-butyloxycarbonyl group, arylmethoxycarbonyl group, for example benzyloxycarbonyl, or aroyl group, for example benzoyl.The deprotection condition of above-mentioned protecting group must change with the selection of protecting group.Therefore, for example, can be by being hydrolyzed with suitable alkali such as alkali metal hydroxide such as lithium hydroxide or sodium hydroxide etc. and remove acyl group such as alkanoyl or alkoxycarbonyl group or aroyl group.Alternately, can be for example by using suitable acid such as hydrochloric acid, sulfuric acid or phosphoric acid or trifluoroacetic acid treatment remove acyl group such as tert-butyloxycarbonyl group, and can for example by through catalyst such as palladium-carbon-hydrogenation, or by using Lewis acid such as boron tris (trifluoroacetate) treatment remove arylmethoxycarbonyl group such as benzyloxycarbonyl group. A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.

The suitable protecting group of hydroxyl group is for example acyl group, for example alkanoyl group such as acetyl, aroyl group, for example benzoyl, or arylmethyl group such as benzyl.The deprotection condition of above-mentioned protecting group must change with the selection of protecting group.Therefore, for example, can remove acyl group such as alkanoyl or aroyl group by hydrolysis with suitable alkali such as alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or ammonia etc. Alternatively, can for example remove arylmethyl group such as benzyl group by hydrogenation through catalyst such as palladium-carbon.

Suitable protecting groups for a carboxyl group are, for example, esterifying groups, such as a methyl or ethyl group which can be removed, for example by hydrolysis with a base such as sodium hydroxide, or, for example, a tert-butyl group which can be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or, for example, a benzyl group which can be removed, for example, by hydrogenation over a catalyst such as palladium on carbon.

The resin can also serve as a protecting group.

The method for synthesizing the compounds of formula I will vary depending on the nature of _X1 , _X2 , _X3 , _X4 , _X5 , W, _R5 , _R1a , _R1b , _R1c , _R1d and _R1e and any substituents associated therewith. Suitable methods for their preparation are further described in the accompanying Examples.

Once a compound of formula I is synthesized by any one of the methods defined herein, the method may then further comprise the additional step of:

(i) removing any protecting groups present;

(ii) converting the compound of formula I into another compound of formula I;

(iii) forming a pharmaceutically acceptable salt, hydrate or solvate thereof; and/or

(iv) forming a prodrug thereof.

An example of (ii) above is when a compound of Formula I is synthesized, and then one or more of _X1 , _X2 , _X3 , _X4 , _X5 , W, _R5 , _R1a , _R1b , _R1c , _R1d , and _R1e can be further reacted to change the nature of the group and provide an alternative compound of Formula I. For example, the compound can be reacted to convert _R1 to a substituent other than hydrogen.

The resulting compound of Formula I can be isolated and purified using techniques well known in the art.

In one aspect of the present invention, the compound of formula I or a pharmaceutically acceptable salt or solvate thereof can be synthesized by any of the following methods:

a) making a compound of formula A:

wherein X ₁ , X ₂ , X ₃ and HET are as defined above, and LG _A is a suitable leaving group;

Reaction with a compound of formula B:

wherein R _1a , R _1b , R _1c , R _1d , R _1e and c are as defined above;

b) making a compound of formula C:

wherein X ₁ , X ₂ , X ₃ , X ₄ , X ₅ , W, R _1a , R _1b , R _1c , R _1d , R _1e , a and c are as defined above;

Reaction with a compound of formula D:

R ₅ -L

Formula D

wherein R ₅ is as defined above, and L is a suitable leaving group (eg, halogen, OMs) or a suitable coupling group (eg, CO ₂ H);

c) making a compound of formula E:

wherein X ₁ , X ₂ , X ₃ , X ₄ , W, R ₅ , R _1a , R _1b , R _1c , R _1d , R _1e , a and c are as defined above;

Reaction with a compound of formula F:

R _7N -LG

Formula F

wherein R _7N is as defined above, and LG is a suitable leaving group (e.g., halogen, OMs);

d) making a compound of formula G:

wherein X ₁ , X ₂ , X ₃ , W, R ₅ , R _1a , R _1b , R _1c , R _1d , R _1e and c are as defined above;

Reactions with compounds of formula H:

R _6C -Q

Formula H

wherein R _6c is as defined above, and Q is a suitable reagent for condensation reaction (eg, CO ₂ H);

e) Optionally, if desired:

i) removing any protecting groups present;

ii) converting the compound of formula I into another compound of formula I; and/or

iii) forming a pharmaceutically acceptable salt or solvate thereof.

Biological activity

The PARG enzyme and cellular assays described in the accompanying Examples section can be used to measure the pharmacological effects of the compounds of the invention.

Although the pharmacological properties of compounds of Formula I vary with structural variation, as expected, compounds of the invention were found to be active in these PARG assays.

In general, compounds of the invention exhibit an _IC50 of 10 μM or less in the PARG enzyme assay described herein, preferred compounds of the invention exhibit an _IC50 of 1000 nM or less or 500 nM or less, and most preferred compounds of the invention exhibit an _IC50 of 200 nM or less.

In general, compounds of the invention exhibit an _IC50 of 1 μM or less in the PARG cell assay described herein, preferred compounds of the invention exhibit an _IC50 of 500 nM or less, and most preferred compounds of the invention exhibit an _IC50 of 200 nM or less.

Pharmaceutical composition

According to another aspect of the present invention, there is provided a pharmaceutical composition comprising the compound of the present invention as defined above, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in combination with a pharmaceutically acceptable diluent or carrier.

The compositions of the invention may be in a form suitable for oral use (e.g., as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), topical use (e.g., as creams, ointments, gels, or aqueous or oily solutions or suspensions), administration by inhalation (e.g., as finely divided powders or liquid aerosols), administration by insufflation (e.g., as finely divided powders) or parenteral administration (e.g., as sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration or as suppositories for rectal administration).

The compositions of the present invention can be obtained by conventional procedures well known in the art using conventional pharmaceutical excipients. Thus, compositions intended for oral use may contain, for example, one or more coloring agents, sweeteners, flavoring agents and/or preservatives.

An effective amount of a compound of the invention for use in therapy is an amount sufficient to treat or prevent a proliferative disorder mentioned herein, slow the progression of the disorder, and/or alleviate the symptoms associated with the disorder.

The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will vary depending on the individual being treated and the particular route of administration. For example, a formulation intended for oral administration to humans will typically contain, for example, from 0.5 mg to 0.5 g (more suitably from 0.5 to 100 mg, e.g., from 1 to 30 mg) of the active agent compounded with an appropriate and convenient amount of excipient (the amount of the excipient may vary from 5% to 98% by weight of the total composition).

According to well-known medical principles, the size of the dose of the compound of formula I for therapeutic or prophylactic purposes will naturally vary depending on the nature and severity of the condition, the age and sex of the animal or patient and the route of administration.

When using the compounds of this invention for treatment or prevention purposes, it is usually given so that if divided doses are needed, a daily dose of, for example, 0.1mg/kg to 75mg/kg body weight is accepted. In general, when using parenteral route, a lower dose will be given. Therefore, for example, for intravenous or intraperitoneal administration, a dosage of, for example, 0.1mg/kg to 30mg/kg body weight will be usually used. Similarly, for administration by inhalation, a dosage of, for example, 0.05mg/kg to 25mg/kg body weight will be used. Oral administration can also be suitable, particularly in tablet form. Typically, a unit dosage form will comprise approximately 0.5mg to 0.5g of the compounds of this invention.

Therapeutic uses and applications

The present invention provides compounds that are useful as PARG inhibitors.

Thus, the present invention provides a method of inhibiting PARG enzyme activity in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

The present invention also provides a method for selectively inhibiting PARG enzyme activity over PARP1 or ARH3 enzyme activity in vitro or in vivo, comprising contacting a cell with an effective amount of a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof.

The present invention also provides a method of treating a disease or disorder involving PARG activity in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition.

The present invention provides a method of inhibiting cell proliferation in vitro or in vivo, the method comprising contacting the cell with an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

The present invention provides a method of treating a proliferative disease in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition.

The present invention provides a method of treating cancer in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition.

The present invention provides a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition, for use in therapy.

The present invention provides a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition, for use in the treatment of a proliferative disorder.

The present invention provides a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition for use in treating cancer. In specific embodiments, the cancer is a human cancer.

The present invention provides a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in inhibiting PARG enzyme activity.

The present invention provides a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in the treatment of a disease or disorder in which PARG activity is implicated.

The present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the preparation of a medicament for the treatment of a proliferative disorder.

The present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the preparation of a medicament for the treatment of cancer. Suitably, the medicament is for the treatment of human cancer.

The present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the preparation of a medicament for inhibiting PARG enzyme activity.

The present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the preparation of a medicament for selectively inhibiting PARG enzyme activity over PARP1 or ARH3 enzyme activity.

The present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the preparation of a medicament for the treatment of a disease or disorder involving PARG activity.

The term "proliferative disease" is used interchangeably herein and relates to unwanted or uncontrolled cell proliferation of an undesirable excess or abnormal cell, such as a neoplastic or proliferative growth in vitro or in vivo. Examples of proliferative disorders include, but are not limited to, precancerous and malignant cell proliferation, including but not limited to malignancies and tumors, cancers, leukemias, psoriasis, bone diseases, fibroproliferative diseases (e.g., connective tissue), and atherosclerosis. Any type of cell can be treated, including but not limited to lung, colon, breast, ovary, prostate, liver, pancreas, brain, and skin.

The antiproliferative effects of the compounds of the present invention are particularly useful in the treatment of human cancers (due to their inhibition of PARG enzyme activity).

The anti-cancer effects may occur through one or more mechanisms including, but not limited to, modulation of cell proliferation, inhibition of angiogenesis (formation of new blood vessels), inhibition of metastasis (spread of a tumor from its origin), inhibition of invasion (spread of tumor cells into adjacent normal structures), or promotion of apoptosis (programmed cell death).

In a particular embodiment of the invention, the proliferative disorder to be treated is cancer.

Ways of Giving

The compounds of the invention, or pharmaceutical compositions comprising these compounds, may be administered to a subject by any convenient route of administration, whether systemically/peripherally or locally (ie, at the site of desired action).

Routes of administration include, but are not limited to, oral (e.g., by swallowing); buccal; sublingual; transdermal (including, for example, by patches, plasters, etc.); transmucosal (including, for example, by patches, plasters, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy, using, for example, via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, e.g., by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcutaneous, intraarticular, subarachnoid, and intrasternal; by implantation of a reservoir or reservoir, e.g., subcutaneously or intramuscularly.

Combination therapy

The antiproliferative treatment defined above may be administered as the sole therapy or may involve, in addition to the compounds of the invention, conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following classes of antineoplastic agents:-

(i) Other antiproliferative/antineoplastic drugs and combinations thereof as used in medical oncology, such as alkylating agents (e.g., cis-platinum, oxaliplatin, carboplatin, cyclophosphamide, mechlorethamine, melphalan, chlorambucil, busulfan, temozolomide, and nitrosoureas); antimetabolites (e.g., gemcitabine and antifolates such as fluoropyrimidines, like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytarabine, and hydroxyurea); antitumor antibiotics (e.g., anthracyclines, like doxorubicin, bleomycin, doxorubicin, daunorubicin, epirubicin, idarubicin, mitomycin-C, actinomycin D, and mithramycin); antimitotic agents (e.g., vinca alkaloids like vincristine, vinblastine, vindesine, and vinorelbine, and taxanes like paclitaxel and taxotere, and polokinase inhibitors); and topoisomerase inhibitors (e.g., epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan, and camptothecin);

(ii) cytostatics, such as antiestrogens (e.g., tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (e.g., bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (e.g., goserelin, leuprorelin and buserelin), progestogens (e.g., megestrol acetate), aromatase inhibitors (e.g., anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5α-reducing agents (e.g., finasteride);

(iii) anti-invasive agents [e.g., c-Src kinase family inhibitors such as 4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline (AZD0530; International Patent Application WO 01/94341), N-(2-chloro-6-methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-ylamino}thiazole-5-carboxamide (dasatinib, BMS-354825; J. Med. Chem. 2004, 47 , 6658-6661), and bosutinib (SKI-606), as well as metalloproteinase inhibitors such as marimastat, urokinase plasminogen activator receptor function inhibitors, or heparanase antibodies];

(iv) Inhibitors of growth factor function: For example, such inhibitors include growth factor antibodies and growth factor receptor antibodies (e.g., the anti-erbB2 antibody trastuzumab [Herceptin ^™ ], the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab [Erbitux, C225], and any of the growth factor or growth factor receptor antibodies disclosed in Stern et al. (Critical reviews in oncology/hematology, 2005, Vol.54, pp11-29); such inhibitors also include tyrosine kinase inhibitors, for example, inhibitors of the epidermal growth factor family (e.g., EGFR family tyrosine kinase inhibitors, such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, ZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib); inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; inhibitors of the platelet-derived growth factor family, such as imatinib and/or nilotinib (AMN107); serine/threonine kinase inhibitors (e.g., Ras/Raf signaling inhibitors, such as farnesyl transferase inhibitors, such as sorafenib (BAY 43-9006), tipifarnib (R115777) and lonafarnib (SCH66336)), cell signaling inhibitors via MEK and/or AKT kinases, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1R kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors; Aurora kinase inhibitors (e.g., AZD1152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 and AX39459) and cyclin-dependent kinase inhibitors such as CDK2 and/or CDK4 inhibitors;

(v) anti-angiogenic agents, such as those that inhibit the action of vascular endothelial growth factor [e.g. the anti-vascular endothelial growth factor antibody bevacizumab (Avastin™) and, for example, VEGF receptor tyrosine kinase inhibitors such as vandetanib (ZD6474), vatalinib (PTK787), sunitinib (SU11248), axitinib (AG-013736), pazopanib (GW786034) and 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (AZD2171; Example 240 in WO 00/47212), such as described in International Patent Applications WO 97/22596, WO 97/30035, WO 97/32856 and WO those disclosed in 98/13354 as well as compounds that act through other mechanisms (e.g., linomide, inhibitors of integrin αvβ3 function, and angiostatin)];

(vi) Vascular damaging agents such as combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;

(vii) endothelin receptor antagonists, such as zilpotentan (ZD4054) or atrasentan;

(viii) antisense therapies, such as those directed against the targets listed above, such as ISIS 2503, anti-ras antisense therapy;

(ix) gene therapy, including, for example, methods that replace abnormal genes (such as abnormal p53 or abnormal BRCA1 or BRCA2), GDEPT (gene-directed enzyme pro-drug therapy) methods, such as those using cytosine deaminase, thymidine kinase, or bacterial nitroreductase, and methods that increase a patient's tolerance to chemotherapy or radiation therapy, such as multi-drug resistance gene therapy; and

(x) Immunotherapy approaches, including, for example, ex vivo and in vivo approaches for increasing the immunogenicity of a patient's tumor cells, such as transfection with cytokines (e.g., interleukin-2, interleukin-4, or granulocyte macrophage colony-stimulating factor), approaches for reducing T cell anergy, approaches using transfected immune cells (e.g., cytokine-transfected dendritic cells), approaches using cytokine-transfected tumor cell lines, and approaches using anti-idiotypic antibodies.

In a particular embodiment, the antiproliferative treatment defined above may involve, in addition to the compounds of the invention, conventional surgery or radiotherapy or chemotherapy.

Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment.Such combination products employ the compounds of this invention within the dosage range described above and the other pharmaceutically active agent within its approved dosage range.

According to this aspect of the invention there is provided a combination for use in the treatment of cancer (eg cancer involving solid tumours) comprising a compound of the invention as defined above, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and another anti-tumour agent.

According to this aspect of the invention, there is provided a combination for the treatment of a proliferative disorder, such as cancer (e.g. cancer involving solid tumors), which combination comprises a compound of the invention as defined above, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and any one of the anti-tumor drugs listed above.

In another aspect of the present invention, there is provided a compound of the present invention or a pharmaceutically acceptable salt, hydrate or solvate thereof for use in treating cancer in combination with another anti-tumor agent, optionally selected from one listed above.

Herein, where the term "combination" is used, it is understood that this refers to simultaneous, separate, or sequential administration. In one aspect of the invention, "combination" refers to simultaneous administration. In another aspect of the invention, "combination" refers to separate administration. In another aspect of the invention, "combination" refers to sequential administration. Where administration is sequential or separate, a delay in administering the second component should not result in a loss of the beneficial effects of the combination.

According to another aspect of the present invention, a pharmaceutical composition is provided, which comprises a compound of the present invention or a pharmaceutically acceptable salt, hydrate or solvate thereof, in combination with a pharmaceutically acceptable diluent or carrier and an anti-tumor drug (optionally selected from one of the ones listed above) therapeutic agent.

Examples

Materials, equipment, and general experimental details

General experiments

Flash chromatography was performed using pre-packed silica gel cartridges (KP-Sil SNAP, Biotage, Hengoed UK or RediSepRf, Isco). Thin-layer chromatography was performed using Merck type 60F ₂₅₄ silica gel coated to 5 x 10 cm plates with a thickness of 0.25 mm. All reagents obtained from commercial sources were used without further purification. Anhydrous solvents were obtained from Sigma-Aldrich Chemical Company Ltd. or Fisher Chemicals Ltd. and used without further drying. HPLC-grade solvents were obtained from Fisher Chemicals Ltd. or Romil Ltd.

Unless otherwise stated, all compounds were >90% pure as determined by both LC-MS and ¹ H NMR spectroscopy. When Cl or Br were present, the expected isotopic distribution pattern was observed.

¹ H NMR

Proton ( ¹ H) NMR spectra were recorded on a 300 MHz or 400 MHz Bruker spectrometer or an ECX 300 MHz or ECX 400 MHz JEOL spectrometer. Solutions were typically prepared in deuterated chloroform (CDCl ₃ ) or deuterated dimethyl sulfoxide (DMSO-d ₆ ), with chemical shifts referenced to tetramethylsilane (TMS) or a deuterated solvent as an internal standard. ¹ H NMR data are reported as chemical shift (δ), integral (as 1 H), multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; dd, doublet of doublets, etc.), and coupling constant (J) (Hz) (approx. means apparent coupling in the broad peak signal). Deuterated solvents were obtained from Sigma-Aldrich, Goss, or Fluorochem.

LC-MS analysis

LC-MS analysis was performed using one of the following methods (indicated in Table 2):

LC-MS Method A

A Waters Acquity UPLC system was used, equipped with a BEH C18 1.7 μM column (2.1 × 50 mm) and UV diode array detection (210–400 nm). Positive and negative ion mass detection was performed using a Waters SQD detector. Analyses were performed using buffered acidic or basic solvents and the following gradients:

Low pH:

Solvent A - water + 10 mM ammonium formate + 0.1% formic acid Solvent B - acetonitrile + 5% water + 0.1% formic acid

High pH:

Solvent A-water + 10mM ammonium bicarbonate + 0.1% ammonia solution Solvent B-acetonitrile + 0.1% ammonia solution

gradient:

LC-MS method

Waters Acquity ZQD (ESI) UPLC system equipped with an XBridge C18 2.1 × 50 mm, 2.5 μm or equivalent and UV diode array detection (215–350 nm)

Low pH:

Solvent A-MeCN

Solvent B - 0.1% formic acid (pH 3)

High pH:

Solvent A-MeCN

Solvent B - 10 mM NH ₄ HCO ₃ (pH 10)

gradient:

LC-MS Method C

Waters X Bridge C18: 50 mm × 4.6 mm, 3.5 μm column, UV diode array detection (214-350 nm)

High pH:

Solvent A - Water (0.01 mol/L NH ₄ HCO ₃ )

Solvent B-MeCN

gradient:

Preparative HPLC

Some compounds were purified by preparative HPLC using a Waters FractionLynx MS automated permeation system with a Waters XBridge 5 μm C18, 100 mm x 19 mm (id) column, operating at a flow rate of 20 mL/min using UV diode array detection (210-400 nm) and mass-directed collection using positive and negative ion mass detection.

Purification was performed using an appropriately buffered acidic or basic solvent system. Compound retention on the system was routinely assessed using 30-50 μL test injections and a standard gradient, and then based on the observed retention time, purification was performed using an appropriately selected focused gradient as described below.

Low pH:

Solvent A - water + 10 mM ammonium formate + 0.1% formic acid Solvent B - acetonitrile + 5% water + 0.1% formic acid

High pH:

Solvent A-water + 10mM ammonium formate + 0.1% ammonia solution Solvent B-acetonitrile + 5% water + 0.1% ammonia solution

Standard gradient:

Concentrated Gradient:

Gilson-GX281 automated purification system, with Waters XBridge 5 μm C18, 100 mm × 30 mm (inner diameter) or Waters XSelect 5 μm C18, 150 mm × 19 mm (inner diameter), operated at a flow rate of 20 mL/min, using UV detection (214 nm, 254 nm). Purification was performed using an appropriate buffered alkaline solvent system. Compound retention times on the system were routinely assessed using LC-MS analytical tests as standard gradients, and then purification was performed using an appropriately selected focused gradient as described below based on the observed retention times.

Column: Waters X-Bridge C18: 100mm×30mm 5um

Mobile phase: A: water (0.05% ammonia) B ₂ : methanol

Concentrated Gradient:

Column: Waters X-Select 5μm C18, 150mm×19mm

Mobile phase: A: water (0.05% ammonia) B ₂ : methanol

Concentrated Gradient:

Column: Waters X-Select 5μm C18, 150mm×19mm

Mobile phase: A: water (10 mmol NH ₄ HCO ₃ ) B ₁ : acetonitrile

Concentrated Gradient:

Solution 1

Option 2

Option 3

Option 4

Option 5

Option 6

Option 7

Option 8

Option 9

Plan 10

Plan 11

Plan 12

Plan 13

Plan 14

General approach

1-Methylcyclopropylamine hydrochloride

1-Methylcyclopropanecarboxylic acid (73.3 g, 0.73 mol), diphenylphosphoryl azide (221.7 g, 0.81 mol) and triethylamine (148.1 g, 1.46 mol) were stirred in tert-butyl alcohol (330 mL) and heated at 75 ° C overnight. The reaction mixture was cooled to room temperature, poured into a mixture of ethyl acetate (750 mL) and water (1500 mL) and stirred for 15 minutes. The resulting precipitate was removed by filtration and the phases were separated. The aqueous layer was extracted with ethyl acetate (2 x 750 mL), and the combined organic extracts were washed with water (750 mL), dried (MgSO ₄ ) and concentrated to give a light brown solid (88 g). The solid was suspended in dioxane (295 mL) and 4M hydrochloric acid (366 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. Ether was added and the mixture was frozen in a methanol/ice bath for 15 minutes. The precipitate was collected by filtration, washed with diethyl ether (2220 mL), and the filter cake was dried for 10 minutes to give 1-methylcyclopropylamine hydrochloride as a shiny white solid (40.5 g, 0.38 mol, 51%).

¹ H NMR (CDCl ₃ ) δ = 1.32 (s, 3H), 0.75-0.68 (m, 2H), 0.60-0.51 (m, 2H)

General procedures for Option 1:

Intermediate S1-A 3-Fluoro-N-(1-methylcyclopropyl)-4-nitrobenzenesulfonamide

1-Methylcyclopropaneamine hydrochloride (9.58 g, 89.1 mmol) was added to a stirred solution of 3-fluoro-4-nitrobenzene-1-sulfonyl chloride (19.4 g, 81.0 mmol) and triethylamine (22.6 mL, 161.9 mmol) in DCM (400 mL) over 15 minutes; the reaction exothermed to 30° C. The reaction mixture was stirred for 1 hour and then concentrated. The residue was dissolved in ethyl acetate (400 mL), washed with 1 M hydrochloric acid (2×400 mL), water (400 mL), and brine (400 mL), dried, and concentrated to yield 3-fluoro-N-(1-methylcyclopropyl)-4-nitrobenzenesulfonamide (19 g, 69.3 mmol, 86%).

¹ H NMR (300MHz, CDCl ₃ ) δ = 8.19 (dd, J = 7.0, 8.7Hz, 1H), 7.88-7.78 (m, 2H), 5.09 (s, 1H), 1.30 (s, 3H), 0.92-0.72 (m, 2H), 0.68-0.50 (m, 2H)

Intermediate S1-B 3-(Methylamino)-N-(1-methylcyclopropyl)-4-nitrobenzenesulfonamide

Methylamine (2M in THF) (100 mL, 200 mmol) was added to a stirred solution of 3-fluoro-N-(1-methylcyclopropyl)-4-nitrobenzenesulfonamide (17.3 g, 66.7 mmol) and triethylamine (14 mL, 100 mmol) in DCM (183 mL) over 15 minutes; the reaction exothermed to 30° C. Once the addition was complete, the reaction mixture was heated to 50° C. for 2 hours. DCM (400 mL) and water (400 mL) were added, the layers were separated, and the aqueous phase was re-extracted with DCM (2×200 mL). The combined organic layers were washed with brine (400 mL) and concentrated to give 3-(methylamino)-N-(1-methylcyclopropyl)-4-nitrobenzenesulfonamide (19 g, 66.6 mmol, quantitative).

¹ H NMR (300MHz, CDCl ₃ )δ＝8.30(d,J＝8.9Hz,1H),8.14(s,1H),7.43(d,J＝2.0Hz,1H),7.05(dd,J＝1.9,8.9Hz,1H ),5.00(s,1H),3.11(d,J＝4.2Hz,3H),1.29(s,3H),0.92-0.77(m,2H),0.63-0.48(m,2H)

Intermediate S1-C 4-amino-3-(methylamino)-N-(1-methylcyclopropyl)benzenesulfonamide

Ammonium chloride (19.3 g, 361 mmol) was dissolved in water (350 mL) and added to a solution of 3-(methylamino)-N-(1-methylcyclopropyl)-4-nitrobenzenesulfonamide (20.6 g, 72.2 mmol) in industrial methylated spirits (350 mL). Iron powder (20.2 g, 361 mmol) was added and the reaction mixture was heated to 80° C. The reaction mixture was filtered through celite and concentrated to yield 4-amino-3-(methylamino)-N-(1-methylcyclopropyl)benzenesulfonamide (14.0 g, 54.8 mmol, 76%).

¹ H NMR (300MHz, CDCl ₃ )δ＝7.25(dd,J＝2.1,8.1Hz,1H),7.13(d,J＝2.1Hz,1H),6.72(d,J＝8.1Hz,1H),5.01(s, 1H),3.73(br.s.,2H),2.89(s,3H),1.18(s,3H),0.89-0.71(m,2H),0.51-0.34(m,2H)

Intermediate S1-D 3-Methyl-N-(1-methylcyclopropyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-sulfonamide

4-Amino-3-(methylamino)-N-(1-methylcyclopropyl)benzenesulfonamide (14.0 g, 54.8 mmol) was dissolved in MeCN (420 mL) and heated to 50 ° C. 1,2-Carbonyldiimidazole (17.8 g, 110 mmol) was added and stirred at 50 ° C for 3 hours. The reaction mixture was cooled and concentrated. The residue was dissolved in 2M HCl (500 mL) and extracted with 5% MeOH in DCM (2×250 mL). The combined organic layers were concentrated and purified by flash column chromatography on silica gel, eluent: 5% MeOH in DCM to give 3-methyl-N-(1-methylcyclopropyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-sulfonamide (12.5 g, 44.4 mmol, 81%).

¹ H NMR (300MHz, DMSO-d ₆ )δ＝12.31(br.s.,1H),8.05(s,1H),7.64(d,J＝1.8Hz,1H),7.59(dd,J＝1.9,8.3Hz,1H) ,7.29(d,J＝8.3Hz,1H),3.53(s,3H),1.06(s,3H),0.65-0.59(m,2H),0.42-0.35(m,2H)

General procedures for Option 2:

Intermediate S2-A Ethylmethyl(phenyl)carbamate

With triethylamine (45mL, 0.33mol) process N-methylaniline (30g, 0.28mol) solution in DCM (100mL) and stir 20 minutes.Through 25 minutes, under ice bath cooling, add ethyl chloroformate (32mL, 0.33mol), keep the temperature at＜25 ℃.Reaction mixture is stirred at room temperature overnight, then poured in water (400mL), acidified with 2M HCl, and extracted with EtOAc (700mL).Organic layer is separated and washed with salt solution (400mL), use _{Na SO} dry and evaporate to dryness, to produce ethyl methyl (phenyl) carbamate (44g, 0.25mol, 88%).

¹ H NMR (300MHz, CDCl ₃ ) δ = 7.40-7.32 (m, 2H), 7.30-7.19 (m, 3H), 4.19 (q, J = 7.1Hz, 2H), 3.32 (s, 3H), 1.25 (t, J = 7.1Hz, 3H)

Intermediate S2-B Ethyl (4-(chlorosulfonyl)phenyl)(methyl)carbamate

Ethyl methyl (phenyl) carbamate (22g, 0.12mol) is added drop-wise in chlorosulfonic acid (80mL, 1.20mol) under cooling, maintenance temperature＜20 ℃.Reaction mixture is heated to 60 ℃ and stirred 3 hours, then allow its cooling and spend the night.Through 30 minutes, reaction mixture was carefully added in ice (400mL).Gained throw out was stirred 30 minutes, collected by filtration and washed with water.Product is dried in a vacuum drying oven, to produce ethyl (4-(chlorosulfonyl) phenyl) (methyl) carbamate (31.7g, 0.11mol, 93%).

¹ H NMR (300MHz, CDCl ₃ ) δ = 8.01 (d, J = 9.0Hz, 2H), 7.58 (d, J = 9.0Hz, 2H), 4.27 (q, J = 7.1Hz, 2H), 3.41 (s, 3H), 1.33 (t, J = 7.2Hz, 3H)

Intermediate S2-C Ethyl (4-(chlorosulfonyl)-2-nitrophenyl)(methyl)carbamate

[0114] A solution of sodium nitrate (9.73 g, 0.114 mol) in sulfuric acid (80 mL) was added to a cooled (0-5°C) stirred solution of ethyl (4-(chlorosulfonyl)phenyl)(methyl)carbamate (30 g, 0.108 mol) in sulfuric acid (100 mL) over 30 minutes. The mixture was stirred at 0-5°C for 2 hours then poured onto ice (500 mL) with stirring. The product was extracted with DCM (2 x 400 mL) and the combined extracts were dried ( _Na2SO4 ) and passed through a plug _of silica gel, washing with DCM. The DCM solution was evaporated to dryness to yield ethyl (4-(chlorosulfonyl)-2-nitrophenyl)(methyl)carbamate (31.4 g, 0.097 mol, 90%).

¹ H NMR (300MHz, CDCl ₃ )δ＝8.57(d,J＝2.3Hz,1H),8.25(dd,J＝2.3,8.6Hz,1H),7.63(d,J＝8.7Hz,1H),4.18(br.s,2H),3.48-3.44(m,3H),1.26(br.s.,3H)

Intermediate S2-D Ethyl methyl (4-(N-(1-methylcyclopropyl)sulfamoyl)-2-nitrophenyl)carbamate

To a solution of ethyl (4-(chlorosulfonyl)-2-nitrophenyl)(methyl)carbamate (15 g, 46.5 mmol) in DCM (450 mL) at 20° C. was added triethylamine (19.5 mL, 141.0 mmol). 1-Methylcyclopropaneamine hydrochloride (5.1 g, 47.2 mmol) was added portionwise over 5 minutes. The reaction was stirred for 30 minutes and poured into 1 M HCl (150 mL). The organic layer was separated, washed with brine, and evaporated to an orange color to yield ethyl methyl (4-(N-(1-methylcyclopropyl)sulfamoyl)-2-nitrophenyl)carbamate (17.2 g, 48.1 mmol, quantitative).

LCMS (high pH): RT 1.10 min, [M+H] ⁺ 358.5, 100% purity

Intermediate S2-E 3-Hydroxy-1-methyl-N-(1-methylcyclopropyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-sulfonamide

A solution of methyl (4-(N-(1-methylcyclopropyl)sulfamoyl)-2-nitrophenyl)ethyl carbamate (17.2g, 48.1mmol) in EtOH (350mL) is added to a 1L autoclave. 5% Pd/C (1.7g) is moistened with toluene and added to the autoclave. The vessel is sealed and filled with hydrogen to a pressure of 14 bar, and stirred at 300rpm for 3 hours. The vessel is evacuated, and the filtered contents are washed with EtOH. Remove the solvent to leave the partially reduced intermediate. A solution of the partially reduced intermediate (10g, approximately 77% purity, 23.5mmol) in AcOH (150mL) is heated to 80°C for 2 hours, then allowed to cool overnight. The precipitate was filtered, washed with acetic acid and dried to yield 3-hydroxy-1-methyl-N-(1-methylcyclopropyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-sulfonamide (4.1 g, 13.8 mmol, 51%).

LCMS (high pH): RT 1.02 min, [M+H] 298.1, 93% purity

Intermediate S2-F 1-methyl-N-(1-methylcyclopropyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-sulfonamide

A solution of 3-hydroxy-1-methyl-N-(1-methylcyclopropyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-sulfonamide (9.75 g, 32.8 mmol) and ammonium acetate (63.2 g, 820 mmol) in MeOH (250 mL) and water (200 mL) was stirred at room temperature. A solution of TiCl ₃ (30% in 2M HCl) (70 mL, 164 mmol) was added at once, and the mixture was stirred for 36 hours. MeOH was removed under reduced pressure, and the resulting suspension was basified to pH 8 with a saturated NaHCO ₃ aqueous solution. The suspension was filtered under vacuum, and the resulting solid was placed in a hot plate and dried for three days. The off-white powdery solid was placed in a Soxhlet cannula and extracted with MeOH for 24 hours. MeOH was concentrated to approximately 100 mL, cooled in ice, and the resulting solid was collected by suction filtration and air-dried to give 2.40 g of product.

LCMS analysis of the remaining material on the Soxhlet cannula showed that it still contained most of the desired product. The solid was stirred in DMSO (25 mL) and 2M NaOH (25 mL) was added. The mixture was heated to 100°C and filtered hot, rinsing the solid with cold water. As the filtrate cooled, a white solid began to crystallize. The filtrate was acidified with 2M HCl (25 mL) to give a thick white suspension. This was cooled in ice water and the solid was collected by suction filtration to give further product. The residual solid from the filtration was treated with the above-mentioned DMSO and NaOH aqueous solution to give a second batch of the desired product after acidification. The two batches were combined to give 5.73 g of product, which was identical to the above by ¹ H NMR. The total yield of 1-methyl-N-(1-methylcyclopropyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-sulfonamide was 8.13 g, 28.9 mmol, 88%).

¹ H NMR (300MHz, DMSO-d ₆ )δ＝11.23(s,1H),7.88(s,1H),7.49(dd,J＝1.8,8.3Hz,1H),7.35(d,J＝1.8Hz,1H),7 .25(d,J＝8.3Hz,1H),3.32(s,3H),1.01(s,3H),0.66-0.51(m,2H),0.42-0.26(m,2H)

General procedures for Option 3:

Intermediate S3-A 4-chloro-N-(1-methylcyclopropyl)-3-nitro-benzenesulfonamide

Triethylamine (1.63 mL, 11.72 mmol) was added dropwise to a stirred solution of 4-chloro-3-nitrobenzenesulfonyl chloride (1. g, 3.91 mmol) and 1-methylcyclopropaneamine hydrochloride (0.46 g, 4.3 mmol) in DCM (20 mL). After 2 hours, a saturated aqueous solution of _NaHCO₃ (20 mL) was added and the mixture was stirred for 5 minutes. The DCM layer was separated by passing through a hydrophobic frit, and the aqueous layer was washed with DCM. The combined DCM extracts were concentrated under reduced pressure and purified by automated column chromatography _{on SiO₂} , eluent being 0-100% EtOAc in isohexane, to yield 4-chloro-N-(1-methylcyclopropyl)-3-nitrobenzenesulfonamide (1.07 g, 3.68 mmol, 94%).

¹ H NMR (300MHz, CDCl ₃ )δ＝8.39(d,J＝2.2Hz,1H),8.03(dd,J＝2.2,8.5Hz,1H),7.72(d,J＝8.5Hz,1H),5.28(s,1H),1.29(s,3H),0.82-0.72(m,2H),0.65-0.49(m,2H)

Intermediate S3-B1 4-[(4-Fluorophenyl)methylamino]-N-(1-methylcyclopropyl)-3-nitro-benzenesulfonamide

4-Fluorobenzylamine (1.87 mL, 16.4 mmol) was added dropwise to a stirred solution of 4-chloro-N-(1-methylcyclopropyl)-3-nitrobenzenesulfonamide (3.97 g, 13.67 mmol) and triethylamine (2.85 mL, 20.5 mmol) in DMF (80 mL). The reaction mixture was heated at 80°C for 2 hours. Water (20 mL) and DCM (20 mL) were added and the mixture was stirred for 5 minutes. The DCM layer was separated by passing through a hydrophobic frit and the aqueous layer was washed with DCM (2 x 10 mL). The combined organics were evaporated to dryness and the crude product was purified by automated column chromatography on _SiO2 with 0-10.0% MeOH in DCM as eluent to yield 4-[(4-fluorophenyl)methylamino]-N-(1-methylcyclopropyl)-3-nitrobenzenesulfonamide (4.3 g, 11.3 mmol, 83%).

¹ H NMR (300MHz, CDCl ₃ )δ＝8.75(d,J＝2.3Hz,1H),8.68(t,J＝5.6Hz,1H),7.82(dd,J＝2.3,9.0Hz,1H),7.36-7.29(m,2H),7.15-7. 04(m,2H),6.90(d,J＝9.1Hz,1H),4.58(d,J＝5.8Hz,2H),1.27(s,3H),0.88-0.70(m,2H),0.60-0.42(m,2H)

The following intermediates were prepared in a similar manner:

Intermediate S3-B2 4-[(2,4-dimethylthiazol-5-yl)methylamino]-N-(1-methylcyclopropyl)-3-nitro-benzenesulfonamide

Prepared from 4-chloro-N-(1-methylcyclopropyl)-3-nitrobenzenesulfonamide, (dimethyl-1,3-thiazol-5-yl)methanamine and triethylamine.

LCMS (low pH): RT 1.07 min, [M+H] ⁺ 397.5, >95% purity

Intermediate S3-C1 3-amino-4-[(4-fluorophenyl)methylamino]-N-(1-methylcyclopropyl)benzenesulfonamide

To the suspension of iron (5.01g, 89.73mmol) in EtOH (25mL), 4-[(4-fluorophenyl)methylamino]-N-(1-methylcyclopropyl)-3-nitrobenzenesulfonamide (6.81g, 17.95mmol), ammonium chloride (4.8g, 89.73mmol) and water (25mL) are added. The mixture is stirred at 80°C for 2 hours, and then filtered through diatomaceous earth, washed with hot EtOH. The filtrate is concentrated to a slurry under vacuum, and water (80mL) and DCM (80mL) are added. The organic layer is separated and the aqueous layer is extracted with DCM (2×30mL). The combined organic matter is passed through a hydrophobic glass frit and concentrated under vacuum. The crude product was purified by automated column chromatography, _SiO2 , eluent 0-10.0% MeOH in DCM to yield 3-amino-4-[(4-fluorophenyl)methylamino]-N-(1-methylcyclopropyl)benzenesulfonamide (3.34 g, 9.56 mmol, 53%).

¹ H NMR (300MHz, CDCl ₃ )δ＝7.42-7.30(m,4H),7.09-6.98(m,2H),6.60(d,J＝8.3Hz,1H),5.08(br .s.,1H),4.36(s,2H),1.17(s,3H),0.81-0.72(m,2H),0.46-0.37(m,2H)

The following intermediates were prepared in a similar manner:

Intermediate S3-C2 3-amino-4-[(2,4-dimethylthiazol-5-yl)methylamino]-N-(1-methylcyclopropyl)benzenesulfonamide

Prepared from 4-[(2,4-dimethylthiazol-5-yl)methylamino]-N-(1-methylcyclopropyl)-3-nitrobenzenesulfonamide, iron and ammonium chloride.

LCMS (low pH): RT 0.88 min, [M+H] ⁺ 367.6, 90% purity

Example 72 1-[(4-Fluorophenyl)methyl]-N-(1-methylcyclopropyl)-2-oxo-3H-benzimidazole-5-sulfonamide

3-Amino-4-[(4-fluorophenyl)methylamino]-N-(1-methylcyclopropyl)benzenesulfonamide (3.g, 8.59mmol) and 1,1'-carbonyldiimidazole (1.81g, 11.16mmol) in MeCN (40mL) were heated to reflux under nitrogen for 4 hours. The reaction mixture was cooled to ambient temperature to form a precipitate. The reaction mixture was cooled to 0°C with stirring, and the precipitate was filtered and washed with diethyl ether to yield 1-[(4-fluorophenyl)methyl]-N-(1-methylcyclopropyl)-2-oxo-3H-benzimidazole-5-sulfonamide (2.94g, 7.83mmol, 91%).

¹ H NMR (300MHz, DMSO-d ₆ )δ＝11.38(s,1H),7.89(s,1H),7.44(dd,J＝1.7,8.2Hz,1H),7.42-7.35(m,3H),7.26(d,J＝8. 3Hz,1H),7.24-7.12(m,2H),5.04(s,2H),1.02(s,3H),0.65-0.50(m,2H),0.41-0.26(m,2H)

The following intermediates were prepared in a similar manner:

Example 89 1-[(2,4-Dimethylthiazol-5-yl)methyl]-N-(1-methylcyclopropyl)-2-oxo-3H-benzimidazole-5-sulfonamide

Prepared from 3-amino-4-[(2,4-dimethylthiazol-5-yl)methylamino]-N-(1-methylcyclopropyl)benzenesulfonamide and 1,1'-carbonyldiimidazole.

¹ H NMR (300MHz, DMSO-d ₆ )δ＝11.36(s,1H),7.90(s,1H),7.49(dd,J＝1.8,8.3Hz,1H),7.36(d,J＝1.8Hz,1H),7.26(d,J＝8.3 Hz,1H),5.16(s,2H),2.50(s,3H),2.43(s,3H),1.02(s,3H),0.66-0.50(m,2H),0.40-0.29(m,2H)

General procedures for Option 4:

Intermediate S4-A1N-(1-methylcyclopropyl)-3-[(5-methyl-1,3,4-oxadiazol-2-yl)amino]-4-nitro-benzenesulfonamide

3-Fluoro-N-(1-methylcyclopropylpropyl)-4-nitrobenzenesulfonamide (6.65 g, 25.5 mmol), 5-methyl-1,3,4-oxadiazol-2-amine (38.25 mmol) and cesium carbonate (24.9 g, 76.5 mmol) in 1,4-dioxane (60 mL) were heated to 100 ° C for 4 hours. After cooling, the solvent was removed under reduced pressure and the residue was diluted with water (300 mL) and DCM (300 mL). The DCM layer was separated and the aqueous layer was extracted with DCM (3×50 mL). The combined DCM extracts were dried and concentrated under reduced pressure to give the crude compound, which was purified by automated column chromatography, _SiO2 , 0-100% EtOAc in hexanes as eluent to yield N-(1-methylcyclopropyl)-3-[(5-methyl-1,3,4-oxadiazol-2-yl)amino]-4-nitrobenzenesulfonamide (4 mg, 11.3 mmol, 44% yield).

¹ H NMR (300MHz, CDCl ₃ )δ＝9.27(d,J＝1.9Hz,1H),8.43(d,J＝8.9Hz,1H),7.66(dd,J＝2.0,8.8Hz,1H),2.55(s,3H),1.33(s,3H),0.91(s,2H),0.61-0.56(m,2H)

The following intermediates were prepared in a similar manner:

Intermediate S4-A2N-(1-methylcyclopropyl)-3-[(5-methyl-1,3,4-thiadiazol-2-yl)amino]-4-nitro-benzenesulfonamide

Prepared from 3-fluoro-N-(1-methylcyclopropyl)-4-nitrobenzenesulfonamide, 2-amino-5-methyl-1,3,4-thiadiazole and cesium carbonate.

¹ H NMR (300MHz, CDCl ₃ )δ＝9.24(d,J＝2.0Hz,1H),8.39(d,J＝8.9Hz,1H),7.61(dd,J＝1.8,8.8Hz,1H),2.76(s,3H),1.32(s,3H),0.95-0.87(m,2H),0.62-0.55(m,2H)

Intermediate S4-A3 3-[[5-(Difluoromethyl)-1,3,4-thiadiazol-2-yl]amino]-N-(1-methylcyclopropyl)-4-nitro-benzenesulfonamide

Prepared from 3-fluoro-N-(1-methylcyclopropyl)-4-nitrobenzenesulfonamide, 5-(difluoromethyl)-1,3,4-thiadiazol-2-amine and cesium carbonate.

LCMS (high pH): RT 1.00 min, [M+H] ⁺ 406.5, 80% purity

Intermediate S4-A4 3-[(3-methoxy-1,2,4-thiadiazol-5-yl)amino]-N-(1-methylcyclopropyl)-4-nitro-benzenesulfonamide

Prepared from 3-fluoro-N-(1-methylcyclopropyl)-4-nitrobenzenesulfonamide, 3-methoxy-1,2,4-thiadiazol-5-amine and cesium carbonate.

LCMS (high pH): RT 1.05 min, [M+H] ⁺ 386.6, 82% purity

Intermediate S4-A5 3-anilino-N-(1-methylcyclopropyl)-4-nitro-benzenesulfonamide

Prepared from 3-fluoro-N-(1-methylcyclopropyl)-4-nitrobenzenesulfonamide, aniline and triethylamine. The reaction mixture was heated at 80°C overnight.

LCMS (high pH): RT 1.1 min, [M+H] ⁺ 348.5, >95% purity

Intermediate S4-B1 4-amino-N-(1-methylcyclopropyl)-3-[(5-methyl-1,3,4-oxadiazol-2-yl)amino]benzenesulfonamide

To a suspension of zinc (1 g, 15.6 mmol) in EtOH (25 mL) was added N-(1-methylcyclopropyl)-3-[(5-methyl-1,3,4-oxadiazol-2-yl)amino]-4-nitrobenzenesulfonamide (1.1 g, 3.1 mmol), ammonium chloride (1.7 g, 31.2 mmol) and water (25 mL). The mixture was stirred at 50 ° C overnight and filtered through celite and washed with hot ethanol. The filtrate was concentrated under vacuum and the residue was diluted with water (80 mL) and DCM (80 mL). The organic layer was separated and the aqueous layer was extracted with DCM (2×30 mL). The combined organic layers were dried and concentrated to give the crude compound, which was purified by flash column chromatography, _SiO2 , eluent 0-10% MeOH in DCM to yield 4-amino-N-(1-methylcyclopropyl)-3-[(5-methyl-1,3,4-oxadiazol-2-yl)amino]benzenesulfonamide (920 mg, 2.84 mmol, 92% yield).

LCMS (high pH): RT 0.76 min, [M+H] ⁺ 324.5, 73% purity

The following intermediates were prepared in a similar manner:

Intermediate S4-B2 4-amino-N-(1-methylcyclopropyl)-3-[(5-methyl-1,3,4-thiadiazol-2-yl)amino]benzenesulfonamide

Prepared from N-(1-methylcyclopropyl)-3-[(5-methyl-1,3,4-thiadiazol-2-yl)amino]-4-nitrobenzenesulfonamide, ammonium chloride and iron.

¹ H NMR (300MHz, CDCl ₃ )δ＝7.38(dd,J＝2.2,8.4Hz,1H),7.23(d,J＝2.2Hz,1H),6.68(d,J＝8.3Hz,1H),4.73(s,1H),4.42(d ,J＝5.5Hz,2H),4.13-4.04(m,1H),2.65(s,1H),1.21(s,3H),0.93-0.73(m,2H),0.53-0.38(m,2H)

Intermediate S4-B3 4-amino-3-[[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]amino]-N-(1-methylcyclopropyl)benzenesulfonamide

Prepared from 3-[[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]amino]-N-(1-methylcyclopropyl)-4-nitrobenzenesulfonamide, ammonium chloride, and iron. Used directly in the synthesis of 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-(1-methylcyclopropyl)-2-oxo-1H-benzimidazole-5-sulfonamide as a crude product.

Intermediate S4-B4 4-amino-3-[(3-methoxy-1,2,4-thiadiazol-5-yl)amino]-N-(1-methylcyclopropyl)benzenesulfonamide

Prepared from 3-[(3-methoxy-1,2,4-thiadiazol-5-yl)amino]-N-(1-methylcyclopropyl)-4-nitrobenzenesulfonamide, ammonium chloride and iron.

LCMS (high pH): RT 0.93 min, [M+H] ⁺ 356.5, >90% purity

Intermediate S4-B5 4-amino-3-anilino-N-(1-methylcyclopropyl)benzenesulfonamide

Prepared from 3-anilino-N-(1-methylcyclopropyl)-4-nitrobenzenesulfonamide, ammonium chloride and iron.

LCMS (low pH): RT 1.06 min, [MH] ^- 316.5, >95% purity

Example 94 N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxo-1H-benzimidazole-5-sulfonamide

A solution of 1,1'-carbonyldiimidazole (1.41 g, 8.54 mmol) and 4-amino-N-(1-methylcyclopropyl)-3-[(5-methyl-1,3,4-oxadiazol-2-yl)amino]benzenesulfonamide (920 mg, 2.84 mmol) in MeCN (20 mL) was heated to reflux for 2 hours. The solvent was evaporated to about 10 mL and cooled to ambient temperature. A precipitate was formed, which was filtered and stirred in 1M HCl. After filtration, the solid was dried to give N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxo-1H-benzimidazole-5-sulfonamide (527 mg, 1.51 mmol, 62%).

¹ H NMR (400MHz, DMSO-d ₆ )δ＝12.06(s,1H),8.22(s,1H),8.09(s,1H),7.68-7.66(m,1H),7.28(d,J＝ 8.4Hz,1H),2.59(s,3H),1.06(s,3H),0.61-0.58(m,2H),0.38-0.35(m,2H)

The following intermediates were prepared in a similar manner:

Example 80 N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-1H-benzimidazole-5-sulfonamide

Prepared from 4-amino-N-(1-methylcyclopropyl)-3-[(5-methyl-1,3,4-thiadiazol-2-yl)amino]benzenesulfonamide and 1,1'-carbonyldiimidazole.

¹ H NMR (400MHz, DMSO-d ₆ )δ＝12.31(s,1H),8.73(d,J＝1.6Hz,1H),8.14(s,1H),7.72-7.7(m,1H),7.35(d ,J＝8.4Hz,1H),2.74(s,3H),1.07(s,3H),0.62-0.59(m,2H),0.38-0.34(m,2H)

Intermediate S4-C3 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-(1-methylcyclopropyl)-2-oxo-1H-benzimidazole-5-sulfonamide

Prepared from crude 4-amino-3-[[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]amino]-N-(1-methylcyclopropyl)benzenesulfonamide and 1,1'-carbonyldiimidazole.

LCMS (high pH): RT 0.99 min, [M+H] ⁺ 402.4, 83% purity

Intermediate S4-C4 3-(3-methoxy-1,2,4-thiadiazol-5-yl)-N-(1-methylcyclopropyl)-2-oxo-1H-benzimidazole-5-sulfonamide

Prepared from 4-amino-3-[(3-methoxy-1,2,4-thiadiazol-5-yl)amino]-N-(1-methylcyclopropyl)benzenesulfonamide and 1,1'-carbonyldiimidazole.

LCMS (high pH): RT 0.81 min, [M+H] ⁺ 382.5, 70% purity

Intermediate S4-C5N-(1-methylcyclopropyl)-2-oxo-3-phenyl-1H-benzimidazole-5-sulfonamide

Prepared from 4-amino-3-anilino-N-(1-methylcyclopropyl)benzenesulfonamide and 1,1'-carbonyldiimidazole.

LCMS (high pH): RT 0.95 min, [M+H] ⁺ 344.5, >95 purity

Alkylation of 2-oxo-1H-benzimidazole

Method A1

Sodium hydride (60% w/w) (1 eq) was added to a stirred solution of the 2-oxo-1H-benzimidazole intermediate (Intermediate S1-D) (1 eq) in DMF. After 5 minutes, an alkyl halide (1 eq) was added and the reaction mixture was stirred at ambient temperature for 1 hour.

Method A2

Sodium hydride (60% w/w) (1.1 eq) was added to a stirred solution of 2-oxo-1H-benzimidazole intermediates (Intermediates S1-D, S2-F, S4-C5) (1 eq) in DMF. After 5 minutes, an alkyl halide, acid chloride, or alkyl isocyanate (1.1 eq) was added and the reaction mixture was stirred at ambient temperature for 1 hour.

For Examples 4, 11 and 12, the reaction mixture was stirred at ambient temperature overnight.

Method A3

Sodium hydride (60% w/w) (1.2 eq) was added to a stirred solution of 2-oxo-1H-benzimidazole intermediates (Intermediates S2-F, S3-D1, S3-D2, S4-C1) (1 eq) in DMF. After 20 minutes, an alkyl or aryl chloroformate or an alkyl halide (1.2 eq) was added and the reaction mixture was stirred at ambient temperature for 2 hours.

For Example 55, 4-nitrophenyl chloroformate was used and after 2 hours at ambient temperature, methylamine (2M in THF) (4 equiv) was added and the reaction mixture was stirred at ambient temperature for 1 hour to give the desired hydrocarbon product.

For Example 117, the reaction mixture was heated at 80°C for 3 hours.

Method A4

Sodium hydride (60% w/w) (1.02 eq) was added to a stirred solution of the 2-oxo-1H-benzimidazole intermediate (Intermediate S1-D) (1 eq) in DMF. After 5 minutes, an alkyl halide or mesylate (1.05 eq) was added (sodium iodide (0.2 eq) was added when a mesylate was used) and the reaction mixture was stirred at ambient temperature overnight.

Method A5

A 2-oxo-1H-benzimidazole intermediate (Intermediate S4-C2) (1 eq), potassium carbonate (4 eq), and an alkyl halide (1.4-1.5 eq) in DMF were heated at 50° C. for 0.5-1 h. When an alkyl chloride was used, potassium iodide (1 eq) was added to the reaction mixture.

For Examples 89 and 100, the reaction mixture was stirred at ambient temperature overnight.

Method A6

A solution of 2-oxo-1H-benzimidazole intermediate (intermediate S4-C1, S4-C2) (1 eq), cesium carbonate (3 eq), alkyl halide or mesylate (1.1 eq), potassium iodide (1.2 eq) in DMF was heated at 100 °C for 1 hour by microwave irradiation.

Method A7

A mixture of 2-oxo-1H-benzimidazole intermediate (intermediate S4-C1, S4-C2) (1 eq), potassium tert-butoxide (3 eq), alkyl halide or mesylate (1.1 eq), potassium iodide (1.2 eq) in DMF was heated at 100 °C for 1 h by microwave irradiation.

Method A8

2-Oxo-1H-benzimidazole intermediate (Intermediate S4-C1, S4-C2) (1 eq), potassium carbonate (3 eq), alkyl halide or mesylate (1 eq), potassium iodide (1 eq) in DMF were stirred at ambient temperature for 48 hours.

Method A9

A solution of 2-oxo-1H-benzimidazole intermediate (Intermediate S4-C2) (1 eq), potassium carbonate (2.2 eq), alkyl halide or mesylate (1.2 eq), potassium iodide (1 eq) in DMF was heated at 80 °C for 15 min by microwave irradiation.

Method A10

2-Oxo-1H-benzimidazole intermediate (Intermediate S1-D) (1 eq), diisopropyl azodicarboxylate (2 eq), alkyl alcohol (2 eq), PS- _PPh3 (2 eq) in CHCl3 were heated to 40 °C for ₁ h.

Method A11

2-Oxo-1H-benzimidazole intermediates (Intermediates S4-C1, S4-C2, S4-C3) (1 eq), diisopropyl azodicarboxylate (2 eq), alkyl alcohol (2 eq), PS- _PPh3 (2 eq) in DMF were heated at 80 °C for 2 h.

Method A12

2-Oxo-1H-benzimidazole intermediates (Intermediates S4-C2, S4-C4, S2-C5) (1 eq), diisopropyl azodicarboxylate (3 eq), alkyl alcohol (3 eq), PS- _PPh3 (4 eq) in DMF were heated at 80 °C for 2 h.

For Example 105, diisopropyl azodicarboxylate (1.5 equiv) was used.

Method A13

Triethylamine (5 eq.) was added along with molecular sieves to a mixture of 2-oxo-3H-benzimidazole intermediate (intermediate S2-F, S3-D2) (1 eq.), arylboronic acid (2 eq.) and copper(II) acetate (2 eq.) in DCM (10 mL) and the reaction mixture was stirred at ambient temperature overnight.

Work-up of Method A13: DCM was added to the reaction mixture which was then filtered through celite, the organics were concentrated under reduced pressure and purified by preparative HPLC.

Method A14

A mixture of 2-oxo-3H-benzimidazole intermediates (Intermediates S2-F, S3-D1) (1 equivalent), copper(I) iodide (0.1 equivalent), aryl bromide (2 equivalents), and potassium carbonate (2 equivalents) in 1,4-dioxane was degassed with nitrogen for 5 minutes. trans-N,N'-dimethylcyclohexane-1,2-diamine (0.2 equivalents) was added dropwise, and the reaction mixture was heated at reflux under nitrogen for 4 hours.

Method A15

A mixture of 2-oxo-3H-benzimidazole intermediates (Intermediates S2-F, S3-D2) (1 equivalent), copper(I) iodide (0.2 equivalent), aryl bromide or iodide (4 equivalents), and potassium carbonate (4 equivalents) in 1,4-dioxane was degassed with nitrogen for 5 minutes. Trans-N,N'-dimethylcyclohexane-1,2-diamine (0.4 equivalents) was added dropwise, and the reaction mixture was heated at reflux under nitrogen for 4 hours.

For Examples 107, 108, and 109, the reaction mixture was heated at 60°C for 4 hours.

For Example 90, aryl bromide (2 equiv.) was used.

Workup of Methods A1-A3, A5, A10-A12, A14, and A15: DCM and water or saturated aqueous NaHCO ₃ were added to the reaction mixture, the organic phase was separated using a hydrophobic frit, and the aqueous phase was washed with DCM. The combined organics were concentrated under reduced pressure and purified by mass-directed preparative HPLC or automated column chromatography, SiO ₂ .

Workup for Methods A4 and A6-9: The mixture was concentrated in vacuo and purified directly or subjected to the following workup, followed by addition of water and ethyl acetate, and the layers separated. The organic layer was washed with water and concentrated under reduced pressure. Purification by mass-directed preparative HPLC or automated column chromatography gave the desired product.

Wittig reaction and acid deprotection

Example 67 (E)-3-[5-[3-Methyl-6-[(1-methylcyclopropyl)sulfamoyl]-2-oxo-benzimidazol-1-yl]-2-furyl]prop-2-enoic acid

Step 1

Synthesis of 3-(5-formyl-2-furyl)-1-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide from 1-methyl-N-(1-methylcyclopropyl)-2-oxo-3H-benzimidazole-5-sulfonamide and 5-bromo-2-furfural using Method A14.

LCMS (high pH): RT 0.97 min, [M+H] ⁺ 376.5, >95% purity

Step 2

3-(5-formyl-2-furyl)-1-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide (500 mg, 1.33 mmol) and (ethoxyformylmethylene)triphenylphosphine (464 mg, 1.33 mmol) in THF (20 mL) were heated at reflux for 4 hours under nitrogen. The reaction mixture was cooled and concentrated under reduced pressure, and DCM (20 mL) and NaHCO ₃ saturated aqueous solution (20 mL) were added, and the mixture was stirred for 5 minutes. The DCM layer was separated by passing through a hydrophobic glass frit and the aqueous layer was washed with DCM (2×3 mL). The combined DCM layer was concentrated under reduced pressure, and the residue was purified by automatic column chromatography (SiO ₂ ), eluent being 0-10% MeOH in DCM. The product contaminated with triphenylphosphine oxide was stirred in diethyl ether (100 mL) for 3 hours and then filtered to yield (E)-3-[5-[3-methyl-6-[(1-methylcyclopropyl)sulfamoyl]-2-oxo-benzimidazol-1-yl]-2-furyl]prop-2-enoic acid ethyl ester (242 mg, 0.53 mmol, 40%).

LCMS (high pH): RT 1.16 min, [MH] ^- 444.5, >95% purity

Step 3

To (E)-3-[5-[3-methyl-6-[(1-methylcyclopropyl)sulfamoyl]-2-oxo-benzimidazol-1-yl]-2-furyl]-2-enoic acid ethyl ester (31.86 mg, 0.070 mmol) and lithium hydroxide (6.85 mg, 0.29 mmol) and water (1 mL) in THF (1 mL) was stirred at ambient temperature for 2 hours. DCM (5 mL) was added, which was then acidified to pH 1 with 2M HCl. The DCM layer was separated by passing through a hydrophobic glass frit, and the aqueous layer was washed with DCM (2 × 3 mL). The combined DCM extracts were concentrated under reduced pressure and purified by preparative HPLC (low pH) to yield (E)-3-[5-[3-methyl-6-[(1-methylcyclopropyl)sulfamoyl]-2-oxo-benzimidazol-1-yl]2-furyl]prop-2-enoic acid (8 mg, 0.0192 mmol, 27%).

The following examples were prepared in a similar manner:

Example 69 (E)-3-[2-[3-Methyl-6-[(1-methylcyclopropyl)sulfamoyl]-2-oxo-benzimidazol-1-yl]thiazol-5-yl]prop-2-enoic acid

Step 1, prepared from 1-methyl-N-(1-methylcyclopropyl)-2-oxo-3H-benzimidazole-5-sulfonamide and 2-bromothiazole-5-carboxaldehyde using Method A14. Steps 2 and 3 followed.

hydrogenation

Example 70 3-[2-[3-Methyl-6-[(1-methylcyclopropyl)sulfamoyl]-2-oxo-benzimidazol-1-yl]thiazol-5-yl]propanoic acid

By (E) -3- [2- [3- methyl -6- [(1- methylcyclopropyl) sulfamoyl] -2- oxo -benzoimidazol -1- base] thiazol -5- base] prop- 2- enoic acid (97.54mg, 0.22mmol) and palladium-supported activated carbon (100.mg, 0.32mmol) in EtOH (4mL) are purged under vacuum and stirred at ambient temperature for 4 hours under a hydrogen atmosphere. EtOH (20mL) is added, and the mixture is stirred for 5 minutes, then filtered through diatomaceous earth, washed with EtOH and DCM. The organic matter combined is concentrated under reduced pressure and purified by preparative HPLC (high pH), to yield 3- [2- [3- methyl -6- [(1- methylcyclopropyl) sulfamoyl] -2- oxo -benzoimidazol -1- base] thiazol -5- base] propionic acid (12mg, 0.0275mmol, 12%) as an ammonium salt.

Amide formation

Example 71 N,N-Dimethyl-3-[2-[3-methyl-6-[(1-methylcyclopropyl)sulfamoyl]-2-oxo-benzimidazol-1-yl]thiazol-5-yl]propionamide

Lithium 3-[2-[3-methyl-6-[(1-methylcyclopropyl)sulfamoyl]-2-oxo-benzimidazol-1-yl]thiazol-5-yl]propanoate (100 mg, 0.23 mmol) was suspended in phosphorus oxychloride (3 mL, 32.19 mmol) and heated at 120° C. for 1 hour. Excess POCl ₃ was removed under reduced pressure, and the residue was dissolved in DCM (5 mL). Dimethylamine solution (2 M in THF) (0.1 mL, 2 mmol) was added, and the reaction mixture was stirred at ambient temperature for 3 hours. A saturated aqueous solution of NaHCO ₃ (5 mL) was added, and the mixture was stirred for 5 minutes. The DCM layer was separated by passing through a hydrophobic frit, concentrated under reduced pressure and purified by preparative HPLC (high pH) to yield N,N-dimethyl-3-[2-[3-methyl-6-[(1-methylcyclopropyl)sulfamoyl]-2-oxo-benzimidazol-1-yl]thiazol-5-yl]propanamide (6 mg, 0.0124 mmol, 5%).

Example 74 N-Methyl-3-[2-[3-methyl-6-[(1-methylcyclopropyl)sulfamoyl]-2-oxo-benzimidazol-1-yl]thiazol-5-yl]propionamide

HATU (61.88 mg, 0.16 mmol) is added to a DMF (5 mL) solution of 3-[2-[3-methyl-6-[(1-methylcyclopropyl)sulfamoyl]-2-oxo-benzimidazol-1-yl]thiazol-5-yl]propionic acid lithium (60. mg, 0.1400 mmol) and N,N-diisopropylethylamine (0.07 mL, 0.41 mmol). After 10 minutes, methylamine solution (2M in THF) (0.2 mL, 0.41 mmol) is added, and the reaction mixture is stirred at ambient temperature overnight. DCM (10 mL) and saturated NaHCO ₃ aqueous solution (10 mL) are added and the mixture is stirred for 5 minutes. The DCM layer is separated by passing through a hydrophobic glass frit, and the aqueous layer is extracted with DCM (2 × 5 mL). The combined organics were concentrated under reduced pressure and the residue was purified by preparative HPLC (high pH) to yield N-methyl-3-[2-[3-methyl-6-[(1-methylcyclopropyl)sulfamoyl]-2-oxo-benzimidazol-1-yl]thiazol-5-yl]propanamide (9 mg, 0.020 mmol, 15%).

Deprotection of amines

Example 81 3-(5-Amino-1,3,4-thiadiazol-2-yl)-1-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide

Step 1

[0266] 3-[5-(2,5-Dimethylpyrrol-1-yl)-1,3,4-thiadiazol-2-yl]-1-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide was synthesized from 1-methyl-N-(1-methylcyclopropyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-sulfonamide and 2-bromo-5-(2,5-dimethylpyrrol-1-yl)-1,3,4-thiadiazole (1.1 equiv) using Method A15.

LCMS (high pH): RT 1.28 min, [M+H] ⁺ 459.5, >95 purity

Step 2

3-[5-(2,5-dimethylpyrrole-1-yl)-1,3,4-thiadiazol-2-yl]-1-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide (30 mg, 0.070 mmol), hydroxylamine hydrochloride (68.17 mg, 0.98 mmol) and sodium hydroxide (26.16 mg, 0.65 mmol) in EtOH (4 mL) and water (4 mL) were heated at reflux for 3 days. The mixture was cooled and concentrated under reduced pressure. DCM (10 mL), saturated _NaHCO3 aqueous solution (10 mL) and water (5 mL) were added to the residue, and the mixture was stirred for 5 minutes. The mixture was passed through a hydrophobic frit and the aqueous layer was washed with DCM, and the combined DCM extracts were concentrated under reduced pressure and purified by preparative HPLC (high pH) to yield 3-(5-amino-1,3,4-thiadiazol-2-yl)-1-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide (4.2 mg, 0.0104 mmol, 16%).

General procedures for Option 5:

Intermediate S5-A1 2-Fluoro-N-methyl-6-nitroaniline

Under nitrogen, to a stirred solution of 2,3-difluoronitrobenzene (3.45 mL, 31.43 mmol) and potassium carbonate (8.69 g, 62.86 mmol) in 1,4-dioxane (50 mL) was added methylamine solution (33% w/w in EtOH) (6.87 mL, 62.86 mmol), and the resulting mixture was stirred overnight at ambient temperature. The reaction mixture was poured into EtOAc (250 mL) and water (250 mL). The organic phase was collected and the aqueous layer was extracted with EtOAc (250 mL). The combined organics were washed with water (200 mL), dried over sodium sulfate and evaporated to dryness to yield 2-fluoro-N-methyl-6-nitro-aniline (5.40 g, 31.7 mmol, quantitative).

¹ H NMR (300MHz, DMSO-d ₆ )δ＝7.86(dt,J＝1.6,8.7Hz,1H),7.75(br.s.,1H),7.44(dddd,J＝0.8,1.6,7.9,14.5Hz,1H),6.70-6.62(m,1H),3.11(dd,J＝5.4,7.7Hz,3H)

The following intermediates were prepared in a similar manner:

Intermediate S5-A2 2-(Trifluoromethyl)-N-methyl-6-nitroaniline

Prepared from 2-fluoro-1-nitro-3-(trifluoromethyl)benzene and methylamine (33% w/w in EtOH).

¹ H NMR (300MHz, DMSO-d ₆ )δ＝8.01(dd,J＝1.7,8.3Hz,1H),7.80(dd,J＝1.7,7.7Hz,1H),6.86(app.t,J＝7.8Hz,1H),6.65(q,J＝5.5Hz,1H),2.71(dd,J＝0.8,5.3Hz,3H)

Intermediate S5-A3 5-Fluoro-N-methyl-2-nitroaniline

Prepared from 2,4-difluoronitrobenzene and methylamine (40% w/w in water).

¹ H NMR (300MHz, DMSO-d ₆ )δ＝8.33(br.s.,1H),8.16(dd,J＝6.3,9.5Hz,1H),6.78(dd,J＝2.7,12.3Hz,1H),6.53(ddd,J＝2.7,7.6,9.5Hz,1H),2.93(d,J＝4.9Hz,3H)

Intermediate S5-B1 3-Fluoro-N2-methyl-benzene-1,2-diamine

2-Fluoro-N-methyl-6-nitroaniline (5.40g, 31.7mmol) is dissolved in EtOH (150mL), and the mixture is then purged 3 times with nitrogen vacuum. Then palladium-supported activated carbon (3.38g, 31.7mmol) is added to the reaction mixture, and the resulting suspension is purged 3 times with nitrogen vacuum. The reaction mixture is then purged 3 times with hydrogen vacuum, and stirred for 4 hours under the positive pressure of hydrogen. The reaction mixture is purged with nitrogen vacuum and filtered through a diatomaceous earth pad. The filter cake is washed with EtOH, and the filtrate is combined. The solvent is removed in vacuo to produce 3-fluoro-N2-methyl-benzene-1,2-diamine (4.15g, 29.6mmol, 93%).

¹ H NMR (300MHz, DMSO-d ₆ )δ＝6.65-6.46(m,1H),6.40(td,J＝1.3,7.7Hz,1H),6.30(ddd,J＝1.5,8.1,11.7Hz,1H),4.90(s,2H),3.92(br.s.,1H),2.70(dd,J＝2.5,5.7Hz,3H)

The following intermediates were prepared in a similar manner:

Intermediate S5-B2N2-methyl-3-(trifluoromethyl)benzene-1,2-diamine

Prepared from N-methyl-2-nitro-6-(trifluoromethyl)aniline, palladium on carbon and hydrogen.

¹ H NMR (300MHz, DMSO-d ₆ ) δ = 6.94-6.85 (m, 2H), 6.79-6.72 (m, 1H), 5.11 (s, 2H), 3.63 (q, J = 5.8Hz, 1H), 2.59 (d, J = 5.9Hz, 3H)

Intermediate S5-B3 4-Fluoro-N2-methyl-benzene-1,2-diamine

Prepared from 5-fluoro-N-methyl-2-nitro-aniline, palladium on carbon and hydrogen.

¹ H NMR (300MHz, DMSO-d ₆ ) δ = 6.52-6.41 (m, 1H), 6.20-6.11 (m, 2H), 4.90 (d, J = 6.0Hz, 1H), 4.28 (s, 2H), 2.69 (d, J = 5.0Hz, 3H)

Intermediate S5-C1 4-Fluoro-3-methyl-1H-benzimidazol-2-one

To a stirred solution of 3-fluoro-N2-methyl-benzene-1,2-diamine (4.20 g, 29.97 mmol) in THF (50 mL) was added 1,1'-carbonyldiimidazole (5.34 g, 32.96 mmol) under nitrogen, and the reaction mixture was stirred at 60 ° C overnight. The solvent was removed in vacuo, and the residue was suspended in DCM (50 mL). The mixture was stirred for 15 minutes and then filtered. The filter cake was washed with DCM (2 × 10 mL) and collected to yield 4-fluoro-3-methyl-1H-benzimidazol-2-one (2.90 g, 17.5 mmol, 58%).

¹ H NMR (300MHz, DMSO-d ₆ ) δ = 11.10 (br.s., 1H), 7.00-6.80 (m, 3H), 3.42 (d, J = 1.8Hz, 3H)

The following intermediates were prepared in a similar manner:

Intermediate S5-C2 3-Methyl-4-(trifluoromethyl)-1H-benzimidazol-2-one

Prepared from N2-methyl-3-(trifluoromethyl)benzene-1,2-diamine and 1,1'-carbonyldiimidazole.

¹ H NMR (300MHz, DMSO-d ₆ ) δ = 11.47 (br.s., 1H), 7.35 (dd, J = 1.4, 8.1Hz, 1H), 7.30 (d, J = 7.9Hz, 1H), 7.16 (app.td, J = 0.8, 8.0Hz, 1H), 3.40 (q, J = 2.4Hz, 3H)

Intermediate S5-C3 5-Fluoro-3-methyl-1H-benzimidazol-2-one

Prepared from 4-fluoro-N2-methyl-benzene-1,2-diamine and 1,1'-carbonyldiimidazole.

¹ H NMR (300MHz, DMSO-d ₆ ) δ = 10.86 (br.s., 1H), 7.06 (dd, J = 2.6, 9.2Hz, 1H), 6.93 (dd, J = 4.6, 8.5Hz, 1H), 6.78 (ddd, J = 2.5, 8.5, 10.0Hz, 1H), 3.26 (s, 3H)

Intermediate S5-D1 4-Fluoro-3-methyl-1-(5-methyl-1,3,4-thiadiazol-2-yl)benzimidazol-2-one

4- fluoro-3-methyl -1H- benzimidazol-2-one (200mg, 1.2mmol), 2- bromo-5-methyl -1,3,4- thiadiazole (646.6mg, 3.61mmol), potassium carbonate (499.1mg, 3.61mmol) and copper (I) iodide (45.85mg, 0.24mmol) 1,4- dioxane (8mL) solution was purged with nitrogen for 5 minutes. Then trans-N, N'- dimethylcyclohexane -1,2- diamine (94.91uL, 0.60mmol) was added to the reaction mixture and then heated at 80 ° C for 16 hours under nitrogen. The reaction mixture was filtered through diatomaceous earth (hot), and the filter cake was washed with 1,4- dioxane (2 × 5mL). The combined filtrates were distilled to dryness and the crude product was purified by automated column chromatography, _SiO2 (RediSep 24g) eluent 0-100% EtOAc in isohexane to yield 4-fluoro-3-methyl-1-(5-methyl-1,3,4-thiadiazol-2-yl)benzimidazol-2-one (130 mg, 0.49 mmol, 41%).

¹ H NMR (300MHz, DMSO-d ₆ ) δ = 8.17 (dd, J = 1.5, 7.4Hz, 1H), 7.31-7.18 (m, 2H), 3.58 (d, J = 2.1Hz, 3H), 2.73 (s, 3H)

The following intermediates were prepared in a similar manner:

Intermediate S5-D2 3-methyl-1-(5-methyl-1,3,4-thiadiazol-2-yl)-4-(trifluoromethyl)benzimidazol-2-one

Prepared from 3-methyl-4-(trifluoromethyl)-1H-benzimidazol-2-one and 2-bromo-5-methyl-1,3,4-thiadiazole.

¹ H NMR (300MHz, DMSO-d ₆ ) δ = 8.73 (d, J = 8.1Hz, 1H), 7.68 (d, J = 8.1Hz, 1H), 7.47 (app.t, J = 8.1Hz, 1H), 3.55 (q, J = 2.4Hz, 3H), 2.75 (s, 3H)

Intermediate S5-D3 5-fluoro-3-methyl-1-(5-methyl-1,3,4-thiadiazol-2-yl)benzimidazol-2-one

Prepared from 5-fluoro-3-methyl-1H-benzimidazol-2-one and 2-bromo-5-methyl-1,3,4-thiadiazole.

¹ H NMR (300MHz, DMSO-d ₆ ) δ = 8.27 (dd, J = 4.9, 8.8Hz, 1H), 7.40 (dd, J = 2.5, 8.9Hz, 1H), 7.10 (ddd, J = 2.6, 8.8, 10.0Hz, 1H), 3.44 (s, 3H), 2.73 (s, 3H)

Intermediate S5-E1 7-Fluoro-1-methyl-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonyl chloride

Chlorosulfonic acid (6.mL, 90.1mmol) is added to solid 4-fluoro-3-methyl-1-(5-methyl-1,3,4-thiadiazol-2-yl)benzimidazole-2-one (110.mg, 0.42mmol) in an ice bath under stirring, and the resulting mixture is stirred for 2 hours at ambient temperature. The reaction mixture is poured into ice (60g) and stirred for 15 minutes, then filtered. The resulting solid is dried under vacuum at 40°C for 2 hours to yield 7-fluoro-1-methyl-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonyl chloride (125mg, 0.345mmol, 83%).

¹ H NMR (300MHz, DMSO-d ₆ ) δ = 8.47 (d, J = 1.4Hz, 1H), 7.34 (dd, J = 1.3, 11.3Hz, 1H), 3.57 (d, J = 2.0Hz, 3H), 2.75 (s, 3H), 1.24 (s, 1H)

The following intermediates were prepared in a similar manner:

Intermediate S5-E2 1-methyl-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-7-(trifluoromethyl)benzimidazole-5-sulfonyl chloride

Prepared from 3-methyl-1-(5-methyl-1,3,4-thiadiazol-2-yl)-4-(trifluoromethyl)benzimidazol-2-one and chlorosulfonic acid.

¹ H NMR (300MHz, DMSO-d ₆ ) δ = 8.97 (d, J = 1.7Hz, 1H), 7.84 (d, J = 1.6Hz, 1H), 3.55 (q, J = 2.4Hz, 3H), 2.76 (s, 3H)

Intermediate S5-E3 6-Fluoro-1-methyl-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonyl chloride

From 5-fluoro-3-methyl-1-(5-methyl-1,3,4-thiadiazol-2-yl)benzimidazol-2-one and chlorosulfonic acid.

¹ H NMR (300MHz, DMSO-d ₆ ) δ = 8.63 (d, J = 6.4Hz, 1H), 7.30 (d, J = 9.6Hz, 1H), 3.43 (s, 3H), 2.73 (s, 3H), 1.23 (s, 1H)

Example 114 7-Fluoro-1-methyl-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide

To a stirred solution of 7-fluoro-1-methyl-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonyl chloride (50 mg, 0.14 mmol) and 1-methylcyclopropaneamine hydrochloride (14.83 mg, 0.14 mmol) in DCM (4 mL) was added triethylamine (38.31 μl, 0.28 mmol) and the reaction mixture was allowed to stand at ambient temperature overnight. The solvent was removed under vacuum and the resulting crude product was purified by preparative HPLC at low pH to yield 7-fluoro-1-methyl-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide (40 mg, 0.10 mmol, 73%).

The following examples were prepared in a similar manner:

Example 123 1-Methyl-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-7-(trifluoromethyl)benzimidazole-5-sulfonamide

Prepared from 1-methyl-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-7-(trifluoromethyl)benzimidazole-5-sulfonyl chloride and 1-methylcyclopropaneamine hydrochloride.

Example 116 6-Fluoro-1-methyl-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide

Prepared from 6-fluoro-1-methyl-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonyl chloride and 1-methylcyclopropylamine hydrochloride.

One-pot sulfonyl chloride formation/sulfonamide synthesis

Example 56 6-Fluoro-1,3-dimethyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide

Step 1

Iodomethane (0.82mL, 13.15mmol) is added to a mixture of 5-fluoro-1,3-dihydro-2H-benzimidazol-2-one (500mg, 3.29mmol) and potassium carbonate (1.81g, 13.15mmol) in DMF (25mL), and the reaction mixture is stirred at ambient temperature for 16 hours. DCM (30mL) and water (60mL) are added, and the mixture is stirred for 5 minutes. The DCM layer is separated by passing through a hydrophobic glass frit, and the aqueous layer is washed with DCM (2×50mL). The combined DCM extracts are concentrated under reduced pressure to yield 5-fluoro-1,3-dimethyl-benzimidazol-2-one (556mg, 2.99mmol, 91%).

¹ H NMR (300MHz, CDCl ₃ ) δ = 6.91-6.71 (m, 3H), 3.42 (s, 3H), 3.41 (s, 3H)

Step 2

Chlorosulfonic acid (3.33mL, 50.06mmol) is added dropwise to 5-fluoro-1,3-dimethyl-benzimidazole-2-one (250mg, 1.39mmol) and stirred at ambient temperature for 2 hours. The reaction mixture is added dropwise to a stirred ice/water slurry (about 30mL). After addition, DCM (20mL) is added, and the mixture is stirred for 5 minutes. The DCM layer is separated by passing through a hydrophobic glass frit, and the aqueous phase is washed with DCM (2×4mL). The DCM extracts are combined, and a mixture of 1-methylcyclopropaneamine hydrochloride (179.12mg, 1.67mmol) and triethylamine (0.77mL, 5.55mmol) in DCM (5mL) is added dropwise with stirring. After 1 hour at ambient temperature, water (30mL) is added, and the mixture is stirred for 5 minutes. The DCM layer is separated by passing through a hydrophobic glass frit, and the aqueous layer is washed with DCM (2×4mL). The combined DCM extracts were concentrated under reduced pressure and the residue was purified by preparative HPLC (high pH) to yield 6-fluoro-1,3-dimethyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide (25 mg, 0.0798 mmol, 6%).

General procedures for Option 6:

Intermediate S6-A 4-[(E)-2-(4-fluorophenyl)vinyl]-N-(1-methylcyclopropyl)-3-nitro-benzenesulfonamide

A mixture of 4-chloro-N-(1-methylcyclopropyl)-3-nitrobenzenesulfonamide (400 mg, 1.38 mmol), trans-2-(4-fluorophenyl)vinylboronic acid (342.52 mg, 2.06 mmol), cesium carbonate (896.59 mg, 2.75 mmol) and tris(dibenzylideneacetone)dipalladium(0) (63. mg, 0.07 mmol) in 1,4-dioxane (15 mL) was degassed with nitrogen. Dicyclohexyl(2',6'-dimethoxydiphenyl-2-yl)phosphine (56.49 mg, 0.14 mmol) was then added and the reaction mixture was heated at reflux for 5 hours. The mixture was cooled and concentrated under reduced pressure. EtOAc (20 mL) and saturated NaHCO ₃ aqueous solution (20 mL) were added and the mixture was stirred for 5 minutes. The EtOAc layer was separated and the water layer was washed with EtOAc. The combined EtOAc extracts were passed through a hydrophobic frit and concentrated under reduced pressure and purified by automated column chromatography _{over SiO2} , eluting with 0-100% EtOAc in isohexane to yield 4-[(E)-2-(4-fluorophenyl)vinyl]-N-(1-methylcyclopropylpropyl)-3-nitrobenzenesulfonamide (436 mg, 1.16 mmol, 84%).

¹ H NMR (300MHz, CDCl ₃ )δ＝8.46(d,J＝2.0Hz,1H),8.07(dd,J＝2.5,8.3Hz,1H),7.91(d,J＝8.4Hz,1H),7.62-7.49( m,3H),7.18-7.06(m,3H),5.09(s,1H),1.30(s,3H),0.85-0.79(m,2H),0.60-0.53(m,2H)

Intermediate S6-B 3-amino-4-[2-(4-fluorophenyl)ethyl]-N-(1-methylcyclopropyl)benzenesulfonamide

4-[(E)-2-(4-fluorophenyl) vinyl]-N-(1-methylcyclopropyl)-3-nitrobenzenesulfonamide (270 mg, 0.72 mmol) and 5% palladium-loaded activated carbon (100. mg, 0.94 mmol) in EtOH (10 mL) are heated to 60 ° C overnight under a hydrogen atmosphere. The reaction mixture is filtered through diatomaceous earth, and the filter cake is washed with MeOH, DCM and EtOAc. The combined organic matter is concentrated under reduced pressure. EtOAc (15 mL) and saturated NaHCO ₃ aqueous solution (15 mL) are added, and the mixture is stirred for 5 minutes. Isolate the EtOAc layer, and wash the water layer with EtOAc. The combined EtOAc extracts were concentrated under reduced pressure and purified by automated column chromatography _{over SiO2} , eluent 0-100% EtOAc in isohexane to yield 3-amino-4-[2-(4-fluorophenyl)ethyl]-N-(1-methylcyclopropyl)benzenesulfonamide (213 mg, 0.61 mmol, 85%).

LCMS (high pH): RT 1.18 min, [M+H] ⁺ 349.3, >90% purity

Intermediate S6-C 3-[(4-Fluorophenyl)methyl]-N-(1-methylcyclopropyl)-1H-indazole-6-sulfonamide

Sodium nitrite (0.06 g, 0.9200 mmol) was added in batches to a stirred solution of 3-amino-4-[2-(4-fluorophenyl) ethyl]-N-(1-methylcyclopropyl) benzenesulfonamide (213 mg, 0.61 mmol) in AcOH (100 mL). After addition, the reaction mixture was heated to 80° C. for 3 hours. The reaction mixture was cooled and concentrated under reduced pressure. EtOAc (150 mL) and water (100 mL) were added and the mixture was stirred for 5 minutes. The EtOAc layer was separated and the aqueous layer was washed with EtOAc. The combined EtOAc extracts were passed through a hydrophobic glass material and concentrated under reduced pressure. The residue was ultrasonically treated in cold diethyl ether to cause precipitation, and the solid was filtered to yield 3-[(4-fluorophenyl) methyl]-N-(1-methylcyclopropyl)-1H-indazole-6-sulfonamide (110 mg, 0.31 mmol, 50%).

¹ H NMR (300MHz, CDCl ₃ )δ＝8.19-8.15(m,1H),7.65-7.58(m,1H),7.58-7.50(m,1H),7.32-7.24(m,2H),7.04-6.9 4(m,2H),5.37(br.s.,1H),4.38(s,2H),1.19(s,3H),0.80-0.73(m,2H),0.49-0.42(m,2H)

Example 146 3-[(4-Fluorophenyl)methyl]-N-(1-methylcyclopropyl)-1-(5-methyl-1,3,4-thiadiazol-2-yl)indazole-6-sulfonamide

A mixture of 3-[(4-fluorophenyl)methyl]-N-(1-methylcyclopropyl)-1H-indazole-6-sulfonamide (45.mg, 0.13mmol), 2-bromo-5-methyl-1,3,4-thiadiazole (0.04mL, 0.31mmol), copper(I) iodide (2.38mg, 0.01mmol) and potassium carbonate (43.26mg, 0.31mmol) in MeCN (2mL) was degassed with nitrogen. (+/-)-trans, 1,2-diaminocyclohexane (3.0 μL, 0.03mmol) was added and the reaction mixture was heated at reflux for 2 hours. The reaction mixture was cooled, DCM (5mL) and saturated NaHCO ₃ aqueous solution were added, and the mixture was stirred for 5 minutes. The DCM layer was separated and the water layer was washed with DCM. The combined DCM extracts were concentrated under reduced pressure and purified by automated column chromatography over _SiO2 , eluent 0-100% EtOAc in isohexane, then by preparative HPLC (high pH) to yield 3-[(4-fluorophenyl)methyl]-N-(1-methylcyclopropyl)-1-(5-methyl-1,3,4-thiadiazol-2-yl)indazole-6-sulfonamide (4 mg, 0.0078 mmol, 6%).

General procedures for Option 7:

Intermediate S7-A 4-Methyl-N-(1-methylcyclopropyl)-3-nitro-benzenesulfonamide

Triethylamine (2.36 mL, 16.98 mmol) was added dropwise to a solution of 4-methyl-3-nitrobenzenesulfonyl chloride (1. g, 4.24 mmol) and 1-methylcyclopropaneamine hydrochloride (547.85 mg, 5.09 mmol) in DCM (20 mL) at 0°C. After the addition was complete, the ice bath was removed and the mixture was stirred at ambient temperature for 3 hours. DCM (30 mL) and saturated aqueous NaHCO ₃ solution (50 mL) were added and the mixture was stirred for 5 minutes. The DCM layer was separated by passing through a hydrophobic frit and the aqueous layer was washed with DCM. The combined DCM layers were concentrated under reduced pressure and the residue was purified by automated column chromatography (SiO 2) using 0-100% EtOAc in isohexane as eluent to yield 4-methyl-N-(1-methylcyclopropyl)-3-nitrobenzenesulfonamide (1.09 g, 4.03 mmol, 95%).

¹ H NMR (300MHz, CDCl ₃ )δ＝8.47(d,J＝2.0Hz,1H),8.00(dd,J＝2.0,8.1Hz,1H),7.52(d,J＝8.1Hz,1H),5 .02(br.s,1H),2.70(s,3H),1.28(s,3H),0.82-0.76(m,2H),0.58-0.51(m,2H)

Intermediate S7-B N-(1-methylcyclopropyl)-3-nitro-4-[(E)-2-pyrrolidin-1-ylvinyl]benzenesulfonamide

1,1-Dimethoxy-N,N-dimethylmethanamine (0.18 mL, 1.33 mmol) was added to a solution of 4-methyl-N-(1-methylcyclopropyl)-3-nitrobenzenesulfonamide (300 mg, 1.11 mmol) and pyrrolidine (0.11 mL, 1.33 mmol) in DMF (5 mL), and the reaction mixture was heated at 100 ° C. under nitrogen for 3 hours. The reaction mixture was cooled and concentrated under reduced pressure. The residue was sonicated in cold diethyl ether, and a precipitate was formed. The solid was filtered to yield N-(1-methylcyclopropyl)-3-nitro-4-[(E)-2-pyrrolidin-1-ylvinyl]benzenesulfonamide (331 mg, 0.94 mmol, 85%).

¹ H NMR (300MHz, CDCl ₃ )δ＝8.36(d,J＝2.1Hz,1H),7.68(dd,J＝2.0,8.5Hz,1H),7.54(d,J＝8.8Hz,1H),7.48(d,J＝13.6Hz,1H),5.94(d,J＝1 3.1Hz,1H),4.87(s,1H),3.51-3.32(m,4H),2.07-1.91(m,4H),1.26(s,3H),0.85-0.78(m,2H),0.55-0.47(m,2H)

Intermediate S7-C N-(1-methylcyclopropyl)-1H-indole-6-sulfonamide

Hydrazine hydrate (1.88mL, 51.36mmol) is added into the stirred mixture of N-(1-methylcyclopropyl)-3-nitro-4-[(E)-2-pyrrolidin-1-yl vinyl] benzenesulfonamide (3.61g, 10.27mmol) and Raney nickel (2.13mL, 323.64mmol) in MeOH (25mL) and THF (25mL), and heated at 60 ℃ for 3 hours.Reaction mixture is cooled and DCM (10mL) is added.Mixture is stirred 5 minutes, and then filtered by diatomite with MeOH and DCM washing.The filtrate merged is concentrated under reduced pressure, and residue passes through automatic column chromatography, 0-100%EtOAc purifying in isohexane, to produce N-(1-methylcyclopropyl)-1H-indole-6-sulfonamide (2.17g, 8.15mmol, 79%).

¹ H NMR (300MHz, DMSO-d ₆ )δ＝11.56(br.s.,1H),7.91-7.87(m,1H),7.82(s,1H),7.70(d,J＝8.4Hz,1H),7.61(dd,J＝2.1,3.1Hz, 1H),7.40(dd,J＝1.6,8.4Hz,1H),6.57-6.53(m,1H),1.00(s,3H),0.61-0.54(m,2H),0.36-0.25(m,2H)

Example 115 N-(1-methylcyclopropyl)-1-(5-methyl-1,3,4-thiadiazol-2-yl)indole-6-sulfonamide

By N- (1- methylcyclopropyl) -1H- indole -6- sulfonamide (40.mg, 0.16mmol), 2- bromo -5- methyl -1,3,4- thiadiazole (57.22mg, 0.32mmol), copper (I) iodide (3.04mg, 0.02mmol) and potassium carbonate (55.21mg, 0.40mmol) in MeCN (2mL) solution degassed with nitrogen. (+/-) - trans -1,2- diaminocyclohexane (3.8 μ L, 0.03mmol) was added, and the reaction mixture was heated to reflux for 2 hours. The reaction mixture was cooled, DCM (5mL) and saturated NaHCO ₃ aqueous solution were added, and the mixture was stirred for 5 minutes. The DCM layer was separated, and the water layer was washed with DCM. The combined DCM extracts were concentrated under reduced pressure and the residue was purified by automated column chromatography _SiO2 , eluent 0-100% EtOAc in isohexane, then by preparative HPLC (high pH) to yield N-(1-methylcyclopropyl)-1-(5-methyl-1,3,4-thiadiazol-2-yl)indole-6-sulfonamide (6 mg, 0.017 mmol, 11%).

Intermediate S7-D1 3-Acetyl-N-(1-methylcyclopropyl)-1H-indole-6-sulfonamide

Intermediate S7-D1 3-Acetyl-N-(1-methylcyclopropyl)-1H-indole-6-sulfonamide

Zirconium tetrachloride (139.65 mg, 0.60 mmol) was added to a solution of N-(1-methylcyclopropyl)-1H-indole-6-sulfonamide (100 mg, 0.40 mmol) and acetyl chloride (0.03 mL, 0.40 mmol) in DCM (4 mL). After stirring at ambient temperature for 3 hours, EtOAc (10 mL) and water (10 mL) were added and the mixture was stirred for 5 minutes. The EtOAc layer was separated and the aqueous layer was extracted with EtOAc. The combined extracts were concentrated under reduced pressure and the residue was purified by automated column chromatography on SiO ₂ , eluent being 0-100% EtOAc in isohexane to yield 3-acetyl-N-(1-methylcyclopropyl)-1H-indole-6-sulfonamide (60 mg, 0.18 mmol, 46%).

¹ H NMR (300MHz, DMSO-d ₆ )δ＝12.32(br.s.,1H),8.55(s,1H),8.31(d,J＝8.3Hz,1H),7.95(s,1H),7.93(dd,J＝0.8,1.7Hz, 1H),7.60(dd,J＝1.6,8.4Hz,1H),2.49(s,3H),1.00(s,3H),0.62-0.53(m,2H),0.36-0.29(m,2H)

The following intermediates were prepared in a similar manner:

Intermediate S7-D2 3-(Cyclopropanecarbonyl)-N-(1-methylcyclopropyl)-1H-indole-6-sulfonamide

Prepared from N-(1-methylcyclopropyl)-1H-indole-6-sulfonamide and cyclopropanecarbonyl chloride.

LCMS (high pH): RT 0.98 min, [M+H] ⁺ 319.3, 93% purity

Intermediate S7-D3 3-(4-Fluorobenzoyl)-N-(1-methylcyclopropyl)-1H-indole-6-sulfonamide

Prepared from N-(1-methylcyclopropyl=propyl)-1H-indole-6-sulfonamide and 4-fluorobenzoyl chloride.

LCMS (high pH): RT 1.09 min, [M+H] ⁺ 373.3, 100% purity

Example 144 3-Acetyl-N-(1-methylcyclopropyl)-1-(5-methyl-1,3,4-thiadiazol-2-yl)indole-6-sulfonamide

The mixture was stirred with nitrogen degassed in MeCN (4 mL) of 3-acetyl-N-(1-methylcyclopropyl)-1H-indole-6-sulfonamide (60.mg, 0.21mmol), 2-bromo-5-methyl-1,3,4-thiadiazole (0.04mL, 0.41mmol), copper (I) iodide (3.91mg, 0.02mmol) and potassium carbonate (85.1mg, 0.62mmol). (+/-)-trans, 1,2-diaminocyclohexane (4.9 μL, 0.040mmol) was added and the mixture was heated at reflux for 2 hours. The reaction mixture was cooled, DCM (5mL) and saturated NaHCO ₃ aqueous solution were added and the mixture was stirred for 5 minutes. The DCM layer was separated and the water layer was washed with DCM. The combined DCM extracts were concentrated under reduced pressure and the residue was purified by automated column chromatography, _SiO2 , 0-100% EtOAc in isohexane then by preparative HPLC (high pH) to yield 3-acetyl-N-(1-methylcyclopropyl)-1-(5-methyl-1,3,4-thiadiazol-2-yl)indole-6-sulfonamide (4.4 mg, 0.0108 mmol, 5%).

The following examples were prepared in a similar manner:

Example 130 3-(Cyclopropanecarbonyl)-N-(1-methylcyclopropyl)-1-(5-methyl-1,3,4-thiadiazol-2-yl)indole-6-sulfonamide

Prepared from 3-(cyclopropanecarbonyl)-N-(1-methylcyclopropyl)-1H-indole-6-sulfonamide and 2-bromo-5-methyl-1,3,4-thiadiazole.

Example 145 3-(Cyclopropanecarbonyl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-(1-methylcyclopropyl)indole-6-sulfonamide

Prepared from 3-(cyclopropanecarbonyl)-N-(1-methylcyclopropyl)-1H-indole-6-sulfonamide and 2-bromo-5-(difluoromethyl)-1,3,4-thiadiazole.

Example 131 3-(4-Fluorobenzoyl)-N-(1-methylcyclopropyl)-1-(5-methyl-1,3,4-thiadiazol-2-yl)indole-6-sulfonamide

Prepared from 3-(4-fluorobenzoyl)-N-(1-methylcyclopropyl)-1H-indole-6-sulfonamide and 2-bromo-5-methyl-1,3,4-thiadiazole.

Intermediate S7-E1 3-Benzyl-N-(1-methylcyclopropyl)-1H-indole-6-sulfonamide

By N- (1- methylcyclopropyl) -1H- indole -6- sulfonamide (200.mg, 0.80mmol), benzyl bromide (0.19mL, 1.6mmol) and silver oxide (370.3mg, 1.6mmol) in 1,4- dioxane (6mL) is heated at 100 DEG C for 6 hours.The reaction mixture is cooled and concentrated under reduced pressure.DCM (10mL) and saturated NaHCO ₃ aqueous solution (10mL) are added, and the mixture is stirred for 5 minutes.The DCM layer is separated by passing through hydrophobic glass frit, and the water layer is washed with DCM.The DCM extracts merged are concentrated under reduced pressure, and the crude product is purified by preparative HPLC (high pH), to yield 3-benzyl-N- (1- methylcyclopropyl) -1H- indole -6- sulfonamide (109mg, 0.32mmol, 40%).

¹ H NMR (300MHz, DMSO-d ₆ )δ＝11.37(br.s.,1H),7.83(br.s,1H),7.60(d,J＝8.4Hz,1H),7.42(d,J＝2.1Hz,1H),7.34(dd,J＝1 .8,8.5Hz,1H),7.32-7.13(m,5H),4.07(s,2H),0.99(s,3H),0.59-0.45(m,2H),0.33-0.25(m,2H)

The following intermediates were prepared in a similar manner:

Intermediate S7-E2 3-[(4-Fluorophenyl)methyl]-N-(1-methylcyclopropyl)-1H-indole-6-sulfonamide

Prepared from N-(1-methylcyclopropyl)-1H-indole-6-sulfonamide and 4-fluorobenzyl bromide.

¹ H NMR (300MHz, DMSO-d ₆ )δ＝11.38(br.s.,1H),7.89-7.79(m,2H),7.60(d,J＝8.2Hz,1H),7.43(d,J＝2.4Hz,1H),7.41-7 .29(m,3H),7.13-7.05(m,2H),4.06(s,2H),1.00(s,3H),0.59-0.51(m,2H),0.33-0.27(m,2H)

Intermediate S7-E3 3-[(2,4-dimethylthiazol-5-yl)methyl]-N-(1-methylcyclopropyl)-1H-indole-6-sulfonamide

Prepared from N-(1-methylcyclopropyl)-1H-indole-6-sulfonamide and 5-(chloromethyl)-2,4-dimethyl-thiazole hydrochloride.

¹ H NMR (300MHz, DMSO-d ₆ )δ＝11.40(br.s,1H),7.84(d,J＝1.0Hz,2H),7.59(d,J＝8.5Hz,1H),7.43(br.s,1H),7.38(dd,J＝1.6,8.4 Hz,1H),4.15(s,2H),2.47(s,3H),2.34(s,3H),1.05-0.94(m,3H),0.66-0.50(m,2H),0.35-0.28(m,2H)

Intermediate S7-E4 3-(Cyclopropylmethyl)-N-(1-methylcyclopropyl)-1H-indole-6-sulfonamide

Prepared from N-(1-methylcyclopropyl)-1H-indole-6-sulfonamide and 1-(bromomethyl)cyclopropane. The crude product was used for the next reaction.

LCMS (high pH): RT 1.19 min, [M+H] ⁺ 305.3, 65% purity

Example 126 3-Benzyl-N-(1-methylcyclopropyl)-1-(5-methyl-1,3,4-thiadiazol-2-yl)indole-6-sulfonamide

A suspension of 3-benzyl-N-(1-methylcyclopropyl)-1H-indole-6-sulfonamide (80.mg, 0.23mmol), 2-bromo-5-methyl-1,3,4-thiadiazole (84.15mg, 0.47mmol), copper (I) iodide (4.48mg, 0.02mmol) and potassium carbonate (81.19mg, 0.59mmol) in MeCN (3mL) was degassed with nitrogen. (+/-)-trans, 1,2-diaminocyclohexane (0.01mL, 0.05mmol) was added and the reaction mixture was heated at reflux for 2 hours. The reaction mixture was cooled, and DCM (5mL) and saturated NaHCO ₃ aqueous solution were added and the mixture was stirred for 5 minutes. The DCM layer was separated and the water layer was washed with DCM. The combined DCM extracts were concentrated under reduced pressure and the residue was purified by automated column chromatography, _SiO2 , 0-100% EtOAc in isohexane then by preparative HPLC (high pH) to yield 3-benzyl-N-(1-methylcyclopropyl)-1-(5-methyl-1,3,4-thiadiazol-2-yl)indole-6-sulfonamide (26 mg, 0.059 mmol, 25%).

The following examples were prepared in a similar manner:

Example 127 3-[(4-Fluorophenyl)methyl]-N-(1-methylcyclopropyl)-1-(5-methyl-1,3,4-thiadiazol-2-yl)indole-6-sulfonamide

Prepared from 3-[(4-fluorophenyl)methyl]-N-(1-methylcyclopropyl)-1H-indole-6-sulfonamide and 2-bromo-5-methyl-1,3,4-thiadiazole.

Example 129 3-[(2,4-Dimethylthiazol-5-yl)methyl]-N-(1-methylcyclopropyl)-1-(5-methyl-1,3,4-thiadiazol-2-yl)indole-6-sulfonamide

Prepared from 3-[(2,4-dimethylthiazol-5-yl)methyl]-N-(1-methylcyclopropyl)-1H-indole-6-sulfonamide and 2-bromo-5-methyl-1,3,4-thiadiazole.

Example 128 3-(Cyclopropylmethyl)-N-(1-methylcyclopropyl)-1-(5-methyl-1,3,4-thiadiazol-2-yl)indole-6-sulfonamide

Prepared from 3-(cyclopropylmethyl)-N-(1-methylcyclopropyl)-1H-indole-6-sulfonamide and 2-bromo-5-methyl-1,3,4-thiadiazole.

Example 132 Ethyl 3-[(2,4-dimethylthiazol-5-yl)methyl]-6-[(1-methylcyclopropyl)sulfamoyl]indole-1-carboxylate

Sodium hydride (60% w / w) (5.9 mg, 0.15 mmol) is added to a stirred solution of ethyl chloroformate saline (0.02 mL, 0.16 mmol) in DMF (2 mL). After 5 minutes, 3- [(2,4- dimethylthiazol-5-yl) methyl] -N- (1- methylcyclopropyl) -1H- indole -6- sulfonamide (50. mg, 0.13 mmol) is added, and the reaction mixture is stirred at ambient temperature for 1 hour. Water (1 mL) is added and the mixture is concentrated under reduced pressure. DCM (5 mL) and saturated NaHCO ₃ aqueous solution (5 mL) are added and the mixture is stirred for 5 minutes. The DCM layer is separated by passing through a hydrophobic glass frit, and the water layer is washed with DCM (2 × 2 mL). The combined DCM extracts were concentrated under reduced pressure and the residue was purified by preparative HPLC (low pH) to yield ethyl 3-[(2,4-dimethylthiazol-5-yl)methyl]-6-[(1-methylcyclopropyl)sulfamoyl]indole-1-carboxylate (12 mg, 0.024 mmol, 18%).

General procedures for Option 8:

Intermediate S8-A 1-acetyl-N-(1-methylcyclopropyl)indoline-6-sulfonamide

A suspension of 1-acetyl-2,3-dihydro-1H-indole-6-sulfonyl chloride (enamine) (3. g, 9.82 mmol) in DCM (60 mL) was treated with 1-methylcyclopropaneamine hydrochloride (1.58 g, 14.73 mmol) and triethylamine (4.09 mL, 29.46 mmol), and the reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was diluted with 2M HCl (60 mL), stirred vigorously for 20 minutes, and the layers were separated. The aqueous phase was re-extracted with DCM (60 mL), and the combined organics were dried with MgSO ₄ and concentrated to dryness to yield 1-acetyl-N-(1-methylcyclopropyl)dihydroindole-6-sulfonamide (1.7 g, 5.78 mmol, 56%).

LCMS (high pH): RT 0.92 min, [M+H] ⁺ 295.5, 96% purity

Intermediate S8-B N-(1-methylcyclopropyl)indoline-6-sulfonamide

A solution of 1-acetyl-N-(1-methylcyclopropyl)indoline-6-sulfonamide (356.mg, 1.21mmol) in THF (4mL) and water (2mL) was treated with potassium hydroxide (678.52mg, 12.09mmol) and the reaction mixture was heated at 100°C by microwave irradiation for 30 minutes. The THF was removed under vacuum and the resulting aqueous solution was carefully adjusted to pH 7 with 2M HCl under stirring and cooling. The neutral mixture was stirred in an ice bath for 20 minutes and the precipitate was then collected by filtration, washed with cold water (2 x 3mL) and oven dried to yield N-(1-methylcyclopropyl)indoline-6-sulfonamide (203mg, 0.81mmol, 67%). ¹ H NMR (300MHz, DMSO-d ₆ )δ＝7.78(s,1H),7.14(d,J＝7.6Hz,1H),6.94(dd,J＝1.7,7.5Hz,1H),6.82(d,J＝1.7Hz,1H),5.94(s,1H) ,3.48(dt,J＝1.9,8.8Hz,2H),2.97(t,J＝8.7Hz,2H),1.07(s,3H),0.71-0.54(m,2H),0.43-0.26(m,2H)

Intermediate S8-C1 2-(3-methyl-2-oxo-imidazolidin-1-yl)acetic acid

Step 1

To a suspension of 1-imidazolidin-2-one (1 g, 9.99 mmol) was added sodium hydride (60% w/w) (439.47 mg, 10.99 mmol), and the reaction mixture was stirred at ambient temperature for 1 hour and then at 40° C. for 2 hours. Tert-butyl bromoacetate (1.47 mL, 9.99 mmol) was added, and the mixture was stirred at ambient temperature for 16 hours. Water was added, and the mixture was extracted with ethyl acetate (3×200 mL). The organic solution was washed with water, dried over MgSO ₄ and evaporated to dryness in vacuo. The residue was purified by automated column chromatography on SiO ₂ , eluent being 0-100% EtOAc in isohexane, to yield tert-butyl 2-(3-methyl-2-oxo-imidazolidin-1-yl)acetate (0.86 g, 4.01 mmol, 40%).

Step 2

Tert-butyl 2-(3-methyl-2-oxo-imidazolidin-1-yl)acetate (800 mg, 3.73 mmol) in HCl (4 M in dioxane) (15. mL, 60 mmol) was stirred at ambient temperature for 4 hours. Excess solvent was removed in vacuo, and the residue was taken up in 1,4-dioxane (20 mL). The solution was evaporated to dryness in vacuo to yield 2-(3-methyl-2-oxo-imidazolidin-1-yl)acetic acid (600 mg, 3.79 mmol, quantitative)

¹ H NMR (300MHz, DMSO-d ₆ ) δ = 12.65 (br.s., 1H), 3.78 (s, 2H), 3.38-3.21 (m, 4H), 2.65 (s, 3H)

The following intermediates were prepared in a similar manner:

Intermediate S8-C2 2-(2-oxoimidazolidin-1-yl)acetic acid

Prepared from 2-imidazolidinone, tert-butyl bromoacetate and HCl (4M in 1,4-dioxane).

¹ H NMR (300MHz, DMSO-d ₆ ) δ = 12.62 (br.s., 1H), 6.42 (br.s., 1H), 3.76 (s, 2H), 3.44-3.36 (m, 2H), 3.31-3.19 (m, 2H)

Intermediate S8-C3 2-(2-oxooxazolidin-3-yl)acetic acid

Prepared from oxazolidinone, tert-butyl bromoacetate and HCl (4M in 1,4-dioxane).

¹ H NMR (300MHz, DMSO-d ₆ ) δ = 12.95 (br.s., 1H), 4.34-4.26 (m, 2H), 3.90 (s, 2H), 3.71-3.49 (m, 2H)

Example 25 N-(1-methylcyclopropyl)-1-[2-(3-methyl-2-oxoimidazolidin-1-yl)acetyl]indoline-6-sulfonamide

1-hydroxy-7-azabenzotriazole (107.91 mg, 0.79 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (151.98 mg, 0.79 mmol) were added to a DMF (4 mL) solution of 2-(3-methyl-2-oxo-imidazolidin-1-yl)acetic acid (125.39 mg, 0.79 mmol). The reaction mixture was stirred for 30 minutes. 2 mL of the above solution was added to N-(1-methylcyclopropyl)indoline-6-sulfonamide (50. mg, 0.20 mmol) and the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was diluted with water and extracted with EtOAc, dried with _MgSO and evaporated to dryness. The crude product was purified by preparative HPLC to yield N-(1-methylcyclopropyl)-1-[2-(3-methyl-2-oxo-imidazolidin-1-yl)acetyl]indoline-6-sulfonamide (10.01 mg, 0.0255 mmol, 13%).

The following examples were prepared in a similar manner:

Example 21 N-(1-methylcyclopropyl)-1-[2-(2-oxoimidazolidin-1-yl)acetyl]indoline-6-sulfonamide

Prepared from N-(1-methylcyclopropyl)indoline-6-sulfonamide and 2-(2-oxoimidazolidin-1-yl)acetic acid.

Example 14 N-(1-methylcyclopropyl)-1-[2-(2-oxooxazolidin-3-yl)acetyl]indoline-6-sulfonamide

Prepared from N-(1-methylcyclopropyl)indoline-6-sulfonamide and 2-(2-oxooxazolidin-3-yl)acetic acid.

General procedures for Option 9:

Step 1

1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.5 equivalents) is added to a solution of substituted carboxylic acid (2.5 equivalents) and triethylamine (6 equivalents) in DMF (8mL). After 10 minutes, 4-amino-N-(1-methylcyclopropyl)-3-[(5-methyl-1,3,4-thiadiazol-2-yl) amino] benzsulfamide (1 equivalent) is added at ambient temperature, and the reaction mixture is heated at 80 DEG C for 2 hours. The reaction mixture is cooled, DCM (10mL) and saturated _NaHCO3 aqueous solution (10mL) are added, and the mixture is stirred for 5 minutes. The DCM layer is separated by passing through a hydrophobic glass frit, and the water layer is washed with DCM. The DCM extracts combined are concentrated under reduced pressure, and purified by preparative HPLC (high pH), to yield intermediate amides.

Step 2

The intermediate amide is taken up in AcOH (4 mL) and heated at 100° C. for 1 hour. The reaction mixture is cooled and concentrated under reduced pressure. DCM (8 mL) and saturated aqueous NaHCO ₃ solution (8 mL) are added, and the mixture is stirred for 5 minutes. The DCM layer is separated by passing through a hydrophobic frit, and the aqueous layer is washed with DCM. The combined DCM extracts are concentrated under reduced pressure and purified by automated column chromatography on SiO ₂ , eluent being 0-5% MeOH in DCM, to yield the desired benzimidazole product.

For Example 119, using formic acid as solvent and reagent and heating at reflux for 3 hours gave complete conversion to the desired benzimidazole.

Intermediate S5-D4 3-methyl-1-(5-methyl-1,3,4-thiadiazol-2-yl)benzimidazol-2-one

From 3-methyl-1H-benzimidazol-2-one and 2-bromo-5-methyl-1,3,4-thiadiazole.

¹ H NMR (300MHz, DMSO-d ₆ ) δ = 8.28-8.33 (m, 1H), 7.24-7.40 (m, 3H), 3.45 (s, 3H), 2.73 (s, 3H)

Example 156 N-[1-(Fluoromethyl)cyclopropyl]-1-methyl-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide

1-methyl-3-(5-methyl-1,3,4-thiadiazole-2-yl) benzimidazole-2-one (75mg, 0.30mmol) is stirred and added in batches to chlorosulfonic acid (35.5mg, 0.300mmol).After adding, the mixture is stirred for 3 hours, and then carefully added into the slurries of ice (about 10g) and 10%MeOH/DCM (10mL) that stir.After stirring for 5 minutes, separate the DCM layer, and the water layer is extracted with 10%MeOH/DCM (10mL).The DCM layer merged is passed through hydrophobic glass frit, and is concentrated into dryness.Gained white solid is added into the stirred mixture of 1-(fluoromethyl) cyclopropane-1-amine hydrochloride (38mg, 0.30mmol) and N, N-diisopropylethylamine (39mg, 0.30mmol) in DMF (3mL). At 4 DEG C, 1H-dextrose (5mg, 0.01mmol) and 4-nitro-2-thiazolyl-1-ol (5mg, 0.01mmol) in 4%MeOH/DCM (10mL) solution in the 4-nitro-2-thiazolyl-1-ol (5mg, 0.01mmol) of 4-nitro-2-thiazolyl-1-ol (5mg, 0.01mmol, 4.1%) ...

Example 157 N-(1-Cyanocyclopropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-1H-benzimidazole-5-sulfonamide

3-(5-methyl-1,3,4-thiadiazole-2-yl)-1H-benzimidazole-2-one (75mg, 0.300mmol) is added portionwise to the chlorosulfonic acid (35.5mg, 0.30mmol) of stirring. After stirring for 2 hours, the solution is carefully added dropwise to the slurries of ice (about 10mL) and 10%MeOH/DCM (10mL) of stirring. After stirring for 5 minutes, the DCM layer is separated, and the water layer is extracted with 10%MeOH/DCM (10mL). The DCM extracts merged are passed through a hydrophobic glass frit and concentrated to dryness, leaving a white powder. This powder is added to a mixture of 1-amino-1-cyclopropanenitrile hydrochloride (36mg, 0.30mmol) in pyridine (3mL) and stirred for 16 hours. The reaction mixture is added to a mixture of about 10%MeOH/DCM (30mL) and 1N HCl (aqueous solution) (30mL) of stirring. After 5 minutes, the DCM layer was separated and the aqueous layer was extracted with 10% MeOH/DCM (20 mL). The combined DCM extracts were passed through a hydrophobic frit, concentrated to dryness, and purified by column chromatography (Hex->EtOAc) to afford N-(1-cyanocyclopropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-1H-benzimidazole-5-sulfonamide (60 mg, 0.159 mmol, 52.3%) as a white solid.

Example 158 N-(1-Cyanocyclopropyl)-1-ethyl-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide

Intermediate S10-A1-(5-methyl-1,3,4-thiadiazol-2-yl)-1H-benzo[d]imidazol-2(3H)-one

By 2-hydroxybenzimidazole (500mg, 3.73mmol), 2-bromo-5-methyl-1,3,4-thiadiazole (801mg, 4.47mmol), copper iodide (71mg, 0.37mmol) and potassium carbonate (1030mg, 7.46mmol) in 1,4-dioxane (10mL) stirring mixture by nitrogen bubbling through mixture degassing 5 minutes.Add trans-N, N'-dimethylcyclohexane-1,2-diamine (118 μ L, 0.745mmol), and the mixture is heated to 135 DEG C 2 hours in microwave.Mixture is added in 10%MeOH/DCM (200mL) and saturated sodium bicarbonate aqueous solution (200mL), and the mixture is stirred 5 minutes.Isolate the DCM layer, and water layer is extracted with 10%MeOH/DCM (100mL). The combined DCM extracts were concentrated under reduced pressure and purified by column chromatography (DCM->10% MeOH/DCM) to give 3-(5-methyl-1,3,4-thiadiazol-2-yl)-1H-benzimidazol-2-one (612 mg, 2.64 mmol, 70.7%) as a white solid.

¹ H NMR (300MHz, DMSO-d ₆ ) δ = 11.98-11.67 (m, 1H), 8.26 (s, 1H), 7.29-7.13 (m, 3H), 2.72 (s, 3H)

Intermediate S10-B 1-ethyl-3-(5-methyl-1,3,4-thiadiazol-2-yl)benzimidazol-2-one

A 60% dispersion of sodium hydride in mineral oil (103 mg, 2.58 mmol) was added portionwise to a stirred solution of 3-(5-methyl-1,3,4-thiadiazol-2-yl)-1H-benzimidazol-2-one (0.3 g, 1.29 mmol) in DMF (10 mL). After 30 minutes, ethanol (0.21 mL, 2.58 mmol) was added. After 16 hours, saturated aqueous sodium bicarbonate solution (10 mL) and EtOAc (10 mL) were added, and the mixture was stirred for 5 minutes. The EtOAc layer was separated and the aqueous layer was extracted with EtOAc (10 mL). The combined EtOAc extracts were passed through a hydrophobic frit and concentrated under reduced pressure and purified by column chromatography (Hex->EtOAc) to yield 1-ethyl-3-(5-methyl-1,3,4-thiadiazol-2-yl)benzimidazol-2-one (261 mg, 1.00 mmol, 77.6%) as a yellow solid.

¹ H NMR (300MHz, DMSO-d ₆ ) δ = 7.19 (dd, J = 3.2, 5.8Hz, 2H), 7.05 (dd, J = 3.2, 5.7Hz, 2H), 4.01 (q, J = 7.2Hz, 2H), 2.73 (s, 2H), 1.29 (t, J = 7.2Hz, 3H)

By 1-ethyl-3-(5-methyl-1,3,4-thiadiazole-2-yl) benzimidazol-2-one (100mg, 0.38mmol) under agitation is joined in chlorosulfonic acid (45mg, 0.38mmol) in batches.After 3 hours, solution is added in the stirring slurry of ice (about 10mL), forms precipitation.Precipitate is filtered and dried on glass frit, and then added in the stirred mixture of 1-amino-1-cyclopropanenitrile hydrochloride (46mg, 0.38mmol) in pyridine (4mL).It is stirred 3 hours, then add EtOAc (10mL) and 1M HCl solution (aqueous solution) (10mL), and mixture is stirred 5 minutes.Separate EtOAc layer, and water layer is extracted with EtOAc (10mL). The combined EtOAc extracts were passed through a hydrophobic frit, concentrated to dryness, and purified by preparative HPLC (low pH) to give N-(1-cyanocyclopropyl)-1-ethyl-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide (12 mg, 0.030 mmol, 7.7%) as a white solid.

Example 159 1-Ethyl-N-[1-(fluoromethyl)cyclopropyl]-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide

1- methyl -3- (5- methyl -1,3,4- thiadiazoles -2- bases) benzimidazolyl -2- ketone (75mg, 0.30mmol) is added to chlorosulfonic acid (45mg, 0.380mmol) under agitation in batches.After 3 hours, solution is joined in the stirring slurries of ice (10g), precipitation is formed.Precipitate is filtered out and dried on glass frit, and then joins in the stirred mixture of 1- (fluoromethyl) cyclopropane -1- amine hydrochloride (48mg, 0.38mmol) in pyridine (3mL).It is stirred 3 hours, and then add EtOAc (10mL) and 1M HCL solution (aqueous solution) (10mL), and mixture is stirred 5 minutes.Separate EtOAc layer, and water layer is extracted with EtOAc (10mL). The combined EtOAc extracts were passed through a hydrophobic frit, concentrated to dryness, and purified by preparative HPLC (low pH) to give 1-ethyl-N-[1-(fluoromethyl)cyclopropyl]-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxobenzimidazole-5-sulfonamide (10 mg, 0.024 mmol, 6.3%) as a white solid.

Example 160 N-[1-(Fluoromethyl)cyclopropyl]-1-(2-methoxyethyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide

Intermediate S11-A1-(2-methoxyethyl)-1H-benzo[d]imidazol-2(3H)-one

2-bromoethyl methyl ether (2.52mL, 26.84mmol) is added in the stirred mixture of 2-hydroxybenzimidazole (3.0g, 22.4mmol) and potassium carbonate (6.18g, 44.7mmol) in DMF (10mL), and is heated to 120 ℃ 1 hour in microwave.Mixture is cooled, and is added in DCM (300mL), saturated sodium bicarbonate aqueous solution (200mL) and water (100mL), and mixture is stirred 5 minutes.By passing through hydrophobic glass frit separation DCM layer, and water layer DCM extraction.The DCM extracts merged are concentrated under reduced pressure, and by column chromatography (Hex-> EtOAc) purifying, obtain 3-(2-methoxyethyl)-1H-benzimidazole-2-one (951mg, 4.95mmol, 22.1%), it is white solid.

¹ H NMR (300MHz, DMSO-d ₆ )δ＝10.99-10.65(m,1H),7.13(d,J＝4.3Hz,1H),7.05-6.92(m,3H),3.94(t,J＝5.6Hz,2H),3.58(t,J＝5.6Hz,2H),3.23(s,3H)

Intermediate S11-B1 1-(2-methoxyethyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-1H-benzo[d]imidazol-2(3H)-one

By 3- (2- methoxyethyl) -1H- benzimidazol -2- ketone (0.2g, 1.04mmol), 2- bromo -5- methyl -1,3,4- thiadiazole (466mg, 2.6mmol), copper iodide (20mg, 0.100mmol) and potassium carbonate (575mg, 4.16mmol) in 1,4- dioxane (10mL) stirring mixture by nitrogen bubbling through the mixture degassed 5 minutes. Add trans- N, N '- dimethylcyclohexane -1,2- diamine (0.03mL, 0.21mmol), and the mixture is heated to 135 DEG C of 2 hours in microwave. The mixture is added in 10% MeOH / DCM (200mL), and saturated sodium bicarbonate aqueous solution (200mL) is added, and the mixture is stirred for 5 minutes. Isolate the DCM layer, and the water layer is extracted with 10% MeOH / DCM (100mL). The combined DCM extracts were passed through a hydrophobic frit, concentrated under reduced pressure, and purified by column chromatography (Hex->EtOAc) to yield 1-(2-methoxyethyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)benzimidazol-2-one (107 mg, 0.369 mmol, 35.4%) as a white solid.

¹ H NMR (300MHz, DMSO-d ₆ ) δ = 8.38-8.28 (m, 1H), 7.43 (s, 1H), 7.30 (s, 2H), 4.14 (t, J = 5.3Hz, 2H), 3.68 (t, J = 5.3Hz, 2H), 3.24 (s, 3H), 2.73 (s, 3H)

Under stirring, add 1-(2-methoxyethyl)-3-(5-methyl-1,3,4-thiadiazole-2-yl)benzimidazol-2-one (70mg, 0.2400mmol) to chlorosulfonic acid (28mg, 0.240mmol) in batches. After 3 hours, the solution is added to the stirring slurry of ice (10g) and 10%MeOH/DCM (10mL). After stirring for 5 minutes, the DCM layer is separated, and the water layer is extracted with 10%MeOH/DCM (10mL). The combined DCM extracts are passed through a hydrophobic glass frit and concentrated under reduced pressure. The gained white solid is added to the stirred mixture of 1-(fluoromethyl)cyclopropane-1-amine hydrochloride (30mg, 0.240mmol) and triethylamine (24.4mg, 0.240mmol) in DMF (3mL). At 4 DEG C, 1H-dextrose (8mg, 0.018mmol) and 4-nitropropane-2-ol (5-nitropropane-2-ol)-1-ol (8mg, 0.018mmol) are added in 4-nitropropane-2-ol (5-nitropropane-2-ol)-1-ol (8mg, 0.018mmol) at ... are added in 4-nitropropane-2-ol (5-nitropropane-2-ol)-1-ol (8mg, 0.018mmol) at 4 DEG C, 1H-dextrose (8mg, 0.018mmol) and 4-nitropropane-2-ol (5-nitropropane-2-ol)-1-ol (8mg, 0.018mmol) at 4 DEG C, 1H-dextrose (8mg, 0.018mmol) are added in 4-nitropropane-2-ol (5-nitropropane-2-ol)-1-ol

Example 161 N-(1-Cyanocyclopropyl)-1-(2-methoxyethyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide

Under stirring, add 1-(2-methoxyethyl)-3-(5-methyl-1,3,4-thiadiazole-2-yl)benzimidazol-2-one (112mg, 0.380mmol) in chlorosulfonic acid (45mg, 0.380mmol) in portions.After 3 hours, the solution is added into the stirring slurry of ice (10g) and 10%MeOH/DCM (10mL).Isolate the DCM layer, and the water layer is extracted with 10%MeOH/DCM (10mL).The DCM extracts merged are passed through a hydrophobic glass frit and concentrated to dryness, and are added into the stirred mixture of 1-amino-1-cyclopropanenitrile hydrochloride (46mg, 0.380mmol) in pyridine (4mL).After 3 hours, add 10%MeOH/DCM (30mL) and 2M HCl solution (aqueous solution) (30mL), and the mixture is stirred for 5 minutes. The DCM layer was separated and the aqueous layer was extracted with 10% MeOH/DCM (20 mL). The combined DCM extracts were passed through a hydrophobic frit, concentrated to dryness, and purified by column chromatography (DCM -> 10% MeOH/DCM) to afford N-(1-cyanocyclopropyl)-1-(2-methoxyethyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxobenzimidazole-5-sulfonamide (15 mg, 0.0345 mmol, 9.0%) as a white solid.

Example 162 N-(1-Cyanocyclopropyl)-3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1-(2-methoxyethyl)-2-oxo-benzimidazole-5-sulfonamide

Intermediate S11-B2 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-3-(2-methoxyethyl)-1H-benzo[d]imidazol-2(3H)-one

A stirred mixture of 3-(2-methoxyethyl)-1H-benzimidazol-2-one (0.22 g, 1.14 mmol), 2-bromo-5-(difluoromethyl)-1,3,4-thiadiazole (0.27 g, 1.25 mmol), copper iodide (22 mg, 0.110 mmol) and potassium carbonate (0.47 g, 3.41 mmol) in DMSO (5 mL) was degassed by bubbling nitrogen through the mixture for 5 minutes. Trans-N,N'-dimethylcyclohexane-1,2-diamine (0.04 mL, 0.230 mmol) was added and the mixture was heated to 80°C for 5 h. Similar workup as described for intermediate S11-B1 afforded 1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-3-(2-methoxyethyl)benzimidazol-2-one (0.211 g, 0.647 mmol, 57.0%) as a white solid.

¹ H NMR (300MHz, DMSO-d ₆ ) δ = 8.41-8.30 (m, 1H), 7.82-7.30 (m, 4H), 4.17 (s, 2H), 3.69 (s, 2H), 3.25 (s, 3H)

Using the method described in Example 161, 1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-3-(2-methoxyethyl)ketone (125 mg, 0.380 mmol) produced N-(1-cyanocyclopropyl)-3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1-(2-methoxyethyl)-2-oxo-benzimidazole-5-sulfonamide (20 mg, 0.0412 mmol, 10.7%) as a white solid.

Example 163 3-[5-(Difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-[1-(fluoromethyl)cyclopropyl]-1-(2-methoxyethyl)-2-oxo-benzimidazole-5-sulfonamide

Using the method described in Example 160, 1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-3-(2-methoxyethyl)benzimidazol-2-one (79 mg, 0.240 mmol) produced 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-[1-(fluoromethyl)cyclopropyl]-1-(2-methoxyethyl)-2-oxo-benzimidazole-5-sulfonamide (5 mg, 0.0105 mmol, 4.3%) as a white solid.

Example 164 3-[5-(Difluoromethyl)-1,3,4-thiadiazol-2-yl]-1-[(2,5-dimethylpyrazol-3-yl)methyl]-N-[1-(fluoromethyl)cyclopropyl]-2-oxo-benzimidazole-5-sulfonamide

2-Hydroxybenzimidazole (3.0 g, 22.4 mmol), 5-(chloromethyl)-1,3-dimethyl-1H-pyrazole (1.82 mL, 24.6 mmol) and potassium carbonate (9.3 g, 67 mmol) in DMF (70 mL) were heated at 100 ° C for 3 hours. The mixture was added to a saturated aqueous sodium bicarbonate solution (500 mL) and EtOAc (500 mL), and the mixture was stirred for 5 minutes. The EtOAc layer was separated and the aqueous layer was extracted with EtOAc (100 mL). The combined EtOAc extracts were passed through a hydrophobic glass frit and concentrated under reduced pressure, and purified by column chromatography (Hex->EtOAc) to give 3-[(2,5-dimethylpyrazol-3-yl)methyl]benzimidazole-2-one (3.1 g, 12.8 mmol, 57.2%) as a yellow solid.

Using the method described for intermediate S11-B2, (3-[(2,5-dimethylpyrazol-3-yl)methyl]-1H-benzimidazol-2-one) (0.4 g, 1.65 mmol) and 2-bromo-5-(difluoromethyl)-1,3,4-thiadiazole (0.36 g, 1.65 mmol) yielded 1-[5-(difluoromethyl)-1,3,4-thiadiazole-2-yl]-3-[(2,5-dimethylpyrazol-3-yl)methyl]-1H-benzimidazol-2-one (141 mg, 0.375 mmol, 22.7%) as a white solid.

¹ H NMR (300 MHz, chloroform-d) δ＝8.70-8.44 (m, 1H), 7.41-7.29 (m, 3H), 7.26-6.87 (m, 2H), 5.18 (s, 2H), 4.03-3.78 (m, 3H), 2.30-2.11 (m, 3H)

Using the method described in Example 160, 1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-3-[(2,5-dimethylpyrazol-3-yl)methyl]benzimidazol-2-one (70 mg, 0.1900 mmol) produced 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1-[(2,5-dimethylpyrazol-3-yl)methyl]-N-[1-(fluoromethyl)cyclopropyl]-2-oxo-benzimidazole-5-sulfonamide (20 mg, 0.038 mmol, 20.4%) as a white solid.

Example 165 N-(1-Cyanocyclopropyl)-3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1-[(2,5-dimethylpyrazol-3-yl)methyl]-2-oxo-benzimidazole-5-sulfonamide

Under stirring, add 1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-3-[(2,5-dimethylpyrazole-3-yl)methyl]benzimidazol-2-one (145mg, 0.380mmol) to chlorosulfonic acid (2.0mL, 0.380mmol) in batches. After stirring for 3 hours, the solution is added to a stirred slurry of ice (about 10g) and 10%MeOH/DCM (10mL). The DCM layer is separated and the water layer is extracted with 10%MeOH/DCM (10mL). The combined DCM extracts are passed through a hydrophobic glass frit and concentrated to dryness and added to a stirred mixture of 1-amino-1-cyclopropanecarbonitrile hydrochloride (91mg, 0.77mmol) in pyridine (4mL). The mixture was stirred for 3 hours and 10%MeOH/DCM (30 mL) and 2M HCl solution (aqueous solution) (30 mL) were added, and the mixture was stirred for 5 minutes. The DCM layer was isolated, and the water layer was extracted with 10%MeOH/DCM (10 mL). The DCM layer was passed through a hydrophobic glass frit, and concentrated to dryness, and purified by column chromatography (DCM->10%MeOH/DCM) to obtain N-(1-cyanocyclopropyl)-3-[5-(difluoromethyl)-1,3,4-thiadiazole-2-yl]-1-[(2,5-dimethylpyrazole-3-yl)methyl]-2-oxobenzimidazole-5-sulfonamide (10 mg, 0.0192 mmol, 5.0%), which was a white solid.

Example 166 1-(Cyanomethyl)-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide

To a magnetically stirred solution of 3-(5-methyl-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-sulfonamide (150 mg, 0.41 mmol) and potassium carbonate (226.9 mg, 1.64 mmol) in DMF (4 mL) at 20° C. under nitrogen was added bromoacetonitrile (0.03 mL, 0.41 mmol) and the resulting mixture was stirred at ambient temperature for 12 hours. The solvent was removed in vacuo and the resulting residue was purified by preparative HPLC (high pH) to give the desired product as a white solid (30 mg; 18%).

Example 167 3-[5-(Difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-fluoro-N-[1-(fluoromethyl)cyclopropyl]-1-(2-methoxyethyl)-2-oxo-benzimidazole-5-sulfonamide

Intermediate S5A6 5-Fluoro-N-(2-methoxyethyl)-2-nitro-aniline

Methoxyethylamine (2.88 mL, 13.2 mmol) was added to a magnetically stirred solution of 2,4-difluoronitrobenzene (2.0 g, 12.6 mmol) and potassium carbonate (3.64 g, 26.4 mmol) in 1,4-dioxane (40 mL), and the resulting mixture was stirred at 5°C for 2 hours. The mixture was poured into ice/water (40 mL), and the resulting yellow suspension was stirred for 15 minutes and then filtered. The filter cake was washed with water (2 x 20 mL) and dried under vacuum at 40°C for 12 hours to give the desired product as a yellow solid (2.78 g, 12.97 mmol, 103%).

¹ H NMR (300 MHz, DMSO-d6) shift = 8.39-8.27 (m, 1H), 8.17 (dd, J = 6.2, 9.5 Hz, 1H), 6.93 (dd, J = 2.6, 12.3 Hz, 1H), 6.55 (ddd, J = 2.6, 7.4, 9.7 Hz, 1H), 3.62-3.46 (m, 4H), 3.31 (s, 3H).

Intermediate S5B6 4-Fluoro-N2-(2-methoxyethyl)benzene-1,2-diamine

By 5-fluoro-N-(2-methoxyethyl)-2-nitroaniline (2.6g, 12.14mmol) solution in ethanol (40mL) with nitrogen vacuum purging 3 times.Then palladium-carrying activated carbon (260mg) is added to the reaction mixture, and the gained suspension is purged 3 times under nitrogen vacuum.Then the reaction mixture is purged 3 times under hydrogen vacuum, and stirred 2 hours under the positive pressure of hydrogen.Mixture is purged under nitrogen vacuum and filtered through diatomaceous earth pad.Filter cake is washed with ethanol (2 × 10mL), and the filtrate merged is evaporated to dryness, to give product, it is lavender oily thing (2.25g, 12.2mmol, 100%).

¹ H NMR (300MHz, DMSO-d6) displacement = 6.49 (dd, J = 6.1, 8.3Hz, 1H), 6.25 (dd, J = 2.8, 11.7Hz, 1H), 6.16 (dt, J = 2.8, 8.6H z, 1H), 4.71 (t, J = 5.1Hz, 1H), 4.34 (br.s., 2H), 3.52 (t, J = 5.6Hz, 2H), 3.29 (s, 3H), 3.19 (q, J = 5.6Hz, 2H).

Intermediate S5C6 5-Fluoro-3-(2-methoxyethyl)-1H-benzimidazol-2-one

To a magnetically stirred solution of 4-fluoro-N2-(2-methoxyethyl)benzene-1,2-diamine (2.3 g, 12.49 mmol) in THF (60 mL) at 20°C under nitrogen was added 1,1'-carbonyldiimidazole (2.22 g, 13.73 mmol), and the resulting mixture was stirred at ambient temperature for 2 hours. The solvent was removed in vacuo to give a residue, which was suspended in diethyl ether (40 mL) with stirring for 10 minutes. The mixture was then filtered, and the filter cake was washed with diethyl ether (3 x 20 mL) to give a solid, which was dried in vacuo at 40°C for 4 hours to give the desired product as a gray solid (1.04 g, 4.95 mmol, 39.6%).

¹ H NMR (300 MHz, DMSO-d6) shift = 10.88 (s, 1H), 7.14-7.06 (m, 1H), 6.93 (dd, J = 4.7, 8.5 Hz, 1H), 6.83-6.73 (m, 1H), 3.94 (t, J = 5.5 Hz, 2H), 3.57 (t, J = 5.5 Hz, 2H), 3.23 (s, 3H)

Intermediate S5D6 1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-5-fluoro-3-(2-methoxyethyl)benzimidazol-2-one

The stirred mixture of 5-fluoro-3-(2-methoxyethyl)-1H-benzimidazol-2-one (140 mg, 0.67 mmol), 2-bromo-5-(difluoromethyl)-1,3,4-thiadiazole (157.5 mg, 0.73 mmol), copper iodide (12.7 mg, 0.07 mmol) and potassium carbonate (276.1 mg, 2.0 mmol) in DMSO (5 mL) was degassed with nitrogen for 5 minutes. Trans-N, N'-dimethylcyclohexane-1,2-diamine (21.0 μL, 0.13 mmol) was added and the resulting mixture was heated at 80 ° C for 16 hours. The reactant was cooled to room temperature and distributed between DCM (30 mL) and saturated sodium bicarbonate solution (30 mL). The two-phase mixture obtained was stirred for 5 minutes and the DCM layer was collected. The aqueous phase was back extracted with DCM (30 mL) and the combined DCM extracts were concentrated under reduced pressure to give a residue that was purified by automated column chromatography ( _SiO2 ; RediSep-12g; 0 to 40% EtOAc in hexanes) to yield the desired product as a white solid (130 mg, 0.37 mmol, 56.7%).

¹ H NMR (300 MHz, DMSO-d6) shift = 8.33 (dd, J = 4.8, 8.9 Hz, 1H), 7.81-7.41 (m, 2H), 7.15 (ddd, J = 2.6, 8.9, 9.8 Hz, 1H), 4.16 (t, J = 5.3 Hz, 2H), 3.67 (t, J = 5.2 Hz, 2H), 3.25 (s, 3H).

Using the method described in Example 160, 1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-5-fluoro-3-(2-methoxyethyl)benzimidazol-2-one (120 mg, 0.34 mmol) produced 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-fluoro-N-[1-(fluoromethyl)cyclopropyl]-1-(2-methoxyethyl)-2-oxo-benzimidazole-5-sulfonamide as a white solid (80 mg, 0.16 mmol, 47%).

Example 168 3-[5-(Difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-fluoro-1-(2-methoxyethyl)-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide

Using the method described in Example 160, 1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-5-fluoro-3-(2-methoxyethyl)benzimidazol-2-one (120 mg, 0.34 mmol) produced 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-fluoro-1-(2-methoxyethyl)-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide as a white solid (82 mg, 0.17 mmol, 50%).

Example 169 3-[5-(Difluoromethyl)-1,3,4-thiadiazol-2-yl]-1-(2-methoxyethyl)-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide

Using the method described in Example 160, 1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-3-(2-methoxyethyl)benzimidazol-2-one (100 mg, 0.31 mmol) produced 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1-(2-methoxyethyl)-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide as a white solid (80 mg, 0.17 mmol, 55%).

Example 170 3-[5-(Difluoromethyl)-1,3,4-thiadiazol-2-yl]-1-[3-(dimethylamino)propyl]-N-[1-(fluoromethyl)cyclopropyl]-2-oxo-benzimidazole-5-sulfonamide

Intermediate S12A1 4-Fluoro-N-[1-(fluoromethyl)cyclopropyl]-3-nitro-benzenesulfonamide

To a magnetically stirred solution of 4-fluoro-3-nitrobenzenesulfonyl chloride (2.97 mL, 20.87 mmol) and N,N-diisopropylethylamine (11.14 mL, 62.6 mmol) in THF (60 mL) at -78 ° C. under nitrogen, 1-(fluoromethyl)cyclopropane-1-amine hydrochloride (2.75 g, 21.91 mmol) was added, and the resulting mixture was stirred at -78 ° C. for 15 minutes, then at -10 ° C. for 30 minutes, and then warmed to ambient temperature and stirred overnight. The mixture was partitioned between EtOAc (60 mL) and water (40 mL). The organic phase was collected and the water was back-extracted with EtOAc (40 mL). The combined organics were dried ( _NaSO4 ) and distilled to dryness to give the crude product, which was purified by automated column chromatography (SiO2; RediSep-80g; 0 to 20% EtOAc in hexanes) to give the desired product as a yellow solid (1.2 g, 4.11 mmol, 19.7%).

¹ H NMR (300 MHz, DMSO-d6) shift = 8.83 (s, 1H), 8.47 (dd, J = 2.4, 7.0 Hz, 1H), 8.17 (ddd, J = 2.4, 4.1, 8.8 Hz, 1H), 7.83 (dd, J = 8.8, 11.1 Hz, 1H), 4.32-4.09 (m, 2H), 0.81-0.73 (m, 4H)

Intermediate S12B1 4-[2-(Dimethylamino)ethylamino]-N-[1-(fluoromethyl)cyclopropyl]-3-nitro-benzenesulfonamide

3-(Dimethylamino)-1-propylamine (0.38 mL, 3.01 mmol) was added to a stirred solution of 4-fluoro-N-[1-(fluoromethyl)cyclopropyl]-3-nitro-benzenesulfonamide (800 mg, 2.74 mmol) and potassium carbonate (832.3 mg, 6.02 mmol) in 1,4-dioxane (10 mL), and the resulting mixture was heated at 40° C. The mixture was partitioned between EtOAc (50 mL) and saturated potassium bicarbonate (50 mL), and the organic phase was collected and evaporated to dryness to give the desired product as an orange solid (800 mg, 2.14 mmol, 78.1%).

¹ H NMR (300MHz, DMSO-d6) displacement = 9.08 (t, J = 5.1Hz, 1H), 8.43 (d, J = 2.3Hz, 1H), 8.36 (br.s., 1H), 7.76 (dd, J = 2.1, 9.1Hz, 1H), 7.23 (d, J＝9.3Hz,1H),4.34-4.08(m,2H),3.51-3.41(m,2H),2.36(t,J＝6.4Hz,2H),2.17(s,6H),1.77(quin,J＝6.4Hz,2H),0.72(s,4H)

Intermediate S12C1 3-amino-4-[3-(dimethylamino)propylamino]-N-[1-(fluoromethyl)cyclopropyl]benzenesulfonamide

At 20 DEG C, to 4-[3-(dimethylamino)propylamino]-N-[1-(fluoromethyl)cyclopropyl]-3-nitrobenzenesulfonamide (1.0g, 2.67mmol) and ammonium chloride (714mg, 13.35mmol) in 1:1 (v/v) of 1:1 ethanol (25mL) and water (25mL) magnetic stirring solution, add iron powder (745.8mg, 13.35mmol) and the resulting mixture is stirred at 80 DEG C for 1 hour.The mixture is filtered through diatomaceous earth heat, and the filter cake is washed with hot ethanol (2 × 20mL).The filtrate merged is evaporated to dryness, and the gained residue is distributed between DCM (50mL) and saturated potassium bicarbonate (50mL).Collect organic phase, and aqueous phase DCM (50mL) back extraction. The combined organics were dried and evaporated to dryness to give the desired product as a grey foam (700 mg, 2.03 mmol, 76.1%).

^1H NMR (300MHz, DMSO-d6) displacement=7.83-7.77(m,1H),7.00-6.87(m,2H),6.45(d,J=8.0Hz,1H),5.20(s,1H),4.91(s,2H),4. 29-4.04(m,2H),3.18-3.05(m,2H),2.31(t,J＝7.0Hz,2H),2.14(s,6H),1.73(quin,J＝7.0Hz,2H),0.73-0.54(m,5H)

Intermediate S12D1 1-[3-(dimethylamino)propyl]-N-[1-(fluoromethyl)cyclopropyl]-2-oxo-3H-benzimidazole-5-sulfonamide

To a magnetically stirred solution of 3-amino-4-[3-(dimethylamino)propylamino]-N-[1-(fluoromethyl)cyclopropyl]benzenesulfonamide (500 mg, 1.45 mmol) in THF (20 mL) at 20° C. under nitrogen was added 1,1′-carbonyldiimidazole (282.4 mg, 1.74 mmol), and the resulting mixture was stirred at ambient temperature overnight. The mixture was distilled to dryness, and the residue was purified by automated column chromatography (SiO ; SNAP-10 g; 0 to 20% MeOH in DCM) to give the desired product as a white solid (320 mg, 0.86 mmol, 59.5%).

^1H NMR (300MHz, DMSO-d6) displacement = 11.23 (s, 1H), 8.27 (s, 1H), 7.47 (dd, J = 1.7, 8.2Hz, 1H), 7.34 (d, J = 1.6Hz, 1H), 7.30 (d, J ＝8.4Hz,1H),4.26-4.05(m,2H),3.85(t,J＝7.1Hz,2H),2.22(t,J＝6.9Hz,2H),2.12(s,6H),1.77(quin,J＝6.9Hz,2H)

Nitrogen was bubbled through a mixture of 1-[3-(dimethylamino)propyl]-N-[1-(fluoromethyl)cyclopropyl]-2-oxo-3H-benzimidazole-5-sulfonamide (100 mg, 0.27 mmol), 2-bromo-5-(difluoromethyl)-1,3,4-thiadiazole (63.8 mg, 0.30 mmol), copper iodide (5.14 mg, 0.03 mmol) and potassium carbonate (111.9 mg, 0.81 mmol) in DMSO (5 mL) for 5 minutes. Trans-N, N'-dimethylcyclohexane-1,2-diamine (8.51 μL, 0.05 mmol) was then added to the reaction, and the resulting mixture was stirred at 80° C. for 2 hours. The reactant was cooled to ambient temperature and filtered through a plug of celite. The DMSO solution was then purified by preparative HPLC (high pH) to give the desired product as a white solid (30 mg, 0.060 mmol, 22%).

Example 171 6-Fluoro-1-methyl-N-(1-methylcyclopropyl)-3-(3-methyl-1,2,4-thiadiazol-5-yl)-2-oxo-benzimidazole-5-sulfonamide

Intermediate S5D7 5-Fluoro-3-methyl-1-(3-methyl-1,2,4-thiadiazol-5-yl)benzimidazol-2-one

Prepared from 5-fluoro-3-methyl-1H-benzimidazol-2-one (100 mg, 0.60 mmol) and 5-bromo-3-methyl-1,2,4-thiadiazole (118.5 mg, 0.66 mmol) to give the desired intermediate as a white solid (90 mg, 0.34 mmol. 56%).

¹ H NMR (300 MHz, DMSO-d6) shift = 8.26 (dd, J = 4.9, 8.8 Hz, 1H), 7.44 (dd, J = 2.5, 8.9 Hz, 1H), 7.13 (ddd, J = 2.5, 8.8, 10.0 Hz, 1H), 3.45 (s, 3H), 2.60 (s, 3H).

Prepared using the method described in Example 160 with 5-fluoro-3-methyl-1-(3-methyl-1,2,4-thiadiazol-5-yl)benzimidazol-2-one (80 mg, 0.303 mmol) to yield 6-fluoro-1-methyl-N-(1-methylcyclopropyl)-3-(3-methyl-1,2,4-thiadiazol-5-yl)-2-oxo-benzimidazole-5-sulfonamide as a white solid (30 mg, 0.075 mmol, 24%).

Example 172 6-Fluoro-N-[1-(fluoromethyl)cyclopropyl]-1-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-2-oxo-benzimidazole-5-sulfonamide

Prepared using the method described in Example 160 with 5-fluoro-3-methyl-1-(3-methyl-1,2,4-thiadiazol-5-yl)benzimidazol-2-one (80 mg, 0.303 mmol) to yield 6-fluoro-N-[1-(fluoromethyl)cyclopropyl]-1-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-2-oxo-benzimidazole-5-sulfonamide as a white solid (30 mg, 0.072 mmol, 24%).

Example 173 3-[5-(Difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-fluoro-1-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide

Intermediate S5D8 1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-5-fluoro-3-methyl-benzimidazol-2-one

Prepared by reaction of 5-fluoro-3-methyl-1H-benzimidazol-2-one (3.0 g, 18.01 mmol) with 2-bromo-5-(difluoromethyl)-1,3,4-thiadiazole (4.27 g, 19.9 mmol) to give the desired intermediate as a white solid (3.33 g, 12.0 mmol, 66%).

¹ H NMR (300 MHz, DMSO-d6) shift = 8.27 (dd, J = 4.8, 8.8 Hz, 1H), 7.80-7.36 (m, 2H), 7.11 (ddd, J = 2.5, 8.9, 9.9 Hz, 1H), 3.43 (s, 3H)

Using the method described in Example 160, 1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-5-fluoro-3-methyl-benzoimidazol-2-one (140 mg, 0.46 mmol) was used to yield 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-fluoro-1-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide as a white solid (50 mg, 0.115 mmol, 25%).

Example 174 3-[5-(Difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-fluoro-N-[1-(fluoromethyl)cyclopropyl]-1-methyl-2-oxo-benzimidazole-5-sulfonamide

Using the method described in Example 160, 1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-5-fluoro-3-methyl-benzoimidazol-2-one (140 mg, 0.46 mmol) was used to yield 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-fluoro-N-[1-(fluoromethyl)cyclopropyl]-1-methyl-2-oxo-benzoimidazol-5-sulfonamide as a white solid (40 mg, 0.089 mmol, 19%).

Example 175 N-[1-(Fluoromethyl)cyclopropyl]-1-methyl-2-oxo-3-(1,2,4-thiadiazol-5-yl)benzimidazole-5-sulfonamide

Intermediate S5D9 1-methyl-3-(1,2,4-thiadiazol-5-yl)benzimidazol-2-one

Prepared by reaction of 3-methyl-1H-benzimidazol-2-one (150 mg, 1.01 mmol) with 5-bromo-1,2,4-thiadiazole (234 mg, 1.41 mmol) to give the desired intermediate as a white solid (190 mg, 0.81 mmol, 80%).

¹ H NMR (300 MHz, DMSO-d6) shift = 8.77-8.70 (m, 1H), 8.35-8.28 (m, 1H), 7.47-7.25 (m, 3H), 3.48 (s, 3H)

Prepared using the method described in Example 160 from 1-methyl-3-(1,2,4-thiadiazol-5-yl)benzimidazol-2-one (20 mg, 0.086 mmol) to yield N-[1-(fluoromethyl)cyclopropyl]-1-methyl-2-oxo-3-(1,2,4-thiadiazol-5-yl)benzimidazole-5-sulfonamide as a white solid (15 mg, 0.039 mmol, 45%).

Example 176 1-Methyl-N-(1-methylcyclopropyl)-3-(3-methyl-1,2,4-thiadiazol-5-yl)-2-oxo-benzimidazole-5-sulfonamide

Intermediate S5D10 1-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)benzimidazol-2-one

Prepared by reaction of 3-methyl-1H-benzimidazol-2-one (150 mg, 1.01 mmol) with 5-bromo-3-methyl-1,2,4-thiadiazole (217 mg, 1.21 mmol) to give the desired intermediate as a white solid (150 mg, 0.60 mmol, 60%).

¹ H NMR (300 MHz, DMSO-d6) shift = 8.34-8.27 (m, 1H), 7.44-7.27 (m, 3H), 3.47 (s, 3H), 2.61 (s, 3H)

Prepared using the method described in Example 160 with 1-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)benzimidazol-2-one (95 mg, 0.386 mmol) to yield N-[1-(fluoromethyl)cyclopropyl]-1-methyl-2-oxo-3-(1,2,4-thiadiazol-5-yl)benzimidazole-5-sulfonamide as a white solid (4 mg, 0.01 mmol, 3%).

Example 177 1-Methyl-N-(1-methylcyclopropyl)-3-(3-methyl-1,2,4-thiadiazol-5-yl)-2-oxo-benzimidazole-5-sulfonamide

Prepared using the method described in Example 160 with 1-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)benzimidazol-2-one (95 mg, 0.386 mmol) to yield 1-methyl-N-(1-methylcyclopropyl)-3-(3-methyl-1,2,4-thiadiazol-5-yl)-2-oxo-benzimidazole-5-sulfonamide as a white solid (20 mg, 0.05 mmol, 16%).

Example 178 1-(Cyanomethyl)-N-[1-(fluoromethyl)cyclopropyl]-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide

Intermediate S10B3 2-[3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazol-1-yl]acetonitrile

Prepared by reaction of 3-(5-methyl-1,3,4-thiadiazol-2-yl)-1H-benzimidazol-2-one (100 mg, 0.43 mmol) with bromoacetonitrile (72 mg, 0.603 mmol) to give the desired intermediate as a white solid (100 mg, 0.369 mmol, 86%).

¹ H NMR (300 MHz, DMSO-d6) shift = 8.39-8.33 (m, 1H), 7.55 (dd, J = 1.6, 7.3 Hz, 1H), 7.44-7.32 (m, 2H), 5.29 (s, 2H), 2.75 (s, 3H)

Using the method described in Example 160, 2-[3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazol-1-yl]acetonitrile (90 mg, 0.332 mmol) was used to yield 1-(cyanomethyl)-N-[1-(fluoromethyl)cyclopropyl]-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide as a white solid (20 mg, 0.047 mmol, 32%).

Example 179 1-(Cyanomethyl)-N-(1-methylcyclopropyl)-3-(3-methyl-1,2,4-thiadiazol-5-yl)-2-oxo-benzimidazole-5-sulfonamide

Intermediate S13A1 3-Methyl-N-(2-nitrophenyl)-1,2,4-thiadiazole-5-amine

To a magnetically stirred solution of o-nitrofluorobenzene (1.87 mL, 17.72 mmol) and cesium carbonate (17.3 g, 53.15 mmol) in dioxane (20 mL) under nitrogen at 20° C. was added 3-methyl-1,2,4-thiadiazol-5-amine (4.08 g, 35.4 mmol), and the resulting mixture was stirred at 100° C. for 2 hours. The mixture was cooled to ambient temperature and partitioned between water (150 mL) and EtOAc (200 mL). The organic phase was distilled to dryness, and the resulting residue was purified by automated column chromatography (SSiO ₂ ; RediSep-80 g; 0 to 40% EtOAc in hexanes) to give the desired product as a yellow solid (3.5 g, 14.81 mmol, 83.6%).

¹ H NMR (300 MHz, DMSO-d6) shift = 10.93 (s, 1H), 8.32 (dd, J = 0.9, 8.4 Hz, 1H), 8.08 (dd, J = 1.5, 8.3 Hz, 1H), 7.77 (dt, J = 1.6, 7.8 Hz, 1H), 7.31 (ddd, J = 1.3, 7.3, 8.3 Hz, 1H), 2.37 (s, 3H)

Intermediate S13B1N2-(3-methyl-1,2,4-thiadiazol-5-yl)benzene-1,2-diamine

Iron powder (4.13 g, 74.1 mmol) and ammonium chloride (3.96 g, 74.1 mmol) are added to a stirred suspension of 3-methyl-N-(2-nitrophenyl)-1,2,4-thiadiazole-5-amine (3.50 g, 14.81 mmol) in ethanol (100 mL) and water (100 mL), and the resulting mixture is stirred at 80 ° C for 1 hour. The mixture is filtered through diatomaceous earth (hot), and the filter cake is washed with EtOH (2 × 40 mL). The combined filtrate is concentrated in vacuo to about 80 mL and then distributed between EtOAc (200 mL) and water (50 mL). The EtOAc layer is collected and dried (Na ₂ SO ₄ ), then distilled to dryness, to give a crude product as a brown solid (2.9 g, 14.1 mmol, 95%).

¹ H NMR (300 MHz, DMSO-d6) shift = 9.75 (br. s., 1H), 7.30 (dd, J = 1.3, 7.9 Hz, 1H), 7.00-6.89 (m, 1H), 6.77 (dd, J = 1.2, 8.0 Hz, 1H), 6.60 (dt, J = 1.4, 7.5 Hz, 1H), 5.03 (s, 2H), 2.31 (s, 3H)

Intermediate S13C1 3-(3-methyl-1,2,4-thiadiazol-5-yl)-1H-benzimidazol-2-one

To a magnetically stirred solution of N2-(3-methyl-1,2,4-thiadiazol-5-yl)benzene-1,2-diamine (2.90 g, 14.1 mmol) in DMF (60 mL) at 20°C under nitrogen was added 1,1'-carbonyldiimidazole (2.73 g, 16.9 mmol), and the resulting mixture was stirred at room temperature overnight. The solvent was removed in vacuo to give a white solid, which was suspended in diethyl ether (40 mL). The mixture was stirred for 30 minutes and filtered to give the desired product as a white solid (2.20 g, 9.47 mmol, 67.4%).

¹ H NMR (300 MHz, DMSO-d6) shift = 11.99 (br. s., 1H), 8.40-8.20 (m, 1H), 7.30-7.18 (m, 3H), 2.61 (s, 3H)

Intermediate S13D1 2-[3-(3-methyl-1,2,4-thiadiazol-5-yl)-2-oxo-benzimidazol-1-yl]acetonitrile

Bromoacetonitrile (0.04 mL, 0.60 mmol) was added to a magnetically stirred solution of 3-(3-methyl-1,2,4-thiadiazol-5-yl)-1H-benzimidazol-2-one (100 mg, 0.43 mmol) and potassium carbonate (178.52 mg, 1.29 mmol) in DMF (2 mL), and the resulting solution was stirred overnight. The solvent was removed in vacuo to give a yellow solid, which was purified by automated column chromatography (SiO ₂ ; RediSep-4g; 0 to 80% EtOAc in hexanes) to give the desired product as a white solid (105 mg, 0.38 mmol, 90%).

¹ H NMR (300 MHz, DMSO-d6) shift = 8.40-8.33 (m, 1H), 7.61-7.54 (m, 1H), 7.48-7.30 (m, 2H), 5.31 (s, 2H), 2.63 (s, 3H)

Using the method described in Example 160, 2-[3-(3-methyl-1,2,4-thiadiazol-5-yl)-2-oxo-benzoimidazol-1-yl]acetonitrile (60 mg, 0.221 mmol) was used to give 1-(cyanomethyl)-N-(1-methylcyclopropyl)-3-(3-methyl-1,2,4-thiadiazol-5-yl)-2-oxo-benzoimidazol-5-sulfonamide as a white solid (20 mg, 0.049 mmol, 22%).

Example 180 1-(Cyanomethyl)-N-[1-(fluoromethyl)cyclopropyl]-3-(3-methyl-1,2,4-thiadiazol-5-yl)-2-oxo-benzimidazole-5-sulfonamide

Using the method described in Example 160, 2-[3-(3-methyl-1,2,4-thiadiazol-5-yl)-2-oxo-benzimidazol-1-yl]acetonitrile (60 mg, 0.221 mmol) was used to yield 1-(cyanomethyl)-N-[1-(fluoromethyl)cyclopropyl]-3-(3-methyl-1,2,4-thiadiazol-5-yl)-2-oxo-benzimidazole-5-sulfonamide as a white solid (20 mg, 0.047 mmol, 21%).

Example 181 3-[5-(Difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-[1-(fluoromethyl)cyclopropyl]-1-methyl-2-oxo-benzimidazole-5-sulfonamide

Intermediate S5D11 1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-3-methyl-benzimidazol-2-one

By reaction of 3-methyl-1H-benzimidazol-2-one (150 mg, 1.01 mmol) with 2-bromo-5-(difluoromethyl)-1,3,4-thiadiazole (240 mg, 1.11 mmol) to give the desired intermediate as a white solid (130 mg, 0.46 mmol, 46%).

¹ H NMR (300 MHz, DMSO-d6) shift = 8.38-8.31 (m, 1H), 7.83-7.29 (m, 4H), 3.49 (s, 3H)

Using the method described in Example 160, 1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-3-methyl-benzoimidazol-2-one (110 mg, 0.39 mmol) was used to yield 1-(cyanomethyl)-N-[1-(fluoromethyl)cyclopropyl]-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzoimidazol-5-sulfonamide as a white solid (60 mg, 0.14 mmol, 35%).

Example 182 1-(2-Methoxyethyl)-N-(1-methylcyclopropyl)-3-(3-methyl-1,2,4-thiadiazol-5-yl)-2-oxo-benzimidazole-5-sulfonamide

Intermediate S11B4 1-(2-methoxyethyl)-3-(3-methyl-1,2,4-thiadiazol-5-yl)benzimidazol-2-one

Nitrogen is bubbled through 1-[3-(dimethylamino)propyl]-N-[1-(fluoromethyl)cyclopropyl]-2-oxo-3H-benzimidazole-5-sulfonamide (100 mg, 0.27 mmol), 2-bromo-5-(difluoromethyl)-1,3,4-thiadiazole (63.84 mg, 0.30 mmol), copper iodide (5.14 mg, 0.03 mmol) and potassium carbonate (111.91 mg, 0.81 mmol) in 1,4-dioxane (4 mL) for 5 minutes. Trans-N, N'-dimethylcyclohexane-1,2-diamine (24.6 μL, 0.16 mmol) is then added to the reaction, and the resulting mixture is stirred at 80 ° C for 2 hours. The reactant is cooled to room temperature and distributed between EtOAc (20 mL) and saturated potassium carbonate (20 mL). The organic phase was collected and distilled to dryness to give the crude product, which was purified by automated column chromatography ( _SiO2 ; SNAP-10g; 0 to 80% EtOAc in hexanes) to afford the desired product as a white solid (120 mg, 0.41 mmol, 52.9%).

¹ H NMR (300 MHz, DMSO-d6) shift = 8.36-8.30 (m, 1H), 7.51-7.44 (m, 1H), 7.39-7.28 (m, 2H), 4.15 (t, J = 5.3 Hz, 2H), 3.69 (t, J = 5.3 Hz, 2H), 3.25 (s, 3H), 2.62 (s, 3H)

Using the method described in Example 160, 1-(2-methoxyethyl)-3-(3-methyl-1,2,4-thiadiazol-5-yl)benzimidazol-2-one (50 mg, 0.189 mmol) was used to yield 1-(2-methoxyethyl)-N-(1-methylcyclopropyl)-3-(3-methyl-1,2,4-thiadiazol-5-yl)-2-oxo-benzimidazole-5-sulfonamide as a white solid (20 mg, 0.047 mmol, 25%).

Example 183 N-[1-(Fluoromethyl)cyclopropyl]-1-(2-methoxyethyl)-2-oxo-3-(1,2,4-thiadiazol-5-yl)benzimidazole-5-sulfonamide

Intermediate S11B5 1-(2-methoxyethyl)-3-(1,2,4-thiadiazol-5-yl)benzimidazol-2-one

Nitrogen is bubbled through 1-(2-methoxyethyl)-1H-benzo [d] imidazole-2 (3H) -one (100mg, 0.78mmol), 5-bromo-1,2,4-thiadiazole (180mg, 1.09mmol), copper iodide (14.8mg, 0.078mmol) and potassium carbonate (324mg, 2.34mmol) in 1,4-dioxane (6mL) for 5 minutes.Then trans-N, N'-dimethylcyclohexane-1,2-diamine (24 μ L, 0.16mmol) is added to the reaction, and the resulting mixture is stirred at 80 ° C for 2 hours. The reactant is cooled to room temperature and distributed between EtOAc (20mL) and saturated potassium carbonate (20mL). The organic phase was collected and distilled to dryness to give the crude product, which was purified by automated column chromatography ( _SiO2 ; SNAP-10g; 0 to 80% EtOAc in hexanes) to afford the desired product as a white solid (150 mg, 0.55 mmol, 69%).

¹ H NMR (300 MHz, DMSO-d6) shift = 8.75 (s, 1H), 8.38-8.30 (m, 1H), 7.53-7.46 (m, 1H), 7.41-7.27 (m, 2H), 4.17 (t, J = 5.3 Hz, 2H), 3.69 (t, J = 5.3 Hz, 2H), 3.25 (s, 3H)

Prepared using the method described in Example 160 from 1-(2-methoxyethyl)-3-(1,2,4-thiadiazol-5-yl)benzimidazol-2-one (25 mg, 0.091 mmol) to yield N-[1-(fluoromethyl)cyclopropyl]-1-(2-methoxyethyl)-2-oxo-3-(1,2,4-thiadiazol-5-yl)benzimidazole-5-sulfonamide as a white solid (10 mg, 0.023 mmol, 26%).

Example 184 N-[1-(Fluoromethyl)cyclopropyl]-1-(2-methoxyethyl)-3-(3-methyl-1,2,4-thiadiazol-5-yl)-2-oxo-benzimidazole-5-sulfonamide

Using the method described in Example 160, prepared from 1-(2-methoxyethyl)-3-(3-methyl-1,2,4-thiadiazol-5-yl)benzimidazol-2-one (50 mg, 0.189 mmol) to yield N-[1-(fluoromethyl)cyclopropyl]-1-(2-methoxyethyl)-3-(3-methyl-1,2,4-thiadiazol-5-yl)-2-oxo-benzimidazole-5-sulfonamide as a white solid (20 mg, 0.045 mmol, 23%).

Example 185 N-[1-(Fluoromethyl)cyclopropyl]-1-(3-methoxypropyl)-3-(3-methyl-1,2,4-thiadiazol-5-yl)-2-oxo-benzimidazole-5-sulfonamide

Intermediate S14A1N-[1-(Fluoromethyl)cyclopropyl]-3-(3-methyl-1,2,4-thiadiazol-5-yl)-2-oxo-1H-benzimidazole-5-sulfonamide

Prepared using the method described in Example 160 with 3-(3-methyl-1,2,4-thiadiazol-5-yl)-1H-benzimidazol-2-one (600 mg, 2.58 mmol) to yield N-[1-(fluoromethyl)cyclopropyl]-3-(3-methyl-1,2,4-thiadiazol-5-yl)-2-oxo-1H-benzimidazole-5-sulfonamide as a white solid (400 mg, 1.043 mmol, 40%).

^1H NMR (300MHz, DMSO-d6) displacement = 12.44 (br.s., 1H), 8.66 (d, J = 1.7Hz, 1H), 8.54 (s, 1H), 7.72 (dd, J＝1.8,8.3Hz,1H),7.37(d,J＝8.3Hz,1H),4.36-4.10(m,2H),2.68-2.60(m,4H),0.71(s,4H)

Intermediate S14B1 N-[1-acetyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-2-oxo-benzimidazol-5-yl]sulfonyl-N-[1-(fluoromethyl)cyclopropyl]acetamide

Acetic anhydride (0.52mL, 5.48mmol) is added to a magnetic stirring solution of N-[1-(fluoromethyl)cyclopropyl]-3-(3-methyl-1,2,4-thiadiazole-5-yl)-2-oxo-1H-benzimidazole-5-sulfonamide (420mg, 1.1mmol) in pyridine (10mL), and the resulting mixture is stirred overnight. The mixture is poured into water (80mL) to obtain a suspension, which is stirred for 30 minutes and then filtered. The solid filter cake is washed with water (2×10mL) and dried in vacuo at 40°C to give the diacetylated product (400mg, 0.86mmol, 78%) as a white solid.

¹ H NMR (300 MHz, DMSO-d6) shift = 8.97 (d, J = 1.9 Hz, 1H), 8.38 (d, J = 8.7 Hz, 1H), 8.00 (dd, J = 2.1, 8.7 Hz, 1H), 5.19-4.91 (m, 1H), 4.51-4.27 (m, 1H), 2.75 (s, 3H), 2.66 (s, 3H), 2.25 (s, 3H), 1.43 (s, 4H)

1-Bromo-3-methoxypropane (11.95 μL, 0.11 mmol) was added to a stirred suspension of N-[1-acetyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-2-oxo-benzimidazol-5-yl]sulfonyl-N-[1-(fluoromethyl)cyclopropyl]acetamide (50 mg, 0.11 mmol), potassium carbonate (30 mg, 0.21 mmol) and potassium iodide (18 mg, 0.11 mmol) in DMF (2 mL), and the resulting mixture was stirred at 50 ° C overnight. The mixture was cooled to ambient temperature and treated with concentrated aqueous ammonia (1 mL). The resulting mixture was stirred for 4 hours. The solvent was removed to give a residue which was purified by automated column chromatography ( _SiO2 ; RediSep-4g; 0 to 80% EtOAc in hexanes) to give the desired product, N-[1-(fluoromethyl)cyclopropyl]-1-(3-methoxypropyl)-3-(3-methyl-1,2,4-thiadiazol-5-yl)-2-oxo-benzimidazole-5-sulfonamide, as a white solid (20 mg, 0.044 mmol, 41%).

Example 186 1-[2-(Dimethylamino)ethyl]-N-[1-(fluoromethyl)cyclopropyl]-3-(3-methyl-1,2,4-thiadiazol-5-yl)-2-oxo-benzimidazole-5-sulfonamide

The product was prepared according to the method described in Example 185 using (2-bromoethyl)dimethylamine hydrobromide (11.9 μL, 0.26 mmol), N-[1-acetyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-2-oxo-benzimidazol-5-yl]sulfonyl-N-[1-(fluoromethyl)cyclopropyl]acetamide (80 mg, 0.1700 mmol), potassium carbonate (47.3 mg, 0.34 mmol) and potassium iodide (28.4 mg, 0.17 mmol) to give 1-[2-(dimethylamino)ethyl]-N-[1-(fluoromethyl)cyclopropyl]-3-(3-methyl-1,2,4-thiadiazol-5-yl)-2-oxo-benzimidazole-5-sulfonamide as a white solid (10 mg, 0.02 mmol, 12%).

Example 187 N-[1-(Fluoromethyl)cyclopropyl]-1-(3-methoxypropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide

Intermediate S14A2N-[1-(Fluoromethyl)cyclopropyl]-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-1H-benzimidazole-5-sulfonamide

Prepared using the method described in Example 160 with 3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-1H-benzimidazole-5-sulfonyl chloride (650 mg, 1.97 mmol) and 1-(fluoromethyl)cyclopropane-1-amine hydrochloride (296 mg, 2.36 mmol) to yield N-[1-(fluoromethyl)cyclopropyl]-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-1H-benzimidazole-5-sulfonamide as a white solid (400 mg, 1.043 mmol, 53%).

¹ H NMR (300MHz, DMSO-d6) displacement = 12.35-12.20 (m, 1H), 8.72 (d, J = 1.8Hz, 1H), 8.74-8.70 (m, 1H), 8.50 (s, 1H), 7.96 (s, 1H), 7 .70(dd,J＝1.8,8.3Hz,1H),7.34(d,J＝8.3Hz,1H),4.34-4.06(m,2H),2.89(s,3H),2.74(d,J＝2.6Hz,6H),0.68(s,4H)

Intermediate S14B2 N-[1-acetyl-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazol-5-yl]sulfonyl-N-[1-(fluoromethyl)cyclopropyl]acetamide

To a magnetically stirred solution of N-[1-(fluoromethyl)cyclopropyl]-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-1H-benzimidazole-5-sulfonamide (400 mg, 1.04 mmol) in pyridine (10 mL) was added acetic anhydride (0.49 mL, 5.22 mmol) and the resulting mixture was stirred overnight. The material was poured into water (40 mL) and the resulting mixture was stirred for 30 minutes and then filtered. The filter cake was washed with water (2×10 mL) and dried under vacuum at 40° C. to give the desired white solid (310 mg, 0.66 mmol, 63.6%).

^1H NMR (300MHz, DMSO-d6) displacement = 9.02 (d, J = 2.0Hz, 1H), 8.37 (d, J = 8.7Hz, 1H), 7.97 (dd, J = 2.1, 8.7Hz, 1 H),5.16-4.87(m,1H),4.46-4.22(m,1H),2.79(s,3H),2.73(s,3H),2.24(s,3H),1.41(br.s.,4H)

Prepared according to the method described in Example 185 from N-[1-acetyl-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazol-5-yl]sulfonyl-N-[1-(fluoromethyl)cyclopropyl]acetamide (100 mg, 0.21 mmol), potassium carbonate (89 mg, 0.64 mmol) and 1-bromo-3-methoxypropane (47.8 μL, 0.43 mmol) in DMF (2 mL) to give the desired product, N-[1-(fluoromethyl)cyclopropyl]-1-(3-methoxypropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide, as a white solid (35 mg, 0.077 mmol, 36%).

Example 188 1-[2-(Dimethylamino)ethyl]-N-[1-(fluoromethyl)cyclopropyl]-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide

Prepared according to the method described in Example 185 from N-[1-acetyl-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazol-5-yl]sulfonyl-N-[1-(fluoromethyl)cyclopropyl]acetamide (100 mg, 0.21 mmol), potassium carbonate (89 mg, 0.64 mmol) and (2-bromoethyl)dimethylhydrobromide (100 mg, 0.43 mmol) in DMF (3 mL) to give the desired product 1-[2-(dimethylamino)ethyl]-N-[1-(fluoromethyl)cyclopropyl]-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide as a white solid (40 mg, 0.088 mmol, 41%).

Example 189 1-Methyl-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide

Prepared by alkylating 3-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(1-methylcyclopropyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-sulfonamide (150 mg, 0.43 mmol) with potassium carbonate (119 mg, 0.86 mmol) and iodomethane (26.7 μL, 0.43 mmol) at 80° C. under microwave irradiation for 30 minutes. The mixture was partitioned between DCM (10 mL) and water (10 mL), and the organic phase was collected. The solvent was removed in vacuo to give a residue, which was purified by automated column chromatography (SiO ₂ ; RediSep-4g; 0 to 100% EtOAc in hexanes) to give the desired product as a white solid (50 mg, 0.138 mmol, 32%).

Example 190 1-Ethyl-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide

Prepared by alkylation of 3-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(1-methylcyclopropyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-sulfonamide (150 mg, 0.43 mmol) with potassium carbonate (119 mg, 0.86 mmol) and iodoethane (0.03 mL, 0.43 mmol) in DMF (2 mL) under microwave irradiation at 80° C. for 30 min to give the desired product as a white solid (40 mg, 0.106 mmol, 25%).

Example 191 1-(2-Fluoroethyl)-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide

Prepared by alkylation of 3-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(1-methylcyclopropyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-sulfonamide (150 mg, 0.43 mmol) with potassium carbonate (119 mg, 0.86 mmol) and 1-bromo-2-fluoroethane (0.03 mL, 0.43 mmol) in DMF (2 mL) under microwave irradiation at 80° C. for 30 min to give the desired product as a white solid (30 mg, 0.076 mmol, 18%).

Example 192 6-Fluoro-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxo-1H-benzimidazole-5-sulfonamide

Intermediate S13A2N-(4-Fluoro-2-nitro-phenyl)-5-methyl-1,3,4-oxadiazol-2-amine

A magnetically stirred solution of 2,5-difluoronitrobenzene (1.36 mL, 12.57 mmol), 5-methyl-1,3,4-oxadiazol-2-amine (1.25 g, 12.57 mmol) and cesium carbonate (8.19 g, 25.14 mmol) in 1,4-dioxane (40 mL) was heated at 80° C. overnight. The mixture was cooled to room temperature and poured into water (100 mL) to give a yellow precipitate, which was collected by filtration. The solid was washed with water (2×20 mL) and dried under vacuum at 40° C. to give the desired product, N-(4-fluoro-2-nitro-phenyl)-5-methyl-1,3,4-oxadiazol-2-amine, as a yellow solid (2.10 g, 8.82 mmol, 70%).

¹ H NMR (300 MHz, DMSO-d6) shift = 10.30 (br.s., 1H), 8.18 (br.s., 1H), 8.02 (dd, J = 2.8, 8.5 Hz, 1H), 7.83-7.63 (m, 1H), 2.42 (s, 3H)

Intermediate S13B2 4-Fluoro-N1-(5-methyl-1,3,4-oxadiazol-2-yl)benzene-1,2-diamine

Iron powder (2.46g, 44.08mmol) and ammonium chloride (2.36g, 44.08mmol) are added to a stirred suspension of N-(4-fluoro-2-nitro-phenyl)-5-methyl-1,3,4-oxadiazole-2-amine (2.10g, 8.82mmol) in ethanol (80mL) and water (80mL), and the resulting mixture is stirred at 60°C for 1 hour. The mixture is filtered through diatomaceous earth (hot), and the filter cake is washed with EtOH (2×40mL). The combined filtrate is concentrated in vacuo to about 80mL, to give a precipitate. The mixture is cooled to 0°C for 1 hour, and then filtered, to give a solid, which is washed with cold water (2×10mL). The solid was dried under vacuum at 40°C to give the desired product, 4-fluoro-N1-(5-methyl-1,3,4-oxadiazol-2-yl)benzene-1,2-diamine (1.2 g, 5.76 mmol, 65%) as a light brown solid.

¹ H NMR (300 MHz, DMSO-d6) shift = 8.92 (br. s., 1H), 7.35 (dd, J = 6.1, 8.8 Hz, 1H), 6.50 (dd, J = 2.9, 11.1 Hz, 1H), 6.33 (dt, J = 3.0, 8.6 Hz, 1H), 5.31 (s, 2H), 2.34 (s, 3H)

Intermediate S13C2 6-Fluoro-3-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-benzimidazol-2-one

To a magnetically stirred solution of 4-fluoro-N1-(5-methyl-1,3,4-oxadiazol-2-yl)benzene-1,2-diamine (1.20 g, 5.76 mmol) in DMF (20 mL) at 20° C. was added 1,1′-carbonyldiimidazole (1.12 g, 6.92 mmol), and the resulting mixture was stirred at ambient temperature overnight. The mixture was poured into water (80 mL) to give a precipitate, which was collected by filtration, washed with water (2×10 mL), and dried under vacuum to give the desired product, 6-fluoro-3-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-benzimidazol-2-one, as a light brown solid (1.25 g, 5.34 mmol, 93%).

¹ H NMR (300 MHz, DMSO-d6) shift = 11.78 (s, 1H), 7.72 (dd, J = 4.8, 9.5 Hz, 1H), 7.06-6.93 (m, 2H), 2.57 (s, 3H)

Using the method described in Example 160, prepared with 6-fluoro-3-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-benzimidazol-2-one (300 mg, 1.33 mmol) and 1-methylcyclopropaneamine hydrochloride (145.5 mg, 1.35 mmol) to yield 6-fluoro-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxo-1H-benzimidazole-5-sulfonamide as a white solid (210 mg, 0.572 mmol, 43%).

Example 193 3-[5-(Difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-[1-(fluoromethyl)cyclopropyl]-2-oxo-1-prop-2-ynyl-benzimidazole-5-sulfonamide

Intermediate S10-A4 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1H-benzimidazol-2-one

This compound was prepared by reacting 2-hydroxybenzimidazole (100 mg, 0.75 mmol) with 2-bromo-5-(difluoromethyl)-1,3,4-thiadiazole (176 mg, 0.82 mmol), copper(I) oxide (16 mg, 0.11 mmol), cesium carbonate (729 mg, 2.24 mmol) and N,N-dimethylglycine hydrochloride (15.61 mg, 0.11 mmol) in DMSO (2 mL) at 90° C. for 16 hours. The desired product, 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1H-benzimidazol-2-one, was isolated as a tan solid (100 mg, 0.372 mmol, 50%).

¹ H NMR (300 MHz, DMSO-d6) shift = 12.02 (s, 1H), 8.32 (d, J = 8.8 Hz, 1H), 7.83-7.39 (m, 1H), 7.35-7.17 (m, 3H)

Intermediate S14A2-3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-[1-(fluoromethyl)cyclopropyl]-2-oxo-1H-benzimidazole-5-sulfonamide

Prepared according to the method described in Example 160 using 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1H-benzimidazol-2-one (600 mg, 2.24 mmol) and 1-(fluoromethyl)cyclopropane-1-amine hydrochloride (309 mg, 2.46 mmol) to give 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-[1-(fluoromethyl)cyclopropyl]-2-oxo-1H-benzimidazole-5-sulfonamide as a yellow solid (377 mg, 0.899 mmol, 40%).

¹ H NMR (300 MHz, DMSO-d6) shift = 12.47 (br. s., 1H), 8.74 (d, J = 1.7 Hz, 1H), 8.54 (s, 1H), 7.84-7.44 (m, 2H), 7.38 (d, J = 8.4 Hz, 1H), 4.37-4.09 (m, 2H), 0.76-0.64 (m, 4H)

Intermediate S14B2-N-[1-acetyl-3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-2-oxo-benzimidazol-5-yl]sulfonyl-N-[1-(fluoromethyl)cyclopropyl]acetamide

To a magnetically stirred solution of 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-[1-(fluoromethyl)cyclopropyl]-2-oxo-1H-benzimidazole-5-sulfonamide (377 mg, 0.90 mmol) in pyridine (5 ml) was added acetic anhydride (0.42 mL, 4.49 mmol) under nitrogen at 20° C., and the resulting mixture was stirred overnight. The material was poured into water (40 mL), and the resulting mixture was stirred for 30 minutes, then filtered. The filter cake was washed with water (2 x 10 mL) and dried under vacuum at 40 °C to give the desired product, N-[1-acetyl-3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-2-oxo-benzimidazol-5-yl]sulfonyl-N-[1-(fluoromethyl)cyclopropyl]acetamide, as a yellow solid (146 mg, 0.29 mmol, 32%).

¹ H NMR (300 MHz, DMSO-d6) shift = 8.74 (d, J = 1.7 Hz, 1H), 8.54 (s, 1H), 7.84-7.44 (m, 2H), 7.38 (d, J = 8.4 Hz, 1H), 5.11 (m, 1H), 5.00-4.87 (m, 1H), 4.48-4.12 (m, 4H), 2.76 (s, 6H), 0.77-0.66 (m, 4H)

To a magnetically stirred solution of N-[1-acetyl-3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-2-oxo-benzimidazol-5-yl]sulfonyl-N-[1-(fluoromethyl)cyclopropyl]acetamide (73 mg, 0.14 mmol) and potassium carbonate (60.12 mg, 0.43 mmol) in DMF (2 mL) was added 3-bromopropyne (25.2 μ L, 0.29 mmol), and the resulting mixture was stirred at 50 ° C for 16 hours. The mixture was cooled to ambient temperature, treated with 4 mL of ammonia and stirred overnight. The solvent was removed in vacuo to give a residue, which was distributed between EtOAc (50 mL) and water (50 mL). The organic layer was collected and evaporated to dryness to give the crude product as a residue, which was purified by preparative HPLC (high pH) to give the desired product, 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-[1-(fluoromethyl)cyclopropyl]-2-oxo-1-prop-2-ynyl-benzimidazole-5-sulfonamide, as a yellow solid (3 mg, 0.0066 mmol, 4.5%).

Example 194 6-Fluoro-N-[1-(fluoromethyl)cyclopropyl]-3-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxo-1H-benzimidazole-5-sulfonamide

Using the method described in Example 160, 6-fluoro-3-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-benzimidazol-2-one (937 mg, 4.00 mmol) and 1-(fluoromethyl)cyclopropane-1-amine hydrochloride (556.1 mg, 4.51 mmol) were used to yield 6-fluoro-N-[1-(fluoromethyl)cyclopropyl]-3-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxo-1H-benzimidazole-5-sulfonamide as a white solid (450 mg, 1.17 mmol, 29%).

Example 195 3-[5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl]-1-methyl-N-(1-methylcyclopropyl)-2-oxobenzimidazole-5-sulfonamide

Intermediate S5D12 1-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-methyl-benzimidazol-2-one

Prepared from 1-methyl-1,3-dihydro-2H-benzimidazol-2-one (100 mg, 0.67 mmol), 2-bromo-5-(difluoromethyl)-1,3,4-oxadiazole (134.3 mg, 0.67 mmol), potassium carbonate (280 mg, 2.02 mmol), copper iodide (12.9 mg, 0.07 mmol) and trans-N,N'-dimethylcyclohexane-1,2-diamine (0.02 mL, 0.1400 mmol) in 1,4-dioxane (5 mL) at 80 °C for 2 hours. The product was obtained as a white solid (65 mg, 0.24 mmol, 36%).

¹ H NMR (300 MHz, DMSO-d6) shift = 7.88 (d, J = 7.6 Hz, 1H), 7.76-7.38 (m, 1H), 7.38-7.32 (m, 2H), 7.31-7.22 (m, 1H), 3.41 (s, 3H)

Prepared using the method described in Example 160 with 1-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-methyl-benzoimidazol-2-one (60 mg, 0.225 mmol) and 1-methylcyclopropaneamine hydrochloride (21.2 mg, 0.20 mmol) to give 3-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1-methyl-N-(1-methylcyclopropyl)-2-oxo-benzoimidazol-5-sulfonamide as a white solid (20 mg, 0.05 mmol, 22%).

Example 196 3-[5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl]-N-[1-(fluoromethyl)cyclopropyl]-1-methyl-2-oxo-benzimidazole-5-sulfonamide

Prepared using the method described in Example 160 with 1-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-methyl-benzimidazol-2-one (60 mg, 0.225 mmol) and 1-(fluoromethyl)cyclopropane-1-amine hydrochloride (24 mg, 0.20 mmol) to give 3-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-N-[1-(fluoromethyl)cyclopropyl]-1-methyl-2-oxo-benzimidazole-5-sulfonamide as a white solid (21 mg, 0.05 mmol, 22%).

Example 197 6-Fluoro-1-methyl-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide

Prepared by alkylation of 6-fluoro-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxo-1H-benzimidazole-5-sulfonamide (40 mg, 0.11 mmol), iodomethane (6.78 μL, 0.11 mmol) and potassium carbonate (30.1 mg, 0.22 mmol) in DMF (2 mL) under microwave irradiation at 80° C. for 45 minutes. The desired product, 6-fluoro-1-methyl-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxo-1H-benzimidazole-5-sulfonamide, was isolated as a white solid (10 mg, 0.026 mmol, 24%).

Example 198 6-Fluoro-1-(2-fluoroethyl)-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide

Prepared by alkylation of 6-fluoro-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxo-1H-benzimidazole-5-sulfonamide (80 mg, 0.22 mmol) with 1-bromo-2-fluoroethane (16.2 μL, 0.22 mmol) and potassium carbonate (60.2 mg, 0.44 mmol) in DMF (2 mL) under microwave irradiation at 80° C. for 45 minutes. The desired product, 6-fluoro-1-(2-fluoroethyl)-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide, was isolated as a white solid (25 mg, 0.061 mmol, 28%).

Example 199 3-[5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl]-1-ethyl-6-fluoro-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide

Intermediate S5C13 3-Ethyl-5-fluoro-1H-benzimidazol-2-one

Prepared by reaction of 1-N-ethyl-5-fluorobenzene-1,2-diamine (2.50 g, 16.21 mmol) and 1,1'-carbonyldiimidazole (3.15 g, 19.46 mmol) in DMF (40 mL) at 20° C. The desired product, 3-ethyl-5-fluoro-1H-benzimidazol-2-one, was obtained as a light brown solid (1.4 g, 7.77 mmol, 47.9%).

¹ H NMR (300 MHz, DMSO-d6) shift = 10.98-10.72 (m, 1H), 7.13 (dd, J = 2.5, 9.3 Hz, 1H), 6.93 (dd, J = 4.7, 8.5 Hz, 1H), 6.83-6.73 (m, 1H), 3.80 (q, J = 7.2 Hz, 2H), 1.18 (t, J = 7.2 Hz, 3H).

Intermediate S5D13 1-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-ethyl-5-fluoro-benzimidazol-2-one

Prepared by stirring 3-ethyl-5-fluoro-1H-benzimidazol-2-one (200 mg, 1.11 mmol) with 2-bromo-5-(difluoromethyl)-1,3,4-oxadiazole (265 mg, 1.33 mmol), potassium carbonate (460 mg, 3.33 mmol), copper(I) iodide (21.1 mg, 0.11 mmol) and trans-N,N′-dimethylcyclohexane-1,2-diamine (0.04 mL, 0.22 mmol) in 1,4-dioxane (6 mL) at 80° C. for 2 hours. The desired product, 1-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-ethyl-5-fluoro-benzimidazol-2-one, was obtained as a white solid (200 mg, 0.67 mmol, 60%).

¹ H NMR (300 MHz, DMSO-d6) shift = 7.88 (dd, J = 4.8, 8.8 Hz, 1H), 7.76-7.37 (m, 2H), 7.09 (ddd, J = 2.5, 8.9, 9.9 Hz, 1H), 3.95 (q, J = 7.1 Hz, 2H), 1.26 (t, J = 7.2 Hz, 3H).

Prepared using the method described in Example 160 using 1-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-ethyl-5-fluoro-benzimidazol-2-one (100 mg, 0.335 mmol) and 1-methylcyclopropane-1-amine hydrochloride (46 mg, 0.363 mmol) to give the desired product 3-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1-ethyl-6-fluoro-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide as a white solid (40 mg, 0.089 mmol, 26%).

Example 200 3-[5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl]-1-ethyl-6-fluoro-N-[1-(fluoromethyl)cyclopropyl]-2-oxo-benzimidazole-5-sulfonamide

Prepared using the method described in Example 160 using 1-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-ethyl-5-fluoro-benzimidazol-2-one (100 mg, 0.335 mmol) and 1-(fluoromethyl)cyclopropane-1-amine hydrochloride (40 mg, 0.362 mmol) to give the desired product 3-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1-ethyl-6-fluoro-N-[1-(fluoromethyl)cyclopropyl]-2-oxo-benzimidazole-5-sulfonamide as a white solid (30 mg, 0.07 mmol, 21%).

Example 201 3-[5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl]-1-ethyl-N-(1-methylcyclopropyl)-2-oxobenzimidazole-5-sulfonamide

Intermediate S5D14 1-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-ethyl-benzimidazol-2-one

Prepared by reacting 1-ethyl-1,3-dihydro-2H-benzimidazol-2-one (200 mg, 1.23 mmol) with 2-bromo-5-(difluoromethyl-1,3,4-oxadiazole (245 mg, 1.23 mmol), potassium carbonate (511 mg, 3.7 mmol), copper iodide (23.5 mg, 0.12 mmol) and trans-N,N'-dimethylcyclohexane-1,2-diamine (0.04 mL, 0.2500 mmol) in 1,4-dioxane (8 mL) at 80°C for 2 hours. The desired product, 1-[5-(difluoromethyl)oxadiazol-2-yl]-3-ethyl-benzimidazol-2-one, was obtained as a white solid (200 mg, 0.714 mmol, 58%).

¹ H NMR (300 MHz, DMSO-d6) shift = 7.94-7.87 (m, 1H), 7.77-7.38 (m, 2H), 7.37-7.20 (m, 2H), 3.96 (q, J = 7.1 Hz, 2H), 1.28 (t, J = 7.2 Hz, 3H)

Prepared using the method described in Example 160 using 1-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-ethyl-benzimidazol-2-one (100 mg, 0.357 mmol) and 1-methylcyclopropane-1-amine hydrochloride (46 mg, 0.363 mmol) to give the desired product 3-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1-ethyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide as a white solid (40 mg, 0.089 mmol, 25%).

Example 202 3-[5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl]-1-ethyl-N-[1-(fluoromethyl)cyclopropyl]-2-oxo-benzimidazole-5-sulfonamide

Using the method described in Example 160, 1-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-ethyl-5-fluoro-benzimidazol-2-one (100 mg, 0.357 mmol) and 1-(fluoromethyl)cyclopropane-1-amine hydrochloride (28 mg, 0.222 mmol) were used to prepare the desired product 3-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1-ethyl-N-[1-(fluoromethyl)cyclopropyl]-2-oxo-benzimidazole-5-sulfonamide as a white solid (30 mg, 0.07 mmol, 20%).

Example 203 6-Fluoro-N-[1-(fluoromethyl)cyclopropyl]-1-(2-methoxyethyl)-3-(6-methylpyridazin-3-yl)-2-oxo-benzimidazole-5-sulfonamide

Intermediate S5D15 5-Fluoro-3-(2-methoxyethyl)-1-(6-methylpyridazin-3-yl)benzimidazol-2-one

Prepared by reacting 5-fluoro-3-(2-methoxyethyl)-1H-benzimidazol-2-one (100 mg, 0.48 mmol) with 3-bromo-6-methylpyridazine (90.54 mg, 0.52 mmol), potassium carbonate (197 mg, 1.43 mmol), copper iodide (9.1 mg, 0.05 mmol) and trans-N,N'-dimethylcyclohexane-1,2-diamine (0.02 mL, 0.10 mmol) in DMSO (2.5 mL) at 80° C. for 3 hours. The desired product, 5-fluoro-3-(2-methoxyethyl)-1-(6-methylpyridazin-3-yl)benzimidazol-2-one, was isolated as a white solid (41 mg, 0.136 mmol, 28%).

^1H NMR (300MHz, DMSO-d6) displacement = 8.29 (d, J = 9.0Hz, 1H), 7.97 (dd, J = 4.9, 8.9Hz, 1H), 7.79 (d, J = 9.0Hz, 1H), 7.35 (dd, J = 2.5, 9.1Hz,1H),6.98(ddd,J＝2.6,8.9,9.9Hz,1H),4.11(t,J＝5.3Hz,2H),3.67(t,J＝5.3Hz,2H),3.26(s,3H),2.68(s,3H)

Using the method described in Example 160, 5-fluoro-3-(2-methoxyethyl)-1-(6-methylpyridazin-3-yl)benzimidazol-2-one (120 mg, 0.397 mmol) and 1-(fluoromethyl)cyclopropane-1-amine hydrochloride (55.2 mg, 0.439 mmol) were prepared to give the desired product 6-fluoro-N-[1-(fluoromethyl)cyclopropyl]-(2-methoxyethyl)-3-(6-methylpyridazin-3-yl)-2-oxo-benzimidazole-5-sulfonamide as a white solid (24 mg, 0.053 mmol, 13%).

Example 204 6-Fluoro-N-[1-(fluoromethyl)cyclopropyl]-1-methyl-3-(6-methylpyridazin-3-yl)-2-oxo-benzimidazole-5-sulfonamide

Intermediate S5D16 5-Fluoro-3-methyl-1-(6-methylpyridazin-3-yl)benzimidazol-2-one

Prepared by reacting 5-fluoro-3-methyl-1H-benzimidazol-2-one (150 mg, 0.90 mmol) with 3-bromo-6-methylpyridazine (172 mg, 0.99 mmol), potassium carbonate (374 mg, 2.71 mmol), copper iodide (17 mg, 0.09 mmol) and trans-N,N'-dimethylcyclohexane-1,2-diamine (0.03 mL, 0.18 mmol) in 1,4-dioxane (2.5 mL) at 80 °C for 16 hours. The desired product, 5-fluoro-3-methyl-1-(6-methylpyridazin-3-yl)benzimidazol-2-one, was isolated as a yellow solid (180 mg, 0.697 mmol, 77%).

¹ H NMR (300MHz, DMSO-d6) displacement = 8.30 (d, J = 9.0Hz, 1H), 7.99 (dd, J = 4.9, 8.9Hz, 1H), 7.78 (d, J = 9.1Hz ,1H),7.31(dd,J＝2.5,8.9Hz,1H),6.98(ddd,J＝2.6,8.9,10.0Hz,1H),3.41(s,3H),2.67(s,3H)

Using the method described in Example 160, prepared from 5-fluoro-3-methyl-1-(6-methylpyridazin-3-yl)benzimidazol-2-one (125 mg, 0.35 mmol) and 1-(fluoromethyl)cyclopropyl-1-amine hydrochloride (48.4 mg, 0.385 mmol) to give the desired product 6-fluoro-N-[1-(fluoromethyl)cyclopropyl]-1-methyl-3-(6-methylpyridazin-3-yl)-2-oxo-benzimidazole-5-sulfonamide as a white solid (14 mg, 0.034 mmol, 10%).

Example 205 6-Fluoro-1-methyl-N-(1-methylcyclopropyl)-3-(6-methylpyridazin-3-yl)-2-oxo-benzimidazole-5-sulfonamide

Using the method described in Example 160, 5-fluoro-3-methyl-1-(6-methylpyridazin-3-yl)benzimidazol-2-one (125 mg, 0.35 mmol) and 1-methylcyclopropaneamine hydrochloride (41.4 mg, 0.385 mmol) were prepared to give the desired product 6-fluoro-1-methyl-N-(1-methylcyclopropyl)-3-(6-methylpyridazin-3-yl)-2-oxo-benzimidazole-5-sulfonamide as a white solid (20 mg, 0.052 mmol, 15%).

Example 206 6-Fluoro-N-[1-(fluoromethyl)cyclopropyl]-1-methyl-2-oxo-3-[6-(trifluoromethyl)pyridazin-3-yl]benzimidazole-5-sulfonamide

Intermediate S5D17 5-Fluoro-3-methyl-1-(6-(trifluoromethyl)pyridazin-3-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

Prepared by reacting 5-fluoro-3-methyl-1H-benzimidazol-2-one (50 mg, 0.30 mmol) with 3-bromo-6-methylpyridazine (57 mg, 0.33 mmol), potassium carbonate (125 mg, 0.90 mmol), copper iodide (5.7 mg, 0.03 mmol) and trans-N,N'-dimethylcyclohexane-1,2-diamine (0.01 mL, 0.06 mmol) in 1,4-dioxane (1 mL) at 80° C. for 2 hours. The desired product, 5-fluoro-3-methyl-1-(6-(trifluoromethyl)pyridazin-3-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one, was isolated as a white solid (40 mg, 0.128 mmol, 43%).

¹ H NMR (300 MHz, DMSO-d6) shift = 8.82 (d, J = 9.4 Hz, 1H), 8.45 (d, J = 9.4 Hz, 1H), 8.24 (dd, J = 4.9, 8.9 Hz, 1H), 7.36 (dd, J = 2.6, 8.9 Hz, 1H), 7.04 (ddd, J = 2.6, 8.9, 9.8 Hz, 1H), 3.43 (s, 3H)

Prepared using the method described in Example 160 with 5-fluoro-3-methyl-1-(6-(trifluoromethyl)pyridazin-3-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (90 mg, 0.288 mmol) and 1-(fluoromethyl)cyclopropane-1-amine hydrochloride (40 mg, 0.321 mmol) to give the desired product 6-fluoro-N-[1-(fluoromethyl)cyclopropyl]-1-methyl-2-oxo-3-[6-(trifluoromethyl)pyridazin-3-yl]benzimidazole-5-sulfonamide as a white solid (4.7 mg, 0.01 mmol, 3.5%).

Example 207 3-[5-(Difluoromethyl)-1,3,4-thiadiazol-2-yl]-1-ethyl-6-fluoro-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide

Intermediate S5D18 1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-3-ethyl-5-fluoro-benzimidazol-2-one

Prepared by reacting 3-ethyl-5-fluoro-1H-benzimidazol-2-one (200 mg, 1.11 mmol) with 2-bromo-5-(difluoromethyl)-1,3,4-oxadiazole (265 mg, 1.33 mmol), potassium carbonate (414 mg, 3.33 mmol), copper(I) iodide (19 mg, 0.10 mmol) and trans-N,N'-dimethylcyclohexane-1,2-diamine (0.03 mL, 0.20 mmol) in DMSO (6 mL) at 80° C. for 2 hours. The desired product, 1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-3-ethyl-5-fluoro-benzimidazol-2-one, was isolated as a white solid (200 mg, 0.636 mmol, 64%).

¹ H NMR (300 MHz, DMSO-d6) shift = 8.32 (dd, J = 4.8, 8.9 Hz, 1H), 7.84-7.40 (m, 2H), 7.15 (ddd, J = 2.6, 8.9, 9.8 Hz, 1H), 4.02 (q, J = 7.2 Hz, 2H), 1.30 (t, J = 7.2 Hz, 3H)

Prepared using the method described in Example 160 using 1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-3-ethyl-5-fluoro-benzimidazol-2-one (100 mg, 0.318 mmol) and 1-methylcyclopropaneamine hydrochloride (25 mg, 0.233 mmol) to give the desired product 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1-ethyl-6-fluoro-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide as a white solid (40 mg, 0.089 mmol, 28%).

Example 208 3-[5-(Difluoromethyl)-1,3,4-thiadiazol-2-yl]-1-ethyl-6-fluoro-N-[1-(fluoromethyl)cyclopropyl]-2-oxo-benzimidazole-5-sulfonamide

Using the method described in Example 160, 1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-3-ethyl-5-fluoro-benzimidazol-2-one (100 mg, 0.318 mmol) and 1-(fluoromethyl)cyclopropane-1-amine hydrochloride (36 mg, 0.291 mmol) were used to prepare the desired product 3-[5-(difluoromethyl)-1,3,4-thiazol-2-yl]-1-ethyl-6-fluoro-N-[1-(fluoromethyl)cyclopropyl]-2-oxo-benzimidazole-5-sulfonamide as a white solid (55 mg, 0.118 mmol, 37%).

Example 209 3-[5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl]-6-fluoro-1-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide

Intermediate S5D19 1-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-5-fluoro-3-methyl-benzimidazol-2-one

Prepared by reacting 5-fluoro-3-methyl-1H-benzimidazol-2-one (204 mg, 1.23 mmol) with 2-bromo-5-(difluoromethyl-1,3,4-oxadiazole (244 mg, 1.23 mmol), potassium carbonate (509 mg, 3.68 mmol), copper iodide (23 mg, 0.12 mmol) and trans-N,N'-dimethylcyclohexane-1,2-diamine (0.04 mL, 0.25 mmol) in 1,4-dioxane (8 mL) at 80°C for 2 hours. The desired product, 1-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-5-fluoro-3-methyl-benzimidazol-2-one, was obtained as a white solid (80 mg, 0.283 mmol, 23%).

¹ H NMR (300 MHz, DMSO-d6) shift = 7.86 (dd, J = 4.7, 8.8 Hz, 1H), 7.75-7.35 (m, 2H), 7.09 (ddd, J = 2.5, 8.9, 9.8 Hz, 1H), 3.40 (s, 3H)

Using the method described in Example 160, prepared with 1-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-5-fluoro-3-methyl-benzoimidazol-2-one (40 mg, 0.141 mmol) and 1-methylcyclopropaneamine hydrochloride (17 mg, 0.157 mmol) to give the desired product 3-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-6-fluoro-1-methyl-N-(1-methylcyclopropyl)-2-oxo-benzoimidazol-5-sulfonamide as a white solid (10 mg, 0.024 mmol, 17%).

Example 210 3-[5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl]-6-fluoro-N-[1-(fluoromethyl)cyclopropyl]-1-methyl-2-oxo-benzimidazole-5-sulfonamide

Using the method described in Example 160, prepared with 1-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-5-fluoro-3-methyl-benzimidazol-2-one (40 mg, 0.141 mmol) and 1-(fluoromethyl)cyclopropane-1-amine hydrochloride (26 mg, 0.209 mmol) to give the desired product 3-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-6-fluoro-N-[1-(fluoromethyl)cyclopropyl]-1-methyl-2-oxo-benzimidazole-5-sulfonamide as a white solid (15 mg, 0.044 mmol, 24%).

Example 211 3-[5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl]-6-fluoro-1-(2-fluoroethyl)-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide

Intermediate S5A20 5-Fluoro-N-(2-fluoroethyl)-2-nitro-aniline

To a magnetically stirred solution of 2,4-difluoronitrobenzene (2.17 mL, 19.8 mmol) and 2-fluoroethylamine hydrochloride (1.97 g, 19.8 mmol) in ethanol (40 mL) at 0°C under nitrogen was added N,N-diisopropylethylamine (6.54 mL, 39.6 mmol), and the resulting mixture was stirred at ambient temperature overnight. The mixture was poured into water (200 mL) to give a suspension, which was stirred for 30 minutes and filtered. The solid was washed with water (2 x 20 mL) and dried under vacuum at 40°C for 3 hours to give the desired product, 5-fluoro-N-(2-fluoroethyl)-2-nitro-aniline, as a yellow solid (3.4 g, 16.82 mmol, 84.9%).

^1H NMR (300MHz, DMSO-d6) displacement = 8.39 (br.s., 1H), 8.23-8.13 (m, 1H), 6.98 (dd, J = 2.6, 12.3Hz, 1H), 6.57 (ddd, J ＝2.6,7.4,9.7Hz,1H),4.73(t,J＝4.9Hz,1H),4.57(t,J＝4.9Hz,1H),3.81-3.72(m,1H),3.71-3.63(m,1H).

Intermediate S5B20 4-Fluoro-N2-(2-fluoroethyl)benzene-1,2-diamine

To a magnetically stirred suspension of 5-fluoro-N-(2-fluoroethyl)-2-nitro-aniline (3.3 g, 16.32 mmol) in ethanol (60 mL) and water (60 mL) was added iron powder (4.5 mg, 81 mmol) and ammonium chloride (4.4 g, 81.62 mmol) at 20 ° C., and the resulting mixture was stirred at 60 ° C for 2 hours. The mixture was filtered hot through a pad of celite, and the filter cake was washed with warm ethanol (2×20 mL). The combined filtrate was then evaporated to dryness to give a residue, which was partitioned between DCM (50 mL) and water (50 mL). The DCM layer was collected and evaporated to dryness to give the desired product, 4-fluoro-N2-(2-fluoroethyl)benzene-1,2-diamine, as a dark purple foam (2.50 g, 14.52 mmol, 89%).

¹ H NMR (300MHz, DMSO-d6) displacement = 6.50 (dd, J = 6.0, 8.4Hz, 1H), 6.29 (dd, J = 2.8, 11.7Hz, 1H), 6.19 (dt, J = 2.8, 8.5Hz, 1H), 4.94 ( t, J＝5.1Hz, 1H), 4.67 (t, J＝5.0Hz, 1H), 4.51 (t, J＝5.0Hz, 1H), 4.38 (s, 2H), 3.41 (q, J＝5.2Hz, 1H), 3.31 (q, J＝5.2Hz, 1H).

Intermediate S5C20 5-Fluoro-3-(2-fluoroethyl)-1H-benzimidazol-2-one

To a magnetically stirred solution of 4-fluoro-N2-(2-fluoroethyl)benzene-1,2-diamine (3.0 g, 17.4 mmol) in THF (80 mL) at 20°C under nitrogen was added 1,1'-carbonyldiimidazole (3.39 g, 20.91 mmol), and the resulting mixture was stirred at ambient temperature for 2 hours. The solvent was removed in vacuo to give a residue that was partitioned between DCM (100 mL) and water (50 mL). The organic phase was collected and distilled to dryness to give a residue that was purified by automated column chromatography ( _SiO2 ; RediSep-40g; 0 to 100% EtOAc in hexanes) to give the desired product, 5-fluoro-3-(2-fluoroethyl)-1H-benzimidazol-2-one, as a light pink solid (2.0 g, 10.09 mmol, 58%).

^1H NMR (300MHz, DMSO-d6) displacement = 11.12-10.84 (m, 1H), 7.13 (dd, J = 2.4, 9.3Hz, 1H), 6.95 (dd, J = 4.8, 8.5Hz, 1H), 6.81 (ddd ,J＝2.4,8.3,10.4Hz,1H),4.74(t,J＝4.9Hz,1H),4.58(t,J＝4.8Hz,1H),4.15(t,J＝4.8Hz,1H),4.07(t,J＝4.8Hz,1H)

Intermediate S5D20 1-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-5-fluoro-3-(2-fluoroethyl)benzimidazol-2-one

The desired compound, 1-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-5-fluoro-3-(2-fluoroethyl)benzimidazol-2-one, was prepared by reacting 5-fluoro-3-(2-fluoroethyl)-1H-benzimidazol-2-one (200 mg, 1.01 mmol) with potassium carbonate (418.46 mg, 3.03 mmol), copper(I) iodide (19 mg, 0.10 mmol), 2-bromo-5-(difluoromethyl)-1,3,4-oxadiazole (241 mg, 1.21 mmol) and trans-N,N'-dimethylcyclohexane-1,2-diamine (0.03 mL, 0.20 mmol) in 1,4-dioxane (6 mL) at 80°C for 2 hours. The desired compound, 1-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-5-fluoro-3-(2-fluoroethyl)benzimidazol-2-one, was isolated as a white solid (200 mg, 0.633 mmol, 63%).

¹ H NMR (300 MHz, DMSO-d6) shift = 7.89 (dd, J = 4.7, 8.9 Hz, 1H), 7.80-7.36 (m, 2H), 7.11 (ddd, J = 2.6, 8.9, 9.8 Hz, 1H), 4.82 (t, J = 4.7 Hz, 1H), 4.66 (t, J = 4.7 Hz, 1H), 4.32 (t, J = 4.7 Hz, 1H), 4.23 (t, J = 4.7 Hz, 1H)

Using the method described in Example 160, prepared with 1-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-5-fluoro-3-(2-fluoroethyl)benzimidazol-2-one (100 mg, 0.316 mmol) and 1-methylcyclopropane-1-amine hydrochloride (25 mg, 0.232 mmol) to give the desired product 3-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-6-fluoro-1-(2-fluoroethyl)-N-(1-methylcyclopropyl)-2-oxobenzimidazole-5-sulfonamide as a white solid (30 mg, 0.067 mmol, 21%).

Example 212 3-[5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl]-6-fluoro-1-(2-fluoroethyl)-N-[1-(fluoromethyl)cyclopropyl]-2-oxo-benzimidazole-5-sulfonamide

Using the method described in Example 160, prepared with 1-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-5-fluoro-3-(2-fluoroethyl)benzimidazol-2-one (100 mg, 0.316 mmol) and 1-(fluoromethyl)cyclopropane-1-amine hydrochloride (29 mg, 0.232 mmol) to give the desired product 3-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-6-fluoro-1-(2-fluoroethyl)-N-[1-(fluoromethyl)cyclopropyl]-2-oxobenzimidazole-5-sulfonamide as a white solid (30 mg, 0.064 mmol, 20%).

Example 213 3-[5-(Difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-fluoro-N-[1-(fluoromethyl)cyclopropyl]-2-oxo-1-prop-2-ynyl-benzimidazole-5-sulfonamide

Intermediate S13A3-5-(Difluoromethyl)-N-(4-fluoro-2-nitro-phenyl)-1,3,4-thiadiazol-2-amine

Under nitrogen, 5-(difluoromethyl)-1,3,4-thiadiazole-2-amine (2.49 g, 16.5 mmol) was added to a magnetically stirred solution of 2,5-difluoronitrobenzene (1.87 mL, 15.7 mmol) and cesium carbonate (15.36 g, 47.1 mmol) in DMSO (50 mL), and the resulting mixture was stirred at 65 ° C for 4 hours. The mixture was cooled to ambient temperature and partitioned between water (250 mL) and EtOAc (100 mL). The organic phase was distilled to dryness, and the resulting residue was purified by automated column chromatography (100 g SNAP-0-100% EtOAc in hexanes) to give 5-(difluoromethyl)-N-(4-fluoro-2-nitro-phenyl)-1,3,4-thiadiazole-2-amine as a yellow solid (1.15 g, 3.95 mmol, 25%).

¹ H NMR (300 MHz, DMSO-d6) shift = 10.77 (s, 1H), 8.35-8.16 (m, 1H), 8.09-7.99 (m, 1H), 7.72 (ddd, J = 3.0, 7.7, 9.2 Hz, 1H), 7.61-7.20 (m, 1H)

Intermediate S13B3-N1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-4-fluoro-benzene-1,2-diamine

Iron powder (1.10 g, 19.73 mmol) and ammonium chloride (1.05 g, 19.7 mmol) were added to a stirred suspension of 5-(difluoromethyl)-N-(4-fluoro-2-nitro-phenyl)-1,3,4-thiadiazole-2-amine (1.14 g, 3.95 mmol) in ethanol (40 mL) and water (40 mL), and the resulting mixture was stirred at 60 ° C for 1 hour. The mixture was filtered through celite (hot) and the filter cake was washed with EtOH (2 × 40 mL). The combined filtrate was concentrated in vacuo to about 20 mL. The aqueous solution was then extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over _MgSO4 and evaporated to give a residue, which was purified by automated column chromatography (40 g SNAP - 0 to 100% EtOAc in hexanes) to give N1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-4-fluoro-benzene-1,2-diamine as a tan solid (727 mg, 2.79 mmol, 71%).

¹ H NMR (300 MHz, DMSO-d6) shift = 9.56 (s, 1H), 7.52-6.89 (m, 2H), 6.45 (dd, J = 2.9, 11.2 Hz, 1H), 6.26 (dt, J = 2.9, 8.5 Hz, 1H), 5.35 (s, 2H)

Intermediate S13C3-3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-fluoro-1H-benzimidazol-2-one

At 20 ℃, under nitrogen, to N1-[5-(difluoromethyl)-1,3,4-thiadiazole-2-yl]-4-fluoro-benzene-1,2-diamine (727mg, 2.79mmol) in DMF (8mL) magnetic stirring solution, add 1,1 '-carbonyldiimidazole (543mg, 3.35mmol), and the resulting mixture is stirred at ambient temperature for 2 hours. The solvent is removed in vacuo, and water (40mL) is added to the brown residue gained. A beige precipitate is formed, collected and washed with water, to obtain 3-[5-(difluoromethyl)-1,3,4-thiadiazole-2-yl]-6-fluoro-1H-benzimidazole-2-one, it is a light brown solid (671mg, 2.34mmol, 84%).

¹ H NMR (300 MHz, DMSO-d6) shift = 12.18 (br. s., 1H), 8.26 (dd, J = 4.8, 9.5 Hz, 1H), 7.92-7.30 (m, 1H), 7.22-6.94 (m, 2H)

Intermediate S14A3 - 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-fluoro-N-[1-(fluoromethyl)cyclopropyl]-2-oxo-1H-benzimidazole-5-sulfonamide

Prepared according to the method described in Example 160 using 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-fluoro-1H-benzimidazol-2-one (671 mg, 2.34 mmol) and 1-(fluoromethyl)cyclopropane-1-amine hydrochloride (170 mg, 1.35 mmol) to give 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-fluoro-N-[1-(fluoromethyl)cyclopropyl]-2-oxo-1H-benzimidazole-5-sulfonamide as an orange solid (250 mg, 0.572 mmol, 24%).

¹ H NMR (300 MHz, DMSO-d6) shift = 12.81-12.38 (m, 1H), 8.78 (s, 1H), 8.68 (d, J = 6.4 Hz, 1H), 7.64 (s, 2H), 7.33 (d, J = 9.8 Hz, 1H), 4.41-4.00 (m, 2H), 0.76 (d, J = 4.1 Hz, 4H).

Intermediate S14B3-N-[1-acetyl-3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-fluoro-2-oxo-benzimidazol-5-yl]sulfonyl-N-[1-(fluoromethyl)cyclopropyl]acetamide

Under nitrogen, acetic anhydride (0.27mL, 2.86mmol) was added to a magnetic stirring solution of 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-fluoro-N-[1-(fluoromethyl)cyclopropyl]-2-oxo-1H-benzimidazole-5-sulfonamide (250mg, 0.57mmol) in pyridine (3ml) at 20°C, and the resulting mixture was stirred overnight. The substance was poured into water (25mL), and the aqueous solution was extracted with DCM (2×50mL). The DCM was passed through a hydrophobic glass frit and concentrated to dryness. The resulting solid was dissolved in a minimum amount of DCM and precipitated by adding hexane. The solid was collected by suction filtration and washed with hexane. The solid was air dried to give N-[1-acetyl-3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-fluoro-2-oxo-benzimidazol-5-yl]sulfonyl-N-[1-(fluoromethyl)cyclopropyl]acetamide as a brown solid (150 mg, 0.28 mmol, 50%).

¹ H NMR (300 MHz, DMSO-d6) shift = 8.78 (d, J = 6.6 Hz, 1H), 7.83-7.45 (m, 1H), 7.36 (d, J = 10.5 Hz, 1H), 5.22-5.06 (m, 1H), 5.03-4.89 (m, 1H), 4.37-4.26 (m, 1H), 4.20-4.09 (m, 3H), 2.32-2.25 (m, 6H), 0.89-0.69 (m, 4H)

At 20 ° C, under nitrogen, to a magnetically stirred solution of N-[1-acetyl-3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-fluoro-2-oxo-benzimidazol-5-yl]sulfonyl-N-[1-(fluoromethyl)cyclopropyl]acetamide (70 mg, 0.13 mmol) and potassium carbonate (55.6 mg, 0.40 mmol) in DMF (2 mL) was added 3-bromopropyne (23.3 μL, 0.27 mmol), and the resulting mixture was stirred at 50 ° C for 16 hours. The mixture was cooled to ambient temperature and treated with 4 mL of aqueous ammonia. The mixture was diluted with water to induce precipitation. The mixture was stirred overnight, then the solid was collected and purified by preparative HPLC (high pH) to give the desired product, 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-fluoro-N-[1-(fluoromethyl)cyclopropyl]-2-oxo-1-prop-2-ynyl-benzimidazole-5-sulfonamide, as a yellow solid (7.4 mg, 0.016 mmol, 12%).

Example 214 2-[3-[5-(Difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-fluoro-5-[[1-(fluoromethyl)cyclopropyl]sulfamoyl]-2-oxo-benzimidazol-1-yl]acetamide

Isolated as an impurity during the preparation of Example 215.

Example 215 1-(Cyanomethyl)-3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-fluoro-N-[1-(fluoromethyl)cyclopropyl]-2-oxo-benzimidazole-5-sulfonamide

Intermediate S10B5-2-[3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-fluoro-2-oxo-benzimidazol-1-yl]acetonitrile

To a magnetically stirred solution of 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-fluoro-1H-benzimidazol-2-one (168 mg, 0.59 mmol) and potassium carbonate (243 mg, 1.76 mmol) in DMF (4 mL) was added bromoacetonitrile (81.7 μL, 1.17 mmol), and the resulting mixture was stirred at 50 ° C for 1 hour. Water (50 mL) was added, which caused a precipitate, which was collected by suction filtration. The solid was dissolved in EtOAc, dried with MgSO ₄ and evaporated to give 2-[3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-fluoro-2-oxo-benzimidazol-1-yl] acetonitrile as a light brown solid (147 mg, 0.452 mmol, 77%).

¹ H NMR (300 MHz, DMSO-d6) shift = 8.41-8.31 (m, 1H), 7.63 (s, 2H), 7.30-7.18 (m, 1H), 5.30 (s, 2H)

Prepared according to the method described in Example 160 using 2-[3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-fluoro-2-oxo-benzimidazol-1-yl]acetonitrile (148 mg, 0.455 mmol) and 1-(fluoromethyl)cyclopropane-1-amine hydrochloride (112 mg, 0.897 mmol) to give the desired 2-[3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-fluoro-2-oxo-benzimidazol-1-yl]acetonitrile (2.6 mg, 0.005 mmol, 1%)

Example 216 3-[5-(Difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-fluoro-1-(2-fluoroethyl)-N-[1-(fluoromethyl)cyclopropyl]-2-oxo-benzimidazole-5-sulfonamide

1-[5-(Difluoromethyl)-1,3,4-thiadiazol-2-yl]-5-fluoro-3-(2-fluoroethyl)benzimidazol-2-one was prepared by reacting 5-fluoro-3-(2-fluoroethyl)-1H-benzimidazol-2-one (250 mg, 1.26 mmol) with potassium carbonate (523 mg, 3.79 mmol), copper (I) iodide (24 mg, 0.13 mmol), 2-bromo-5-(difluoromethyl)-1,3,4-thiadiazole (298 mg, 1.21 mmol) and trans-N,N'-dimethylcyclohexane-1,2-diamine (0.04 mL, 0.25 mmol) in DMSO (3 mL) at 80°C for 2 hours. The mixture was cooled to ambient temperature and filtered through celite, washing with EtOAc (100 mL). The organic phase was collected and washed with water (3 x 50 mL), dried over MgSO4 and distilled to dryness. The resulting residue was purified by automated column chromatography (12 g SNAP-0-100% EtOAc in hexanes) to afford the desired compound, 1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-5-fluoro-3-(2-fluoroethyl)benzimidazol-2-one, as a light green solid (241 mg, 0.725 mmol, 57%).

¹ H NMR (300MHz, DMSO-d6) displacement = 8.34 (dd, J = 4.9, 8.9 Hz, 1H), 7.82-7.42 (m, 2H), 7.17 (ddd, J = 2.6, 9.3, 10 .6Hz,1H),4.85(t,J＝4.6Hz,1H),4.69(t,J＝4.7Hz,1H),4.38(t,J＝4.7Hz,1H),4.29(t,J＝4.7Hz,1H)

Using the method described in Example 160, prepared with 1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-5-fluoro-3-(2-fluoroethyl)benzimidazol-2-one (120 mg, 0.363 mmol) and 1-(fluoromethyl)cyclopropane-1-amine hydrochloride (73 mg, 0.58 mmol) to give the desired product 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-fluoro-1-(2-fluoroethyl)-N-[1-(fluoromethyl)cyclopropyl]-2-oxo-benzimidazole-5-sulfonamide as a white solid (24 mg, 0.05 mmol, 17%).

Example 217 3-[5-(Difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-fluoro-1-(2-fluoroethyl)-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide

Using the method described in Example 160, 1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-5-fluoro-3-(2-fluoroethyl)benzimidazol-2-one (120 mg, 0.363 mmol), which was prepared as described in Example 216, and 1-methylcyclopropyl-1-amine hydrochloride (62 mg, 0.58 mmol) were used to give the desired product 3-[5-(difluoromethyl)-1,3,4-3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-fluoro-1-(2-fluoroethyl)-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide as a white solid (42 mg, 0.09 mmol, 31%).

Example 218 Ethyl 3-methyl-5-[(1-methylcyclopropyl)sulfamoyl]benzofuran-2-carboxylate

To a solution of N,N-diisopropylethylamine (0.12 mL, 0.70 mmol) in THF (5 mL) cooled in an ice bath was added 1-methylcyclopropylamine hydrochloride (0.04 mL, 0.34 mmol) and ethyl 5-(chlorosulfonyl)-3-methyl-1-benzofuran-2-carboxylate (100 mg, 0.33 mmol) in DCM (3 mL), and the mixture was stirred at ambient temperature overnight. The mixture was diluted with water and extracted twice with DCM. The extracts were evaporated to dryness, and the crude product mixture was purified by preparative HPLC (high pH) to give the desired product (47 mg, 0.14 mmol, 42%) as a white solid.

PARG assay (biological activity)

PARG assay

The PARG in vitro assay was performed in a standard 384-well plate format with a total volume of 15 μl. 5 μl of human full-length PARG (manufactured in-house by the manufacturer, AstraZeneca Pharmaceuticals) was added to 5 μl of Ribosylated PARP substrate (also manufactured in-house by the manufacturer, AstraZeneca Pharmaceuticals) at a final reaction concentration of 4.5 nM in assay buffer (50 mM Tris pH 7.4, 0.1 mg/ml BSA, 3 mM EDTA, 0.4 mM EGTA, 1 mM DTT, 0.01% Tween 20, 50 mM KCl) at a final reaction concentration of 80 pM. The reaction was incubated at room temperature for 10 minutes, and then 5 μl of detection reagent was added. The detection reagent consisted of 42 nM MAb anti-6HIS XL665 (CisBio: 61HISXLB) and 2.25 nM Streptavidin Cryptate Europium (CisBio: 610SAKLB) in 50 mM Tris pH 7.4, 0.1 mg/ml BSA, and 100 mM KF assay buffer, both at 3X working stock concentrations (final concentrations of 14 nM and 0.75 nM, respectively). After incubation for 60 minutes at room temperature in the dark, TR-FRET signals were measured at Ex 340, Em 665, and Em 620. The ratio for each well was calculated as Em 665/EM 620 × 10 4 and used to calculate the percentage of inhibition by the test compound.

PARG cell assay

The method is based on indirect immunofluorescence detection of endogenous levels of poly(ADP)-ribose chains present in the nucleus of HeLa cell lines. MMS stimulation increases PAR chain length for up to 25 minutes. Thereafter, PARG activates and disaggregates PAR chains, until no PAR chains are detected 1 hour after stimulation.

Inhibition of PARG maintains PAR chains.

In brief, after carrying out compound treatment and treatment with DNA damaging agent methyl methanesulfonate (MMS), fixed cell monolayer, then permeabilization and incubation with mouse monoclonal antibody to poly (ADP) ribose polymer. After overnight incubation, excess antibody is removed by washing, and the secondary antibody of Alexafluor 488 connection of recognition mouse monoclonal antibody is added together with nuclear stain (Hoechst 33342). The image of cell is then captured and analyzed on high content screening platform, and the total intensity of nuclear fluorescence signal at 488nM is quantified. Fluorescence increase shows that there are more PAR chains, and therefore there is the intensity of PARG inhibition.

HeLa cells seeded at 4,000 cells/well in a 384-well plate were incubated overnight at 37° C. under 5% CO 2 in 30 μL RPMI 1640 medium supplemented with 10% FBS and 2 mM Glutamax.

The following day, cells were dosed in quadruplicate with compound (10-point dose response) and incubated for 1 hour at 37°C, 5% CO2.

At the end of the 1 hour dosing period, MMS was added in duplicate at a final concentration of 50 μg/mL for an additional hour.

The medium was poured off and the cells were fixed with 50 μL of ice-cold 95% MetOH/PBS at -20°C for 15 minutes. After PBS washing, 50 μL of PBS/0.1% Triton was added to the cells for 20 minutes. After another PBS wash, anti-PAR antibody (Calbiochem AM80) was diluted 1:4000 in buffer (PBS + 0.5% FBS + 0.05% Tween 20) and added to the cells and incubated overnight at 4°C.

The next day, cells were washed three times with PBS and then incubated with secondary antibody (Alexa488 goat anti-mouse IgG (H+L)) diluted 1:1000 and Hoechst diluted 1:5000 in buffer (5% FBS in PBS + 0.05% Tween 20) for 1 hour.

The cells were washed three times with PBS and the plates were sealed with a light-tight seal.

Images of cells were captured on a Thermo Fisher Scientific CellInsight and the average total intensity of fluorescent spots in the nucleus at 485 nm was reported.

Table 1 - Synthesis methods and PARG activities (biochemical and cellular activities)

Table 2 - LCMS data

Table 3- ¹ H NMR data

ARH3 and PARP1 assays (selectivity data)

ARH3 assay

The ARH3 in vitro selectivity assay was performed in a standard 384-well plate format with a total volume of 15 μl. Five μl of full-length human ARH3 (Enzo Life Sciences: ALX-201-292) was added to 5 μl of Ribosylated PARP substrate (also manufactured in-house by the manufacturer, AstraZeneca Pharmaceuticals) at a final reaction concentration of 4.5 nM in assay buffer (50 mM Tris pH 7.4, 0.1 mg/ml BSA, 3 mM EDTA, 0.4 mM EGTA, 1 mM DTT, 0.01% Tween 20, 50 mM KCl). The reaction was incubated at room temperature for 30 minutes, followed by the addition of 5 μl of detection reagent. The detection reagent consisted of 42 nM MAb anti-6HISXL665 (CisBio: 61HISXLB) and 2.25 nM Streptavidin Cryptate Europium (CisBio: 610SAKLB) in 50 mM Tris pH 7.4, 0.1 mg/ml BSA, and 100 mM KF assay buffer, both at 3X working stock concentrations (final concentrations of 14 nM and 0.75 nM, respectively). After incubation for 60 minutes at room temperature in the dark, TR-FRET signals were measured at Ex 340, Em 665, and Em 620. The ratio for each well was calculated as Em 665/EM 620 × 10 4 and used to calculate the percentage of inhibition by the test compound.

PARP1 assay

The PARP1 in vitro selectivity assay was performed in a 10 μl reaction volume in a NUNC Maxisorp 384-well assay plate pre-coated with histones. A final reaction concentration of 0.02 units/ml in 1X PARP buffer and 5 μl of 1X PARP mix (a mixture of 10X PARP mix (Trevigen: 4671-096-03), 10X active DNA (Trevigen: 4671-096-06), and 20X PARP buffer (described above) were used. The reaction was incubated at room temperature for 60 minutes to allow the histones on the coated plate to become PARylated. The wells were then washed with PBS/0.1% Triton X100. PARP1 activity was then measured by measuring the extent of PARylation. First, 10 μl of a 1:250 dilution of streptavidin-HRP (Trevigen: 4800-30-06) in 1X PARG assay buffer (Trevigen: 4680-096-02) was added to each well and incubated at room temperature for 60 minutes. Next, after another wash with PBS/0.1% Triton X100, equal amounts of peroxidase fluorescent reagents A and B (Trevigen: 4675-096-01 and 4675-096-02) were mixed before use and 100 μl was added to each well. The luminescent signal was then measured immediately.

Table 4 - ARH3 and PARP1 activity data (selectivity data)

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Claims (15)

1. A compound having the following structural formula (II) or a pharmaceutically acceptable salt thereof: in: R _1a is selected from fluorine, chlorine, cyano, formyl, (1-2C)alkyl, (1-2C)haloalkyl, (2C)alkenyl or (2C) ynyl; _R1b , _R1c , _R1d and _R1e are each independently selected from H, fluorine or methyl; _X1 is _CR2 ; where _R2 is H or fluorine; _X2 is _CR3 ; where _R3 is H or fluorine; _X3 is _CR4 ; where _R4 is H, halogen, cyano, or (1-2C) haloalkyl; HET is a fused 5-membered saturated, partially saturated, or unsaturated heterocycle with the following formula: in Key 'a' can be either a double bond or a double bond. R ₅ is H, (1-4C) alkyl, or a group having the following chemical formula: -L ₁ -L ₅ -Q ₅ in _L1 is absent or selected from (1-3C) alkylene groups optionally substituted with (1-2C) alkyl or oxo groups, or (2-3C) alkenyl or (2-3C) alkyne groups optionally substituted with (1-2C) alkyl groups; _L5 is absent or selected from C(O), C(O)O, OC(O), C( _O )N(Ra), N( _Ra )C(O), N( _Ra )C(O)N( _Rb ), S(O) _2N ( _Ra ), N( _Ra ) _SO2 , wherein _Ra and _Rb are each independently selected from hydrogen or (1-2C)alkyl; and Q ₅ is selected from hydrogen, (1-4C)alkyl, phenyl, 5-6-membered heteroaryl, (4-6C)cycloalkyl, (4-6C)cycloalkenyl, (2C)alkenyl or 5-6-membered heterocyclic group; Furthermore, _Q5 is optionally substituted with one or more substituents selected from (1-4C) alkyl, halogen, amino, cyano, carboxyl, carbamoyl, aminosulfonyl, trifluoromethoxy, haloalkyl, NRc _Rd , _ORc , _C (O) _Rc , C(O) _ORc , OC(O) _Rc , C(O)N( _Rc ) _Rd , N( _Rc )C(O) _Rd , _S ( _O ) _yRc , _SO2N (Rc) _Rd , N( _Rc ) _SO2Rd or _{( CH2 ) zNRcRd} , wherein _Rc and _{Rd are} each independently selected from H or (1-4C) alkyl; Alternatively, _Q5 may be substituted with a group having the following chemical formula; -W ₅ -Y ₅ -Z ₅ in W ₅ is absent or selected from (1-3C) alkylene groups optionally substituted with (1-2C) alkyl or oxo groups, or (2-3C) alkenyl or (2-3C) alkyne groups optionally substituted with (1-2C) alkyl groups; _Y5 is absent or selected from C(O), C(O)O, OC(O), C(O)N( _Re ), N( _Re )C(O), N( _Re )C(O)N( _Rf ), S(O) _2N ( _Re ), N( _Re ) _SO2 , wherein _Re and _Rf are each independently selected from hydrogen or (1-2C)alkyl; and Z ₅ is selected from hydrogen, (1-4C)alkyl; and wherein Z ₅ is optionally substituted by one or more substituents selected from (1-4C)alkyl, halogen, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxyl, carboxyl, carbamoyl or aminosulfonyl; When bond a is a single bond, _X4 is selected from C (=O) or CHR _6c ; or when bond a is a double bond, _X4 is selected from CR _6c or N. in R _6c is selected from hydrogen or a group having the following chemical formula: -L ₆ -L _6C -Q _6C in _L6 is absent or is an (1-3C) alkylene group optionally substituted with (1-2C) alkyl or oxo group; _L6C is absent or selected from O, S, SO, _SO2 , N( _Rg ), C(O), C(O)O, OC(O), C(O)N( _Rg ), N( _Rg )C(O), N( _Rg )C(O)N( _Rh ), S(O) _2N ( _Rg ) or N( _Rg ) _SO2 , wherein _Rg and _Rh are each independently selected from hydrogen or (1-2C)alkyl; and Q _6C is hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, phenyl, 4-6-membered heterocyclic or 5-6-membered heteroaryl, each optionally substituted by one or more substituents selected from: (1-4C)alkyl, halogen, trifluoromethyl; When bond a is a single bond, X ₅ is selected from C (=O), C (=NH), C (=S), CHR _7c or NR _7N , or when bond a is a double bond, X ₅ is selected from CR _7c or N; in R _7c is selected from hydrogen, cyano, halogen, or groups having the following chemical formulas: -L ₇ -L _7C -Q _7C in _L7 is absent or is an (1-3C) alkylene group optionally substituted with (1-2C) alkyl or oxo group; L _7C is absent or selected from O, S, SO, SO ₂ , N( _Ro ), C(O), C(O)O, OC(O), C(O)N( _Ro ), _N (Ro)C(O), N( _Ro )C(O)N( _Rp ), S(O) _2N ( _Ro ) or N( _Ro )SO ₂ , wherein _Ro and _Rp are each independently selected from hydrogen or (1-2C)alkyl; and Q _7C is hydrogen, cyano, (1-6C)alkyl, (2C)ynyl, (2-3C)alkenyl, (3-6C)cycloalkyl, phenyl, 4-6-membered heterocyclic or 5-6-membered heteroaryl; and wherein Q _7C is optionally substituted by one or more substituents selected from (1-4C)alkyl, halogen, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxyl, amino, carboxyl, carbamoyl, aminosulfonyl, NR _q R _r , OR _q , C(O)R _q , C(O)OR _q , OC(O)R _q , C(O)N(R _q )R _r , N(R _q )C(O)R _r , S(O) _y R _q , SO ₂ N(R _q )R _r , N(R _q )SO ₂ R _r or (CH ₂ ) _z NR _q R _r , wherein R _q and R _r are each independently selected from H or (1-4C) alkyl groups; or Q _7C may be optionally substituted with groups having the following chemical formulas: -W _7C -L _7' -Z _7C in W _7C is absent or is a (1-3C) alkylene group substituted with (1-2C) alkyl or oxo group; L _7' is absent or selected from C(O), C(O)O, OC(O), C(O)N( _Rs ), N( _Rs )C(O), N( _Rs )C(O)N( _Rt ), S(O) _2N ( _Rs ), N( _Rs ) _SO2 , wherein _Rs and _Rt are each independently selected from hydrogen or (1-2C)alkyl; and Z _7C is a phenyl or a 5-6 heteroaryl group; wherein each is optionally substituted by one or more substituents selected from (1-4C)alkyl, halogen, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxy, carboxyl, carbamoyl or aminosulfonyl. R _7N is selected from hydrogen or groups having the following chemical formulas: -L ₇₁ -L _7N -Q _7N in L ₇₁ is absent or is optionally a (1-3C) alkylene group substituted with a (1-2C) alkyl group; L _7N is absent or selected from O, S, SO, SO ₂ , N( _Ru ), C(O), C(O)O, OC(O), C(O)N( _Ru ), N( _Ru )C(O), N( _Ru )C(O)N( _Rv ), S(O) _2N ( _Ru ) or N( _Ru )SO ₂ , wherein _Ru and _Rv are each independently selected from hydrogen or (1-2C)alkyl; and Q _7N is hydrogen, cyano, (1-6C)alkyl, (2C)ynyl, (2-3C)alkenyl, (3-6C)cycloalkyl, phenyl, 4-6-membered heterocyclic, or 5-6-membered heteroaryl, each optionally substituted by one or more substituents selected from: (1-4C)alkyl, halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, amino, carboxyl, carbamoyl, aminosulfonyl, NR _w R _x , OR _w , C(O)R _w , C(O)OR _{w, OC(O)R w} , C(O)N(R _w )R _x , N(R _{w )} C(O)R _x , S(O) _y R _w , SO ₂ N(R _w )R _x , N(R _w )SO ₂ R _x or (CH ₂ ) _z NR _w R _x , wherein R _w and R _x are each independently selected from H or (1-4C)alkyl; or _Q7N may be optionally substituted with groups having the following chemical formulas: -W _7N -L _71' -Z _7N in W _7N is absent or is an (1-3C) alkylene group optionally substituted with (1-3C) alkyl groups; L _71' is absent or selected from C(O), C(O)O, OC(O), C(O)N( _Ry ), N( _Ry )C(O), N( _Ry )C(O)N( _Rz ), S(O) _2N ( _Ry ), N( _Ry ) _SO2 , wherein _Ry and _Rz are each independently selected from hydrogen or (1-2C)alkyl; and Z _7N is a phenyl or a 5-6 heteroaryl group; wherein each is optionally substituted by one or more substituents selected from (1-4C) alkyl, halogen, (1-4C) haloalkyl, (1-4C) haloalkoxy, (1-4C) alkoxy, (1-4C) alkylamino, amino, cyano, hydroxy, carboxyl, carbamoyl or aminosulfonyl. Where each y is 0, 1 or 2; Each z is 1, 2, or 3; Each heteroaryl group and each heterocyclic group has 1-4 heteroatom ring vertices selected from N, O and S; The premise is: (i) Only one or two of the substituents in R _1b-e are selected from any substituent other than H; (ii) Het contains up to two cyclic nitrogen atoms; and (iii) Only one of _X4 or _X5 is selected from C (=O), C (=NH) or C (=S). 2. The compound according to claim 1, wherein R _1a is selected from fluorine, cyano, formyl, (1-2C)alkyl, (1-2C)haloalkyl, or (2C)ynyl. 3. The compound according to claim 2, wherein R _1a is selected from cyano or (1-2C)alkyl. 4. The compound according to claim 1, wherein _X1 is CH. 5. The compound according to claim 1, wherein _X3 is CH, CF, or _CF3 . 6. The compound according to any one of claims 1-4, wherein _R1b , _R1c , _R1d and _R1e are H. 7. The compound according to any one of claims 1-4, wherein _R5 is H, (1-4C) alkyl, or a group having the following chemical formula: -L ₁ -L ₅ -Q ₅ in _L1 is absent or selected from (1-3C) alkylene groups optionally substituted with (1-2C) alkyl or oxo groups; _L5 is absent or selected from C(O), C(O)O, OC(O), C(O)N( _Ra ), N( _Ra )C(O), wherein _Ra is selected from hydrogen or (1-2C)alkyl; and Q ₅ is selected from hydrogen, (1-4C)alkyl, phenyl, 5-6-membered heteroaryl, (4-6C)cycloalkyl, (4-6C)cycloalkenyl, (2C)alkenyl or 5-6-membered heterocyclic group; Furthermore, _Q5 is optionally substituted by one or more substituents selected from (1-4C) alkyl, halogen, amino, cyano, carboxyl, carbamoyl, aminosulfonyl, trifluoromethoxy, _haloalkyl , _NRcRd , _ORc , C(O) _Rc , C(O) _ORc , OC(O) _Rc , C(O)N( _Rc ) _Rd , N( _Rc )C(O) _Rd , wherein _Rc and _Rd are each independently selected from H or (1-4C) alkyl; Alternatively, _Q5 may be substituted with a group having the following chemical formula; -W ₅ -Y ₅ -Z ₅ in W ₅ is absent or selected from (1-3C) alkylene groups optionally substituted with (1-2C) alkyl or oxo groups, or (2-3C) alkenyl or (2-3C) alkyne groups optionally substituted with (1-2C) alkyl groups; _Y5 is absent or selected from C(O), C(O)O, OC(O), C(O)N( _Re ), N( _Re )C(O), N( _Re )C(O)N( _Rf ), S(O) _2N ( _Re ), N( _Re ) _SO2 , wherein _Re and _Rf are each independently selected from hydrogen or (1-2C)alkyl; and Z ₅ is selected from hydrogen, (1-4C)alkyl; and wherein Z ₅ is optionally substituted by one or more substituents selected from (1-2C)alkyl, halogen, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)alkoxy, (1-2C)alkylamino, amino, cyano, hydroxyl, carboxyl, carbamoyl or aminosulfonyl. 8. The compound according to any one of claims 1-4, wherein _R5 is H, (1-4C) alkyl, or a group having the following chemical formula: -L ₁ -L ₅ -Q ₅ in _L1 is absent or is an (1-3C) alkylene group optionally substituted with (1-2C) alkyl or oxo group; _L5 is absent or selected from C(O), C(O)O, OC(O), C(O)N( _Ra ), N( _Ra )C(O), wherein _Ra is selected from hydrogen or (1-2C)alkyl; and Q ₅ is selected from hydrogen, (1-4C)alkyl, phenyl, 5-6-membered heteroaryl, (4-6C)cycloalkyl, (4-6C)cycloalkenyl, (2C)alkenyl or 5-6-membered heterocyclic group; Furthermore, _Q5 is optionally substituted by one or more substituents selected from (1-4C) alkyl, halogen, amino, _cyano , _haloalkyl , NRcRd, _ORc , C(O) _Rc , wherein _Rc and _Rd are each independently selected from H or (1-2C) alkyl. Alternatively, _Q5 may be substituted with a group having the following chemical formula; -W ₅ -Y ₅ -Z ₅ in W ₅ is absent or is a (1-3C) alkylene group; _Y5 is absent or selected from C(O), C(O)O, OC(O), C(O)N(R _e ), wherein _Re and R _f are each independently selected from hydrogen or (1-2C)alkyl; and _Z5 is selected from hydrogen, (1-4C) alkyl; and wherein _Z5 is optionally substituted by one or more substituents selected from (1-2C) alkyl or halogen. 9. The compound according to any one of claims 1-4, wherein when bond a is a single bond, _X4 is selected from C (=O), CHR _6c , or when bond a is a double bond, X4 is selected from CR _6c or N; in R _6c is selected from hydrogen or a group having the following chemical formula: -L ₆ -L _6C -Q _6C in _L6 is absent or is an (1-3C) alkylene group optionally substituted with (1-2C) alkyl or oxo group; _L6C is absent or selected from O, S, SO, _SO2 , N( _Rg ), C(O), C(O)O, OC(O), C(O)N( _Rg ), N( _Rg )C(O), N( _Rg )C(O)N( _Rh ), S(O) _2N ( _Rg ) or N( _Rg ) _SO2 , wherein _Rg is selected from hydrogen or (1-2C)alkyl; and Q _6C is hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, phenyl, 4-6-membered heterocyclic or 5-6-membered heteroaryl, each optionally substituted by one or more substituents selected from (1-2C)alkyl, halogen or trifluoromethyl. 10. The compound according to any one of claims 1-4, wherein when bond a is a single bond, _X5 is selected from C(=O), C(=NH), C(=S), CHR _7c or NR _7N , or when bond a is a double bond, _X4 is selected from CR _7c or N; in R _7c is selected from hydrogen, cyano, halogen, or groups having the following chemical formulas: -L ₇ -L _7C -Q _7C in _L7 is absent or is an (1-3C) alkylene group optionally substituted with (1-2C) alkyl or oxo group; L _7C is absent or selected from O, S, SO, SO ₂ , N( _Ro ), C(O), C(O)O, OC(O), C(O)N( _Ro ) or N( _Ro )C(O), wherein _Ro is selected from hydrogen or (1-2C)alkyl; and Q _7C is hydrogen, cyano, (1-4C)alkyl, (2C)alkynyl, (2-3C)alkenyl, (3-6C)cycloalkyl, phenyl, 4-6-membered heterocyclic or 5-6-membered heteroaryl; and wherein Q _7C is optionally substituted by one or more substituents selected from (1-2C)alkyl, halogen, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, carboxyl, carbamoyl or aminosulfonyl; R _7N is selected from hydrogen or groups having the following chemical formulas: -L ₇₁ -Q _7N in L ₇₁ is absent or is optionally a (1-3C) alkylene group substituted with a (1-2C) alkyl group; Q _7N is hydrogen, cyano, (1-6C)alkyl, (2C)alkynyl, (2-3C)alkenyl, (3-6C)cycloalkyl, phenyl, 4-6-membered heterocyclic or 5-6-membered heteroaryl, each optionally substituted by one or more substituents selected from: (1-4C)alkyl, halogen, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxyl, carboxyl, carbamoyl, aminosulfonyl, NR _w R _x , OR _w , C(O)R _w , C(O)OR _w , OC(O)R _w , C(O)N(R _w )R _x , N(R _w )C(O)R _x , wherein R _w and R _x are each independently selected from H or (1-4C)alkyl. 11. The compound according to any one of claims 1-4, wherein when bond a is a single bond, _X5 is selected from C (=O), CHR _7c or NR _7N , or when bond a is a double bond, _X4 is selected from CR _7c or N; in R _7c is selected from hydrogen or a group having the following chemical formula: -L ₇ -L _7C -Q _7C in _L7 is absent or is an (1-3C) alkylene group optionally substituted with (1-2C) alkyl or oxo group; L _7C is absent or selected from O, S, N( _Ro ), C(O), C(O)O, C(O)N( _Ro ), N( _Ro )C(O), wherein _Ro is selected from hydrogen or (1-2C)alkyl; and Q _7C is hydrogen, cyano, (1-2C)alkyl, (2C)ynyl, (2-3C)alkenyl, (3-6C)cycloalkyl, phenyl, 4-6-membered heterocyclic or 5-6-membered heteroaryl; and wherein Q _7C is optionally substituted by one or more substituents selected from (1-2C)alkyl, halogen, trifluoromethyl, amino or cyano; R _7N is selected from hydrogen or groups having the following chemical formulas: -L ₇₁ -Q _7N in L ₇₁ is absent or is optionally a (1-3C) alkylene group substituted with a (1-2C) alkyl group; Q _7N is hydrogen, cyano, (1-6C)alkyl, (2C)ynyl, (2-3C)alkenyl, (3-6C)cycloalkyl, phenyl, 4-6-membered heterocyclic or 5-6-membered heteroaryl, each optionally substituted by one or more substituents selected from: (1-2C)alkyl, halogen, trifluoromethyl, amino, cyano, carbamoyl, NR _w R _x , OR _w , C(O)N(R _w )R _x , N(R _w )C(O)R _x , wherein R _w and R _x are each independently selected from H or (1-2C)alkyl. 12. A compound selected from one of the following: 1-[(2,6-dichlorophenyl)methyl]-3-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide; 1-(cyclopropylmethyl)-3-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide; 1-Benzyl-3-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide; 1-(cyclopropylmethyl)-N-(1-methylcyclopropyl)-2-oxo-3-phenyl-benzimidazole-5-sulfonamide; 3-Methyl-N-(1-methylcyclopropyl)-2-oxo-1-(3-pyridylmethyl)benzimidazole-5-sulfonamide; 1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide; 1-Isobutyl-3-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide; 3-Methyl-N-(1-methylcyclopropyl)-1-[(2-methylcyclopropyl)methyl]-2-oxo-benzimidazole-5-sulfonamide; 3-Methyl-N-(1-methylcyclopropyl)-1-[(1-methylcyclopropyl)methyl]-2-oxo-benzimidazole-5-sulfonamide; 3-Methyl-N-(1-methylcyclopropyl)-1-[(3-methyloxetane-3-yl)methyl]-2-oxo-benzimidazole-5-sulfonamide; 1-(cyclobutylmethyl)-3-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide; 1-(cyclohexylmethyl)-3-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide; 3-Methyl-N-(1-methylcyclopropyl)-2-oxo-1-(4-pyridylmethyl)benzimidazole-5-sulfonamide; N-(1-Methylcyclopropyl)-1-[2-(2-oxooxazolidine-3-yl)acetyl]dihydroindole-6-sulfonamide; 1-(2,2-Dimethylpropyl)-3-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide; 1-(cyclopentylmethyl)-3-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide; 3-Methyl-N-(1-methylcyclopropyl)-2-oxo-1-prop-2-ynyl-benzimidazole-5-sulfonamide; 1-Allyl-3-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide; 1-(2-Cyclopropylethyl)-3-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide; 3-Methyl-N-(1-methylcyclopropyl)-1-[(5-methyl-2-furanyl)methyl]-2-oxo-benzimidazole-5-sulfonamide; N-(1-methylcyclopropyl)-1-[2-(2-oxoimidazolidine-1-yl)acetyl]dihydroindole-6-sulfonamide; 2-[3-methyl-5-[(1-methylcyclopropyl)aminosulfonyl]-2-oxo-benzimidazol-1-yl]ethyl acetate; 3-Methyl-N-(1-methylcyclopropyl)-1-[(1-methylpyrazol-3-yl)methyl]-2-oxo-benzimidazole-5-sulfonamide; 3-Acetyl-1-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide; N-(1-Methylcyclopropyl)-1-[2-(3-Methyl-2-oxoimidazolidine-1-yl)acetyl]dihydroindole-6-sulfonamide; 1-Methyl-N-(1-methylcyclopropyl)-2-oxo-3-(3-thienyl)benzimidazole-5-sulfonamide; 3-Benzoyl-1-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide; 3-(cyclohexanecarbonyl)-1-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide; 1-Methyl-3-(4-methylbenzoyl)-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide; 1-Methyl-3-(3-methylbenzoyl)-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide; 1-Methyl-3-(2-methylbenzoyl)-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide; N-Ethyl-3-methyl-6-[(1-methylcyclopropyl)aminosulfonyl]-2-oxo-benzimidazole-1-carboxamide; 3-Methyl-N-(1-methylcyclopropyl)-1-(m-tolylmethyl)-2-oxo-benzimidazole-5-sulfonamide; 3-Methyl-N-(1-methylcyclopropyl)-2-oxo-1-(p-tolylmethyl)benzimidazole-5-sulfonamide; 1-[(2-methoxyphenyl)methyl]-3-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide; 1-[(3-methoxyphenyl)methyl]-3-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide; 1-[(4-methoxyphenyl)methyl]-3-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide; 1-[(3-chlorophenyl)methyl]-3-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide; 1-[(4-chlorophenyl)methyl]-3-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide; 1-[(2-fluorophenyl)methyl]-3-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide; 1-[(3-fluorophenyl)methyl]-3-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide; 1-[(4-fluorophenyl)methyl]-3-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide; 1-[(2-cyanophenyl)methyl]-3-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide; 1-[(3-cyanophenyl)methyl]-3-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide; 1-[(4-cyanophenyl)methyl]-3-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide; 3-Methyl-N-(1-methylcyclopropyl)-2-oxo-1-[[2-(trifluoromethyl)phenyl]methyl]benzimidazole-5-sulfonamide; 1-[(2,6-difluorophenyl)methyl]-3-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide; 1-[(3,5-dichlorophenyl)methyl]-3-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide; 1-[(3,5-dimethylphenyl)methyl]-3-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide; 1-[(3,5-dimethoxyphenyl)methyl]-3-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide; 1-[(3,5-difluorophenyl)methyl]-3-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide; 3-(2-furanyl)-1-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide; 1-Methyl-N-(1-methylcyclopropyl)-2-oxo-3-thiazo-2-yl-benzimidazole-5-sulfonamide; 3-(5-formyl-2-thienyl)-1-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide; N,3-Dimethyl-6-[(1-methylcyclopropyl)aminosulfonyl]-2-oxo-benzimidazole-1-carboxamide; 6-Fluoro-1,3-Dimethyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide; 3-Methyl-N-(1-methylcyclopropyl)-2-oxo-1-phenyl-benzimidazole-5-sulfonamide; 1-[(4-cyano-3-fluoro-phenyl)methyl]-3-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide; 4-[[3-methyl-5-[(1-methylcyclopropyl)aminosulfonyl]-2-oxo-benzimidazol-1-yl]methyl]benzamide; N-Methyl-5-[[3-Methyl-5-[(1-methylcyclopropyl)aminosulfonyl]-2-oxo-benzimidazol-1-yl]methyl]-1,2,4-oxadiazole-3-carboxamide; 3-[[3-methyl-5-[(1-methylcyclopropyl)aminosulfonyl]-2-oxo-benzimidazol-1-yl]methyl]benzamide; 3-Methyl-N-(1-methylcyclopropyl)-1-[(5-nitro-2-furanyl)methyl]-2-oxo-benzimidazole-5-sulfonamide; N-[4-[[3-methyl-5-[(1-methylcyclopropyl)aminosulfonyl]-2-oxo-benzimidazol-1-yl]methyl]phenyl]acetamide; 3-Methyl-N-(1-methylcyclopropyl)-1-[(2-methylpyrazol-3-yl)methyl]-2-oxo-benzimidazole-5-sulfonamide; 3-Methyl-N-(1-methylcyclopropyl)-1-[(2-methylthiazolyl-5-yl)methyl]-2-oxo-benzimidazole-5-sulfonamide; 3-Methyl-6-[(1-methylcyclopropyl)aminosulfonyl]-2-oxo-benzimidazole-1-carboxylic acid ethyl ester; (E)-3-[5-[3-methyl-6-[(1-methylcyclopropyl)aminosulfonyl]-2-oxo-benzimidazol-1-yl]-2-furanyl]prop-2-enoic acid; 1-Methyl-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide; (E)-3-[2-[3-methyl-6-[(1-methylcyclopropyl)aminosulfonyl]-2-oxo-benzimidazol-1-yl]thiazolyl-5-yl]prop-2-enoic acid; 3-[2-[3-methyl-6-[(1-methylcyclopropyl)aminosulfonyl]-2-oxo-benzimidazol-1-yl]thiazolyl-5-yl]propionic acid; N,N-Dimethyl-3-[2-[3-methyl-6-[(1-methylcyclopropyl)aminosulfonyl]-2-oxo-benzimidazol-1-yl]thiazolyl-5-yl]propionamide; 1-[(4-fluorophenyl)methyl]-N-(1-methylcyclopropyl)-2-oxo-3H-benzimidazole-5-sulfonamide; 1-[(4-fluorophenyl)methyl]-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide; N-Methyl-3-[2-[3-methyl-6-[(1-methylcyclopropyl)aminosulfonyl]-2-oxo-benzimidazol-1-yl]thiazolyl-5-yl]propionamide; 3-[(4-fluorophenyl)methyl]-6-[(1-methylcyclopropyl)aminosulfonyl]-2-oxo-benzimidazole-1-carboxylic acid ethyl ester; 1-[(4-fluorophenyl)methyl]-N-(1-methylcyclopropyl)-2-oxo-3-thiazolyl-2-ylbenzimidazole-5-sulfonamide; 1-Methyl-N-(1-methylcyclopropyl)-2-oxo-3-(1,3,4-thiadiazol-2-yl)benzimidazole-5-sulfonamide; 1-Methyl-N-(1-methylcyclopropyl)-2-oxo-3-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]benzimidazole-5-sulfonamide; 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1-methyl-N-(1-methylcyclopropyl)-2-oxobenzimidazole-5-sulfonamide; N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-1H-benzimidazole-5-sulfonamide; 3-(5-amino-1,3,4-thiadiazol-2-yl)-1-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide; 1-(cyclopropylmethyl)-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide; N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-1-[(2-methylthiazol-5-yl)methyl]-2-oxo-benzimidazole-5-sulfonamide; 1-[(2,5-dimethylpyrazol-3-yl)methyl]-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide; 1-[2-(dimethylamino)ethyl]-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide; 1-[(4-methoxyphenyl)methyl]-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide; 1-[(2,4-dimethylthiazolyl-5-yl)methyl]-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide; 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1-[(2,4-dimethylthiazol-5-yl)methyl]-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide; 1-[(2,4-dimethylthiazolyl-5-yl)methyl]-N-(1-methylcyclopropyl)-2-oxo-3H-benzimidazole-5-sulfonamide; 1-[(2,4-dimethylthiazolyl-5-yl)methyl]-N-(1-methylcyclopropyl)-2-oxo-3-(1,2,4-thiadiazol-5-yl)benzimidazole-5-sulfonamide; 1-[(2,4-dimethylthiazolyl-5-yl)methyl]-3-(1H-imidazol-5-yl)-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide; 1-[(2,4-dimethylthiazolyl-5-yl)methyl]-N-(1-methylcyclopropyl)-2-oxo-3-(1H-pyrazol-4-yl)benzimidazole-5-sulfonamide; 1-[(2,4-dimethylthiazolyl-5-yl)methyl]-3-isothiazolyl-4-yl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide; N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxo-1H-benzimidazole-5-sulfonamide; 1-[(2,4-dimethylthiazolyl-5-yl)methyl]-N-(1-methylcyclopropyl)-2-oxo-3-thiazolyl-4-ylbenzimidazole-5-sulfonamide; 1-[(2,4-dimethylthiazolyl-5-yl)methyl]-N-(1-methylcyclopropyl)-3-(1-methylpyrazol-3-yl)-2-oxo-benzimidazole-5-sulfonamide; 1-[(2,4-dimethylthiazolyl-5-yl)methyl]-N-(1-methylcyclopropyl)-2-oxo-3-thiazolyl-5-ylbenzimidazole-5-sulfonamide; 1-Methyl-N-(1-methylcyclopropyl)-2-oxo-3-(1,2,4-thiadiazol-5-yl)benzimidazole-5-sulfonamide; 1-[(2,4-dimethylthiazolyl-5-yl)methyl]-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide; N-(1-Methylcyclopropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-1-prop-2-ynyl-benzimidazole-5-sulfonamide; N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-1-(oxazol-2-ylmethyl)-2-oxo-benzimidazole-5-sulfonamide; N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-1-(1H-pyrazol-4-ylmethyl)benzimidazole-5-sulfonamide; N-(1-Methylcyclopropyl)-1-[(5-methyl-2-furanyl)methyl]-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide; N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-1-[(5-methyl-2-thienyl)methyl]-2-oxo-benzimidazole-5-sulfonamide; 1-[(2,4-dimethylthiazolyl-5-yl)methyl]-3-(3-methoxy-1,2,4-thiadiazol-5-yl)-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide; 1-[(2,4-dimethylthiazolyl-5-yl)methyl]-N-(1-methylcyclopropyl)-3-(4-methylthiazolyl-2-yl)-2-oxo-benzimidazole-5-sulfonamide; 1-[(2,4-dimethylthiazolyl-5-yl)methyl]-N-(1-methylcyclopropyl)-3-(5-methylthiazolyl-2-yl)-2-oxo-benzimidazole-5-sulfonamide; 3-(3-bromo-1,2,4-thiadiazol-5-yl)-1-[(2,4-dimethylthiazol-5-yl)methyl]-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide; 1-[(2,4-dimethylthiazolyl-5-yl)methyl]-N-(1-methylcyclopropyl)-2-oxo-3-pyridazine-3-yl-benzimidazole-5-sulfonamide; 1-[(2,4-dimethylthiazolyl-5-yl)methyl]-N-(1-methylcyclopropyl)-2-oxo-3-(1,3,4-thiadiazol-2-yl)benzimidazole-5-sulfonamide; 1-[(2,4-dimethylthiazolyl-5-yl)methyl]-N-(1-methylcyclopropyl)-2-oxo-3-thiazolyl-2-ylbenzimidazole-5-sulfonamide; 3-[(2,4-dimethylthiazolyl-5-yl)methyl]-6-[(1-methylcyclopropyl)aminosulfonyl]-2-oxo-benzimidazole-1-carboxylic acid ethyl ester; 3-(cyclopenten-1-yl)-1-[(2,4-dimethylthiazolyl-5-yl)methyl]-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide; 7-Fluoro-1-methyl-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide; N-(1-methylcyclopropyl)-1-(5-methyl-1,3,4-thiadiazol-2-yl)indole-6-sulfonamide; 6-Fluoro-1-methyl-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide; N-Methyl-5-[[5-[(1-methylcyclopropyl)aminosulfonyl]-3-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxo-benzimidazol-1-yl]methyl]-1,2,4-oxadiazol-3-carboxamide; N-(1-Methylcyclopropyl)-2-[(3-methylisoxazol-5-yl)methyl]-3-(5-methyl-1,3,4-thiadiazol-2-yl)benzimidazole-5-sulfonamide; N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)benzimidazole-5-sulfonamide; N-(1-Methylcyclopropyl)-2-[(1-methylpyrazol-4-yl)methyl]-3-(5-methyl-1,3,4-thiadiazol-2-yl)benzimidazole-5-sulfonamide; N-(1-Methylcyclopropyl)-2-[2-(1-Methylpyrazol-4-yl)ethyl]-3-(5-methyl-1,3,4-thiadiazol-2-yl)benzimidazole-5-sulfonamide; 2-Methyl-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)benzimidazole-5-sulfonamide; 1-Methyl-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-7-(trifluoromethyl)benzimidazole-5-sulfonamide; N-[[6-[(1-methylcyclopropyl)aminosulfonyl]-1-(5-methyl-1,3,4-thiadiazol-2-yl)benzimidazol-2-yl]methyl]acetamide; 2-(2-aminoethyl)-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)benzimidazole-5-sulfonamide; 3-Benzyl-N-(1-methylcyclopropyl)-1-(5-methyl-1,3,4-thiadiazol-2-yl)indole-6-sulfonamide; 3-[(4-fluorophenyl)methyl]-N-(1-methylcyclopropyl)-1-(5-methyl-1,3,4-thiadiazol-2-yl)indole-6-sulfonamide; 3-(cyclopropylmethyl)-N-(1-methylcyclopropyl)-1-(5-methyl-1,3,4-thiadiazol-2-yl)indole-6-sulfonamide; 3-[(2,4-dimethylthiazolyl-5-yl)methyl]-N-(1-methylcyclopropyl)-1-(5-methyl-1,3,4-thiadiazol-2-yl)indole-6-sulfonamide; 3-(cyclopropanecarbonyl)-N-(1-methylcyclopropyl)-1-(5-methyl-1,3,4-thiadiazol-2-yl)indole-6-sulfonamide; 3-(4-fluorobenzoyl)-N-(1-methylcyclopropyl)-1-(5-methyl-1,3,4-thiadiazol-2-yl)indole-6-sulfonamide; 3-[(2,4-dimethylthiazolyl-5-yl)methyl]-6-[(1-methylcyclopropyl)aminosulfonyl]indole-1-carboxylic acid ethyl ester; 1-[3-(dimethylamino)propyl]-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide; 1-(2-methoxyethyl)-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide; 1-[3-(dimethylamino)propyl]-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide; N-(1-Methylcyclopropyl)-1-[(1-Methyl-3-piperidinyl)methyl]-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide; 1-[2-(dimethylamino)ethyl]-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide; N-(1-Methylcyclopropyl)-3-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[(1-methyl-2-piperidinyl)methyl]-2-oxo-benzimidazole-5-sulfonamide; N-(1-Methylcyclopropyl)-3-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[(1-methyl-3-piperidinyl)methyl]-2-oxo-benzimidazole-5-sulfonamide; N-(1-Methylcyclopropyl)-3-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxo-1-[2-(1-piperidinyl)ethyl]benzimidazole-5-sulfonamide; N-(1-Methylcyclopropyl)-3-(5-methyl-1,3,4-oxadiazol-2-yl)-1-(2-morpholinoethyl)-2-oxo-benzimidazole-5-sulfonamide; N-(1-Methylcyclopropyl)-3-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxo-1-(2-pyrrolidone-1-ylethyl)benzimidazole-5-sulfonamide; N-(1-Methylcyclopropyl)-1-[(1-Methyl-2-piperidinyl)methyl]-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide; 3-Acetyl-N-(1-methylcyclopropyl)-1-(5-methyl-1,3,4-thiadiazol-2-yl)indole-6-sulfonamide; 3-(cyclopropanecarbonyl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-(1-methylcyclopropyl)indole-6-sulfonamide; 3-[(4-fluorophenyl)methyl]-N-(1-methylcyclopropyl)-1-(5-methyl-1,3,4-thiadiazol-2-yl)indazole-6-sulfonamide; 1-(2-Methoxyethyl)-N-(1-Methylcyclopropyl)-3-(5-Methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide; 1-(3-methoxypropyl)-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide; N-(1-Methylcyclopropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-1-[2-(1-piperidinyl)ethyl]benzimidazole-5-sulfonamide; 1-(3-methoxypropyl)-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide; 3-[5-[(1-methylcyclopropyl)aminosulfonyl]-3-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxo-benzimidazol-1-yl]propionamide; N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-1-(2-morpholinoethyl)-2-oxo-benzimidazole-5-sulfonamide; N-(1-Methylcyclopropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-1-(2-pyrrolidone-1-ylethyl)benzimidazole-5-sulfonamide; 3-[5-[(1-methylcyclopropyl)aminosulfonyl]-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazol-1-yl]propionamide; N-(1-Methylcyclopropyl)-1-[(1-Methylpyrrolid-2-yl)methyl]-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide; N-[1-(fluoromethyl)cyclopropyl]-1-methyl-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide; N-(1-cyanocyclopropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-1H-benzimidazole-5-sulfonamide; N-(1-Cyanocyclopropyl)-1-Ethyl-3-(5-Methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide; 1-Ethyl-N-[1-(fluoromethyl)cyclopropyl]-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide; N-[1-(fluoromethyl)cyclopropyl]-1-(2-methoxyethyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide; N-(1-Cyanocyclopropyl)-1-(2-Methoxyethyl)-3-(5-Methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide; N-(1-cyanocyclopropyl)-3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1-(2-methoxyethyl)-2-oxo-benzimidazole-5-sulfonamide; 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-[1-(fluoromethyl)cyclopropyl]-1-(2-methoxyethyl)-2-oxo-benzimidazole-5-sulfonamide; 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1-[(2,5-dimethylpyrazol-3-yl)methyl]-N-[1-(fluoromethyl)cyclopropyl]-2-oxo-benzimidazole-5-sulfonamide; N-(1-cyanocyclopropyl)-3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1-[(2,5-dimethylpyrazol-3-yl)methyl]-2-oxo-benzimidazole-5-sulfonamide; 1-(cyanomethyl)-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide; 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-fluoro-N-[1-(fluoromethyl)cyclopropyl]-1-(2-methoxyethyl)-2-oxo-benzimidazole-5-sulfonamide; 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-fluoro-1-(2-methoxyethyl)-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide; 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1-(2-methoxyethyl)-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide; 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1-[3-(dimethylamino)propyl]-N-[1-(fluoromethyl)cyclopropyl]-2-oxo-benzimidazole-5-sulfonamide; 6-Fluoro-1-methyl-N-(1-methylcyclopropyl)-3-(3-methyl-1,2,4-thiadiazol-5-yl)-2-oxo-benzimidazole-5-sulfonamide; 6-Fluoro-N-[1-(fluoromethyl)cyclopropyl]-1-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-2-oxo-benzimidazole-5-sulfonamide; 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-fluoro-1-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide; 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-fluoro-N-[1-(fluoromethyl)cyclopropyl]-1-methyl-2-oxo-benzimidazole-5-sulfonamide; N-[1-(fluoromethyl)cyclopropyl]-1-methyl-2-oxo-3-(1,2,4-thiadiazol-5-yl)benzimidazole-5-sulfonamide; 1-Methyl-N-(1-methylcyclopropyl)-3-(3-methyl-1,2,4-thiadiazol-5-yl)-2-oxo-benzimidazole-5-sulfonamide; N-[1-(fluoromethyl)cyclopropyl]-1-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-2-oxo-benzimidazole-5-sulfonamide; 1-(cyanomethyl)-N-[1-(fluoromethyl)cyclopropyl]-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide; 1-(cyanomethyl)-N-(1-methylcyclopropyl)-3-(3-methyl-1,2,4-thiadiazol-5-yl)-2-oxo-benzimidazole-5-sulfonamide; 1-(cyanomethyl)-N-[1-(fluoromethyl)cyclopropyl]-3-(3-methyl-1,2,4-thiadiazol-5-yl)-2-oxo-benzimidazole-5-sulfonamide; 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-[1-(fluoromethyl)cyclopropyl]-1-methyl-2-oxo-benzimidazole-5-sulfonamide; 1-(2-Methoxyethyl)-N-(1-Methylcyclopropyl)-3-(3-Methyl-1,2,4-thiadiazol-5-yl)-2-oxo-benzimidazole-5-sulfonamide; N-[1-(fluoromethyl)cyclopropyl]-1-(2-methoxyethyl)-2-oxo-3-(1,2,4-thiadiazol-5-yl)benzimidazole-5-sulfonamide; N-[1-(fluoromethyl)cyclopropyl]-1-(2-methoxyethyl)-3-(3-methyl-1,2,4-thiadiazol-5-yl)-2-oxo-benzimidazole-5-sulfonamide; N-[1-(fluoromethyl)cyclopropyl]-1-(3-methoxypropyl)-3-(3-methyl-1,2,4-thiadiazol-5-yl)-2-oxo-benzimidazole-5-sulfonamide; 1-[2-(dimethylamino)ethyl]-N-[1-(fluoromethyl)cyclopropyl]-3-(3-methyl-1,2,4-thiadiazol-5-yl)-2-oxo-benzimidazole-5-sulfonamide; N-[1-(fluoromethyl)cyclopropyl]-1-(3-methoxypropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide; 1-[2-(dimethylamino)ethyl]-N-[1-(fluoromethyl)cyclopropyl]-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide; 1-Methyl-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide; 1-Ethyl-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide; 1-(2-Fluoroethyl)-N-(1-Methylcyclopropyl)-3-(5-Methyl-1,3,4-oxadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide; 6-Fluoro-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxo-1H-benzimidazole-5-sulfonamide; 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-[1-(fluoromethyl)cyclopropyl]-2-oxo-1-prop-2-ynyl-benzimidazole-5-sulfonamide; 6-Fluoro-N-[1-(fluoromethyl)cyclopropyl]-3-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxo-1H-benzimidazole-5-sulfonamide; 3-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1-methyl-N-(1-methylcyclopropyl)-2-oxobenzimidazole-5-sulfonamide; 3-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-N-[1-(fluoromethyl)cyclopropyl]-1-methyl-2-oxo-benzimidazole-5-sulfonamide; 6-Fluoro-1-methyl-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide; 6-Fluoro-1-(2-Fluoroethyl)-N-(1-Methylcyclopropyl)-3-(5-Methyl-1,3,4-oxadiazol-2-yl)-2-oxo-benzimidazole-5-sulfonamide; 3-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1-ethyl-6-fluoro-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide; 3-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1-ethyl-6-fluoro-N-[1-(fluoromethyl)cyclopropyl]-2-oxo-benzimidazole-5-sulfonamide; 3-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1-ethyl-N-(1-methylcyclopropyl)-2-oxobenzimidazole-5-sulfonamide; 3-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1-ethyl-N-[1-(fluoromethyl)cyclopropyl]-2-oxo-benzimidazole-5-sulfonamide; 6-Fluoro-N-[1-(fluoromethyl)cyclopropyl]-1-(2-methoxyethyl)-3-(6-methylpyridazin-3-yl)-2-oxo-benzimidazole-5-sulfonamide; 6-Fluoro-N-[1-(fluoromethyl)cyclopropyl]-1-methyl-3-(6-methylpyridazin-3-yl)-2-oxo-benzimidazole-5-sulfonamide; 6-Fluoro-1-methyl-N-(1-methylcyclopropyl)-3-(6-methylpyridazin-3-yl)-2-oxo-benzimidazole-5-sulfonamide; 6-Fluoro-N-[1-(fluoromethyl)cyclopropyl]-1-methyl-2-oxo-3-[6-(trifluoromethyl)pyridazin-3-yl]benzimidazole-5-sulfonamide; 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1-ethyl-6-fluoro-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide; 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1-ethyl-6-fluoro-N-[1-(fluoromethyl)cyclopropyl]-2-oxo-benzimidazole-5-sulfonamide; 3-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-6-fluoro-1-methyl-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide; 3-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-6-fluoro-N-[1-(fluoromethyl)cyclopropyl]-1-methyl-2-oxo-benzimidazole-5-sulfonamide; 3-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-6-fluoro-1-(2-fluoroethyl)-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide; 3-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-6-fluoro-1-(2-fluoroethyl)-N-[1-(fluoromethyl)cyclopropyl]-2-oxo-benzimidazole-5-sulfonamide; 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-fluoro-N-[1-(fluoromethyl)cyclopropyl]-2-oxo-1-prop-2-ynyl-benzimidazole-5-sulfonamide; 2-[3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-fluoro-5-[[1-(fluoromethyl)cyclopropyl]aminosulfonyl]-2-oxo-benzimidazol-1-yl]acetamide; 1-(cyanomethyl)-3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-fluoro-N-[1-(fluoromethyl)cyclopropyl]-2-oxo-benzimidazole-5-sulfonamide; 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-fluoro-1-(2-fluoroethyl)-N-[1-(fluoromethyl)cyclopropyl]-2-oxo-benzimidazole-5-sulfonamide; 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-fluoro-1-(2-fluoroethyl)-N-(1-methylcyclopropyl)-2-oxo-benzimidazole-5-sulfonamide; 3-Methyl-5-[(1-methylcyclopropyl)aminosulfonyl]benzofuran-2-carboxylic acid ethyl ester; Or its pharmaceutically acceptable salt. 13. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12 for the preparation of a medicament for treating cancer. 14. A pharmaceutical composition comprising a compound according to claims 1 to 12 or a pharmaceutically acceptable salt thereof, mixed with a pharmaceutically acceptable diluent or carrier. 15. Use of the compounds according to claims 1 to 12 or pharmaceutically acceptable salts thereof for the preparation of a medicament for treating proliferative diseases.