COMPOUNDS. COMPOSITIONS CONTAINING THEM. PREPARATION THEREOF AND USES THEREOF H
BACKGROUND OF THE INVENTION
1. Field of the invention
The invention is related to therapeutic compounds, pharmaceutical compositions containing these compounds, manufacturing processes thereof and uses thereof. Particularly, the present invention is related to compounds that may be effective in treating pain, cancer, multiple sclerosis, Parkinson's disease, Huntington's chorea, Alzheimer's disease, anxiety disorders, gastrointestinal disorders and/or cardiovascular disorders.
2. Discussion of Relevant Technology Pain management has been studied for many years. It is known that cannabinoid receptor (e.g., CB1 receptor, CB2 receptor) ligands including agonists, antagonists and inverse agonists produce relief of pain in a variety of animal models by interacting with CB1 and/or CB2 receptors. Generally, CB1 receptors are located predominately in the central nervous system, whereas CB2 receptors are located primarily in the periphery and are primarily restricted to the cells and tissues derived from the immune system.
While CB1 receptor agonists, such as Δ9-tetrahydrocannabinol (Δ9-THC) and anadamide, are useful in anti-nociception models in animals, they tend to exert undesired CNS side-effects, e.g., psychoactive side effects, the abuse potential, drug dependence and tolerance, etc. These undesired side effects are known to be mediated by the CBi receptors located in CNS. There are lines of evidence, however, suggesting that CB1 agonists acting at peripheral sites or with limited CNS exposure can manage pain in humans or animals with much improved overall in vivo profile. Therefore, there is a need for new CB1 receptor ligands such as agonists that may be useful in managing pain or treating other related symptoms or diseases with reduced or minimal undesirable CNS side-effects.
DESCRIPTION OF THE EMBODIMENTS
The present invention provides CB1 receptor ligands which may be useful in treating pain and/or other related symptoms or diseases.
The term "Cm-n" or "Cm.n group" used alone or as a prefix, refers to any group having m to n carbon atoms.
The term "alkyl" refers to a saturated monovalent straight or branched chain hydrocarbon radical comprising 1 to about 12 carbon atoms. Illustrative examples of alkyls include, but are not limited to, Ci-4alkyl groups, such as methyl, ethyl, propyl, isopropyl, 2-methyl-l -propyl, 2-methyl-2-propyl, butyl, isobutyl, t-butyl. The term "cycloalkyl" refers to a saturated monovalent ring-containing hydrocarbon radical comprising at least 3 up to about 12 carbon atoms. Examples of cycloalkyls include, but are not limited to, C3-7cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, and saturated cyclic and bicyclic terpenes. A cycloalkyl can be unsubstiruted or substituted by one or two suitable substituents. Preferably, the cycloalkyl is a monocyclic ring or bicyclic ring.
The term "alkoxy" refers to radicals of the general formula -O-R, wherein R is an alkyl. Exemplary alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, and isobutoxy.
The term "heterocycle" used alone or as a suffix or prefix, refers to a ring- containing structure or molecule having one or more multivalent heteroatoms, independently selected from N, O, P and S, as apart of the ring structure and including at least 3 and up to about 20 atoms in the ring(s). Heterocycle may be saturated or unsaturated, containing one or more double bonds, and heterocycle may contain more than one ring. When a heterocycle contains more than one ring, the rings may be fused or unfused. Fused rings generally refer to at least two rings sharing two atoms therebetween. Heterocycle may have aromatic character or may not have aromatic character.
Heterocycle includes, for example, monocyclic heterocycles such as: aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazoline, dioxolane, sulfolane 2,3-dihydrofuran, 2,5- dihydrofuran tetrahydrofuran, thiophane, piperidine, 1,2,3,6-tetrahydro-pyridine, piperazine, morpholine, thiomorpholine, pyran, thiopyran, 2,3-dihydropyran, tetrahydropyran, 1,4-dihydropyridine, 1,4-dioxane, 1,3-dioxane, dioxane,
homopiperidine, 2,3,4,7-tetrahydro-li/:-azepme homopiperazine, 1,3-dioxepane, 4,7- dihydro-l,3-dioxepin, and hexamethylene oxide.
In addition, heterocycle includes aromatic heterocycles, for example, pyridine, pyrazine, pyrimidine, pyridazine, thiophene, furan, furazan, pyrrole, imidazole, thiazole, oxazole, pyrazole, isothiazole, isoxazole, 1,2,3-triazole, tetrazole, 1,2,3- thiadiazole, 1,2,3-oxadiazole, 1,2,4-triazole, 1,2,4-thiadiazole, 1,2,4-oxadiazole, 1,3,4- triazole, 1,3,4-thiadiazole, and 1,3,4- oxadiazole.
Additionally, heterocycle encompass polycyclic heterocycles, for example, indole, indoline, isoindoline, quinoline, tetrahydroquinoline, isoquinoline, tetrahydroisoquinoline, 1,4-benzodioxan, coumarin, dihydrocoumarin, benzofuran,
2,3-dihydrobenzofuran, isobenzofuran, chromene, chroman, isochroman, xanthene, phenoxathiin, thianthrene, indolizine, isoindole, indazole, purine, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, phenanthridine, perimidine, phenanthroline, phenazine, phenothiazine, phenoxazine, 1,2- benzisoxazole, benzothiophene, benzoxazole, benzthiazole, benzimidazole, benztriazole, thioxanthine, carbazole, carboline, acridine, pyrolizidine, and quinolizidine.
In addition to the polycyclic heterocycles described above, heterocycle includes polycyclic heterocycles wherein the ring fusion between two or more rings includes more than one bond common to both rings and more than two atoms common to both rings. Examples of such bridged heterocycles include quinuclidine, diazabicyclo[2.2.1]heptane and 7-oxabicyclo[2.2.1]heptane.
Preferably, the heterocycle is a monocyclic or bicyclic ring, more preferably, a monocyclic ring, wherein the ring comprises from 2 to 6 carbon atoms and from 1 to 3 heteroatoms, referred to herein as C2.6heterocycle.
The term "heterocylcoalkyl" used alone or as a suffix or prefix, refers to a monocyclic or polycyclic ring comprising carbon and hydrogen atoms and at least one heteroatom, preferably, 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, and having no unsaruration. Examples of heterocycloalkyl groups include pyrrolidinyl, pyrrolidino, piperidinyl, piperidino, piperazinyl, piperazino, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, and pyranyl. A heterocycloalkyl group can be unsubstituted or substituted with one or two suitable substituents. Preferably, the heterocycloalkyl group is a monocyclic or bicyclic ring,
more preferably, a monocyclic ring, wherein the ring comprises from 2 to 5 carbon atoms and from 1 to 3 heteroatoms, referred to herein as C2-5heterocycloalkyl.
The term "heterocyclyl" refers a monovalent radical derived from a heterocycle by removing one hydrogen therefrom. Halogen includes fluorine, chlorine, bromine and iodine.
"RT" or "rt" means room temperature.
" Acyl" refers to -C(=O)-R, wherein R is an alkyl. C2-5ACyI groups include, for example, acetyl, propionyl, 2,2-dimethylpropionyl, and methyl-propionyl.
"Link," "linked," or "linking," unless otherwise specified, means covalently linked or bonded.
In one aspect, an embodiment of the invention provides a compound of Formula I, a pharmaceutically acceptable salt thereof, diastereomers, enantiomers, or mixtures thereof:
G is selected from -O-, -CHF-, and -CF2-;
R1 is a C2-6heterocyclyl, wherein said C2-6heterocyclyl includes at least one nitrogen on said C2-6heterocyclyl ring, one of said at least one nitrogen is directly linked to the sulfonyl group of formula I, and said C2-6heterocyclyl is optionally substituted with one or more groups selected from halogen, hydroxy, R5-C(=O)-5 R5- C(=O)-NH-, R5R6-NH-C(=O)-, R5R6-NH-C(=O)-NH-, R5-O-C(=O)-, R5-O-C(=O)- NH-, C1-6alkoxy, and C^alkylamino, wherein said R5, R6 are independently selected from -H, C1-6alkyl, C6-i0aryl, C2-6alkenyl, C3-6cycloalkyl, C2.6heterocyclyl, halogenated C1-6alkyl, and hydroxy-C1-6alkyl; and
R2, R3 and R4 are independently selected from fluoro and methyl. In another embodiment, the compounds are those of formula I, wherein
G is selected from -O- and -CF2-;
R1 is a C2-6heterocycloalkyl, wherein said C2-6heterocycloalkyl includes at least one nitrogen on said C2-6heterocycloalkyl ring, one of said at least one nitrogen is directly linked to the sulfonyl group of formula I, and said Ca-βheterocycloalkyl is optionally substituted with one or more groups selected from halogen, hydroxy, R5- C(=O)-, R5-C(=O)-NH-, R5R6-NH-C(=O)-, R5R6-NH-C(=O)-NH-, R5-O-C(=O)-, R5- O-C(=O)-NH-, C1-6alkoxy, and C1-6alkylamino, wherein said R5, R6 are independently selected from -H, C1^aIkVl, C2-6alkenyl, C3,6cycloalkyl, C2-5heterocycloalkyl, halogenated Ci-6alkyl, and hydroxy-C1-6alkyl; and
R2, R3 and R4 are independently selected from fluoro and methyl. Another embodiment of the invention provides a compound of formula I, wherein
G is selected from -O- and -CF2-;
R1 is selected from Cs-sheterocycloalkyl and C2-5heteroaryl, wherein said C3-5heterocycloalkyl or C2-5heteroaryl includes at least one nitrogen on said C3-5heterocycloalkyl or C2-5heteroaryl rings, respectively, one of said at least one nitrogen is directly linked to the sulfonyl group of formula I, and said Cs-sheterocycloalkyl and C2-5heteroaryl are optionally substituted with one or more groups selected from halogen, C1.3alk.oxy, Q.salkylamino and C2-sacylamino; R2, R3 and R4 are independently selected from fluoro and methyl. A further embodiment of the invention provides a compound of formula I, wherein
G is selected from -O- and -CF2-;
R1 is selected from piperidinyl, imidazolyl, pyrazolyl, morpholinyl, pyrrolidinyl, azetidinyl, and isoxazolidinyl, wherein said piperidinyl, imidazolyl, pyrazolyl, morpholinyl, pyrrolidinyl, azetidinyl, and isoxazolidinyl are optionally substituted with one or more groups selected from fluoro and C2-5acylamino; R2, R3 and R4 are selected from fluoro and methyl with a proviso that R2, R3 and R4 are the same.
An even further embodiment of the invention provides a compound of formula I, wherein
G is selected from -O- and -CF2-;
R1 is selected from
and are optionally substituted by one or more groups
selected from fluoro,
; and
R2, R3 and R4 are selected from fluoro and methyl with a proviso that R2, R3 and R4 are the same.
A further embodiment of the invention provides a compound selected from
pharmaceutically acceptable salts thereof.
In another embodiment, the compound of formula I is selected from: N-( 1 - { [ {2-tert-Butyl- 1 - [(4,4-difiuorocyclohexyl)methyl]- 1H-benzimidazol-5- yl}(methyl)amino]sulfonyl}piperidin-4-yl)acetamide;
N-[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-berizimidazol-5-yl]-N- methylisoxazolidine-2-sulfonamide;
N-[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-N- methylazetidine- 1 -sulfonamide;
Λr-[2-ter^-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-l/i-benzimidazol-5-yl]-N- methylpyrrolidine- 1 -sulfonamide; N-[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-N- methylmorpholine-4-sulfonamide;
N- [2-tert-Butyl- 1 -(tetrahydro-2H-pyran-4-ylmethy I)- 1H-benzimidazol-5 -yl] -N- methylpiperidine- 1 -sulfonamide; N-{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-li:/-benzimidazol-5-yl}-Λr-. methylpiperidine-1 -sulfonamide;
7V"-[2-(l,l-difluoroethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]- N-methylisoxazolidine-2-sulfonamide;
N-(I - { [[2-(1 , 1 -difluoroethyl)- l-(tetrahydro-2H-pyran-4-ylmethyl)- 1H-benzimidazol-
5-yl](methyl)amino]sulfonyl}piperidin-4-yl)acetamide; 1-{[[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino]sulfonyl}-N-cyclopropylpiperidine-4-carboxamide;
1 - { [[2-tert-butyl- 1 -(tetrahydro^H-pyran^-ylmethyl)- li-T-benzimidazol-5- yl](methyl)amino]sulfonyl}-N-isopropylpiperidine-4-carboxamide; 1-{[[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-ljyr-benzimidazol-5- yl](methyl)amino]sulfonyl}-N-cyclobutylpiperidine-4-carboxamide;
1 - { [[2-tert-butyl- 1 -(tetrahydro-2H-pyran-4-ylmethyl)- 1H-benzimidazol-5- ylKmethyl)amino]sulfonyl}-N-cyclopentylpiperidine^-carboxamide;
1 - {[[2-tert-Wty\-l -(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino]sulfonyl}-N-pyrrolidin-1-ylpiperidine-4-carboxamide; 1 - { [[2-tert-butyl- 1 -(tetrahydro-2H-pyran-4-ylmethyl)- 1H-benzimidazol-5- yl](methyl)amino]sulfonyl}-N-1H-pyrrol-1-ylpiperidine-4-carboxamide; 1-{[[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino]sulfonyl}-N-ethylpiperidine-4-carboxamide;
N-(tert-butyl)-1-{[[2-tert-butyl4-(tetrahydro-2H-pyran-4-ylmethyl)-1H- benzimidazol-5-yl](methyl)amino]sulfonyl}piperidine-4-carboxamide;
1 - { [[2-tert-butyl- 1 -(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino]sulfonyl}-N,N-dimethylpiperidine-4-carboxamide; 1-{[[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzirQidazol-5- yl](methyl)amino]sulfonyl}-N,N-diethylpiperidine-4-carboxamide;
1 - { [[2-tert-butyl- 1 -(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino]sulfonyl}-N-methylpiperidine-4-carboxamide;
1 - { [[2-tert-butyl- 1 -(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino]sulfonyl}-N-propylpiperidme-4-carboxamide;
N-butyl-1-{[[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino]sulfonyl}piperidine-4-carboxamide;
1 - { [[2-tert-butyl- 1 -(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino]sulfonyl}-N-(2,2,2-trifluoroethyl)piperidine-4-carboxamide; N-allyl- 1 - {[[2-tert-butyl- 1 -(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](metbyl)amino]sulfonyl}piperidine-4-carboxamide;
1 - { [[2-tert-butyl- 1 -(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)arαino]sulfonyl}-N-isobutylpiperidine-4-carboxamide;
1 - { [[2-tert-butyl- 1 -(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino]sulfonyl}-N-(2-hydroxy-1-methylethyl)ρiperidine-4-carboxamide;
1 - {[[2-tert-butyl-l -(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino]sulfonyl}-N-(2-hydroxyethyl)piperidine-4-carboxamide;
Ethyl 1 - { [[2-tert-butyl- 1 -(tetrahydro-2Η-pyran-4-ylmethyl)-1H-benzimidazol-5- yl] (methy l)amino] sulfony 1} piperidine-4-carboxylate ; N-(1-{[[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino]sulfonyllazetidin-3-yl)cyclopropanecarboxamide;
N-( 1 - { [[2-tert-butyl- 1 -(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino]sulfonyl}azetidin-3-yl)-2-methylpropanamide;
N-(I- { [[2-tert-butyl- 1 -(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino]sulfonyl}azetidin-3-yl)cyclobutanecarboxamide;
N-(I- { [[2-tert-butyl- 1 -(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino]sulfonyl}azetidin-3-yl)butanamide;
N-(1-{[[2-tert-butyl-1-(tetrahydro-2H;-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino]sulfonyl}azetidin-3-yl)propanamide;
Methyl 1-{[[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino]sulfonyl}azetidine-3-carboxylate; N-[2-(l,l-dimethylethyl)-1-[(tetrahydro-2H-pyran-4-yl)methyl]-1H-beiizimidazol-5- yl]hexahydro-N-methyl-1H-azepine- 1 -sulfonamide;
N-[2-(l,l-dimethylethyl)-1-[(tetrahydro-2H-pyran-4-yl)methyl]-1H-benzimidazol-5- yl]-N,4-dimethyl-1-piperidinesulfonamide;
N-[2-(l , 1 -dimethylethyl)-l -[(tetrahydro-2H-pyran-4-yl)methyl]-1H-benzimidazol-5- ylJ-S-^ydroxymethy^-N-methyl-1-piperidinesulfonamide;
N-[2-(l,l-dimethylethyl)-1-[(tetrahydro-2H-pyran-4-yl)methyl]-lF-benzimidazol-5- yl]-4-hydroxy-N-methyl-1-piperidinesulfonamide;
N-[2-(l,l-dimethylethyl)-1-[(tetrahydro-2H-pyran-4-yl)methyl]-1H-benzimidazol-5- yl]-4-methoxy-N-methyl-1-piperidmesulfonamide; N-[2-(l,l-dimethylethyl)-1-[(tetrahydro-2H-pyran-4-yl)methyl]-1H-benzimidazol-5- yl]-3-hydroxy-N-methyl-1-piperidinesulfonamide;
N-[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-N- methylazetidine- 1 -sulfonamide ;
N-[2-tert-butyl-1-(tetxahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-4,4- difluoro-N-methylpiperidine- 1 -sulfonamide;
N-[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-3,3- difluoro-N-methylpyrrolidine- 1 -sulfonamide;
Methyl 1 - { [[2-tert-butyl- 1 -(tetrahy dro-2H-pyran-4-ylmethyl)- 1 H-benzimidazol-5- yl](methyl)amino]sulfonyl}piperidine-4-carboxylate; N-[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-N- methylisoxazolidine-2-sulfonamide;
(4R)-N- [2-tert-butyl- 1 -(tetrahydro-2H-pyran-4-ylmethyl)- 1 H-benzimidazol-5-yl]-4- hydroxy-N,4-dimethylisoxazolidine-2-sulfonamide;
N-( 1 - { [[2-tert-butyl- 1 -(tetrahydro-2H-pyran-4-ylmethyl)- lH-benzimidazol-5- yl](memyl)amino]sulfonyl}piperidin-4-yl)acetamide;
N-(1-{[[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino]sulfonyl}piperidin-4-yl)-2,2-dimethylpropanamide;
tert-Butyl [1 -( {methyl[l -(tetrahydro-2H-pyran-4-ylmethyl)-2-(trifluoromethyl)- IH- benzimidazol-5-yl]amino}sulfonyl)piρeridin-4-yl]carbamate tert-Butyl 4-( {methyl[ 1 -(tetrahydro-2H-pyran-4-ylmethyl)-2-(trifluoromethyl)- IH- benzimidazol-5-yl]amino} sulfonyl)piperazine-l -carboxylate; 4-{[(Cyclopropylamino)carbonyl]amino}-N-methyl-N-[l-(tetrahydro-2H-pyran-4- ylmethyl)-2-(trifluoromethyl)-1H-benzimidazol-5-yl]piperidine-1-sulfonamide; N-cyclopropyl-4-( {methyl[ 1 -(tetrab.ydro-2H-pyran-4-ylmethyl)-2-(trifluoromethyl)- 1H-benzimidazol-5 -yl] amino } sulfonyl)piperazine- 1 -carboxamide ;
4-{[(isopropylamino)carbonyl]amino}-N-methyl-N-[l-(tetrab.ydro-2H-pyran-4- ylmethyl)-2-(trifluoromethyl)-1H-benzimidazol-5-yl]piperidme-1-sulfonamide; N-isopropyl-4-({methyl[l-(tetrahydro-2H-pyran-4-ylmethyl)-2-(trifluoromethyl)-1H- benzimidazol-5-yl]amino}sulfonyl)piperazine-1-carboxamide; N-[l-({methyl[l-(tetrahydro-2H-pyran-4-ylmethyl)-2-(trifluoromethyl)-1H- benzimidazol-5-yl]amino}sulfonyl)piperidin-4-yl]acetamide; 2,2-Dimethyl-N-[l-({methyl[l-(tetrahydro-2H-pyran-4-ylmethyl)-2-(trifluoromethyl)- 1H-benzimidazol-5-yl]amino}sulfonyl)piperidin-4-yl]propanamide;
2-Methyl-N- [ 1 -( {methyl[ 1 -(tetrahy dro-2H-pyran-4-ylmethyl)-2-(trifluoromethyl)- IH- benzimidazol-5-yl]amino}sulfonyl)piperidin-4-yl]propanamide;
4-Acetyl-N-methyl-N-[l-(tetrahydro-2H-pyran-4-ylmethyl)-2-(trifluoromethyl)-1H- benzimidazol-5-yl]piperazine-1-sulfonamide;
4-(2,2-Dimethylpropanoyl)-N-methyl-N-[l-(tetrahydro-2H-pyran-4-ylinethyl)-2-
(trifluoromethyl)-1H-benzimidazol-5-yl]piperazine-1-sulfonamide; N-(1-{[{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5- yl}(methyl)amino]sulfonyl}piperidin-4-yl)acetamide; N-(1-{[{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5- yl}(methyl)amino]sulfonyl}piperidin-4-yl)-2,2-dimethylpropanamide; N-{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}-N- methylmorpholine-4-sulfonamide; N-{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}-N- methylpyrrolidine-1 -sulfonamide; N-{2-tert-Butyl-1-[(4,4-difiuorocyclohexyl)methyl]-1H-benzimidazol-5-yl}-3,3- difluoro-N-methylpyrrolidine- 1 -sulfonamide;
N-{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}-N- methylisoxazolidine-2-sulfonamide;
N- {2-tert-Butyl- 1 - [(4,4-difluorocyclohexyl)methyl] -1H-benzimidazol-5-yl} -4,4- difmoro-N-methylpiperidine-1-sulfonamide; tert-Butyl 4-{[{2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5- yl}(methyl)amino]sulfonyl}piperazine-1-carboxylate;
4- { [ {2-tert-Butyl-l -[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5- yl}(methyl)amino]sulfonyl}-N-isopropylpiperazine-1-carboxamide;
4-{[{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5- yl}(methyl)amino]sulfonyl}-N-methylpiperazine-1-carboxamide;
4-{[{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5- yl}(methyl)amino]sulfonyl}-N-cyclopropylpiperazine-1-carboxamide;
4-{[{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5- yl}(methyl)amino]sulfonyl}-N-cyclobutylpiperazine-1-carboxamide; N- {2-tert-Butyl- 1 -[(4,4-difluorocyclohexyl)methyl] -1H-benzimidazol-5-yl} -N- methyl-4-{[(methylamino)carbonyl]amino}piperidine-1-sulfonamide;
N-[2-tert-Butyl-1-(tetrahydro-2Η-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-Ν- methylisoxazolidine-2-sulfonamide;
4-Acetyl-N-[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]- N-methylpiperazine- 1 -sulfonamide;
N-[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-4-(2,2- dimethylpropanoyl)-N-methylpiperazine- 1 -sulfonamide;
4-Benzoyl-N-[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl] -N-methylpiperazine- 1 -sulfonamide; N-[2-tert-Butyl- 1 -(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-N- methyl-4-(3-methylbutanoyl)piperazine-1-sulfonamide;
N-[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-4-
(cyclopropylcarbonyl)-N-methylpiperazine- 1 -sulfonamide;
N-[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-N- methyl-4-propionylpiperazine-1-sulfonamide;
N-[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-4- isobutyryl-N-methylpiperazine- 1 -sulfonamide;
N-[2-tert-Butyl-1-(tetrahydro-2/i-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-4-
(cyclobutylcarbonyl)-N-methylρiperazine- 1 -sulfonamide; N-[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-4- butyryl-N-methylpiperazine-1-sulfonamide; 4- { [[2-tert-Butyl- 1 -(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino]sulfonyl}-N,N-dimethylpiperazine-1-carboxamide;
4- { [[2-tert-Butyl- 1 -(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino]sulfonyl}-N-isopropylpiperazme-1-carboxamide;
4- { [[2-tert-Butyl- 1 -(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino]sulfonyl}-N-cyclopentylpiperazme-1-carboxamide;
4-{[[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino]sulfonyl}-N-methylpiperazine-1-carboxamide;
4-{[[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- ylj^ethyl)amino]sulfonyl}-N-cyclopropylpiperazine-1-carboxamide; 4- { [[2-tert-Butyl- 1 -(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- ylJ^ethyl)amino]sulfonyll-N-cyclobutylpiperazine-1-carboxamide;
N-(tert-Butyl)-4- { [[2-tert-butyl- 1 -(tetrahydro-2H-pyran-4-ylmethyl)- IH- benzimidazol-5-yl](methyl)amino]sulfonyl}piperazine-1-carboxamide; N-butyl-4- {[[2-tert-Butyl- 1 -(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl] (methyl)amino] sulfonyl } piperazine- 1 -carboxamide ; N-Allyl-4-{[[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino]sulfonyl}piperazine-1-carboxamide;
4-{[[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino]sulfonyl} -N-ethylpiperazine-l -carboxamide; 4- { [[2-tert-Butyl- 1 -(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino]sulfonyl}-N-propylpiperazme-1-carboxamide;
4- { [[2-tert-Butyl- 1 -(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino]sulfonyl}-N-(cyclopropylmethyl)piperazine-1-carboxainide;
N-[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-4-(1H- imidazol- 1 -ylcarbony^-N-methylpiperazine- 1 -sulfonamide;
Isopropyl 4-{[[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino]sulfonyl}piperazine-1-carboxylate;
N-(1-{[[2-tert-Butyl4-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl] (methyl) amino] sulfonyl} pyrrolidin-3 -yl)acetamide;
N-( 1 - { [[2-tert-Butyl- 1 -(tetrahydro-2H-pyran-4-ylmethyl)- 1H-benzimidazol-5- yl](methyl)amino]sulfonyl}pyrrolidin-3-yl)-2,2-dimethylpropanamide; N-(1-{[[2-tert-Butyl-1-(tetrahydro-2/i-pyran-4-ylmethyl)-li/-benzimidazol-5- yl](methyl)amino]sulfonyl}azetidin-3-yl)acetamide;
N-{2-te^Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}-N- methyl-1H-imidazole-1-sulfonamide; N-{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}-N- methyl- IH-1 ,2,4-triazole- 1 -sulfonamide;
N- {2-tert-Butyl-l -[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl} -N- methyl- IH-1 ,2,3-triazole- 1 -sulfonamide;
N-[2-tert-Butyl- 1 -(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-4- formyl-N-methyl-1H-pyrazole- 1 -sulfonamide; 1 - { [[2-tert-Butyl- 1 -(tetrahydro-2H-pyran-4-ylmethyl)- 1H-benzimidazol-5- yl](methyl)amino]sulfonyl}-N-cyclopropyl-1H-pyrazole-4-carboxamide;
1 - { [[2-tert-Butyl- 1 -(tetrahydro-2H-pyran-4-ylmethyl)- 1H-benzimidazol-5- yl](methyl)amino]sulfonyl}-N-ethyl-1H-pyrazole-4-carboxamide;
N-AlIyI- 1 - { [[2-tert-butyl- 1 -(tetrahydro-2H-pyran-4-ylmethyl)- 1H-benzimidazol-5- yl] (methyl) amino] sulfonyl} -1H-pyrazole-4-carboxamide; 1-{[[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino]sulfonyl}-N-propyl-1H-pyrazole-4-carboxamide;
1 - { [[2-tert-Butyl- 1 -(tetrahydro-2H-pyran-4-ylmethyl)- 1H-benzimidazol-5- yl](methyl)amino]sulfonyl}-N:)N-dimethyl-1H-pyrazole-4-carboxamide; 1-{[[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl] (methyl) amino] sulfonyl} -N-methyl-1H-pyrazole-4-carboxamide;
N-(tert-Butyl)- 1 - { [[2-tert-butyl- 1 -(tetrahydro-2H-pyran-4-ylmethyl)- IH- benzimidazol-5-yl](methyl)amino]sulfonyl}-1H-pyrazole-4-carboxamide;
N-(I- { [[2-tert-Butyl- 1 -(tetrahydro-2H-pyran-4-ylmethyl)- 1H-benzimidazol-5- yl](methyl)amino]sulfonyl}-1H-pyrazol-3-yl)acetamide; N-[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-4- formyl-N-methyl-1H-imidazole- 1 -sulfonamide;
1- { [[2-f ert-Butyl- 1 -(tetrahydro-2H-pyran-4-ylmethyl)- 1H-benzimidazol-5- ylj^ethyl)aminojsulfonyl}-N-cyclopropyl-1H-imidazole^-carboxamide; 1 - { [ [2-fert-Butyl- 1 -(tetrahydro-2H-pyran-4-ylmethyl)- 1H-benzimidazol-5- ylj^ethyl)amino]sulfonyl}-N-cyclopropyl-1H-pyrazole-S-carboxainide; 1 - { [[2-fert-Butyl- 1 -(tefrahydro-2H-pyran-4-ylmethyl)- 1H-benzimidazol-5- yl](memyl)amino]sulfonyl}-N-isopropyl-1H-pyrazole-3-carboxamide; 1-{[[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-lϋ-'-benzimidazol-5- ylj^ethyl)aminojsulfonyl}-N-propyl-1H-pyrazole-S-carboxainide; N- Allyl- 1 - { [[2-tert-butyl- 1 -(tetrahy dro-2H-pyran-4-ylmethyl)- 1H-benzimidazol-5- yl] (methyl)amino]sulfonyl} -1H-pyrazole-3-carboxamide;
1 - {[[2-tert-Butyl-l -(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino]sulfonyl}-N-ethyl-l/i-pyrazole-3-carboxamide; N-[2-^rt-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benziinidazol-5-yl]-N- methyl-4-(morpholm-4-ylcarbonyl)piperazine- 1 -sulfonamide; 4- { [[2-tert-Butyl- 1 -(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl] (methyl)amino] sulfonyl} -N-(2-hydroxyethyl)piperazine- 1 -carboxamide; N-[2-tert-Butyl-l<tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-N- methyl-4-(l.fir-pyrazol- 1 -ylcarbonyl)piperazine- 1 -sulfonamide; N-[2-tert-Butyl- 1 -(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-N- methyl-4-(pyrrolidin- 1 -ylcarbonyl)piperazine- 1 -sulfonamide; and pharmaceutically acceptable salts thereof.
It will be understood that when compounds of the present invention contain one or more chiral centers, the compounds of the invention may exist in, and be isolated as, enantiomeric or diastereomeric forms, or as a racemic mixture. The present invention includes any possible enantiomers, diastereomers, racemates or mixtures thereof, of a compound of Formula I. The optically active forms of the compound of the invention may be prepared, for example, by chiral chromatographic separation of a racemate, by synthesis from optically active starting materials or by asymmetric synthesis based on the procedures described thereafter. It will also be appreciated that certain compounds of the present invention may exist as geometrical isomers, for example E and Z isomers of alkenes. The present invention includes any geometrical isomer of a compound of Formula I. It will
farther be understood that the present invention encompasses tautomers of the compounds of the Formula I.
It will also be understood that certain compounds of the present invention may exist in solvated, for example hydrated, as well as unsolvated forms. It will further be understood that the present invention encompasses all such solvated forms of the compounds of the Formula I.
Within the scope of the invention are also salts of the compounds of the Formula I. Generally, pharmaceutically acceptable salts of compounds of the present invention may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound, for example an alkyl amine with a suitable acid, for example, HCl or acetic acid, to afford a physiologically acceptable anion. It may also be possible to make a corresponding alkali metal (such as sodium, potassium, or lithium) or an alkaline earth metal (such as a calcium) salt by treating a compound of the present invention having a suitably acidic proton, such as a carboxylic acid or a phenol with one equivalent of an alkali metal or alkaline earth metal hydroxide or alkoxide (such as the ethoxide or methoxide), or a suitably basic organic amine (such as choline or meglumine) in an aqueous medium, followed by conventional purification techniques.
In one embodiment, the compound of Formula I above may be converted to a pharmaceutically acceptable salt or solvate thereof, particularly, an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, methanesulphonate or jσ-toluenesulphonate.
We have now found that the compounds of the invention have activity as pharmaceuticals, in particular as modulators or ligands such as agonists, partial agonists, inverse agonist or antagonists Of CB1 receptors. More particularly, the compounds of the invention exhibit selective activity as agonist of the CB1 receptors and are useful in therapy, especially for relief of various pain conditions such as chronic pain, neuropathic pain, acute pain, cancer pain, pain caused by rheumatoid arthritis, migraine, visceral pain etc. This list should however not be interpreted as exhaustive. Additionally, compounds of the present invention are useful in other disease states in which dysfunction Of CB1 receptors is present or implicated. Furthermore, the compounds of the invention may be used to treat cancer, multiple
sclerosis, Parkinson's disease, Huntington's chorea, Alzheimer's disease, anxiety disorders, gastrointestinal disorders and cardiovascular disorders.
Compounds of the invention are useful as immunomodulators, especially for autoimmune diseases, such as arthritis, for skin grafts, organ transplants and similar surgical needs, for collagen diseases, various allergies, for use as anti-tumour agents and anti viral agents.
Compounds of the invention are useful in disease states where degeneration or dysfunction of cannabinoid receptors is present or implicated in that paradigm. This may involve the use of isotopically labelled versions of the compounds of the invention in diagnostic techniques and imaging applications such as positron emission tomography (PET).
Compounds of the invention are useful for the treatment of diarrhoea, depression, anxiety and stress-related disorders such as post-traumatic stress disorders, panic disorder, generalized anxiety disorder, social phobia, and obsessive compulsive disorder, urinary incontinence, premature ejaculation, various mental illnesses, cough, lung oedema, various gastro-intestinal disorders, e.g. constipation, functional gastrointestinal disorders such as Irritable Bowel Syndrome and Functional Dyspepsia, Parkinson's disease and other motor disorders, traumatic brain injury, stroke, cardioprotection following miocardial infarction, spinal injury and drug addiction, including the treatment of alcohol, nicotine, opioid and other drug abuse and for disorders of the sympathetic nervous system for example hypertension.
Compounds of the invention are useful as an analgesic agent for use during general anaesthesia and monitored anaesthesia care. Combinations of agents with different properties are often used to achieve a balance of effects needed to maintain the anaesthetic state (e.g. amnesia, analgesia, muscle relaxation and sedation). Included in this combination are inhaled anaesthetics, hypnotics, anxiolytics, neuromuscular blockers and opioids.
Also within the scope of the invention is the use of any of the compounds according to the Formula I above, for the manufacture of a medicament for the treatment of any of the conditions discussed above.
A further aspect of the invention is a method for the treatment of a subject suffering from any of the conditions discussed above, whereby an effective amount of
a compound according to the Formula I above, is administered to a patient in need of such treatment.
Thus, the invention provides a compound of Formula I or pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined for use in therapy. In a further aspect, the present invention provides the use of a compound of
Formula I or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined in the manufacture of a medicament for use in therapy.
In the context of the present specification, the term "therapy" also includes "prophylaxis" unless there are specific indications to the contrary. The term "therapeutic" and "therapeutically" should be contrued accordingly. The term "therapy" within the context of the present invention further encompasses to administer an effective amount of a compound of the present invention, to mitigate either a pre-existing disease state, acute or chronic, or a recurring condition. This definition also encompasses prophylactic therapies for prevention of recurring conditions and continued therapy for chronic disorders.
The compounds of the present invention are useful in therapy, especially for the therapy of various pain conditions including, but not limited to: acute pain, chronic pain, neuropathic pain, back pain, cancer pain, and visceral pain.
In use for therapy in a warm-blooded animal such as a human, the compound of the invention may be administered in the form of a conventional pharmaceutical composition by any route including orally, intramuscularly, subcutaneously, topically, intranasally, intraperitoneally, intrathoracially, intravenously, epidurally, intrathecally, transdermally, intracerebroventricularly and by injection into the joints. In one embodiment of the invention, the route of administration may be oral, intravenous or intramuscular.
The dosage will depend on the route of administration, the severity of the disease, age and weight of the patient and other factors normally considered by the attending physician, when determining the individual regimen and dosage level at the most appropriate for a particular patient. For preparing pharmaceutical compositions from the compounds of this invention, inert, pharmaceutically acceptable carriers can be either solid and liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories.
A solid carrier can be one or more substances, which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or table disintegrating agents; it can also be an encapsulating material.
In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided compound of the invention, or the active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
For preparing suppository compositions, a low-melting wax such as a mixture of fatty acid glycerides and cocoa butter is first melted and the active ingredient is dispersed therein by, for example, stirring. The molten homogeneous mixture in then poured into convenient sized moulds and allowed to cool and solidify.
Suitable carriers are magnesium carbonate, magnesium- stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low-melting wax, cocoa butter, and the like. The term composition is also intended to include the formulation of the active component with encapsulating material as a carrier providing a capsule in which the active component (with or without other carriers) is surrounded by a carrier which is thus in association with it. Similarly, cachets are included.
Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.
Liquid form compositions include solutions, suspensions, and emulsions. For example, sterile water or water propylene glycol solutions of the active compounds may be liquid preparations suitable for parenteral administration. Liquid compositions can also be formulated in solution in aqueous polyethylene glycol solution.
Aqueous solutions for oral administration can be prepared by dissolving the active component in water and adding suitable colorants, flavoring agents, stabilizers, and thickening agents as desired. Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water together with a viscous material such as natural synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art.
Depending on the mode of administration, the pharmaceutical composition will preferably include from 0.05% to 99%w (per cent by weight), more preferably from 0.10 to 50%w, of the compound of the invention, all percentages by weight being based on total composition. A therapeutically effective amount for the practice of the present invention may be determined, by the use of known criteria including the age, weight and response of the individual patient, and interpreted within the context of the disease which is being treated or which is being prevented, by one of ordinary skills in the art.
Within the scope of the invention is the use of any compound of Formula I as defined above for the manufacture of a medicament.
Also within the scope of the invention is the use of any compound of Formula I for the manufacture of a medicament for the therapy of pain.
Additionally provided is the use of any compound according to Formula I for the manufacture of a medicament for the therapy of various pain conditions including, but not limited to: acute pain, chronic pain, neuropathic pain, back pain, cancer pain, and visceral pain.
A further aspect of the invention is a method for therapy of a subject suffering from any of the conditions discussed above, whereby an effective amount of a compound according to the Formula I above, is administered to a patient in need of such therapy.
Additionally, there is provided a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.
Particularly, there is provided a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier for therapy, more particularly for therapy of pain.
Further, there is provided a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier use in any of the conditions discussed above.
In a further aspect, the present invention provides a method of preparing the compounds of the present invention.
In one embodiment, the invention provides a process for preparing a compound of Formula I, comprising:
I reacting a compound of Formula II with a compound of formula III,
followed by treating the reaction product with MeOTf and subsequently with R
1H, wherein R
1, R
2, R
3, R
4 and G are as defined above. Compounds of the present invention may also be prepared according to the synthetic routes as depicted in Schemes 1-5.
Scheme 1
H2, Pd
reducing agent base, e.g. DMAP e.g. AIH
3 solvent, e.g. DMF solvent, e.g. THF coupling reagent, e.g. HATU
3) solvent, e.g. AcOH acid, e.g. AcOH microwave oven heating, 100-1900C
solvent, e.g. AcCN
base, e.g. (IPr)
2EtN AcCN
G, R1, R2, R3 and R4 are as defined above.
Scheme 2
cone. HCI °C
G, R1, R2, R3 and R4 are as defined above.
Scheme 3
base
G, R2, R3 and R4 are as defined above.
N ^ is a C2.6heterocyc!yl as used in defining the R1 above
X is Acyl-O- or halogen
Scheme 4
Re-N=CO solvent, e.g. CH2CI2
G, R2, R3 and R4 are as defined above. R4 R.3
is a C
2.
βheterocyclyl as used in defining the R
1 above
X is Acyl-O- or halogen
Scheme 5
HATU base
G, R2, R3 and R4 are as defined above. R6 is C1-6 alkyl or C3.6 cycloalkyl
N "I" is a C2.6heterocyclyl as used in defining the R1 above
X is Acyl-O- or halogen
Biological Evaluation hCB^ and hCB? receptor binding Human CBi receptor from Receptor Biology (hCBi) or human CB2 receptor from BioSignal (hCB2) membranes are thawed at 37 °C, passed 3 times through a 25- gauge blunt-end needle, diluted in the cannabinoid binding buffer (50 mM Tris, 2.5 mM EDTA, 5 mM MgCl2, and 0.5 mg/mL BSA fatty acid free, pH 7.4) and aliquots containing the appropriate amount of protein are distributed in 96-well plates. The IC50 of the compounds of the invention at hCBi and hCB2 are evaluated from 10-point dose-response curves done with 3H-CP55,940 at 20000 to 25000 dpm per well (0.17- 0.21 nM) in a final volume of 300 μl. The total and non-specific binding are determined in the absence and presence of 0.2 μM of HU210 respectively. The plates are vortexed and incubated for 60 minutes at room temperature, filtered through Unifilters GF/B (presoaked in 0.1% polyethyleneimine) with the Tomtec or Packard harvester using 3 mL of wash buffer (50 mM Tris, 5 mM MgCl2, 0.5 mg BSA pH 7.0). The filters are dried for 1 hour at 55 0C. The radioactivity (cpm) is counted in a TopCount (Packard) after adding 65 μl/well of MS-20 scintillation liquid.
hCB, and hCB? GTPYS binding
Human CBi receptor from Receptor Biology (!1CB1) or human CB2 receptor membranes (BioSignal) are thawed at 37 °C, passed 3 times through a 25-gauge blunt-end needle and diluted in the GTPγS binding buffer (50 rnM Hepes, 20 mM NaOH, 100 mM NaCl, 1 mM EDTA, 5 mM MgCl2, pH 7.4, 0.1% BSA). The EC50 and Emax of the compounds of the invention are evaluated from 10-point dose- response curves done in 300μl with the appropriate amount of membrane protein and 100000-130000 dpm Of GTPg35S per well (0.11 -0.14 nM). The basal and maximal stimulated binding is determined in absence and presence of 1 μM (hCB2) or 10 μM (hCBi) Win 55,212-2 respectively. The membranes are pre-incubated for 5 minutes with 56.25 μM (hCB2) or 112.5 μM (!1CB1) GDP prior to distribution in plates (15 μM (hCB2) or 30 μM (!1CB1) GDP final). The plates are vortexed and incubated for 60 minutes at room temperature, filtered on Unifilters GF/B (presoaked in water) with the Tomtec or Packard harvester using 3 ml of wash buffer (50 mM Tris, 5 mM MgCl2, 50 mM NaCl, pH 7.0). The filters are dried for 1 hour at 55 °C. The radioactivity (cpm) is counted in a TopCount (Packard) after adding 65 μl/well of MS-20 scintillation liquid. Antagonist reversal studies are done in the same way except that (a) an agonist dose-response curve is done in the presence of a constant concentration of antagonist, or (b) an antagonist dose-response curve is done in the presence of a constant concentration of agonist. Based on the above assays, the dissociation constant (Ki) for a particular compound of the invention towards a particular receptor is determined using the following equation:
Ki = IC50/(l+[rad]/Kd),
Wherein IC50 is the concentration of the compound of the invention at which 50% displacement has been observed;
[rad] is a standard or reference radioactive ligand concentration at that moment; and
Kd is the dissociation constant of the radioactive ligand towards the particular receptor. Using the above-mentioned assays, the Ki towards human CB1 receptors for certain compounds of the invention are in the range of between 1 nM and 2897 nM. EC50 for these compounds are in the range of between 0.58 nM and 7647 nM. Emax for these compounds are in the range of between 72% and 161%.
EXAMPLES
The invention will further be described in more detail by the following Examples which describe methods whereby compounds of the present invention may be prepared, purified, analyzed and biologically tested, and which are not to be construed as limiting the invention.
Example 1 N-(1-{[{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-lJ3r-benziinidazol-5- yl}(methyl)amino]sulfonyl}piperidin-4-yl)acetamide
Step A: N-(1-{[{2-ter^-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-lJH-benziraidazol- 5-yl}(methyl)amino]sulfonyl}piperidin-4-yl)acetaraide
Acetic anhydride (2.0 mmol) was added into a solution of triethylamine (2.0 mmol) and 4-amino-N-{2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5- yl}-N-methylpiperidine-l~sulfonamide (crude product from step J, 0.9 mmol) in CH2Cl2 (20 mL). After being stirred at room temperature for 1 hr, the reaction mixture was concentrated under reduced pressure. The residue was then purified by silica gel chromatography (AcOEt to MeOH/AcOEt (1:9)) to give N-(1-{[{2-tert-butyl-1-[(4,4- difluorocyclohexyl)methyl]-1H-benzimidazol-5- yl}(methyl)amino]sulfonyl}piperidin-4-yl)acetamide as a solid (235 mg, 48 % for
steps A-D). 1HNMR (400 MHz, CD3OD, TFA salt) δ 1.28 (m, 2H), 1.40-1.76 (m, 8H), 1.64 (s, 9H), 1.88 (s, 3H), 2.04 (m, 2H), 2.24 (m, 1H), 2.90 (m, 2H), 3.28 (s, 3H), 3.68 (m, 3H), 4.50 (d, J= 8.0 Hz, 2H), 7.60 (d, J= 8.0 Hz, 1H), 7.77 (s, 1H), 7.86 (d, J= 8.0 Hz, 1H).
Step B. N-(4-Fluoro-3-nitrophenyl)acetamide
4-Fluoro-3-nitro-aniline (45.0 g, 0.288 mol) was added in portions to acetic anhydride (150 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The white solid was collected and dried in vacuo to give the title compound (42.0 g, 70%). 1H NMR (400 MHz, CDCl3): δ 2.23 (s, 3 H), 7.26 (m, 1 H), 7.50 (s broad, 1 H), 7.87 (m, 1 H), 8.23 (dd, J=6.44, 2.73 Hz, 1 H).
Step C. N-(4-Fluoro-3-nitrophenyl)-N-methylacetamide
Sodium hydride (2.40 g, 60 mmol) was added in portions to a solution of N-(4-fluoro- 3-nitrophenyl)acetamide (7.93 g, 40 mmol) in THF (120 mL) at 0 0C. Stirring for 20 min, iodomethane (17.0 g, 120 mmol) was added. The reaction mixture was stirred at room temperature for 2 h, quenched with saturaed NaHCO3 (30 mL) and extracted with EtOAc (3x100 mL). The combined organic phases were washed with saturated NaCl (2x30 mL). After filtration and concentration, 8.73 g (100%) of the title compound was obtained as a brown solid. 1H NMR (400 MHz, CDCl3): δ 1.92 (s, 3 H), 3.30 (s, 3 H), 7.38 (s, 1 H), 7.52 (s, 1 H), 7.95 (s, 1 H).
Step D. N-(4-{[(4,4-Difluorocyclohexyl)methyl]ammo}-3-nitrophenyl)-N- methylacetamide
[(4,4-difluorocyclohexyl)methyl]amine TFA salt (780 mg, 2.96 mmol) was added to a mixture of N-(4-fluoro-3-nitrophenyl)-N-methylacetamide (628 mg, 2.96 mmol) and DIPEA (1.29 mL, 7.40 mmol) in EtOH (15 mL) at room temperature. The reaction mixture was heated for 18 hrs at 70 0C. Removal of the solvent, the crude product was purified by MPLC using EtOAc/Heptane 70-100% to give 855 mg (85%) of the title compound as an orange-red solid (84%). MS (ESI) (M+H)+: 341.96.
Step E. N-(3-Amino-4-{[(4,4-difluorocyclohexyl)inethyl] amino} pheny I)-N- methylacetamide
N-(4- { [(4,4-Difluorocyclohexyl)methyl] amino } -3 -nitrophenyl)-N-methy lacetamide (855 mg, 2.50 mmol) was hydrogenated in ethyl acetate (50 mL) catalyzed by 10% Pd/C at 50 psi H2 in Parr shaker for 18 h at room temperature. After filtration through celite and concentration, 716 mg (92%) of a white solid was obtained, which was used in the next step without further purification. MS (ESI) (M+H)+: 311.99
Step F. N-{2-te//-ButyI-1-[(4,4-difluorocyclohexyl)methyl]-1H-benziinidazol-5- yl}-N-methylacetamide
Trimethylacetyl chloride (0.29 mL, 2.41 mmol) was dropwise added to a solution of N-(3-amino-4-{[(4,4-difluorocyclohexyl)methyl]atriino}phenyl)-N-methylacetamide (716 mg, 2.30 mmol) and Et3N (0.38 mL, 2.75 mmol) in dichloromethane (100 mL) at 0 0C. The resulting mixture was stirred for 4h at room temperature. After evaporation of the solvent, the residue was dissolved in acetic acid (16 mL) and then divided to 4 sealed test tubes. The mixture was heated at 150°C in a Personal Chemistry SmithSynthesizer microwave instrument for 3 hrs. The combined reaction mixture was evaporated and then dissolved in EtOAc (200 mL), washed with saturated sodium bicarbonate solution, brine and dried over Na2SO4. After filtration and evaporation, the residue was purified by MPLC using MeOH 5% and acetone 10% in DCM as eluent on silica gel to give 570 mg (65%) of the title compound as a white solid. MS (ESI) (M+H)+: 378.23.
Step G. 2-fe^-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-N-methyl-lHr- benzimidazol-5-amine
N-{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}-N- methylacetamide (570 mg, 1.51 mmol ) and cone, hydrochloric acid (15 mL) were heated together at 8O
0C for 18 hrs. Upon cooling down to room temperature, the reaction mixture was poured into ice-water (100 mL), brought the pH tol3 by using cone. NaOH and extracted with EtOAc (3x50 mL). The combined organic layers were washed with brine and dried with Na
2SO
4. After filtration and evaporation, 459 mg
(90%) of the title compound was obtained as a white solid. MS (ESI) (M+H)
+: 336.04.
Step H: 1-{[{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-lir-benzimidazol-5- yl](methyl)amino]sulfonyl}-3-methyl-1H-imidazol-S-ium triflate
3-(Imidazole-1-sulfonyl)-1-methyl-3H-imidazol-1-ium triflate (508 mg; 1.4 mmol) was added into a solution of 2-fert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-N- methyl-1H-benzimidazol-5-amine (300 mg, 0.9 mmol) in acetonitrile (10 mL). After being stirred at room temperature for 2 hr, the reaction mixture was concentrated under reduced pressure. The residue was then dissolved in AcOEt (60 mL), washed with brine, and dried over Na2SO4. Removal of solvents provided a mixture (1 : 1) of N-{2-fert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}-N- methyl-1H-imidazole-l -sulfonamide and 1-{[{2-tert-butyl-1-[(4,4- difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl](methyl)aminojsulfonyl}-3- methyl-1H-imidazol-3-ium triflate, which was dissolved in dichloromethane (10 mL). The resulting solution was treated with methyl trifluoromethanesulfonate (0.5 mmol) at 0°C for 2 hr. The reaction mixture was then concentrated under reduced pressure to give 1-{[{2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5- yl}(methyl)amino]sulfonyl}-3-methyl-1H-imidazol-3-ium triflate as a solid, which was used in the step I without any purification.
Step I: tert-Butyl (l-{[{2-terj;-butyl-1-[(4,4-difluorocyclohexyl)methyl]-lJ9r- benzimidazoi-5-yl}(methyl)amino]sulfonyl}piperidin-4-yl)carbamate
A solution of Hunig's base (1.0 mmol), 1-{[{2-tert-butyl-1-[(4,4- difluorocyclohexy^methyy-1H-benzimidazol-5-yl}(methyl)amino]sulfonyl}-3- methyl-1H-imidazol-3-ium triflate (crude product from Step H, 0.9 mmol) and tert- butyl piperidin-4-ylcarbamate (200 mg, 1.0 mmol) in MeCN (20 mL) was heated for 1 hr at 80°C. The reaction mixture was then concentrated under reduced pressure to give crude tert-hvAyl (1-{[{2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H- benzimidazol-5-yl}(methyl)amino]sulfonyl}piperidin-4-yl)carbamate as a solid, which was used directly in Step J.
Step J: 4-Amino-N-{2-ter-1-butyl-1-[(4,4-difluorocyclohexyl)methyl]-lJΪ- benzimidazol-5-yl}-N-methylpiperidine-1-sulfonamide
A solution of tert-butyl (1-{[{2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H- benzimidazol-5-yl} (methyl)amino]sulfonyl}piperidin-4-yl)carbamate (crude product from Step I, 0.9 mmol) in 10 mL CH2Cl2 was treated with 10 mL TFA at room temperature. After being stirred at room temperature for 1 hr, the reaction mixture was concentrated under reduced pressure. The residue was then dissolved in AcOEt (60 mL), washed with Na2CO3 solution and brine, and dried over Na2SO4. Removal of solvents provided the crude 4-amino-N-{2-tert-butyl-1-[(4,4-
difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl} -N-methylpiperidine- 1 - sulfonamide, which was used in Step A without purification.
Example 2 Ν-[2-^r/-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-Ν- methylisoxazolidine-2-sulfbnamide
Step A: N-[2-ter^-ButyI-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl]-N-methylisoxazolidine-2-sulfonamide
Following the procedure in Step I of Example 1, 1-{[[2-teri;-butyl-1-(tetrahydro-2H- pyran-4-ylmethyl)-1H-benzimidazol-5-yl](methyl)amino]sulfonyl}-3-methyl-liir- imidazol-3-ium triflate (crude product from Step G, 1.67 mmol) was reacted with isoxazolidine hydrochloride (220 mg, 2.0 mmol) and Hunig's base (0.72 mL, 4.2 mml), after being purified by silica gel chromatography by using 20-30 % AcOEt in dichloromethane, to provide N-[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H- benzimidazol-5-yl]-N-methylisoxazolidine-2-sulfonamide (TFA salt, 807 mg, 88 %): 1H NMR (600 MHz, CD3OD) δ 1.43-1.56 (m, 4H), 1.60 (s, 9H), 2.22-2.35 (m, 3H), 3.26 (t, J= 11.14Hz, 2H), 3.37 (s, 3H), 3.47 (t, J= 7.17Hz, 2H), 3.85 (dd, J= 11.26, 3.33Hz, 2H), 4.03 (t, J= 7.30Hz, 2H), 4.46 (d, J= 7.17Hz, 2H), 7.63 (dd, J= 8.70, 1.02Hz, 1H), 7.80-7.84 (d, J= 1.28Hz, 1H), 7.88 (d, J= 8.96Hz, 1H).
Step B: Methyl (4-fluoro-3-nitrophenyl)carbamate
Methyl chloroformate (13.2 mL, 170.2 mmol) was added dropwise to a cold (00C) dichloromethane (200 mL) solution of 4-fluoro-3-nitro aniline (24.15 g, 154.7 mmol) and DIPEA (35 mL, 201 mmol). The reaction mixture was stirred at rt overnight. The solution was then diluted with 200 mL of dichloromethane and washed with 2M HCl, brine and dried over anhydrous MgSO4. The solvent was concentrated and the product was directly used for next step without further purification. Yield: 35.5 g (99%); 1H NMR (400 MHz, CHLOROFORM-D): δ 3.81 (s, 3H), 7.02 (s, 1H), 7.23 (m, 1H), 7.72 (d, J = 8.59Hz, 1H), 8.17 (dd, J = 6.35, 2.64Hz, 1H).
Step C. Methyl {3-nitro-4-[(tetrahydro-2H-pyran-4- ylmethyl)amino] phenyl} carbamate
Methyl (4-fluoro-3-nitrophenyl)carbamate (2.0 g, 9.32 mmol) and 4-aminomethyl tetrahydropyran (1.28g, 11.2 mmol) were stirred in 50 mL of EtOH containing TEA (2.0 mL, 14.0 mmol) at 75°C for 48 h. The solvent was evaporated. The residue was dissolved in EtOAc and washed with aqueous 5% KHSO4, saturated aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. The crude product was purified by silica gel flash chromatography using 1:1 / hexanes : EtOAc as eluent. Yield: 2.53 g (88%); 1H NMR (400 MHz, CHLOROFORM-D): δ 1.42 (m, 4.49 Hz, 2 H), 1.73 (d, J=W 6 Hz, 1 H), 1.76 (d, J=1.95 Hz, 1 H), 1.88 - 2.01 (m, 1 H), 3.22 (dd, J=6.74, 5.57 Hz, 2 H), 3.42 (m, 2 H), 3.78 (s, 3 H), 4.01 (d, J=4.30 Hz, 1 H), 4.04 (d, J=3.51 Hz, 1 H), 6.48 (br.s, 1 H), 6.85 (d, J=9.37 Hz, 1 H), 7.65 (br.s, 1 H), 8.03 - 8.09 (m, 2 H).
Step D. Methyl {3-amino-4-[(tetrahydro-2H-pyran-4- ylmethyl)amino]phenyl} carbamate
Methyl {3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl} carbamate (2.53 g, 8.18 mmol) was dissolved in 50 mL of EtOAc containing a catalytic amount of 10% Pd/C. The solution was shaken under H2 atmosphere (40 psi) using a Parr hydrogenation apparatus overnight at it The solution was filtered through Celite and the solvent was evaporated. Yield: 2.29 g (99%); 1H NMR (400 MHz, CHLOROFORM-D): δ 1.40 (m, 2 H), 1.70 - 1.74 (m, 1 H), 1.74 - 1.77 (m. 1 H), 1.81 - 1.92 (m, 1 H), 2.99 (d, J=6.64 Hz, 2 H), 3.34 (br.s, 2 H)3 3.41 (m, 2 H), 3.74 (s, 3 H), 3.99 (d, J=3.51 Hz, 1 H), 4.02 (d, J=3.51 Hz, 1 H), 6.38 (br.s, 1 H), 6.55 - 6.60 (m, 1 H), 6.62 - 6.68 (m, 1 H), 6.95 (br.s, 1 H).
Step E. Methyl [2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H- benzimidazol-5-yl] carbamate
Methyl {3-amino-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}carbamate (2.29 g, 8.20 mmol) and DMAP (0.20 g, 1.64 mmol) were dissolved in 75 mL of DCM. Trimethylacetyl chloride (1.10 mL, 9.02 mmol) was added dropwise and the solution was stirred at rt for 2h. The solution was washed with aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. The residue was dissolved in 25 mL of AcOH and was heated at 1250C for Ih using a Personal Chemistry microwave apparatus. The solvent was evaporated. The residue was dissolved in EtOAc and washed with aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. The
crude product was purified by silica gel flash chromatography using 4:3 / hexanes : acetone as eluent. Yield: 1.81 g (64%); 1H NMR (400 MHz, CHLOROFORM-D): δ 1.48 - 1.54 (m, 4 H) 1.56 (s, 9 H) 2.23 - 2.35 (m, 1 H) 3.27 - 3.35 (m, 2 H) 3.78 (s, 3 H) 3.96 (t, J=2.93 Hz, 1 H) 3.99 (t, J=3.03 Hz, 1 H) 4.18 (d, J=7.42 Hz, 2 H) 6.63 (br.s, 1 H) 7.24 - 7.28 (m, 1 H) 7.41 (br.s, 1 H) 7.61 (d, J=I.95 Hz, 1 H).
Step F: 2-tert-Butyl-N-methyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H- benzimidazol-5-amine
Methyl [2-tert-butyl- 1 -(tetrahydro-2H-pyran-4-ylmethyl)- lH-benzimidazol-5- yljcarbamate (1.8Og, 5.21 mmol) (for preparation, see Steps B to E) was dissolved in 75 mL of THF at O
0C. IM HCl/ether (7.3 mL, 7.29 mmol) was added dropwise and the solution was stirred at 0
0C for 15 min. LiAlH
4 (988 mg, 26.1 mmol) was added slowly and the solution was stirred at rt overnight. The reaction was quenched at 0°C by the addition of MeOH (5 mL) followed by water (10 mL) and the solution was left to stir at rt for 30 min. Anhydrous Na
2SO
4 (10 g) was added and the solution was stirred at rt for another 30 min. The solution was filtered and the solvent was evaporated. The residue was dissolved in EtOAc and washed with aqueous NaHCO
3 solution, brine and dried over anhydrous MgSO
4. The solvent was evaporated. Yield: 1.54g (98%);
1H NMR (400 MHz, CHLOROFORM-D): δ 1.49 - 1.53 (m, 4 H), 1.53 - 1.57 (m, 9 H), 2.22 - 2.32 (m, 1 H), 2.87 (s, 3 H), 3.26 - 3.35 (m, 2 H), 3.95 (t, J=3.03 Hz, 1 H), 3.97 - 4.00 (m, 1 H), 4.13 (d, J=7.42 Hz, 2 H), 6.61 (dd, J=8.59, 2.15 Hz, 1 H), 6.99 (d, J=1.95 Hz, 1 H), 7.11 (d, J=8.59 Hz, 1 H).
Step G: 1-{[[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-ljH-benzimidazol- 5-yl](methyl)amino]sulfonyl}-3-raethyl-1H-imidazol-3-ium triflate.
Following the procedure in Step H of Example 1, 2-tert-butyl-N-methyl-1- (tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-amine (1.51 g, 5.0 mmol) was converted to 1 - { [[2-tert-butyl- 1 -(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol- 5-yl](methyl)amino]sulfonyl}-3-methyl-1H-imidazol-3-ium triflate, which was used in Step A without any purification.
Example 3
N-[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-N- methylazetidine-1 -sulfonamide
N-[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl]-N- methylazetidine-1 -sulfonamide
Following the procedure in Step A of Example 2, 1-{[[2-tert-butyl-1-(tetrahydro-2H- pyran-4-ylmethyl)-1H-benzimidazol-5-yl](methyl)amino]sulfonyl}-3-methyl-1H- imidazol-3-ium triflate (3.33 mmol) was reacted with trimethlene amine (4.99 mmol), after being purified by silica gel chromatography by using 20-50 % AcOEt in dichloromethane, to provide N-[2-tert-butyl-1-(tetrahydro-2/-
r-pyran-4-ylmethyl)-1H- benzimidazol-5.-yl]-N-methylazetidine-1-sulfonamide (TFA salt, 675 mg, 38 %). MS (M+l): 421.01.
1H NMR (600 MHz, CD
3OD) δ 1.40-1.53 (m, 4H)
3 1.57 (s, 9H), 2.14 (quint, J= 7.68Hz, 2H), 2.23-2.33 (m, 1H), 3.22 (s, 3H), 3.25 (m, 2H), 3.80 (t, J= 7.68Hz, 4H), 3.84 (m, 2H), 4.41 (d, J= 7.42Hz, 2H), 7.51 (d, J= 8.70Hz, 1H), 7.67 (d, J= 1.79Hz, 1H), 7.80 (d, J= 8.45Hz, 1H).
Example 4 N-[2-tert-Butyl-1-(tetrahydro-2JHr-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-A'- methylpyrrolidine-1 -sulfonamide
Step A: N-[2-tert-Butyl-1-(tetrahydro-2Jδr-pyran-4-ylmethyl)-lJH-benzimidazol-5- yl]-N-methylpyrrolidine-1-sulfonamide
N-[2-tert-Butyl- 1 -(tetrahydro-2H-pyran-4-ylmethyl)- 1 H-benzimidazol-5-yl]-N- methylsulfamide (for preparation see the following steps B to H) (45 mg, 0.118 mmol) was dissolved in 5 mL of DMF at 0°C. NaH (60% dispersion in oil) (14 mg, 0.354 mmol) was added and the solution was stirred at 0°C for 10 min. 1,4- Dibromobutane (0.014 mL, 0.118 mmol) was added and the solution was stirred at rt
for 3h. Another 0.118 mmol of 1,4-dibrombutane was added and the solution was stirred at rt for another 3h. The reaction was quenched by the addition of saturated aqueous NaHCO
3 solution and the solvent was evaporated. The residue was dissolved in EtOAc and washed with saturated aqueous NaHCO
3 solution, brine and dried over anhydrous MgSO
4. The product was purified by reversed-phase HPLC using 10-60% CH
3CN/H
2O and lyophilized affording the title compound as the corresponding TFA salt. Yield: 53 mg (82%).
1HNMR (400 MHz, METHANOL- D
4) δ 1.52 - 1.58 (m, 2 H), 1.59 - 1.67 (m, 2 H), 1.69 (s, 9 H), 1.87 - 1.92 (m, 4 H), 2.35 - 2.43 (m, 1 H), 3.29 - 3.32 (m, 7 H), 3.35 (m, 2 H), 3.93 (d, J=3.12 Hz, 1 H), 3.96 (d, J=3.71 Hz, 1 H), 4.55 (d, J=7.42 Hz, 2 H), 7.67 (dd, J=8.98, 1.95 Hz, 1 H), 7.81 (d, J=2.15 Hz, 1 H), 7.97 (d, J=8.98 Hz, 1 H); MS (ESI) (M+H)
+ 435.0; Anal. Calcd(%) for C
22H
34N
4O
3S + 2.4 TFA + 0.2 H
2O: C, 45.22; H, 5.21; N, 7.87. Found: C, 45.20; H, 5.27; N, 7.90.
Step B : (tert-Butoxy carb onyl) { [4-(dimethyKminio)pyridin-l (4H)- yl] sulf onyl} azanide
Chlorosulfonyl isocyanate (1.2 mL, 13.8 mmol) was added dropwise to a stirring DCM solution (10 mL) of t-butanol (1.3 mL, 13.8 mmol). DMAP (3.45g, 27.6 mmol) was added slowly and the solution was stirred at rt for 2h. The solution was diluted with DCM and washed with water (3X), brine and dried over anhydrous MgSO4. The solvent was evaporated. The product was recrystallized from acetonitrile. Yield (1.68g (40%). 1H NMR (400 MHz, DMSO-D6) δ 1.25 (s, 9 H), 3.21 (s, 6 H), 6.96 (d, J=8.20 Hz, 2 H), 8.45 (d, J=8.01 Hz, 2 H).
Step C : N-[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl]-N-methylsulfamide
2-tert-Butyl-N-methyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-amine (60 mg, 0.199mmol) (for preparation, see Example 2, Steps B to F) and (terϊ- butoxycarbonyl){[4-(dimethyliminio)pyridin-l(4H)-yl]sulfonyl}azanide (66 mg, 0.219 mmol) were stirred in 3 mL of DCE at 70°C for 2h. The solution was then passed through a plug of silica gel using EtOAc as eluent. The solvent was evaporated. The residue was dissolved in 3 mL of IM HCl/ AcOH and the solution was stirred at rt for Ih. The solvent was evaporated. The product was purified by reversed-phase HPLC using 10-60% CH3CN/H2O and then lyophilized affording the title compound as the corresponding TFA salt. The fractions were pooled and the solvent was concentrated. The residue was dissolved in 2M Na2CO3 and extracted with DCM (3X). The organic phase was dried over anhydrous MgSO4 and the solvent was evaporated. Yield: 45 mg (59%). 1H NMR (TFA salt) (400 MHz, METHANOL-D4) δ 1.50 - 1.56 (m, 2 H), 1.57 - 1.62 (m, 2 H), 1.67 (s, 9 H), 2.33 - 2.42 (m, 1 H), 3.28 (s, 3 H), 3.34 (m, 2 H), 3.93 (m, 2 H), 4.53 (d, J=7.62 Hz, 2 H), 7.64 (dd, J=8.98, 1.95 Hz, 1 H), 7.77 (d, J=I.56 Hz, 1 H), 7.91 (d, J=8.98 Hz, 1 H); MS (ESI) (M+H)+381.0.
Example 5 N-[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yI]-N- methylmorpholine-4-sulfonamide
Following Step A in Example 4 using N-[2-tert-butyl-1-(tetrahydro-2H-pyran-4- ylmethyl)-1H-benzimidazol-5-yl]-N-methylsulfamide (45 mg, 0.118 mmol), NaH (14 nig, 0.354 mmol) and 2-bromoethyl ether (0.030 mL, 0.236 mmol) in 4 mL of DMF. The product was purified by reversed-phase HPLC using 10-60% CH
3CN/H
2O and lyophilized affording the title compound as the corresponding TFA salt. Yield: 42 mg (63%).
1H NMR (400 MHz, METHANOL-D
4) δ 1.52 - 1.58 (m, 2 H), 1.59 - 1.66 (m, 2 H), 1.69 (s, 9 H), 2.34 - 2.43 (m, 1 H), 3.20 - 3.24 (m, 4 H), 3.32 - 3.40 (m, 5 H), 3.63 - 3.67 (m, 4 H), 3.93 (d, J=3.32 Hz, 1 H), 3.96 (d, J=3.71 Hz, 1 H), 4.54 (d, J=7.42 Hz, 2 H), 7.69 (dd, J=8.98, 1.95 Hz, 1 H), 7.82 (d, J=I.76 Hz, 1 H), 7.96 (d, J=8.98 Hz, 1 H); MS (ESI) (M+H)
+451.0; Anal. Calcd(%) for C
22H
34N
4O
4S + 1.2 TFA + 1.0 H
2O: C, 48.41; H, 6.19; N, 9.25. Found: C, 48.29; H, 6.00; N, 9.53.
Example 6 N-[2-ferf-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-ljH-benzimidazol-5-yl]-N- methylpiperidine-1-sulfonamide
Following Step A in Example 4 using N-[2-tert-butyl-1-(tetrahydro-2H-pyran-4- ylmethyl)-1H-benzimidazol-5-yl]-N-methylsulfamide (40 mg, 0.105 mmol), NaH (13 mg, 0.315 mmol) and 1 ,5-dibromopentane (0.042 mL, 0.315 mmol) in 4 mL of DMF. The product was purified by reversed-phase HPLC using 10-60% CH3CN/H2O and lyophilized affording the title compound as the corresponding TFA salt. Yield: 42 mg (71%). 1HNMR (400 MHz, METHANOL-D4) δ 1.52 - 1.60 (m, 8 H), 1.59 - 1.67 (m, 2 H), 1.69 (s, 9 H), 2.34 - 2.43 (m, 1 H), 3.20 - 3.25 (m, 4 H)5 3.31 (s, 3 H), 3.35 (m, 2 H), 3.93 (d, J=3.12 Hz, 1 H), 3.96 (d, J=3.91 Hz, 1 H), 4.54 (d, J=7.62 Hz, 2 H), 7.67 (dd, J=8.98, 1.95 Hz, 1 H), 7.80 (d, J=I.76 Hz, 1 H), 7.95 (d, J=8.98 Hz, 1 H); MS (ESI) (M+H)+ 449.0; Anal. Calcd(%) for C23H36N4O3S + 1.3 TFA + 0.9 H2O: C, 50.15; H, 6.43; N, 9.14. Found: C, 50.22; H, 6.52; N, 9.10.
Example 7 N-{2-terf-Butyl-1-[(4,4-diifluorocyclohexyl)methyl]-lJHr-benziinidazol-5-yl}-N- methylpiperidine-1 -sulfonamide
2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-N-methyl-1H-benzimidazol-5-ainine (55 mg, 0.164 mmol) (for preparation, see Example 1, Steps B to G) and (tert- butoxy carbonyl) { [4-(dimethyliminio)pyridin- 1 (4/f)-yl] sulfonyl } azanide (54 mg, 0.180 mmol) were stirred in 3 mL of DCE at 70°C for 2h. The crude product was purified by silica gel flash chromatography using 1:1 / hexanes : EtOAc to EtOAc as a gradient. The resulting product was dissolved in 3 mL of IM ΗCl/AcOΗ and stirred at rt for Ih. The solvent was evaporated. The residue was dissolved in EtOAc and washed with saturated aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. The solvent was evaporated. The product was dissolved in 3 mL of DMF at O0C and NaH (20 mg, 0.492 mmol) was added, followed by 1,5-dibromopentane (0.033 mL, 0.246 mmol). The solution was stirred at rt for 2h. The reaction was quenched with saturated aqueous NaHCO3 solution and the solvent was evaporated. The residue was dissolved in EtOAc and washed with saturated aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. The product was purified by reversed-phase HPLC using 10-60% CH3CN/H2O and lyophilized affording the title compound as the corresponding TFA salt. Yield: 15 mg (15%). 1H NMR (400 MHz, METHANOL-D4) δ 1.54 - 1.61 (m, 8 H), 1.68 (s, 9 H), 1.71 - 1.85 (m, 4 H)5 2.01 - 2.12 (m, 2 H), 2.21 - 2.33 (m, 1 H), 3.20 - 3.25 (m, 4 H), 3.31 (s, 3 H)3 4.56 (d, J=7.62 Hz, 2 H), 7.67 (dd, J=9.08, 2.05 Hz, 1 H), 7.81 (d, J-2.15 Hz, 1 H), 7.94 (d, J=9.18 Hz, 1 H); MS (ESI) (M+H)+ 483.0; Anal. Calcd(%) for C24H36N4O2SF2 + 1.8 TFA + 0.4 H2O: C, 47.69; H, 5.60; N, 8.06. Found: C, 47.66; H, 5.58; N, 8.07.
Example 8 N-[2-(l,l-Difluoroethyl)-1-(tetrahydro-2J3-pyran-4-ylmethyl)-lir-benzimidazol-
5-yl]-N-methylisoxazolidine-2-sulfonamide
Step A- N-^-Cl-l-Difluoroethy^-1-Ctetrahydro-lH-pyran^-ylmethyl)-1H- benzimidazol-5-yl]-N-methylisoxazolidine-2-sulfonamide
Isoxazolidin-2-ium chloride (80 mg, 0.72 mmol) and DIPEA (0.12 mL, 0.72 mmol) were added to the reaction mixture (18 mL) prepared in step B in this example. The resulting reaction mixture was heated to 6O
0C overnight and the solvent was concentrated. . The product was purified by reverse-phase preparative HPLC using MeCN 10 to 90% gradient in water to provide the TFA salt of the title compound as white solid. Yield: 50 mg (18%);
1HNMR (400 MHz, CD
3OD) δ 1.38 - 1.51 (m, 4 H), 2.21 (t, J=19.34 Hz, 3 H)
5 2.28 - 2.39 (m, 2 H), 3.29 - 3.35 (m, 2 H), 3.41 (s, 3 H), 3.53 (dd, J=8.01, 6.64 Hz, 2 H), 3.84 - 3.93 (m, 2 H), 4.12 (t, J=7.42 Hz, 2 H)
5 4.32 (d, J=7.62 Hz, 2 H), 7.51 (dd, J=8.89, 2.05 Hz, 1 H)
5 7.66 (d
5 J=8.98 Hz, 1 H)
5 7.83 (d
5 J=1.95 Hz, 1 H); MS (ESI) (M+H)
+ 445.0; Anal. Calcd for C
19H
26F
2N
4O
4S + 0.3 TFA + 0.1 H
2O: C, 48.99; H, 5.56; N
5 11.16. Found: C, 49.02; H
5 5.60; N, 11.67.
Step B. 1-{[[2-(l,l-Difluoroethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-LH- benzimidazol-5-yl](methyl)amino]suIfonyl}-3-methyl-1H-imidazol-3-ium
l-(li7-Imidazol-1-ylsulfonyl)-3-methyl-li/-imidazol-3-ium difluoromethanesulfonate (1.05 g, 2.90 mmol) was added to a solution of 2-(l,l-difluoroethyl)-N-methyl-1- (tetrahydro-2H-pyran-4-ylmethyl)-lϋf-benzimidazol-5 -amine (0.60 g, 1.93 mmol) in MeCN (70 mL) at ambient temperature. The reaction mixture was stirred for 4 hrs. and methyl trifluoromethyl sulfone (0.21 mL, 1.93 mmol) was added. The reaction mixture was stirred for 2hrs and used directly for the next step.
Example 9 N-(1-{[[2-(l?l-Difluoroethyl)-1-(tetrahydro-2fir-pyran-4-ylmethyl)-1H- benzimidazol-5-yl](methyl)amino]sulfonyl}piperidin-4-yl)acetamide
fert-Butyl piperidin-4-ylcarbamate (0.43 mg, 1.45 mmol) was added to the reaction mixture (52 mL) prepared in example 1, step B. The resulting reaction mixture was heated to 90
0C overnight. tert-Butyl piperidin-4-ylcarbamate (0.43 mg, 1.45 mmol) was added again and the reaction mixture was heated to 90°C overnight. The solvent was concentrated and DCM (50 mL) was added to the residue. The resulting precipitate was filtered and air-dried to provide 404 mg of tert-butyl (1-{[[2-(l,l- difluoroethyl)- 1 -(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino]sulfonyl}piperidin-4-yl)carbamate intermediate. The solid was treated with TFA (10 mL) for 1.5 hr. and the solvent was concentrated. The resulting 4-amino-N-[2-(l,l-difluoroemyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-lJ
:f-
benzimidazol-5-yl]-N-πiethylpiperidme-l -sulfonamide TFA salt intermediate was dissolved in DCM (100 mL) and the solution was neutralized with Et
3N (2 mL) at O
0C. Acetyl chloride (10 drops) was added to the solution at 0°C, the reaction mixture was allowed to warm to ambient temperature and stirred overnight. The solvent was concentrated and the product was purified by reverse-phase preparative HPLC using MeCN 10 to 90% gradient in water to provide the TFA salt of the title compound as white solid. Yield: 160 mg (21%);
1H NMR (400 MHz, CD
3OD) δ 1.35 - 1.54 (m, 6 H), 1.78 - 1.87 (m, 2 H), 1.90 (s, 3 H), 2.24 (t, J=19.33 Hz, 3 H), 2.30 (s, 1 H), 2.83 - 2.94 (m, 2 H), 3.27 - 3.30 (m, 3 H), 3.30 - 3.38 (m, 2 H), 3.60 - 3.77 (m, 4 H), 3.86 - 3.96 (m, 2 H), 4.35 (d, J=7.62 Hz, 2 H), 7.51 (dd, J=8.79, 2.15 Hz, 1 H), 7.71 (d,
J=8.98 Hz, 1 H), 7.79 (d, J=1.95 Hz, 1 H); MS (ESI) (M+H)+ 514.0; Anal. Calcd for C23H33F2N5O4S + 0.7 TFA + 0.2 H2O: C, 49.09; H, 5.76; N, 11.73. Found: C, 49.06; H, 5.69; N, 11.68.
Example 10 1-{[[2-terϊ-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino]sulfonyl}-N-cyclopropylpiperidine-4-carboxamide
Step A. 1-{[[2-tert-Butyl-1-(tetrahydro-2J3
r-pyran-4-ylmethyl)-1H-benzimidiazol- 5-yl](methyl)amino]sulfonyl}-N-cyclopropylpiperidine-4-carboxamide
To a solution of 1-{[[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H- benzimidazol-5-yl](methyl)amino]sulfonyl}piperidine-4-carboxylic acid (70 mg, 0.142 mmol, see Steps B to E for its preparation), diisopropylethylamine (0.029 mL, 0.170 mmol), and cyclopropylamine (30 μL, excess) at room temperature in DMF (3 mL), was added HATU (64.6 mg, 0.170 mmol) in one portion. The solution was stirred at room temperature overnight. After evaporation of the solvent, the residue was purified by reversed-phase HPLC (10-60% CH3CN in H2O) to provide the title compound as its TFA salt (29.1 mg, 32%). 1H NMR (400 MHz, CDCl3) δ 0.47 - 0.54 (m, 2 H), 0.69 - 0.77 (m, 2 H), 1.52 - 1.70 (m, 6 H), 1.73 (s, 9 H), 1.75 - 1.82 (m, 2 H), 2.13 - 2.24 (m, 1 H), 2.26 - 2.39 (m, 1 H), 2.65 - 2.71 (m, 1 H), 2.71 - 2.81 (m, 2 H), 3.31 (s, 3 H), 3.32 - 3.41 (m, 2 H), 3.57 - 3.65 (m, 2 H), 4.00 - 4.07 (m, 2 H), 4.38 (d, J=7.42 Hz, 2 H), 6.43 - 6.48 (m, 1 H), 7.55 (d, J=8.98 Hz, 1 H), 7.66 (dd, J=8.98, 1.37 Hz, 1 H), 7.90 - 7.93 (m, 1 H); MS (ESI) (M+H)+ 532.0; Anal. (C, H, N) calcd for C27H41N5O4S+2.30CF3COOH: C 47.80, H 5.50, N 8.82; found C 47.93, H 5.22, N 8.91.
Step B. N-[2-tert-ButyH-(tetrahydro-2H-pyran-4-ylmethyl)-lfT-benzimidazol-5- yl]-N-methyl-1H-imidazole-1-sulfonamide
To a solution of 2-fer^-butyl-N-methyl-1-(tetrahydro-2iϊ'-pyran-4-ylmethyl)-1H- benzimidazol-5-amine (1.97 g, 6.54 mmol) at room temperature in MeCN (40 mL),
was added l-(1H-imidazol-1-ylsulfonyl)-3-methyl-1H-imidazol-3-ium (3.6g, 9.81 mmol) in one portion. The solution was stirred at room temperature overnight. After evaporation of the solvent, the residue was purified by flash chromatography (0-100% EtOAc in hexanes, 50min; 100% EtOAc, lOmin; 0-2% MeOH in EtOAc, lOmin) to afford the product (1.24 g, 44%). MS (ESI) (M+H)+ 432.0.
Step C. 1-{[[2-tert-Butyl-1-(tetrahydro-2J3-pyran-4-ylmethyl)-1H-benzimidazol- 5-yl](methyl)amino]sulfonyl}-3-methyHH-imidazol-3-ium
To a solution of N- [2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethy I)-ITf - benzimidazol-5-yl]-N-methyl-liϊ'-imidazole-1-sulfonamide (1.24 g, 2.88 mmol) at room temperature in MeCN (20 mL), was added methyl trifluoromethanesulfonate (0.49 mL, 4.32 mmol) dropwise. The solution was stirred at room temperature for 5 hours. After evaporation of the solvent, the residue was used directly for the next step without purification (1.0 g, 76%). MS (ESI) (M+H)+ 446.0.
Step D. 1-{[[2-ter^-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol- 5-yl](methyl)amino]sulfonyl}piperidine-4-carboxylate
To a solution of 1-{[[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H- benzimidazol-5-yl](methyl)amino]sulfonyl}-3-methyl-1H-imidazol-3-ium (1 g, 2.2 mmol) and diisopropylethylamine (0.38 mL, 2.2 mmol) at room temperature in MeCN (15 mL), was added methyl isonipecotate (0.61 mL, 4.5 mmol) in one portion. The solution was stirred at room temperature overnight. After evaporation of the solvent, the residue was purified by flash chromatography (0-100% EtOAc in hexanes, 50min; 100% EtOAc, lOmin; 0-2% MeOH in EtOAc, lOmin) to provide the title compound (1.08 g, 97%). MS (ESI) (M+H)
+ 507.0.
Step E. 1-{[[2-ter<-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benziinidazol- 5-yl] (methyl) amino] sulfonyl}piperidine-4-carboxylic acid
To a solution of methyl 1-{[[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-li/'- benzimidazol-5-yl](methyl)amino]sulfonyl}piperidine-4-carboxylate (1.08 g, 2.13 mmol) at O0C in MeOH:H2O (3:1, 20 mL), was added LiOH (178.5 mg, 7.46 mmol) in one portion. The solution was stirred at O0C, slowly warmed to room temperature and stirred at room temperature overnight. The solution was adjusted to pH 2 with IN HCl (12 mL), the aqueous layer was extracted with DCM. The organic layers were dried over Na2SO4, and subjected to filtration. Evaporation of the solvent provided the title compound (2.2 g, 92%). MS (ESI) (M+H)+ 493.0.
Example 11 1-{[[2-te/^-Butyl-1-(tetrahydro-2N-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino]sulfonyl}-N-isopropylpiperidine-4-carboxamide
Following the procedure for Step A in Example 10, using 1-{[[2-tert-butyl-1- (tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino]sulfonyl}piperidine-4-carboxylic acid (200 mg, 0.41 mmol), diisopropylethylamine (0.17 mL, 0.96 mmol), isopropylamine (0.11 mL, 1.22 mmol), DMF (6 mL), and HATU (182.6 mg, 0.48 mmol) provided the title compound as its TFA salt (150 mg, 57 %) following purification by reversed-phase HPLC (10-60% CH3CN in H2O). 1H NMR (400 MHz, CDCl3) δ 1.13 (d, J=6.64 Hz, 6 H) 1.52 - 1.70 (m, 6 H) 1.72 (s, 9 H) 1.76 - 1.84 (m, 2 H) 2.13 - 2.23 (m, 1 H) 2.27 - 2.40 (m, 1 H) 2.71 - 2.85 (m, 2 H) 3.32 (s, 3 H) 3.34 - 3.41 (m, 2 H) 3.62 - 3.72 (m, 2 H) 3.98 - 4.09 (m, 3 H) 4.37 (d, J=7.42 Hz, 2 H) 5.97 (d, J=7.62 Hz, 1 H) 7.54 (d, J=8.98 Hz, 1 H) 7.68 (dd, J=8.98, 1.76 Hz, 1 H) 7.89 (d, J=I.76 Hz, 1 H); MS (ESI) (M+H)+ 534.0; Anal. (C, H, N) calcd for C27H43N5O4S+2.00CF3COOH+0.1 OCH3OH: C 48.83, H 5.98, N 9.15; found C 48.83, H 5.93, N 9.07.
Example 12 1-{[[2-tert-Butyl-1-(tetrahydro-2Jfir-pyran-4-ylmethyl)-lHr-benziraidazol-5- yl](methyl)amino]sulfonyl}-N-cyclobutylpiperidme-4-carboxamide
Following the procedure for Step A in Example 10, using l~{[[2-tert-butyl-l-
(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-
yl](methyl)amino]sulfonyl}piperidine-4-carboxylic acid (70 mg, 0.14 mmol), diisopropylethylamine (0.029 mL, 0.17 mmol), cyclobutylamine (0.030 mL, excess), DMF (3 mL), and HATU (64.6 mg, 0.17 mmol) provided the title compound as its TFA salt (37.8 mg, 40 %) following purification by reversed-phase HPLC (10-70% CH3CN in H2O). 1H NMR (400 MHz, CDCl3) δ 1.52 - 1.71 (m, 10 H), 1.72 (s, 9 H), 1.77 - 1.95 (m, 3 H), 2.12 - 2.23 (m, 1 H), 2.23 - 2.39 (m, 3 H), 2.74 - 2.85 (m, 2 H), 3.33 (s, 3 H), 3.34 - 3.41 (m, 2 H), 3.66 (d, J=15.04 Hz, 2 H), 4.04 (d, J=10.94 Hz, 2 H), 4.37 (d, J=7.42 Hz, 2 H), 6.35 (d, J=8.01 Hz, 1 H), 7.53 (d, J=8.98 Hz, 1 H), 7.69 (dd, J=9.08, 1.86 Hz, 1 H), 7.90 (d, J=I .76 Hz, 1 H); MS (ESI) (M+H)+ 546.0; Anal. (C, H, N) calcd for C2SH43N5O4S+2.1 OCF3COOH: C 49.26, H 5.79, N 8.92; found C 49.21, H 5.65, N 9.07.
Example 13 1-{[[2-tert-Butyl-1-(tetrahydro-2J?-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino]sulfonyl}-N-cyclopentylpiperidine-4-carboxamide
Following the procedure for Step A in Example 10, using 1-{[[2-ter£-butyl-1- (tetrahydro-2H-pyran-4-ylmethyl)-l//-benzimidazol-5- yl](methyl)amino]sulfonyl}piperidine-4-carboxylic acid (70 mg, 0.14 mmol), diisopropylethylamine (0.029 mL, 0.17 mmol), cyclopentylamine (0.030 mL, excess), DMF (3 mL), and HATU (64.6 mg, 0.17 mmol) provided the title compound as its TFA salt (37.8 mg, 40 %) following purification by reversed-phase HPLC (10-70% CH3CN in H2O). 1H NMR (400 MHz, CDCl3) δ 1.32 - 1.42 (m, 2 H), 1.52 - 1.69 (m, 10 H), 1.72 (s, 9 H), 1.76 - 1.85 (m, 3 H), 1.89 - 2.01 (m, 2 H), 2.75 - 2.86 (m, 2 H), 3.34 (s, 3 H), 3.34 - 3.41 (m, 2 H), 3.65 - 3.73 (m, 2 H), 4.00 - 4.07 (m, 2 H), 4.11 - 4.21 (m, 1 H), 4.36 (d, J=6.84 Hz, 2 H), 7.52 (d, J=8.79 Hz, 1 H), 7.67 - 7.73 (m, J=7.81 Hz, 1 H), 7.91 - 7.95 (m, 1 H); MS (ESI) (M+H)+ 560.0; Anal. (C, H, N) calcd
for C29H45N5O4S+I.7OCF3COOH+O.2OH2O +0.40CH3OH: C 51.16, H 6.37, N 9.09; found C 51.15, H 6.34, N 9.00.
Example 14 1-{ [ [2-tørt-Butyl-1-(tetrahy dro-2i?-pyran-4-ylmethyl)-ljHr-benzimidazol-5- yl](methyl)amino]sulfonyl}-N-pyrrolidin-1-ylpiperidine-4-carboxamide
Following the procedure for Step A in Example 10, using 1-{[[2-te?t-butyl-1- (tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino]sulfonyl}piperidine-4-carboxylic acid (70 mg, 0.14 mmol), diisopropylethylamine (0.029 mL, 0.17 mmol), 1-aminopyrrolidine hydrochloride (20.8 mg, 0.17 mmol), DMF (3 mL), and HATU (64.6 mg, 0.17 mmol) provided the title compound as its TFA salt (37.8 mg, 40 %) following purification by reversed- phase HPLC (10-60% CH3CN in H2O). 1HNMR (400 MHz, CDCl3) δ 1.52 - 1.70 (m, 7 H)5 1.72 (s, 9 H), 1.74 - 1.84 (m, 2 H), 2.12 - 2.23 (m, 4 H), 2.37 - 2.48 (m, 1 H), 2.87 - 3.00 (m, 3 H), 3.33 (s, 3 H), 3.34 - 3.41 (m, 2 H), 3.44 - 3.53 (m, 2 H), 3.65 - 3.74 (m, 4 H), 3.99 - 4.07 (m, 2 H), 4.38 (d, J=7.42 Hz, 2 H), 7.57 (d, J=8.89 Hz, 1 H), 7.69 (dd, J=8.89, 2.05 Hz, 1 H), 7.88 (d, J=2.05 Hz, 1 H); MS (ESI) (M+H)+ 561.0; Anal. (C5 H, N) calcd for C2sH44N6O4S+2.75CF3COOH+0.55H2O +0.15CH3OH: C 45.46, H 5.49, N 9.45; found C 45.47, H 5.495 N 9.46.
Example 15 1-{[[2-tert-Butyl-1-(tetrahydro-2Jy-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino]sulfonyl}-N-1H-pyrrol-1-ylpiperidine-4-carboxamide
Following the procedure for Step A in Example 10, using l-{[[2-tert-buty\-l- (tetrahydro-2H-pyran-4-ylmemyl)-1H-benzimidazol-5- yl](methyl)amino]sulfonyl}piperidine-4-carboxylic acid (70 mg, 0.14 mmol), diisopropylethylamine (0.029 mL, 0.17 mmol), 1-aminopyrrole (0.030 mL, excess), DMF (3 mL), and HATU (64.6 mg, 0.17 mmol) provided the title compound as its TFA salt (37.8 mg, 40 %) following purification by reversed-phase HPLC (10-70% CH3CN in H2O). 1H NMR (400 MHz, CDCl3) δ 1.50 - 1.63 (m, 4 H), 1.71 (s, 9 H), 1.72 - 1.95 (m, 2 H), 2.26 - 2.50 (m, 2 H), 2.75 - 2.86 (m, 2 H), 3.23 - 3.41 (m, 6 H), 3.58 - 3.72 (m, 3 H), 3.96 - 4.08 (m, 2 H), 4.37 (d, J=7.42 Hz, 2 H), 6.06 - 6.15 (m, 2 H), 6.56 - 6.61 (m, 2 H), 7.56 (d, J=9.18 Hz, 1 H), 7.68 - 7.73 (m, 1 H), 7.91 (d, J=I.17 Hz, 1 H); MS (ESI) (M+H)+ 557.0; Anal. (C3 H, N) calcd for C28H40N6O4S+1.75CF3COOH+0.35CH3OH: C 49.85, H 5.67, N 10.95; found C 49.97, H 5.61, N 10.84.
Example 16 1-{[[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino]sulfonyl}-N-ethylpiperidine-4-carboxamide
Following the procedure for Step A in Example 10, using 1-{[[2-tert-butyl-1- (tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino]sulfonyl}piperidine-4-carboxylic acid (70 mg, 0.14 mmol),
diisopropylethylamine (0.029 mL, 0.17 mmol), ethylamine (0.21 mL, 0.43 mmol), DMF (3 mL), and HATU (64.6 mg, 0.17 mmol) provided the title compound as its TFA salt (41.5 mg, 46 %) following purification by reversed-phase HPLC (10-65% CH3CN in H2O). 1HNMR (400 MHz, CDCl3) δ 1.12 (t, J=7.13 Hz, 3 H), 1.51 - 1.69 (m, 6 H), 1.72 (s, 9 H), 1.75 - 1.86 (m, 2 H)5 2.19 - 2.41 (m, 2 H), 2.70 - 2.82 (m, 2 H), 3.21 - 3.28 (m, 2 H), 3.30 (s, 3 H), 3.31 - 3.41 (m, 2 H), 3.56 - 3.67 (m, 2 H), 3.98 - 4.08 (m, 2 H), 4.39 (d, J=7.42 Hz, 2 H), 6.47 - 6.56 (m, 1 H), 7.56 - 7.62 (m, 1 H), 7.63 - 7.69 (m, 1 H), 7.87 (s, 1 H); MS (ESI) (M+H)+ 520.0; Anal. (C, H, N) calcd for C26H41N5O4S+2.35CF3COOH: C 46.81, H 5.55, N 8.89; found C 46.49, H 5.09, N 9.32.
Example 17 N-(tert-Butyl)-1-{[[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H- benzimidazol-5-yl](methyl)amino]sulfonyl}piperidine-4-carboxamide
Following the procedure for Step A in Example 10, using 1-{[[2-ter^-butyl-1- (tetrahydro-2H-pyran-4-ylmethyl)-li/-benzimidazol-5- yl](methyl)amino]sulfonyl}piperidine-4-carboxylic acid (70 mg, 0.14 mmol), diisopropylethylamine (0.029 mL, 0.17 mmol), f-butylamine (0.045 mL, 0.43 mmol), DMF (3 mL), and HATU (64.6 mg, 0.17 mmol) provided the title compound as its TFA salt (44.2 mg, 47 %) following purification by reversed-phase HPLC (10-70% CH3CN in H2O). 1H NMR (400 MHz, CDCl3) δ 1.32 (s, 9 H), 1.52 - 1.70 (m, 6 H), 1.71 (s, 9 H), 1.73 - 1.81 (m, 2 H), 2.05 - 2.18 (m, 1 H), 2.26 - 2.40 (m, 1 H), 2.69 - 2.81 (m, 2 H), 3.31 (s, 3 H), 3.32 - 3.42 (m, 2 H), 3.63 - 3.71 (m, 2 H)3 3.99 - 4.07 (m, 2 H), 4.38 (d, J=7.42 Hz, 2 H), 5.79 - 5.85 (m, 1 H), 7.57 (d, J=8.98 Hz, 1 H)5 7.68 (dd, J=8.98, 1.37 Hz, 1 H)5 7.82 - 7.86 (m, 1 H); MS (ESI) (M+H)+ 548.0; Anal. (C5
H, N) calcd for C28H45N5O4S+2.10CF3COOH+1.25H2O: C 47.76, H 6.17, N 8.65; found C 47.45, H 5.88, N 8.96.
Example 18 1-{ [ [2-ter?-Butyl-1-(tetrahydro-2J?-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino]sulfonyl}-Λr,N-dimethylpiperidine-4-carboxamide
Following the procedure for Step A in Example 10, using 1-{[[2-tert-butyl-1- (tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino]sulfonyl}piperidine-4-carboxylic acid (70 mg, 0.14 mmol), diisopropylethylamine (0.029 μL, 0.17 mmol), NjN-dimethylamine (0.21 mL, 0.43 mmol), DMF (3 mL), and HATU (64.6 mg, 0.17 mmol) provided the title compound as its TFA salt (33.7 mg, 37 %) following purification by reversed-phase HPLC (10- 60% CH3CN in H2O). 1H NMR (400 MHz, CDCl3) δ 1.52 - 1.65 (m, 5 H), 1.65 - 1.79 (m, 12 H), 2.25 - 2.40 (m, 1 H), 2.63 - 2.75 (m, 1 H), 2.84 - 2.92 (m, 2 H), 2.93 (s, 3 H), 3.06 (s, 3 H), 3.32 (s, 3 H), 3.33 - 3.41 (m, 2 H), 3.68 - 3.77 (m, 2 H), 3.98 - 4.08 (m, 2 H), 4.37 (d, J=7.42 Hz, 2 H), 7.54 (d, J=8.98 Hz, 1 H), 7.68 (dd, J=8.98, 0.98 Hz, 1 H), 7.89 - 7.93 (m, 1 H); MS (ESI) (M+H)+ 520.0; Anal. (C, H, N) calcd for C26H41N5O4S+1.80CF3COOH+0.75H2O: C 48.14, H 6.05, N 9.48; found C 48.09, H 6.00, N 9.57.
Example 19 1-{[[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-beiizimidazol-5- yl](methyl)amino]sulfonyl}-N,iV-diethylpiperidine-4-carboxamide
Following the procedure for Step A in Example 10, using 1-{[[2-fert-butyl-1- (tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino]sulfonyl}piperidine-4-carboxylic acid (70 mg, 0.14 mmol), diisopropylethylamine (0.029 mL, 0.17 mmol), ΛζN-diethylamine (0.044 mL, 0.43 mmol), DMF (3 mL), and HATU (64.6 mg, 0.17 mmol) provided the title compound as its TFA salt (12.1 mg, 13 %) following purification by reversed-phase HPLC (10- 70% CH3CN in H2O). 1H NMR (400 MHz, CDCl3) δ 1.08 (t, J=7.13 Hz, 3 H), 1.19 (t, J=7.03 Hz, 3 H), 1.52 - 1.62 (m, 4 H), 1.65 - 1.69 (m, 1 H), 1.72 (s, 9 H), 1.72 - 1.87 (m, 3 H), 2.54 - 2.64 (m, 1 H), 2.86 - 2.96 (m, 2 H), 3.28 - 3.40 (m, 10 H), 3.71 - 3.80 (m, 2 H), 3.99 - 4.07 (m, 2 H), 4.35 (d, J=7.42 Hz, 2 H), 7.49 (d, J=8.98 Hz, 1 H), 7.70 (dd, J=8.98, 1.76 Hz, 1 H), 7.93 (d, J=I.76 Hz, 1 H); MS (ESI) (M+H)+ 548.0.
Example 20 1-{ [ P-tert-Butyl-1-Ctetrahydro-lH-pyran^-ylmethyl)-lN-benzimidazol-S- yl](methyl)amino]sulfonyl}-N-methylpiperidine-4-carboxamide
Following the procedure for Step A in Example 10, using 1-{[[2-tert-butyl~l- (tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino]sulfonyl}piperidine-4-carboxylic acid (70 mg, 0.14 mmol), diisopropylethylamine (0.029 mL, 0.17 mmol), methylamine (0.21 mL, 0.43 mmol),
DMF (3 mL), and HATU (64.6 mg, 0.17 mmol) provided the title compound as its TFA salt (22.9 mg, 26 %) following purification by reversed-phase HPLC (10-60% CH3CN in H2O). 1H NMR (400 MHz, CDCl3) δ 1.57 (d, 4 H), 1.65 - 1.76 (m, 12 H), 1.81 - 1.90 (m, 3 H), 2.79 (d, J=4.49 Hz, 3 H), 2.80 - 2.87 (m, 2 H), 3.33 (s, 3 H), 3.34 - 3.41 (m, 2 H), 3.61 - 3.69 (m, 2 H), 3.99 - 4.08 (m, 2 H), 4.36 (d, J=7.42 Hz, 2 H), 7.52 (d, J=9.18 Hz, 1 H), 7.70 (dd, J=9.18, 1.66 Hz, 1 H), 7.96 - 7.99 (m, 1 H); MS (ESI) (M+H)+ 506.0; Anal. (C, H, N) calcd for
C25H39N5O4S+I.9OCF3COOH+O.2OH2O +0.25CH3OH: C 47.54, H 5.81, N 9.54; found C 47.54, H 5.82, N 9.53.
Example 21 1-{[[2-tert-Butyl-1-(tetrahydro-2JH-pyran-4-ylmethyl)-1Hr-benzimidazol-5- yl](methyl)amino]sulfonyl}-N-propylpiperidine-4-carboxamide
Following the procedure for Step A in Example 10, using 1-{[[2-tert-butyl-1- (tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino]sulfonyl}piperidine-4-carboxylic acid (70 mg, 0.14 mmol), diisopropylethylamine (0.074 mL, 0.43 mmol), λζN-diethylamine (0.035 mL, 0.43 mmol), DMF (3 mL), and ΗATU (81 mg, 0.21 mmol) provided the title compound as its TFA salt (31.1 mg, 34 %) following purification by reversed-phase ΗPLC (10-70% CH
3CN in H
2O).
1H NMR (400 MHz, CDCl
3) δ 0.89 (t, J=7.42 Hz, 3 H), 1.44 - 1.71 (m, 8 H), 1.72 (s, 9 H), 1.75 - 1.87 (m, 2 H), 2.17 - 2.41 (m, 2 H)
5 2.72 - 2.85 (m, 2 H), 3.14 - 3.23 (m, 2 H), 3.32 (s, 3 H), 3.33 - 3.42 (m, 2 H), 3.59 - 3.70 (m, 2 H), 3.98 - 4.09 (m, 2 H), 4.38 (d, J=7.42 Hz, 2 H), 6.30 - 6.42 (m, 1 H), 7.55 (d, J=8.98 Hz, 1 H), 7.68 (dd, J=8.98, 1.76 Hz, 1 H), 7.91 (d, J=I.76 Hz, 1 H); MS (ESI) (M+H)
+ 534.0; Anal. (C, H, N) calcd for C
27H
43N
5O
4S+1.80CF
3COOH+0.90CH
3OH: C 49.28, H 6.29, N 9.06; found C 49.25, H 6.29, N 9.06.
Example 22 N-Butyl-1-{[[2-ter-
I-butyl-1-(tetrahydro-2J9
r-pyran-4-yIraethyI)-l
Jff-benzimidazol-
5-yl](methyl)amino]sulfonyl}piperidine-4-carboxamide
Following the procedure for Step A in Example 10, using 1-{[[2-tert-butyl-1- (tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimiάazol-5- yl](methyl)amino]sulfonyl}piperidine-4-carboxylic acid (70 mg, 0.14 mmol), diisopropylethylamine (0.074 mL, 0.43 mmol), ΛζN-butylamine (42 μL, 0.43 mmol), DMF (3 mL), and HATU (81 mg, 0.21 mmol) provided the title compound as its TFA salt (31.1 mg, 34 %) following purification by reversed-phase HPLC (10-70%
CH3CN in H2O). 1H NMR (400 MHz, CDCl3) δ 0.90 (t, J=7.32 Hz, 3 H), 1.24 - 1.39 (m, 2 H), 1.41 - 1.52 (m, 2 H), 1.52 - 1.70 (m, 6 H), 1.72 (s, 9 H), 1.77 - 1.87 (m, 2 H), 2.15 - 2.41 (m, 2 H), 2.74 - 2.87 (m, 2 H), 3.16 - 3.26 (m, 2 H), 3.32 (s, 3 H), 3.33 - 3.41 (m, 2 H), 3.60 - 3.72 (m, 2 H), 3.98 - 4.08 (m, 2 H), 4.37 (d, J=7.42 Hz, 2 H), 6.18 - 6.30 (m, 1 H), 7.54 (d, J=8.98 Hz, 1 H), 7.67 (dd, J=8.98, 1.76 Hz, 1 H), 7.94 (d, J=I.76 Hz, 1 H); MS (ESI) (M+H)+ 548.0; Anal. (C, H, N) calcd for C28H45N5O4S+!.55CF3COOH: C 50.56, H 6.48, N 9.67; found C 50.95, H 5.92, N 10.27.
Example 23 1-{[[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1-H
r-benzimidazol-5- yl](methyl)amino]sulfonyl}-N-(2,2,2-trifluoroethyl)piperidine-4-carboxamide
Following the procedure for Step A in Example 10, using 1-{[[2-tert-butyl-1- (tetrahydro-2i/-pyran-4-ylmetriyl)-lijr-benzimidazol-5- yl](methyl)amino]sulfonyl}piperidine-4-carboxylic acid (100 mg, 0.20 mmol), diisopropylethylamine (0.1 mL, 0.61 mmol), 2,2,2-trifluoroethylamine (0.050 mL, 0.61 mmol), DMF (3 mL), and HATU (116 mg, 0.31 mmol) provided the title compound as its TFA salt (59.2 mg, 42 %) following purification by reversed-phase HPLC (10-70% CH3CN Ui H2O). 1H NMR (400 MHz, CDCl3) δ 1.51 - 1.70 (m, 6 H), 1.72 (S5 9 H), 1.76 - 1.85 (m, 2 H), 2.25 - 2.39 (m, 2 H), 2.72 - 2.84 (m, 2 H), 3.28 - 3.41 (m, 5 H), 3.58 - 3.65 (m, 2 H), 3.82 - 3.94 (m, 2 H), 4.00 - 4.07 (m, 2 H), 4.38 (d, J=7.42 Hz, 2 H), 7.05 - 7.14 (m, 1 H), 7.56 (d, J=8.98 Hz, 1 H), 7.68 (dd, J=8.98, 1.46 Hz, 1 H), 7.91 - 7.94 (m, 1 H); MS (ESI) (M+H)+ 573.8; Anal. (C, H, N) calcd for C26H38F3N5O4S-Hl.85CF3COOH: C 54.44, H 6.68, N 12.21; found C 45.49, H 4.94, N 8.87.
Example 24 N-Allyl-1-{[[2-tert-butyl-1-(tetrahydro-2jH-pyran-4-ylmethyl)-lJH-benzimidazol-
5-yl](methyl)amino]sulfonyl}piperidine-4-carboxamide
Following the procedure for Step A in Example 10, using 1-{[[2-tert-butyl-1-
(tetrahydro-27f-pyran-4-ylmethyl)-1H-benzimidazol-5-
yl](methyl)amino]sulfonyl}piperidine-4-carboxylic acid (100 mg, 0.20 mmol), diisopropylethylamine (0.1 mL, 0.61 mmol), allylamine (0.1 mL, 0.61 mmol), DMF (3 mL), and HATU (116 mg, 0.31 mmol) provided the title compound as its TFA salt (27.6 mg, 25 %) following purification by reversed-phase HPLC (10-60% CH3CN in H2O). 1H NMR (400 MHz, CDCl3) δ 1.51 - 1.79 (m, 17 H), 1.80 - 1.90 (m, 2 H), 2.76 - 2.88 (m, 2 H), 3.33 (s, 3 H), 3.34 - 3.41 (m, 2 H), 3.63 - 3.72 (m, 2 H), 3.82 - 3.89 (m, 2 H), 3.98 - 4.08 (m, 2 H), 4.36 (d, J=7.42 Hz, 2 H), 5.07 - 5.20 (m, 2 H), 5.75 - 5.89 (m, 1 H), 6.25 - 6.33 (m, 1 H), 7.52 (d, J=8.98 Hz, 1 H), 7.69 (dd, JM8.98, 1.95 Hz, 1 H), 7.94 (d, J=I.95 Hz, 1 H); MS (ESI) (M+H)+ 532.0;
Example 25 1-{[[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino]sulfonyl}-N-isobutylpiperidine-4-carboxamide
Following the procedure for Step A in Example 10, using 1-{[[2-tert-butyl-1-
(tetrahydro-2Jf-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino]sulfonyl}piperidine-4-carboxylic acid (200 mg, 0.41 mmol), diisopropylethylamine (0.2 mL, 1.22 mmol), isobutylamine (0.12 mL, 1.22 mmol), DMF (6 mL), and HATU (236 mg, 0.62 mmol) provided the title compound as its TFA salt (99.6 mg, 37 %) following purification by reversed-phase HPLC (10-70% CH3CN in H2O). 1H NMR (400 MHz, CD3OD) δ 0.87 (d, J=6.84 Hz, 6 H) 1.51 - 1.67 (m, 7 H) 1.69 (s, 9 H) 1.70 - 1.77 (m, 3 H) 2.23 - 2.33 (m, 1 H) 2.81 - 2.91 (m, 2 H) 2.91 - 2.99 (m, 2 H) 3.33 (s, 3 H) 3.33 - 3.39 (m, 2 H) 3.66 - 3.74 (m, 2 H) 3.90 - 3.97 (m, 2 H) 4.54 (d, J=7.42 Hz, 2 H) 7.68 (dd, J=8.98, 1.95 Hz, 1 H) 7.81 (d, J=I.95 Hz, 1 H) 7.96 (d, J=8.98 Hz, 1 H); MS (ESI) (M+H)+ 458.0.
Example 26
1-{[[2-tert-Butyl-1-(tetrahydro-2iar-pyran-4-ylmethyl)-lJ3r-benzimidazol-5- yl](methyl)amino]sulfonyl}-N-(2-hydroxy-1-methylethyl)piperidme-4- carboxamide
Following the procedure for Step A in Example 10, using 1-{[[2-tert-butyl-1- (tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino]sulfonyl}piperidine-4-carboxylic acid (175 mg, 0.36 mmol), diisopropylethylamine (0.15 mL, 0.85 mmol), DL-2-amino-1-propanol (0.08 mL, 1.07 mmol), DMF (5 mL), and HATU (162 mg, 0.43 mmol) provided the title compound as its TFA salt (66.9 mg, 28 %) following purification by reversed-phase HPLC (10- 40% CH
3CN in H
2O).
1H NMR (400 MHz, CDCl
3) δ 1.13 (d, J=6.64 Hz, 3 H) 1.51 - 1.68 (m, 7 H) 1.72 (s, 9 H) 1.75 - 1.86 (m, 1 H) 2.19 - 2.41 (m, 2 H) 2.67 - 2.91 (m, 2 H) 3.32 (s, 2 H) 3.33 - 3.41 (m, 3 H) 3.43 - 3.70 (m, 4 H) 3.97 - 4.09 (m, 3 H) 4.39 (d, J=7.62 Hz, 2 H) 6.76 (d, J=7.42 Hz, 1 H) 7.55 - 7.60 (m, 1 H) 7.64 - 7.68 (m, 1 H) 7.84 (d, J=I.95 Hz, 1 H); MS (ESI) (M+H)
+ 549.8.
Example 27 1-{[[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-lJHr-benzimidazol-5- yl](methyl)amino]sulfonyl}-N-(2-hydroxyethyl)piperidine-4-carboxamide
Following the procedure for Step A in Example 10, using 1-{[[2-tert-butyl-1-
(tetrahydro-2if-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino]sulfonyl}piperidine-4-carboxylic acid (70 mg, 0.14 mmol),
diisopropylethylamine (0.042 mL5 0.24 mmol), ethanolamine (0.010 mL, 0.17 mmol), DMF (3 mL), and HATU (59.4 mg, 0.16 mmol) provided the title compound as its TFA salt (46.4 mg, 50 %) following purification by reversed-phase HPLC (10-60% CH3CN in H2O). 1HNMR (400 MHz, CDCl3) δ 1.52 - 1.66 (m, 6 H), 1.72 (s, 9 H), 1.82 (d, J=12.50 Hz, 2 H), 2.22 - 2.42 (m, 2 H), 2.71 - 2.83 (m, 2 H), 3.30 (s, 3 H), 3.32 - 3.44 (m, 4 H), 3.52 - 3.65 (m, 2 H), 3.66 - 3.78 (m, 2 H), 3.98 - 4.07 (m, 2 H), 4.39 (d, J=7.42 Hz, 2 H), 7.15 - 7.24 (m, J=32.62 Hz, 1 H), 7.56 - 7.62 (m, 1 H), 7.63 - 7.67 (m, 1 H), 7.81 - 7.88 (m, 1 H); MS (ESI) (MH-H)+ 536.0; Anal. (C, H5 N) calcd for C26H41N5O5S+2.20CF3COOH+1.00H2O: C 45.38, H 5.66, N 8.70; found C 47.93, H 5.22, N 8.91.
Example 28
Ethyl 1-{[[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benziraidiazol-5- yl] (methyl) amino] sulf onyl} pip eridine-4-carboxylate
Following the procedure for Step J in Example 10, using 1-{[[2-tert-butyl-1-
(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl](methyl)amino]sulfonyl}-3- methyl- lif-imidazol-3-ium (1.9 g, 4.25 mmol) and diisopropylethylamine (0.1 mL, 0.6 mmol) at room temperature in MeCN (40 mL) and ethyl isonipecotate (1.9 mL, 12.75 mmol), the solution was concentrated and the residue was redissolved in EtOAc (100 mL). The solution was washed with H2O (3 x 30 mL), brine (30 mL), dried over Na2SO4 and filtered. After evaporation of the solvent, the residue was purified by flash chromatography (0-100% EtOAc in hexanes, 50mm; 100% EtOAc, lOmin; 0- 2% MeOH in EtOAc, lOmin) to provide the title compound (445 mg, 20%). 1H NMR (400 MHz, CDCl3) δ 1.24 (t, J=7.23 Hz, 3 H), 1.49 - 1.59 (m, 13 H), 1.64 - 1.77 (m, 2 H), 1.86 - 1.95 (m, 2 H), 2.22 - 2.39 (m, 2 H), 2.78 - 2.89 (m, 2 H), 3.28 (s, 3 H), 3.29 - 3.37 (m, 2 H), 3.63 - 3.71 (m, 2 H), 3.95 - 4.02 (m, 2 H), 4.13 (q, J=7.23 Hz, 2 H), 4.20 (d, J=7.42 Hz, 2 H), 7.30 (s, 1 H), 7.32 (d, J=I.95 Hz, 1 H), 7.72 (d, J=I.56 Hz, 1
H); MS (ESI) (M+H)+ 521.0; Anal. (C, H, N) calcd for C26H40N4O5S-HO-OOCH3OH: C 59.17, H 7.92, N 10.38; found C 59.23, H 8.03, N 10.45.
Example 29 N-(1-{[[2-tert-Butyl-1-(tetrahydro-2J7-pyran-4-ylmethyl)-1H-benzimidazoI-5- yl](methyl)amino]sulfonyl}azetidin-3-yl)cyclopropanecarboxamide
Step A. N-(l-{ [[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-lJΪ- benzimidazol-5-yl] (methyl)amino] sulfonyl} azetidin-3- ytycyclopropanecarboxamide
To a solution of 3-amino-N-[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H- benzimidazol-5-yl]-N-methylazetidine-1-sulfonamide (150 mg, 0.27 mmol, see Steps B and C for its preparation), diisopropylethylamine (0.14 mL, 0.82 mmol), and cyclopropanecarboxylic acid (0.33 mL, 0.41 mmol) at room temperature in DMF (1.5 mL), was added HATU (125.5 mg, 0.33 mmol) in one portion. The solution was stirred at room temperature for 3 hours. After evaporation of the solvent, the residue was purified by reversed-phase HPLC (10-65% CH3CN in H2O) to provide the title compound as its TFA salt (27.3 mg, 16%). 1H NMR (400 MHz, CD3OD) δ 0.72 - 0.85 (m, 4 H) 1.50 - 1.68 (m, 5 H) 1.69 (s, 9 H) 2.31 - 2.46 (m, 1 H) 3.31 - 3.40 (m, 5 H) 3.80 - 3.86 (m, 2 H) 3.91 - 3.98 (m, 2 H) 4.00 - 4.06 (m, 2 H) 4.50 - 4.59 (m, 3 H)
7.67 (dd, J=8.98, 2.15 Hz, 1 H) 7.79 (d, J=2.15 Hz, 1 H) 7.96 (d, J=8.98 Hz, 1 H); MS (ESI) (M+H)+ 503.8; Anal. (C, H, N) calcd for
C25H39N5O4S+1.80CF3COOH+0.05H2O +0.45CH3OH: C 48.18, H 5.66, N 9.67; found C 48.19, H 5.67, N 9.69.
Step B. 3-Araino-N-[2-fe^-butyl-1-(tetrahydro-2ir-pyran-4-ylmethyl)-lHr- benziraidazol-5-yl]-N-methylazetidine-1-sulfonamide
To a solution of 1-{[[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H- benzimidazol-5-yl](methyl)amino]sulfonyl}-3-methyl-1H-imidazol-3-ium (2.2 g, 4.9 mmol, see Example 10, Steps B-I for its preparation) and diisopropylethylamine (2.6 mL, 14.7 mmol) at rt in MeCN (30 mL), was added 3-N-Boc-ammo-azetidine (1.0 g, 5.9 mmol). The solution was stirred at rt overnight. After evaporation of the solvent, the residue was purified by flash chromatography (0-100% EtOAc in hexanes, 50 min; 100% EtOAc 10 min; 0-2% MeOH in EtOAc, 10 min) to provide the title compound (0.95 g, 36%). 1H NMR (400 MHz, CD3OD) δ 1.40 (s, 9 H) 1.49 - 1.65 (m, 5 H) 1.68 (s, 9 H) 2.30 - 2.45 (m, 1 H) 3.32 (s, 3 H) 3.33 - 3.39 (m, 2 H) 3.75 - 3.81 (m, 2 H) 3.89 - 4.00 (m, 4 H) 4.53 (d, J=7.62 Hz, 2 H) 7.65 (dd, J=8.98, 2.15 Hz, 1 H) 7.78 (d, J=2.15 Hz, 1 H) 7.95 (d, J=8.98 Hz, 1 H); MS (ESI) (M+H)+ 535.8; Anal. (C, H, N) calcd for C26H41N5O5S+2.10CF3COOH+0.60H2O+0.45CH3CN: C 46.44, H 5.72, N 9.49; found C 46.42, H 5.73, N 9.51.
Step C. 3-Amino-iV- [2-tert-butyl-1-(tetrahydro-2
JH
r-pyran-4-ylmethyl)-1H- benzimidazol-5-yl]-N-methylazetidine-l -sulfonamide
To a solution of terf-butyl (l-ltP-terf-butyl-1-Ctetrahydro^H-pyran^-ylmethyl)-!!/- benzimidazol-5-yl](methyl)amino]sulfonyl}azetidin-3-yl)carbamate (0.95 g, 1.77 mmol, see Step B for its preparation) at O0C in DCM (6 mL), was added TFA (6 mL, excess) dropwise. The solution was stirred at O0C for 20 min. The solution was concentrated. The residue was redissolved in DCM, washed with IN NaOH (x2), the aqueous layers were extracted with DCM (x4), the combined organic layers were dried over Na2SO4, and subjected to filtration. Evaporation of the solvent provided the title compound (778 mg, 100%). MS (ESI) (M+H)+ 436.1.
Example 30
N-(1-{[[2-tert-Butyl-1-(tetrahydro-2JHr-pyran-4-yImethyl)-lflr-benzimidazol-5- yl] (methyl)amino] sulf onyl} azetidm-3-yl)-2-methylpr op anamide
To a solution of 3-amino-N-[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H- benzimidazol-5-yl]-N-methylazetidine-1-sulfonamide (150 mg, 0.27 mmol, see Example 29, Steps B and C for its preparation) and diisopropylethylamine (0.1 mL, 0.57 mmol) in DCM (3 mL) at O
0C, was added isobutyryl chloride (0.06 mL, 0.57 mmol) dropwise. The solution was stirred at room temperature for 1.5 hours. After evaporation of the solvent, the residue was purified by reversed-phase ΗPLC (10-60% CH
3CN in H
2O) to provide the title compound as its TFA salt (21.7 mg, 15%).
1H NMR (400 MHz, CD
3OD) δ 1.07 (d, J=7.03 Hz, 6 H) 1.49 - 1.67 (m, 5 H) 1.68 (s, 9
H) 2.32 - 2.46 (m, 2 H) 3.30 - 3.39 (m, 5 H) 3.78 - 3.84 (m, 2 H) 3.90 - 3.97 (m, 2 H) 3.99 - 4.05 (m, 2 H) 4.53 (d, J=7.42 Hz, 2 H) 7.65 (dd, J=8.98, 1.95 Hz, 1 H) 7.78 (d, J=I.95 Hz, 1 H) 7.95 (d, J=8.98 Hz, 1 H); MS (ESI) (M+H)
+ 505.8; Anal. (C, H, N) calcd for C
25H
39N
5O
4S+!.60CF
3COOH+0.35CH
3CN: C 49.41, H 5.98, N 10.67; found C 49.55, H 5.84, N 10.61.
Example 31
Ar-(1-{[[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-lHr-benzimidazol-5- yl](methyl)amino]sulfonyl}azetidin-3-yl)cyclobutanecarboxamide
Following the procedure for Step A in Example 30, using 3-amino-N-[2-tert-butyl-1- (tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-N-methylazetidine- 1 - sulfonamide (100 mg, 0.23 mmol), diisopropylethylamine (0.1 mL, 0.57 mmol), DCM (3 mL), and cyclobutane carbonyl chloride (0.07 mL, 0.57 mmol) provided the title compound as its TFA salt (11.8 mg, 8 %) following purification by reversed- phase ΗPLC (10-60% CH3CN in H2O). 1H NMR (400 MHz, CD3OD) δ 1.26 - 1.32 (m, 1 H) 1.49 - 1.66 (m, 5 H) 1.68 (s, 9 H) 1.78 - 1.88 (m, 1 H) 1.92 - 2.01 (m, 1 H) 2.04 - 2.24 (m, 4 H) 3.32 (s, 3 H) 3.33 - 3.40 (m, 2 H) 3.78 - 3.84 (m, 2 H) 3.90 - 3.98 (m, 2 H) 3.99 - 4.05 (m, 2 H) 4.47 - 4.56 (m 3 H) 7.64 (dd, J=9.08, 2.05 Hz, 1 H) 7.77 (d, J=2.05 Hz, 1 H) 7.94 (d, J=9.08 Hz, 1 H); MS (ESI) (M+H)+ 517.8.
Example 32 N-(1-{[[2-tert-Butyl-1-(tetrahydro-2i?-pyran-4-ylmethyl)-l
Jfir-benzimidazol-5- yl](methyl)amino]sulfonyl}azetidin-3-yl)butanamide
Following the procedure for Step A in Example 30, using 3-amino-N-[2-?ert-butyl-1- (tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5--yl]-N-methylazetidine-1- sulfonamide (100 mg, 0.23 mmol), diisopropylethylamine (0.1 mL, 0.57 mmol), DCM (3 mL), and butyryl chloride (0.06 mL, 0.57 mmol) provided the title compound as its TFA salt (11.8 mg, 8 %) following purification by reversed-phase HPLC (10-60% CH3CN in H2O). 1H NMR (400 MHz, CD3OD) δ 0.90 (t, J=7.42 Hz, 3 H) 1.50 - 1.66 (m, 7 H) 1.68 (s, 9 H) 2.14 (t, J=7.42 Hz, 2 H) 2.31 - 2.44 (m, 1 H) 3.32 (s, 3 H) 3.33 - 3.39 (m, 2 H) 3.78 - 3.84 (m, 2 H) 3.90 - 3.97 (m, 2 H) 4.00 - 4.05 (m, 2 H) 4.53 (d, J=7.62 Hz, 2 H) 7.65 (dd, J=8.98, 1.95 Hz, 1 H) 7.78 (d, J=1.95 Hz, 1 H) 7.95 (d, J=8.98 Hz, 1 H); MS (ESI) (M+H)+ 505.8; Anal. (C, H, N) calcd for C25H39N5O4S+1.75CF3COOH+0.20H2O+0.10CH3CN: C 48.35, H 5.86, N 10.02; found C 48.33, H 5.86, N 10.01.
Example 33 N-(1-{[[2-fer^-Butyl-1-(tetrahydro-2J&-pyran-4-ylmethyl)-1H-benzimidazol-5- yl] (methyl)amino] sulfonyl} azetidin-3-yl)propanamide
Following the procedure for Step A in Example 29, using 3-amino-N-[2-tert-butyl-1- (tetrahydro-2H-pyran-4-ylmethyl)-ljyr-benzimidazol-5-yl]-N-methylazetidine-1- sulfonamide (150 mg, 0.27 mmol), diisopropylethylamine (0.14 mL, 0.82 mmol), DMF (1.5 mL), propionic acid (0.031 mL, 0.41 mmol) and HATU (125.5 mg, 0.33 mmol) provided the title compound as its TFA salt (15.5 mg, 9.5 %) following
purification by reversed-phase HPLC (10-40% CH3CN in H2O). 1H NMR (400 MHz, CD3OD) δ 1.13 (t, J=7.62 Hz, 3 H) 1.51 - 1.72 (m, 5 H) 1.74 (s, 9 H) 2.28 (q, J=7.62 Hz, 2 H) 3.31 (s, 3 H) 3.32 - 3.40 (m, 2 H) 3.71 - 3.77 (m, 2 H) 4.00 - 4.07 (m, 2 H) 4.30 - 4.40 (m, 4 H) 4.64 - 4.75 (m, 1 H) 7.50 - 7.54 (m, 1 H) 7.57 - 7.61 (m, 1 H) 8.26 - 8.31 (m, 1 H) 8.34 (d, J=I .37 Hz, 1 H); MS (ESI) (M+H)+ 491.8.
Example 34
Methyl l-{ [ [2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl] (methyl)amino] sulf onyl} azetidine-3-carboxylate
Step A. Methyl 1-{[[2-tert-butyl-1-(tetrahydro-2N-pyran-4-ylmethyl)-1H- benzimidazol-5-yl](methyl)amino]sulfonyl} azetidine-3-carboxylate
To a solution of 1 - { [[2-tert-hutyl- 1 -(tetrahydro-2H-pyran-4-ylmethyl)- IH- benzimidazol-5-yl](methyl)amino]sulfonyl}-3-methyl-1H-imidazol-3-iuni (100 nig, 0.17 mmol, see Example 10, Steps B-I for its preparation) and diisopropylethylamine (0.12 mL, 0.68 mmol) at rt in MeCN (0.8 mL), was added methyl azetidine-3- carboxylate hydrochloride (51.5 mg, 0.34 mmol). The solution was stirred at rt overnight. After evaporation of the solvent, the residue was purified by flash chromatography (0-100% EtOAc in hexanes, 50 min; 100% EtOAc 10 min; 0-2% MeOH in EtOAc, 10 min) to provide the title compound (7.8 mg, 8%).
1H NMR (400 MHz, CD
3OD) δ 1.50 - 1.55 (m, 5 H) 1.56 (s, 9 H) 2.23 - 2.36 (m, 1 H) 3.29 (s, 3 H)
3.30 - 3.42 (m, 2 H) 3.75 (s, 3 H) 3.95 - 4.08 (m, 4 H) 4.10 - 4.23 (m, 4 H) 7.28 - 7.31 (m, 2 H) 7.71 - 7.74 (m, 1 H); MS (ESI) (M+H)
+ 478.8.
Step B. Methyl azetidine-3-carboxylate hydrochloride
To a stirring suspension of 3-azetidine carboxylic acid in MeOH at O0C3 was added SOCl2 dropwise. After 20 minutes, the ice bath was removed, the solution was warmed to rt and was stirred for 2 hours. The solvent was removed in vaccuo to afford the title compound as its HCl salt (1.5g, 100%). 1H NMR (400 MHz, CD3OD) δ 3.71 - 3.77 (m, 1 H) 3.77 (s, 3 H) 4.18 - 4.31 (m, 4 H).
Example 35 N-tZKljl-Dimethylethy^-1-I^etrahydro-aH-pyran^-yOmethylJ-1H- benzimidazol-S-yyhexahydro-N-methyl-1H-azepme-1-sulfonamide
Step A. N-[2-(l,l-Dimethylethyl)-1-[(tetrahydro-2J7-pyran-4-yl)methyl]-llT- benzimidazol-5-yl]hexahydro-N-methyl-liir-azepine-l -sulfonamide
To a solution of 1-{[[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H- benzimidazol-5-yl](methyl)amino]sulfonyl}-3-methyl-1H-imidazol-3-ium (100 mg, 0.22 mmol, see Example 10, Steps B-I for its preparation) and diisopropylethylamine
(0.045 mL, 0.26 mmol) at rt in DMF (1.2 mL), was added hexamethyleneimine (0.025 niL, 0.22 mmol). The solution was stirred at 8O0C for 1 hour. After evaporation of the solvent, the residue was purified by reversed-phase HPLC (20-50% MeCN in H2O) to provide the title compound as its TFA salt (23 mg, 18%). 1H NMR (400 MHz, CDCl3) δ 1.54-1.61 (m, 8 H), 1.71 (m, 13 H), 2.27-2.35 (m, 1 H), 3.26 (s, 3 H), 3.30- 3.37 (m, 6 H), 4.01-4.03 (m, 2 H), 4.34 (d, J=7.42 Hz, 2 H), 7.48 (d, J=8.96 Hz, 1 H), 7.68 (dd, J=8.96, 1.79 Hz, 1 H), 7.88 (d, J=I.79 Hz, 1 H); MS (ESI) (M+H)+ 463.0; Anal. (C, H, N) calcd for C24H38N4O3SH-1.30CF3COOH+1.10H2O: C 50.66, H 6.63, N 8.88;. found C 50.64, H 6.59, N 8.92.
Example 36 N-[2-(l,l-Dimethylethyl)-1-[(tetrahydro-2iϊ-pyran-4-yl)methyl]-lJEr- benzimidazol-5-yl]-N,4-dimethyl-1-piperidinesulfonamide
To a solution of 1-{[[2-tert-butyl-1-(tetrahydro-2K-pyran-4-ylmethyl)-1H- benzimidazol-5-yl](methyl)amino]sulfonyl}-3-methyl-li-
'-imidazol-3-ium (100 mg, 0.22 mmol, see Example 10, Steps B-I for its preparation) and diisopropylethylamine (0.045 mL, 0.26 mmol) at rt in DMF (1.0 mL), was added 4-methylpiperidine (0.026 mL, 0.22 mmol). The solution was stirred at 8O
0C for 1.5 hours. After evaporation of the solvent, the residue was purified by reversed-phase HPLC (20-50% MeCN in H
2O) to provide the title compound as its TFA salt (27.3 mg, 22%).
1H NMR (600 MHz, CDCl
3) δ 0.93 (d, J=6.67 Hz, 3 H), 1.17-1.25 (m, 2 H), 1.46-1.66(m, 7 H), 1.71 (s, 9 H), 2.27-2.35 (m, 1 H), 2.79-2.83 (m, 2 H), 3.29 (s, 3 H), 3.33-3.37 (m, 2 H), 3.65-3.67 (m, 2 H), 4.02-4.03 (m, 2 H), 4.34-4.35 (d, 2 H), 7.49 (d, J=8.96 Hz, 1 H), 7.67 (d, J=8.96 Hz, 1 H), 7.91 (s, 1 H); MS (ESI) (M+H)
+ 463.0; Anal. (C, H, N) calcd for C
24H
38N
4O
3S+! .40CF
3COOH+0.30H
2O: C 51.28, H 6.42, N 8.93; found C 51.36, H 6.34, N 8.79.
Example 37 N-IZ-Cl^-DimethylethyO-1-lCtetrahydro^H-pyran^-yl)methyll-1H- benzimidazol-5-yl]-3-(hydroxymethyl)-N-methyl-1-piperidinesulfonamide
To a solution of 1 - { [[2-tert-butyl- 1 -(tetrahydro-2H-pyran-4-ylmethyl)- IH- benzimidazol-5-yl](methyl)amino]sulfonyl}-3-methyl-1H-imidazol-3-ium (100 mg, 0.22 mmol, see Example 10, Steps B-I for its preparation) and diisopropylethylamine (0.045 mL, 0.26 mmol) at rt in DMF (1.0 mL), was added 3-piperidine methanol (25.3 mg, 0.22 mmol). The solution was stirred at 8O
0C for 1.5 hours. After evaporation of the solvent, the residue was purified by reversed-phase ΗPLC (10-90% MeCN in H
2O) to provide the title compound as its TFA salt (24.3 mg, 19%).
1H NMR (600 MHz, CDCl
3) δ 1.04-1.10 (m, 1 H), 1.52-1.61 (m, 5 H), 1.71 (m, 12 H), 1.79-1.87 (m, 1 H), 2.28-2.35 (m, 1 H), 2.59-2.62 (m, 1 H), 2.87-2.90 (m, 1 H), 3.31 (s, 3 H), 3.32- 3.38 (m, 3 H), 3.60-3.65 (m, 3 H), 4.02-4.04 (m, 2 H), 4.36 (d, J=7.42 Hz, 2 H), 7.50 (d, J=8.70 Hz, 1 H), 7.67 (d, J=8.70 Hz, 1 H), 8.07 (s, 1 H); MS (ESI) (M+H)
+ 479.0; Anal. (C, H, N) calcd for C
24H
38N
4O
4S+1.30CF
3COOH+0.90H
2O +0.20CH
3OH: C 49.56, H 6.50, N 8.63; found C 49.53, H 6.48, N 8.58.
Example 38 N-[2-(l,l-Dimethylethyl)-1-[(tetrahydro-2J9r-pyran-4-yl)methyl]-1H- benzimidazol-5-yl]-4-hydroxy-N-methyl-1-piperidinesulfonamide
To a solution of 1-{[[2-tert-butyl-1-(tetrahydro-2ijr-pyran-4-ylmethyl)-1H- benzimidazol-5 -yl] (methy l)amino] sulfonyl} -3 -methyl- 1H-imidazol-3 -ium (100 mg, 0.22 mmol, see Example 10, Steps B-I for its preparation) and diisopropylethylamine (0.045 mL, 0.26 mmol) at rt in DMF (1.0 mL), was added 4-hydroxypiperidine (22.3 mg, 0.22 mmol). The solution was stirred at 8O
0C for 1.5 hours. After evaporation of the solvent, the residue was purified by reversed-phase HPLC (10-95% MeCN in H
2O) to provide the title compound as its TFA salt (18.9 mg, 15%).
1HNMR (600 MHz, CDCl
3) δ 1.54-1.65 (m, 6 H), 1.72 (s, 9 H)
5 1.86-1.90 (m, 2 H)
3 2.28-2.36 (m, 1 H), 3.07-3.11 (m, 2 H), 3.33 (s, 3 H), 3.33-3.38 (m, 2 H), 3.48-3.52 (m, 2 H), 3.79- 3.82 (m, 1 H), 4.02-4.04 (m, 2 H), 4.36 (d, J=7.42 Hz, 2 H), 7.51 (d, J=8.96 Hz, 1 H), 7.68 (dd, J=8.96, 1.66 Hz, 1 H), 8.07 (d, J=I.66 Hz, 1 H); MS (ESI) (M+H)
+ 465.0; Anal. (C, H, N) calcd for C
23H
36N
4O
4S+1.10CF
3COOH+0.30H
2O +0.40CH
3OH: C 50.55, H 6.51, N 9.21; found C 50.53, H 6.50, N 9.19.
Example 39
^-^-(ljl-Dimethylethy^-1-f^etrahydro^H-pyran^-yOmethyll-1H- benzimidazol-5-yl]-4-methoxy-N-methyl-1-piperidinesulfonaniide
To a solution of 1-{[[2-tert-butyl-1-(tetrahydro-2/f-pyran-4-ylmethyl)-1H- benzimidazol-5-yl](methyl)amino]sulfonyl}-3-methyl-1H-imidazol-3-ium (100 mg, 0.22 mmol, see Example 10, Steps B-I for its preparation) and diisopropylethylamine (0.090 mL, 0.53 mmol) at rt in DMF (1.0 mL), was added 4-methoxypiperidine hydrochloride (25.3 mg, 0.22 mmol). The solution was stirred at 8O0C for 1 hour. After evaporation of the solvent, the residue was purified by reversed-phase HPLC (20-50% MeCN in H2O) to provide the title compound as its TFA salt (6.74 mg, 5%). MS (ESI) (M+H)+ 479.0.
Example 40
N-[2-(l,l-Dimethylethyl)-1-[(tetrahydro-2H-pyran-4-yl)methyl]-1H- benzimidazol-5-yl]-3-hydroxy-N-methyl-1-piperidinesulfonamide
To a solution of 1-{[[2-tert-butyl-1-(tetrahydro-2/i
'-pyran-4-ylmethyl)-1H- benzimidazol-5 -yl] (methyl)aniino] sulf onyl} -3 -methyl- l/i-imidazol-3 -ium ( 100 mg, 0.22 mmol, see Example 10, Steps B-I for its preparation) and diisopropylethylamine (0.090 mL, 0.53 mmol) at rt in DMF (1.0 mL), was added 3-hydroxypiperidine (22.3 mg, 0.22 mmol). The solution was stirred at 8O
0C for 1 hour. After evaporation of the solvent, the residue was purified by reversed-phase HPLC (10-90% MeCN in H
2O) to provide the title compound as its TFA salt (16.0 mg, 13%). MS (ESI) (M+H)
+ 465.0.
Example 41 N-[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-N- methylazetidine-1 -sulfonamide
To a solution of 1-{[[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H- benzimidazol-5-yl](methyl)amino]sulfonyl} -3-methyl-1H-imidazol-3-ium triflate in acetonitrile (2.8 mL, 0.344 mmol) (for preparation, see Example 2, Step G) was added azetidine (35 μL; 0.516 mmol). The reaction mixture was stirred at room temperature overnight, then Hunig's base (72 μL; 0.413 mmol) was added and the reaction mixture stirred at room temperature for another day. The reaction mixture was
concentrated under reduced pressure. The residue was taken in ethyl acetate and washed with IN hydrochloric acid, 2N sodium hydroxide, brine and water. The aqueous layers were combined and extracted with ethyl acetate. Organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by reverse phase chromatography provided the title compound (14.5 mg, 10 %). 1H NMR (600 MHz, CD3OD) δ 1.40-1.53 (m, 4H), 1.57 (s, 9H), 2.14 (q, J= 7.68Hz, 2H), 2.23-2.33 (m, 1H), 3.22 (s, 3H), 3.25 (m, 2H), 3.80 (t, J= 7.68Hz, 4H), 3.84 (dd, J= 11.26, 3.58Hz, 2H), 4.41 (d, J= 7.42Hz, 2H), 7.51 (d, J= 8.70Hz, 1H), 7.67 (d, J= 1.79Hz, 1H), 7.80 (d, J= 8.45Hz, 1H); MS (ESI) (M+H)+ 421.0
Example 42
N-[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-4,4- difluoro-N-methylpiperidine-1 -sulfonamide
Following the procedure for Step A in Example 41, using 4,4-difluoropiperidine (63 mg; 0.516 mmol) and Hunig's base (72 μL; 0.413 mmol) provided the title compound (68.4 mg; 41%). 1H NMR (600 MHz, CD3OD) δ 1.42-1.57 (m, 4H), 1.60 (s, 9H), 1.90 (m, 4H), 2.26-2.34 (br s, 1H), 3.24 (s, 3H), 3.25-3.34 (m, 6H), 3.84 (dd, J= 10.75, 2.56Hz, 2H), 4.46 (d, J= 6.91Hz, 2H), 7.60 (d, J= 8.19Hz, 1H), 7.76 (s, 1H), 7.90 (d, J= 8.70Hz, 1H); MS (ESI) (M+H)+ 485.0
Example 43
N-[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-3,3- difluoro-N-methylpy r rolidine-1-sulf onamide
Following the procedure for Step A in Example 41, using 3,3-difluoropyrrolidine (55 mg; 0.516 mmol) and Hunig's base (72 μL; 0.413 mmol) provided the title compound (40.0 mg; 24%). 1HNMR (600 MHz, CD3OD) δ 1.40-1.55 (m, 4H), 1.59 (s, 9H), 2.22-2.37 (m, 3H), 3.21-3.31 (m, 2H), 3.25 (s, 3H), 3.44 (t, J= 7.17Hz, 2H), 3.52 (t, J = 12.80Hz, 2H), 3.84 (m, 2H), 4.45 (d, J= 7.17Hz, 2H), 7.59 (d, J= 7.94Hz, 1H), 7.74 (s, 1H), 7.89 (d, J= 8.70Hz, 1H); MS (ESI) (M+H)+ 471.0
Example 44 Methyl 1-{[[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol- 5-yl](methyl)amino]sulfonyl}piperidine-4-carboxylate
Following the procedure for Step A in Example 41, using methyl isonipecotate (70 μL; 0.516 mmol) and Hunig's base (72 μL; 0.413 mmol) provided the title compound (71.5 mg; 41%). 1HNMR (600 MHz, CD3OD) δ 1.37-1.55 (m, 6H), 1.59 (s, 9H)3 1.78 (m, 2H), 2.24-2.33 (br. s, 1H), 2.38 (m, 1H), 2.82 (m, 2H), 3.17-3.30 (m, 2H), 3.22 (s, 3H), 3.47-3.61 (m, 2H), 3.54 (s, 3H), 3.83 (d, J= 8.45Hz, 2H), 4.45 (d, J= 7.17Hz, 2H), 7.57 (d, J= 7.94Hz, 1H), 7.75 (s, 1H), 7.87 (d, J= 8.45Hz, 1H); MS (ESI) (M+H)+ 507.0
Example 45
N-[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-N- methylisoxazolidine-2-sulfonamide
Following the procedure for Step A in Example 41, using isoxazolidine (57 mg; 0.516 mmol) and Hunig's base (132 μL; 0.757 mmol) provided the title compound (51.3 mg; 34%). 1H NMR (600 MHz, CD3OD) δ 1.43-1.56 (m, 4H), 1.60 (s, 9H), 2.22-2.35 (m, 3H), 3.26 (m, 2H), 3.37 (s, 3H), 3.47 (t, J= 7.17Hz, 2H), 3.85 (m, 2H), 4.03 (t, J = 7.30Hz, 2H), 4.46 (d, J= 7.17Hz, 2H), 7.63 (dd, J= 8.70, 1.02Hz, 1H), 7.80-7.84 (d, J= 1.28Hz, 1H), 7.88 (d, J= 8.96Hz, 1H); MS (ESI) (M+H)+ 437.0
Example 46 (4R)-N-[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl]-4-hydroxy-N,4-dimethylisoxazolidine-2-sulfonamide
Following the procedure for Step A in Example 41, using 4-methylisoxazolidin-4-ol (57 mg; 0.41 mmol) and Hunig's base (57 μL; 0.33 mmol) provided the title compound. 1H NMR (600 MHz, CD3OD) δ 1.35 (s, 3H), 1.41-1.55 (m, 4H), 1.57 (s, 9H), 2.22-2.33 (m, 1H), 3.19 (s, 3H), 3.24 (m, 2H), 3.30-3.36 (m, 2H), 3.46 (d, J= 11.52Hz, 1H), 3.77-3.90 (m, 4H), 4.43 (d, J= 7.42Hz, 2H), 7.61 (d, J= 8.96Hz, 1H), 7.79 (s, 1H), 7.85 (d, J= 8.96Hz, 1H); MS (ESI) (M+H)+ 467.0
Example 47
N-(1-{[[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazoI-5- yl](methyl)amino]sulfonyl}piperidin-4-yl)acetamide
Step B. N-(l-{ [[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H- benziraidazol-5-yl](raethyl)amino]sulfonyl}piperidin-4-yl)acetamide
To a solution of 4-amino-N-[2-tert-butyl-1-(tetrahydro-2/i-pyran-4-ylmethyl)-1H- benzimidazol-5-yl]-N-methylpiperidine-1-sulfonamide in dichloromethane (0.516 mmol) (the preparation of it has followed the same procedure as for the synthesis of a compound in Example 1, Step J, by using 4-tetrahydropyranmethylamine as the coupling reagent for the SNAr reaction) was added triethylamine (143 μL; 1.032 mmol) followed by acethyl chloride (44 μL; 0.619 mmol). The reaction mixture was stirred at room temperature for two hours then was washed with water. The aqueous layer was extracted with dichloromethane. Combined dichloromethane extracts were dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. Purification by reverse phase chromatography provided the title compound (143.8 mg, 55%).
1H NMR (600 MHz, CD
3OD) δ 1.29-1.40 (m, 2H), 1.40-1.54 (m, 4H), 1.58 (s, 9H), 1.74 (m, 2H), 1.81 (s, 3H), 2.27 (br s, 1H), 2.83 (m, 2H), 3.21 (s, 3H), 3.24 (m, 2H), 3.57 (m, 2H), 3.62 (t, J = 10.88Hz, 1H), 3.83 (dd, J = 11.52, 2.56Hz, 2H), 4.44 (d, J= 7.42Hz, 2H), 7.58 (d, J= 8.70Hz, 1H), 7.72 (s, 1H), 7.87 (d, J= 8.96Hz, 1H); MS (ESI) (M+H)+ 506.0
Example 48
N-(1-{[[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino]sulfonyl}piperidin-4-yl)-2,2-dimethylpropanamide
Following the procedure for Step B in Example 47, using trimethyl acetyl chloride (76 μL; 0.619 mmol) and triethylamine (143 μL; 1.032 mmol) provided the title compound (138.1 mg; 49%). 1HNMR (600 MHz, CD3OD) δ 1.04 (s, 9H), 1.37-1.53 (m, 6H), 1.55 (s, 9H), 1.68 (m, 2H), 2.21-2.32 (m, 1H), 2.77 (m, 2H), 3.20 (s, 3H), 3.24 (m, 2H), 3.57-3.67 (m, 3H), 3.83 (m, 2H), 4.38 (d, J= 7.42Hz, 2H), 7.48 (dd, J= 8.83, 1.41Hz, 1H), 7.68 (d, J= 1.54Hz, 1H), 7.75 (d, J= 8.96Hz, 1H); MS (ESI) (M+H)+ 548.0.
Example 49 tert-Butyl [l-({methyl[l-(tetrahydro-2fl-pyran-4-ylmethyl)-2-(trifluoromethyl)- lJϊ-benzimidazol-5-yl] amino}sulfonyl)piperidin-4-yl] carbamate
Step A. tert-Butyl [l-({methyl[l-(tetrahydro-2H-pyran-4-ylmethyl)-2- (trifluor omethyl)-1H-benzimidazol-5-yl] amino} sulfbnyl)piperidin-4- yl] carbamate
Following the procedure in Step I of Example I3 3 -methyl- l-({methyl[l -(tetrahydro- 2H-pyran-4-ylmethyl)-2-(trifluoromethyl)-1H-berizimidazol-5-yl]amino}sulfonyl)- 1H-imidazol-3-ium (crude product, 1.0 mmol) (see following steps B, C3 D3 E, F3 G
and H for preparation) was reacted with tert-butyl piperidin-4-ylcarbamate (0.40 g, 2.0 mmol). The crude product was purified by MPLC using Hex/EtOAc (1:1) on silica gel to give 0.33 g (55%) of a white solid as the title compound. 1HNMR (400 MHz, CHLOROFORM-D): δ 1.41 (s, 9 H), 1.44 - 1.54 (m, 4 H), 1.77 - 1.93 (m, 3 H), 2.20 - 2.33 (m, 1 H), 2.83 - 2.97 (m, 3 H), 3.29 (s, 3 H), 3.32 - 3.44 (m, 3 H), 3.57 - 3.69 (m, 3 H), 3.88 - 3.97 (m, 2 H), 4.33 (d, J=7.42 Hz, 2 H), 7.58 (dd, J=8.79, 1.95 Hz, 1 H), 7.78 (d, J=8.79 Hz, 1 H), 7.85 (d, J=2.15 Hz, 1 H). MS (ESI) (M+H)+ = 576.0. Anal. Calcd for C25H36F3N5O5S+ 0.10 TFA+0.10 H2O+0.40 CH3OH(624.10): C, 51.58; H, 6.38; N, 11.22; Found: C, 51.56; H, 6.31; N, 11.27.
Step B. N-(4-Fluoro-3-nitrophenyl)acetamide
4-Fluoro-3-nitro-aniline (45.0 g, 0.288 mol) was added in portions to acetic anhydride (150 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The white solid was collected and dried in vacuo to give the title compound (42.0 g, 70%). 1H NMR (400 MHz, CHLOROFORM-D): δ 2.23. (s, 3 H), 7.26 (m, 1 H), 7.50 (s broad, 1 H), 7.87 (m, 1 H), 8.23 (dd, J=6.44, 2.73 Hz, 1 H).
Step C. N-(4-Fluoro-3-nitrophenyl)-N-methylacetamide
Sodium hydride (4.22 g, 60%, 106 mmol) was added portionwise to a solution of N- (4-fluoro-3-nitrophenyl)acetamide(13.9 g, 70 mmol) (for preparation, see the step B in Example 1) in THF (200 mL) at 0 0C. Stirring for 20 min, iodomethane (18.5 g, 130 mmol) was added. The reaction mixture was stirred at room temperature for 2 h, quenched with saturaed NaHCO3 (30 mL) and extracted with EtOAc (3x100 mL). The combined organic phases were washed with saturated NaCl (2x50 mL). After filtration and concentration, 13.1 g (88%) of the title compound was obtained as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-D): δ 1.92 (s, 3 H), 3.30 (s, 3 H), 7.38 (s, 1 H), 7.52 (s, 1 H), 7.95 (s, 1 H).
Step D. N-Methyl-N-{3-nitro-4-[(tetrahydro-2J5r-pyran-4- ylmethyl)amino] phenyl} acetamide
4-Aminomethyltetrahydropyran (10.0 g, 86.5 mmol ) was added to a mixture of N-(4- fluoro-3-nitrophenyl)-N-methylacetarnide (15.6 g, 73.3 mmol) and TEA (15.3 mL, 11.1 g, 110 mmol) in EtOH (300 mL) at room temperature. The reaction mixture was heated for 6 h at reflux. Upon evaporation of ethanol, the residue was dissolved in EtOAc (400 mL), washed with H
2O (3x50 mL), saturated NaCl (3x50 mL), and dried over Na
2SO
4. After filtation and concentration, 21.7 g (96%) of the title compound was obtained as an orange-red solid.
1H NMR (400 MHz, CHLOROFORM-D)
: δ 1.38 - 1.52 (m, 2 H), 1.72 - 1.81 (m, 2 H), 1.90 (s, 3 H), 1.93 - 2.02 (m, 1 H), 3.23 (s, 3 H), 3.23 - 3.27 (m, 2 H), 3.36 - 3.49 (m, 2 H), 4.01 - 4.07 (m, 2 H), 6.91 (d, J=9.18 Hz, 1 H), 7.29 (dd, J=9.08, 2.64 Hz, 1 H), 8.05 (d, J=2.34 Hz, 1 H), 8.22 (t, J=5.37 Hz, 1 H). MS (ESI) (M+H)
+ = 309.12.
Step E. N-{3-Amino-4-[(tetrahydro-2jHr-pyran-4-ylmethyl)ainino]phenyl}-N- methylacetamide
N-Methyl-N- {3-nitro-4-[(tetrahydro-2H-pyran-4-yltnethyl)amino]phenyl} acetamide (21.7 g, 70.5 mmol) was hydrogenated in ethyl acetate (500 mL) catalyzed by 10% Pd/C (1.0 g) at 30-40 psi H
2 in Parr shaker for 18 h at room temperature. After filtration through celite and concentration, 19.6 g (100%) of a purple solid was obtained.
1H NMR (400 MHz, CHLOROFORM-D): δ 1.35 - 1.50 (m, 2 H), 1.67 (s, 1
H), 1.73 - 1.81 (m, 2 H), 1.88 (s, 3 H)
5 1.88 - 1.99 (m, 1 H), 3.04 (d, J=6.64 Hz, 2 H), 3.20 (s, 3 H), 3.33 - 3.48 (m, 4 H), 3.97 - 4.08 (m, 2 H), 6.54 (d, J=I.76 Hz, 1 H), 6.60 - 6.63 (m, 2 H); MS (ESI) (M+H)
+ = 278.7
Step F. N-Methyl-N-[l-(tetrahydro-2H-pyran-4-yImethyl)-2-(trifluoromethyl)- liZ-benziπiidazol-5-yl] acetamide
A solution of ΛL{3-amino-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}-N- methylacetamide hydrochoride (2.77 g, 10 mmol) in trifluoroacetic acid (60 mL) was heated to reflux for 18 h. After evaporation of the solvent, the residue was disolved in EtOAc (200 mL), washed with 2JVNaOH (2x10 mL) and dried over Na2SO4. The crude product was purified by MPLC using EtOAc on silica gel to give 3.18 g (90%) of a white solid as the title compound. MS (ESI) (M+H)+ = 356.02.
Step G. N-Methyl-1-Ctetrahydro-ljEr-pyran^-ylmethyl)-1-Ctrifluoromethy^-lJΪ- benzimidazol-5-amine
N-Methyl-N-[l-(tetrahydro-2H-pyran-4-ylme%l)-2-(1xiiluorome%l)-1H- benzimidazol-5-yl]acetamide (3.18 g, 8.95 mmol) was dissolved in hydrochloric acid (37%, 60 mL) and then heated overnight at 95
0C. After concentration, the residue was treated with 20 mL of 2JVNaOH, extracted with EtOAc (4x50 mL). The combined organic phaese were washed with brine (20 mL) and dried over Na
2SO
4. After evaporation, 2.80 g (100%) of a purple white solid was obtained as the title product, which was used directly for Step H. MS (ESI) (M+H)
+ = 314.20.
Step H. 3-Methyl-1-({methyl[l-(tetrahydro-2H-pyran-4-yImethyl)-2- (trifluoromethyl)-lJ3-benziinidazoI-5-yl]amino}sulfonyl)-1H-imidazol-3-ium.
Following the procedure in Step H of Example 1, N-methyl-1-(tetrahydro-2H-pyran- 4-ylmethyl)-2-(trifluoromethyl)-1H-benzimidazol-5-amme (0.32 g, 1.0 mmol) was converted to 3 -methyl- 1 -( {methyl[l -(tetrahydro-2H-pyran-4-ylmethyl)-2- (trifluoromethyl)- l#-benzimidazol-5-yl]amino} sulfonyl)- li7-imidazol-3-ium, which was used in Step A without any purification.
Example 50 tert-Butyl 4-({methym-(tetrahydro-2H-pyran-4-ylmethyl)-2-(trifluoromethyl)- liϊ-benziinidazol-5-yl]amino}sulfonyl)piperazine-1-carboxylate
Following the procedure in Step I of Example 1, 3 -methyl- l-({methyl[l -(tetrahydro- 2H-pyran-4-ylmethyl)-2-(trifluoromethyl)- li7-benzimidazol-5-yl]amino } sulfonyl)- 1H-imidazol-3-ium (crude product, 1.10 mmol) (for preparation see the step H in
example 4) was reacted with tert-buty\ piperazine-1-carboxylate (0.38 g, 2.0 mmol). The.crude product was purified by MPLC using Hex/EtOAc (1:1) on silica gel to give 0.28 g (45%) of a white solid as the title compound. 1HNMR (400 MHz, CHLOROFORM-D): δ 1.43 (s, 9 H), 1.45 - 1.54 (m, 4 H), 2.19 - 2.33 (m, 1 H), 3.15 - 3.22 (m, 4 H), 3.32 (s, 3 H)5 3.33 - 3.37 (m, 2 H), 3.38 - 3.45 (m, 4 H), 3.87 - 3.97 (m, 2 H)3 4.33 (d, J=7.62 Hz, 2 H), 7.60 (dd, J=8.89, 2.05 Hz, 1 H), 7.79 (d, J=8.59 Hz, 1 H), 7.87 (d, J=I.76 Hz, 1 H); MS (ESI) (M+H)+ = 562.0; Anal. Calcd for C24H34F3N5O5S+0.70 EtOAc(623.30): C, 51.64; H, 6.40; N, 11.24; Found: C, 51.60; H, 5.80; N, 11.13.
Example 51
4-{[(Cyclopropylamino)carbonyl]amino}-N-methyl-N-[l-(tetrahydro-2Hr-pyran-
4-ylmethyl)-2-(trifluoromethyl)-lJΪ-benzimidazol-5-yl]piperidine-1-sulfonamide
Step A. 4-{[(CycIopropylamino)carbonyl]amino}-Λ'-methyl-N-[l-(tetrahydro-2H- pyran-4-ylmethyl)-2-(trifluoromethyl)-1H-benzimidazol-5-yl]piperidine-1- sulfonamide
A solution of isocyanatocyclopropane in THF (1 mmol) (freshly prepared from cyclopropylamine and triphosgene) was added to a solution of 4-ammo~N-methyl--V- [ 1 -(tetrahydro-27f-pyran-4-ylmethyl)-2-(trifluoromethyl)- 1H-benzimidazol-5- yl]piperidine-l -sulfonamide (38 mg, 0.08 mmol) (see following step B for preparation) in THF (3 mL) at room temperature. The mixture was stirred for 1 h. After evaporation, the crude product was purified by MPLC using EtOAc/MeOH
(20:1) on silica gel to give 45 mg (100%) of a white solid as the title compound. 1HNMR (400 MHz, METHANOL-D4): δ 0.34 - 0.47 (m, 2 H), 0.59 - 0.71 (m, 2 H), 1.33 - 1.53 (m, 6 H), 1.77 - 1.87 (m, 2 H), 2.16 - 2.30 (m, 1 H), 2.36 - 2.46 (m, 1 H), 2.83 - 2.94 (m, 2 H), 3.28 (s, 3 H), 3.30 - 3.37 (m, 2 H), 3.51 - 3.59 (m, 1 H), 3.58 - 3.68 (m, 2 H), 3.82 - 3.95 (m, 2 H), 4.31 (d, J=7.62 Hz, 2 H), 7.57 (dd, J=8.89, 2.05 Hz, 1 H), 7.76 (d, J=8.98 Hz, 1 H), 7.83 (d, J=I .76 Hz, 1 H); MS (ESI) (M+H)+ = 559.0; Anal. Calcd for C24H33N6O4SF3+0.60 TFA+ 0.30 H2O + 0.10 CH3OH (635.65): C, 47.81; H, 5.49; N, 13.22; Found: C, 47.83; H, 5.45; N, 13.20.
Step B. 4-Amino-N-methyl-N-[l-(tetrahydro-2JHr-pyran-4-ylmethyl)-2- (trifluoromethyl)-1H-benziinidazol-5-yl]piperidine-1-sulfonamide
TFA (3 mL) was added to a solution of tert-butyl [l-({methyl[l-(tetrahydro-2H- pyran-4-ylmethyl)-2-(trifluoromethyl)-1H-benzimidazol-5- yl]amino}sulfonyl)piρeridin-4-yl]carbamate (210 mg, 0.365 mmol) in DCM (3 mL) at 0 0C. The mixture was stirred for 1 h. Upon evaporation, the residue was dissolved in DCM (50 mL), washed with 2iVNaOH (2x5 mL), brine (5 mL) and dried over Na2SO4. After concentration, 168 mg (97%) of a white solid was obtained the title compound. MS (ESI) (M+H)+ = 475.99.
Example 52 N-CyclopropyI-4-({methyl[l-(tetrahydro-2Jfir-pyran-4-ylmethyl)-2- (trifluoromethyl)-llϊ-benzimidazol-5-yl]amino}sulfonyl)piperazine-1- carboxamide
Step A. N-Cyclopropyl-4-({methyl[l-(tetrahydro-2H-pyran-4-ylmethyl)-2-
(trifluoromethy^-lH-benzimidazol-S-yyaminolsulfony^piperazine-1- carboxamide
Following the procedure in Step A of Example 51, using N-methyl-N-[l-(tetrahydro- 2H-pyran-4-ylmethyl)-2-(trifluoromethyl)-1H-benzimidazol-5-yl]piperazine-1- sulfonamide (38 mg, 0.083 mmol) (see following step B for preparation) and a solution of isocyanatocyclopropane in THF (1 mmol). The crude product was purified by MPLC using EtOAcMeOH (20: 1) on silica gel to give 45 mg (99%) of a white solid as the title compound. 1HNMR (400 MHz, METHANOL-D4): δ 0.39 - 0.44 (m, 2 H), 0.60 - 0.68 (m, 2 H), 1.44 - 1.47 (m, 4 H), 2.19 - 2.35 (m, 1 H), 2.47 - 2.55 (m, 1 H), 3.13 - 3.22 (m, 4 H), 3.32 (s, 3 H), 3.32 - 3.38 (m, 6 H), 3.86 - 3.99 (m, 2 H), 4.33 (d, J=7.81 Hz, 2 H), 7.59 (dd, J=8.89, 2.05 Hz, 1 H), 7.79 (d, J=8.98 Hz, 1 H), 7.86 (d, J=I.76 Hz, 1 H); MS (ESI) (M+H)+ = 545.0; Anal. Calcd for
C23H3iF3N6O4S+0.70 TFA(624.42): C, 46.94; H, 5.12; N5 13.46; Found: C, 46.90; H, 4.65; N, 13.45.
Step B . N-Methyl-N-[l-(tetrahydro-2J3r-pyran-4-ylmethyl)-2-(trifluoromethyl)- lJ?-benzimidazol-5-yl]piperazine-l-sulfonamide
Following the procedure in Step B of Example 51, tert-butyl 4-({methyl[l-
(tetrahydro-2i-r-pyran-4-ylmethyl)-2-(trifluoromethyl)-1H-benzimidazol-5- yl]amino}sulfonyl)piperazine-1-carboxylate (234 mg, 0.417 mmol) was treated with
TFA (3 mL) in DCM (3 mL). 176 mg (91%) of a white solid was obtained as the title compound. MS (ESI) (M+H)+ = 461.96.
Example 53
4-{[(Isopropylamino)carbonyl]amino}-N-methyl-N-[l-(tetrahydro-2H-pyran-4- ylmethy^-1-^rifluoromethy^-lJΪ-benziraidazol-S-yypiperidine-1-sulfonamide
Following the procedure in Step A of Example 51, using 4-amino-N-methyl-N-[l- (tetrahy dro-2H*-pyran-4-ylmethyl)-2-(trifluoromethyl)- lif-benzimidazol-5- yl]piperidine-l -sulfonamide (38 mg, 0.08 mmol) and 2-isocyanatopropane (0.2 mL) in THF (3 mL). The crude product was purified by MPLC using EtOAc/MeOH (20:1) on silica gel to give 38 mg (85%) of a white solid as the title compound. 1HNMR (400 MHz, METHANOL-D4): δ 1.07 (d, J=6.45 Hz, 6 H)3 1.29 - 1.40 (m, 2 H)5 1.40 - 1.53 (m, 4 H), 1.78 - 1.87 (m, 2 H), 2.17 - 2.31 (m, 1 H), 2.85 - 2.95 (m, 2 H), 3.28 (s, 3 H), 3.30 - 3.37 (m, 2 H), 3.48 - 3.56 (m, 1 H), 3.56 - 3.66 (m, 2 H), 3.68 - 3.81 (m, 1 H), 3.85 - 3.98 (m, 2 H), 4.31 (d, J=7.62 Hz, 2 H), 7.57 (dd, J=8.89, 2.05 Hz, 1 H), 7.76 (d, J=8.98 Hz, 1 H), 7.83 (d, J=I.56 Hz, 1 H); MS (ESI) (M+H)+ = 561.0; Anal. Calcd for C24H35F3N6O4S+0.70 TFA+ (640.46): C, 47.63; H, 5.62; N, 13.12; Found: C, 47.64; H, 5.51; N, 13.26.
Example 54 N-Isopropyl-4-({methyl[l-(tetrahydro-2H-pyran-4-ylmethyl)-2-(trifluoromethyl)- liϊ-benzimidazol-5-yl]amino}sulfonyl)piperazine-1-carboxamide
Following the procedure in Step A of Example 51, using N-methyl-N-[ l-(tetrahydro- 2i¥-pyran-4-ylmethyl)-2-(trifluoromethyl)-1H-benzimidazol-5-yl]piperazine- 1 - sulfonamide (40 mg, 0.087 mmol) and 2-isocyanatopropane (0.2 mL) in THF (3 mL). The crude product was purified by MPLC using EtOAc/MeOH (20: 1) on silica gel to give 48 mg (100%) of a white solid as the title compound. 1HNMR (400 MHz, METHANOL-D4): δ 1.09 (d, J=6.45 Hz, 6 H), 1.38 - 1.53 (m, 4 H), 2.15 - 2.34 (m, 1 H), 3.14 - 3.21 (m, 4 H), 3.31 (s, 3 H), 3.33 - 3.40 (m, 6 H), 3.78 - 3.87 (m, 1 H), 3.87 - 3.95 (m, 2 H), 4.31 (d, J=7.62 Hz, 2 H), 7.58 (dd, J=8.89, 2.05 Hz, 1 H)3 7.77 (d, J=8.79 Hz, 1 H), 7.85 (d, J=I.76 Hz, 1 H); MS (ESI) (M+H)+ = 547.0; Anal. Calcd for C23H33F3N6O4S+0.50 TFA+ 0.20 H2O + 0.40 CH3OH (613.64): C, 47.37; H, 5.70; N, 13.70; Found: C547.41; H, 5.62; N, 13.65.
Example 55 N-ll-CIMethylll-^etrahydro-lH-pyran^-ylmethy^-1-Ctrifluoromethy^-lJΪ- benzimidazol-5-yl] amino} sulfonyl)piperidin-4-yl] acetamide
Acetyl chloride (9 mg, 0.11 mmol) was added to a solution of 4-amino-N-methyl-N- [l-(tetrahydro-2H-pyran-4-ylmethyl)-2-(trifluoromethyl)-1H-benzimidazol-5- yl]piperidine-l -sulfonamide (45 mg, 0.094 mmol) and triethylamine (12 mg, 0.12 mmol) in DCM (5 mL) at 0 0C. The mixture was stirred for 3 h at room temperature. After evaporation, the crude product was purified by MPLC using EtOAc/MeOH (10:1) on silica gel to give 49 mg (100%) of a white solid as the title compound.
1HNMR (400 MHz, METHANOL-D4): δ 1.36 - 1.55 (m, 6 H)5 1.79 - 1.87 (m, 2 H)5 1.90 (s, 3 H), 2.19 - 2.33 (m, 1 H), 2.86 - 2.96 (m, 2 H), 3.30 (s, 3 H), 3.32 - 3.38 (m, 2 H), 3.63 - 3.70 (m, 2 H), 3.70 - 3.78 (m, 1 H), 3.89 - 3.96 (m, 2 H), 4.33 (d, J=7.62 Hz, 2 H), 7.59 (dd, J=8.89, 2.05 Hz, 1 H), 7.78 (d, J=8.98 Hz, 1 H), 7.85 (d, J=I .95 Hz, 1 H); MS (ESI) (M+H)+ = 518.0 Anal. Calcd for C22H30F3N5O4S+0.60 TFA+ 0.10 CH3OH (589.19): C, 47.50; H, 5.30; N, 11.89; Found: C, 47.61; H, 5.32; N, 11.82.
Example 56 2,2-Dimethyl-N-[l-({methyl[l-(tetrahydro-2JH-pyran-4-ylmethyl)-2- (trifluororaethyl)-1H-benziraidazol-5-yl]amino}sulfonyl)piperidin-4- yl]propanamide
Following the procedure in Example 55, using 4-amino-N-methyl-N-[l-(tetrahydro- 2H-pyran-4-ylmethyl)-2-(trifluoromethyl)-1H-benzimidazol-5-yl]piperidine-1- sulfonamide (45 mg, 0.094 mmol), 2,2-dimethylpropanoyl chloride (14 mg, 0.11 mmol) was and triethylamine (12 mg, 0.12 mmol) in DCM (5 mL). The crude product was purified by MPLC using EtO Ac/Hex (2:1) on silica gel to give 44 mg (84%) of a white solid as the title compound. 1HNMR (400 MHz, METHANOL-D4): δ 1.12 (s, 9 H), 1.38 - 1.56 (m, 6 H), 1.75 - 1.78 (m, 2 H), 2.14 - 2.34 (m, 1 H) 2.80 - 2.90 (m, 2 H), 3.28 (s, 3 H), 3.30 - 3.39 (m, 2 H), 3.61 - 3.79 (m, 3 H), 3.86 - 3.98 (m, 2 H), 4.32 (d, J=7.62 Hz, 2 H), 7.57 (dd, J=8.98, 1.95 Hz, 1 H), 7.76 (d, J=8.79 Hz, 1 H), 7.84 (d, J=I.95 Hz, 1 H); MS (ESI) (M+H)+ = 560.0; Anal Calcd for C25H36F3N5O4S+0.50 TFA (616.67): C, 50.64; H, 5.97; N, 11.36; Found: C, 50.76; H, 5.99; N, 11.37.
Example 57
2-Methyl-N-[l-({methyl[l-(tetrahydro-2H-pyran-4-ylmethyl)-2-
(trifluoromethyl)-1H-benzimidazol-5-yl]amino}sulfonyl)piperidin-4- yljpropanamide
Following the procedure in Example 55, using 4-amino-N-methyl-N-[l-(tetrahydro- 2H-pyran-4-ylmethyl)-2-(trifluoromethyl)-1H-benzimidazol-5-yl]piperidine- 1 - sulfonamide (45 mg, 0.094 mmol), 2-methylpropanoyl chloride (11 mg, 0.11 mmol) was and triethylamine (12 mg, 0.12 mmol) in DCM (5 niL) The crude product was purified by MPLC using EtO Ac/Hex (2: 1) on silica gel to give 46 mg (89%) of a white solid as the title compound. 1HNMR (400 MHz, METHANOL-D4): δ 1.05 (d, J=6.84 Hz, 6 H), 1.35 - 1.54 (m, 6 H), 1.76 - 1.86 (m, 2 H), 2.17 - 2.30 (m, 1 H), 2.32 - 2.44 (m, 1 H), 2.83 - 2.95 (m, 2 H), 3.28 (s, 3 H), 3.29 - 3.37 (m, 2 H), 3.58 - 3.76 (m, 3 H), 3.85 - 3.98 (m, 2 H)5 4.31 (d, J=7.42 Hz, 2 H), 7.57 (dd, JM8.89, 2.05 Hz, 1 H) 7.76 (d, J=8.98 Hz, 1 H), 7.83 (d, J=I.95 Hz, 1 H); MS (ESI) (M+H)+ = 546.0; Anal. Calcd for C24H34F3N5O4S+0.10 TFA (557.03): C, 52.18; H, 6.17; N, 12.57; Found: C3 52.44; H, 6.03; N, 12.44.
Example 58 4-Acetyl-Λ'-methyl-N-[l-(tetrahydro-2Hr-pyran-4-ylmethyl)-2-(trifluoromethyl)- lJ?-benzimidazol-5-yl]piperazine-1-sulfonamide
Following the procedure in Example 55, using N-methyl-N-[ l-(tetrahy dro-2//-pyran- 4-ylmethyl)-2-(trifluoromethyl)-1H-benzimidazol-5-yl]ρiρerazine-1-sulfonamide (43
mg, 0.096 mmol), triethylamine (12 mg, 0.12 mmol) and acetyl chloride (9 mg, 0.12 mmol) in DCM (5 mL) .The crude product was purified by MPLC using EtOAc/MeOH (20:1) on silica gel to give 45 mg (92%) of a white solid as the title compound. 1HNMR ^OO MHZ3 METHANOL-D4): δ 1.39 - 1.52 (m, 4 H), 2.06 (s, 3 H), 2.17 - 2.33 (m, 1 H), 3.17 - 3.27 (m, 4 H), 3.31 (s, 3 H), 3.32 - 3.36 (m, 2 H), 3.49 - 3.59 (m, 4 H), 3.86 - 3.96 (m, 2 H), 4.31 (d, J=7.62 Hz, 2 H), 7.58 (dd, JM8.79, 2.15 Hz, 1 H), 7.77 (d, J=8.98 Hz, 1 H), 7.85 (d, J=I.76 Hz, 1 H); MS (ESI) (M+H)+ = 504.0; Anal. Calcd for C21H28F3N5(WCOO TFA +0.10 CH3OH (575.17): C3 46.57; H, 5.08; N, 12.18; Found: C, 46.67; H, 5.13; N, 12.16.
Example 59
4-(2,2-Dimethylpropanoyl)-N-methyl-N-[l-(tetrahydro-2H-pyran-4-ylmethyl)-2-
(trifluoromethy^-1H-benzimidazol-S-yllpiperazine-1-sulfonamide
Following the procedure in Example 55, using N-methyl-N-[l-(tetrahydro-2H-pyran- 4-ylmethyl)-2-(trifiuoromethyl)-1H-benzimidazol-5-yl]piperazine-1-sulfonamide (43 mg, 0.096 mmol), triethylamine (12 mg, 0.12 mmol) and 2,2-dimethylpropanoyl chloride (14 mg, 0.12 mmol) in DCM (5 mL). The crude product was purified by MPLC using EtOAc/Ηex(2:l) on silica gel to give 51 mg (97%) of a white solid as the title compound.
1HNMR (400 MHz, METHANOL-D
4): δ 1.22 (s, 9 H), 1.40 - 1.54 (m, 4 H), 2.17 - 2.31 (m, 1 H), 3.17 - 3.23 (m, 4 H), 3.30 - 3.36 (m, 2 H), 3.31 (s, 3 H), 3.61 - 3.68 (m, 4 H), 3.86 - 3.95 (m, 2 H), 4.31 (d, J=7.62 Hz, 2 H), 7.58 (dd, J=8.89, 2.05 Hz, 1 H), 7.77 (d, J=8.79 Hz, 1 H), 7.85 (d, J=I.95 Hz, 1 H); MS (ESI) (M+H)
+ = 546.0; Anal. Calcd for C
24H
34F
3N
5O
4S+0.30 TFA +0.20 CH
3OH (586.24): C, 50.81; H, 6.03; N, 11.95; Found: C, 50.81; H, 5.99; N, 11.90.
Example 60 N-(1-{[{2-tert-Butyl-1-[(4,4-difluorocycloliexyl)methyl]-lN-benzimidazol-5- yl}(methyl)amino]sulfonyl}piperidin-4-yl)acetamide
Step A. N-(1-{[{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H- benzimidazol-5-yl}(methyl)amino]sulfonyl}piperidin-4-yl)acetamide
Acetic anhydride (2.0 mmol) was added into a solution of triethylamine (2.0 mmol) and 4-amino-N-{2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-l//
'-benzimidazol-5- yl}-N-methylpiperidine-l -sulfonamide (crude product from step D, 0.9 mmol) in CH
2Cl
2 (20 mL). After being stirred at room temperature for 1 hr, the reaction mixture was concentrated under reduced pressure. The residue was then purified by silica gel chromatography (AcOEt to MeOH/AcOEt (1:9)) to give N-(1-{[{2-tert-butyl-1-[(4,4- difluorocyclohexyl)methylJ-1H-benzimidazol-5- yl}(methyl)amino]sulfonyl}piperidin-4-yl)acetamide as a solid (235 mg, 48 % for steps A-D).
1H NMR (400 MHz, CD
3OD, TFA salt) δ 1.28 (m, 2H), 1.40-1.76 (m, 8H), 1.64 (s, 9H), 1.88 (s, 3H), 2.04 (m, 2H), 2.24 (m, 1H), 2.90 (m, 2H), 3.28 (s, 3H), 3.68 (m, 3H), 4.50 (d, J = 8.0 Hz, 2H), 7.60 (d, J = 8.0 Hz, 1H), 7.77 (s, 1H), 7.86 (d, J= 8.0 Hz, 1H).
Step B. 1-{[{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5- yl}(methyl)amino]sulfonyl}-3-methyl-li3-imidazol-3-ium triflate
3-(Imidazole-1-sulfonyl)-1-methyl-3H-imidazol-1-ium triflate (508 mg; 1.4 mmol) was added into a solution of 2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-N- methyl-l.H-benzimidazol-5 -amine (300 nig, 0.9 mmol) in acetonitrile (10 mL). After being stirred at room temperature for 2 hr, the reaction mixture was concentrated under reduced pressure. The residue was then dissolved in AcOEt (60 mL), washed with brine, and dried over Na2SO4. After removing of solvents provided a mixture (1 : 1) of N- {2-tert-butyl- 1 -[(4,4-difluorocyclohexyl)methyl]- 1H-benzimidazol-5ryl} - N-methyl- lϋf-imidazole- 1 -sulfonamide and 1 - { [ {2-tert-bntyl- 1 -[(4,4- difluorocyclohexyl)methyl]-l//-benzimidazol-5-yl}(methyl)amino]sulfonyl}-3- methyl-1H-imidazol-3-ium triflate, which was dissolved in dichloromethane (10 mL). The resulting solution was treated with methyl trifluoromethanesulfonate (0. 5 mmol) at O0C for 2 hr. The reaction mixture was then concentrated under reduced pressure to give 1 - { [ {2-tert-butyl- 1 -[(4,4-difluorocyclohexyl)methyl]- 1H-benzimidazol-S- yl}(methyl)amino]sulfonyl}-3-methyl-1H-imidazol-3-ium triflate as a solid, which was used in the step C without any purification.
Step C. tert-Butyl (1-{[{2-/ert-butyI-1-[(4,4-difluorocyclohexyl)methyl]-l
JH- benzimidazol-5-yl}(methyl)amino]sulfonyl}piperidin-4-yl)carbamate
A solution of Hunig's base (1.0 mmol), 1-{[{2-tert-butyl-1-[(4,4- difluorocyclohexy^methylJ-liϊ'-benzimidazol-5-ylJ^ethy^aininoJsulfonyll-S- memyl-1H-imidazol-3-ium triflate (crude product from Step B, 0.9 mmol) and tert- butyl piperidin-4-ylcarbamate (200 mg, 1.0 mmol) in MeCN (20 mL) was heated for 1 hr at 800C. The reaction mixture was then concentrated under reduced pressure to give crude tert-butyl (1-{[{2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H- benzimidazol-5-yl}(methyl)amino]sulfonyl}piperidin-4-yl)carbamate as a solid, which was used directly in Step D.
Step D. 4-Araino-N-{2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H- benzimidazol-5-yl}-N-methylpiperidine-1-sulfonaraide
A solution of tert-butyl (1-{[{2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1Hr- benzimidazol-5-yl}(methyl)amino]sulfonyl}piperidin-4-yl)carbamate (crude product from Step C, 0.9 mmol) in 10 mL CH2Cl2 was treated with 10 mL TFA at room temperature. After being stirred at room temperature for 1 hr, the reaction mixture was concentrated under reduced pressure. The residue was then dissolved in AcOEt (60 mL), washed with Na2CO3 solution and brine, and dried over Na2SO4. fter removing of solvents provided the crude 4-amino-N- {2-tert-butyl-l -[(4,4- difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl} -N-methylpiperidine- 1 - sulfonamide, which was used in Step A without purification.
Example 61 N-(1-{[{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5- yl}(methyl)amino]sulfonyl}piperidin-4-yl)-2,2-dimethylpropanamide
Following the procedure in Step A of Example 60, 4-amino-N-{2-tert-butyl-1-[(4,4- difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}-N-methylpiperidine-1- sulfonamide (50 mg, 0.1 mmol) was reacted with 2,2-dimethylpropanoyl chloride (24 mg, 0.2 mmol), after being purified by reverse phase HPLC, to provide N-(1-{[{2- tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5- yl}(methyl)amino]sulfonyl}piperidin-4-yl)-2,2-dimethylpropanamide (TFA salt, 7 mg, 10 %). 1H NMR (400 MHz, CD3OD, TFA salt) δ 1.13 (s, 9H), 1.28 (m, 2H), 1.53 (m, 3H), 1.64 (s, 9H), 1.76 (m, 5H), 2.04 (m, 2H), 2.24 (m, 1H), 2.87 (m, 2H), 3.28 (s, 3H), 3.68 (m, 3H), 4.50 (d, J = 7.6 Hz, 2H), 7.60 (d, J = 9.0 Hz, 1H), 7.77 (s, 1H), 7.86 (d, J = 9.0 Hz, 1H); MS (ESI) (M+H)+ 582.0.
Example 62 N-{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}-N- methylmorphoIine-4-sulfonamide
Following the procedure in Step C of Example 60, 1-{[{2-tert-butyl-1-[(4,4- difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}(methyl)amino]sulfonyl}-3-
methyl-1H-imidazol-3-ium triflate (0.1 mmol) was reacted with morpholine (35 mg, 0.4 mmol), after being purified by reverse phase HPLC, to provide N-{2-tert-butyl-1- [(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}-N-methylmorpholme-4- sulfonamide (TFA salt, 56 mg, 93 %). 1HNMR (400 MHz, CD3OD, TFA salt) δ 1.40- 1.76 (m, 6H), 1.64 (s, 9H), 2.04 (m, 2H), 2.24 (m, 1H)5 3.19 (m, 4H), 3.33 (s, 3H), 3.62 (m, 4H), 4.50 (d, J = 7.4 Hz, 2H), 7.61(d, J=9.0 Hz, 1H), 7.79 (s, 1H), 7.87(d, J=9.0 Hz, 1H).
Example 63 N-{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-lJHr-benzimidazol-5-yl}-N- methylpyrrolidine-1 -sulfonamide
Following the procedure in Step C of Example 60, 1-{[{2-tert-butyl-1-[(4,4- difluorocyclohexyl)methyl]-li/-benzimidazol-5-yl}(methyl)amino]sulfonyl}-3- methyl-1H-imidazol-3-ium triflate (0.1 mmol) was reacted with pyrrolidine (28 mg, 0.4 mmol), after being purified by reverse phase HPLC, to provide N-{2-tert-butyl-1- [(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}-N-methylpyrrolidine-1- sulfonamide (TFA salt, 26 mg, 48 %). 1H NMR (400 MHz, CD3OD, TFA salt) δ 1.23 (m, 2H), 1.40-1.76 (m, 6H), 1.64 (s, 9H), 1.86 (m, 2H), 2.01 (m, 2H), 2.24 (m, 1H), 3.04 (m, 2H), 3.27 (m, 2H), 3.28(s, 3H), 4.49 (d, J = 7.4 Hz, 2H), 7.58(d, J=9.0 Hz, 1H), 7.77 (s, 1H), 7.84(d, J=9.0 Hz, 1H); MS (ESI) (M+H)+ 469.0.
Example 64
N-{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-lJE?-benzimidazol-5-yl}-3,3- difluoro-N-methylpyrrolidine-1-suIfonamide
Following the procedure in Step C of Example 60, 1-{[{2-tert-butyl-1-[(4,4- difluorocyclohexy^methylJ-1H-benzimidazol-5-ylj^ethy^aininolsulfonyl}-3- methyl-li/-imidazol-3-ium triflate (0.1 mmol) was reacted with 3,3- difluoropyrrolidine (42 mg, 0.4 mmol), after being purified by reverse phase HPLC, to provide N-{2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5- yl}-3,3-difluoro-N-methylpyrrolidme-1-sulfonamide (TFA salt, 18 mg, 26 %). 1H NMR (400 MHz, CD3OD, TFA salt) δ 1.40-1.76 (m, 6H)3 1.64 (s, 9H), 2.04 (m, 2H), 2.24 (m, 1H), 2.38 (m, 2H), 3.32 (s, 3H), 3.52 (m, 2H), 3.60 (m, 2H), 4.50 (d, J = 7.4 Hz, 2H), 7.59(d, J=9.0 Hz, 1H), 7.77 (s, 1H), 7.86(d, J=9.0 Hz, 1H); MS (ESI) (M+H)+ 505.0.
Example 65 N-{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-lJH-benzimidazol-5-yl}-N- methylisoxazolidine-2-sulfonamide
Following the procedure in Step C of Example 60, 1-{[{2-fert-butyl-1-[(4,4- difluorocyclohexyl)methyl]- l.H-benzimidazol-5-yl} (methyl)amino]sulfonyl} -3- methyl-1H-imidazol-3-ium triflate (0.1 mmol) was reacted with isoxazolidine hydrochloride (44 mg, 0.4 mmol) and Hunig's base (1.0 mL), , after being purified by reverse phase HPLC, to provide N-{2-tert-butyl-1-[(4,4- difluorocyclohexyl)methyl]-li-':-benzimidazol-5-yl}-N-methylisoxazolidine-2-
sulfonamide (TFA salt, 58 mg, 99 %). 1H NMR (400 MHz, CD3OD, TFA salt) δ 1.40- 1.76 (m, 6H), 1.64 (s, 9H), 2.04 (m, 2H), 2.31 (m, 1H), 2.33 (m, 2H), 3.44 (s, 3H), 3.55 (m, 2H), 4.11 (m, 2H), 4.51 (d, J = 7.4 Hz, 2H), 7.60 (m, 1H), 7.87 (m, 2H); MS (ESI) (M+H)+ 471.0.
Example 66 N-{2-^^-Butyl-1-[(4,4-d[ifluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}-4,4- difluoro-N-methylpiperidine-1-sulfonamide
Following the procedure in Step C of Example 60, 1-{[{2-terf-butyl-1-[(4,4- difluorocyclohexyl)methyl]-lH-benzimidazol-5-ylJ^ethy^ammojsulfonyl}-3- methyl-1H-imidazol-3-ium triflate (0.1 mmol) was reacted with 4,4- difluoropiperidine hydrochloride (62 mg, 0.4 mmol) and Hunig's base (1.0 mL), , after being purified by reverse phase HPLC, to provide N-{2-tert-butyl-1-[(4,4- difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl} -4,4-difluoro-N-methylpiperidine- 1-sulfonamide (TFA salt, 36 mg, 57 %).
1H NMR (400 MHz, CD
3OD, TFA salt) δ 1.40-1.76 (m, 6H), 1.64 (s, 9H), 1.97 (m, 6H), 2.24 (m, 1H), 3.31 (s, 3H), 3.38 (m, 4H), 4.50 (m, 2H), 7.60(d, J=9.0 Hz, 1H), 7.78 (s, 1H), 7.87(d, J=9.0 Hz, 1H); MS (ESI) (M+H)
+ 519.0.
Example 67 tert-Butyl 4-{[{2-ter_'-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazoI-
5-yl}(methyl)amino]suIfonyI}piperazine-1-carboxylate
Following the procedure in Step C of Example 60, 1-{[{2-tert-butyl-1-[(4,4- difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}(methyl)amino]sulfonyl}-3- methyl-1H-imidazol-3-ium triflate (2.0 mmol) was reacted with tert-butyl piperazine- 1-carboxylate (930 mg, 5.0 mmol) and Hunig's base (1.0 mL), after being purified by silica gel chromatography, to provide tert-butyl 4-{[{2-tert-butyl-1-[(4,4- difluorocyclohexyl)methyl]-1H-benzimidazol-5- yl}(methyl)amino]sulfonyl}piperazine-1-carboxylate (730 mg, 63 %). 1HNMR (400 MHz, CDCl3) δ 1.39 (s, 9H), 1.46 (m, 3H), 1.51 (s, 9H), 1.67 (m, 3H), 2.09 (m, 3H), 3.12 (m, 4H), 3.25 (s, 3H), 3.35 (m, 4H), 4.16 (m, 2H), 7.22 (m, 2H), 7.28 (d, J = 8.6 Hz, 1H), 7.67 (s, 1H); MS (ESI) (M+H)+ 584.0.
Example 68
4-{[{2-tert-ButyI-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5- yl}(methyl)amino]sulfonyl}-N-isopropylpiperazine-1-carboxamide
Step A. 4-{[{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5- yl}(methyl)amino]sulfonyl}-N-isopropylpiperazine-1-carboxamide
Isopropyl isocyanate (85 mg, 1.0 mmol) was added into a solution of triethylamine (1.0 mmol) and N-{2-fer^-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-beiizimidazol- 5-yl}-N-methylpiperazine-1-sulfonamide (100 mg, 0.21 mmol) in CH2Cl2 (10 mL). After being stirred at room temperature for 1 hr, the reaction mixture was concentrated under reduced pressure. The residue was then purified by silica gel chromatography (Hexane to AcOEt ) to give 4-{[{2-tert-Butyl-1-[(4,4- difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl} (methyl)amino]sulfonyl} -N- isopropylρiperazine-1-carboxamide (114 mg, TFA salt, 81 %). 1H NMR (400 MHz, CDCl3) δ 1.14 (d, J=6.5 Hz, 6H), 1.52 (m, 3H), 1.56 (s, 9H), 1.72 (m, 3H)5 2.14 (m, 3H), 3.20 (m, 4H), 3.30 (s, 3H), 3.35 (m, 4H), 3.94 (m, 1H), 4.22 (m, 2H), 4.35 (m, 1H), 7.28 (d, J = 8.6 Hz, 1H), 7.32 (d, J = 8.6 Hz, 1H), 7.72 (s, 1H); MS (ESI) (M+H)+ 569.0.
Step B. Λ/-{2-terϊ'-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-lJfir-benzimidazol-5- yI}-N-methylpiperazine-1-sulfonamide
A solution of tert-bntyl 4-{[{2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H- benzimidazol-5-yl}(methyl)amino]sulfonyl}piperazine-1-carboxylate (720 mg, 1.23 mmol) in 10 mL CH2Cl2 was treated with 10 mL TFA at room temperature. After being stirred at room temperature for 1 hr, the reaction mixture was concentrated under reduced pressure. The residue was then dissolved in AcOEt (60 mL), washed with Na2CO3 solution and brine, and dried over Na2SO4. Removal of solvents
provided crude N- {2-tert-butyl- 1 -[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol- 5-yl}-N-methylpiperazine-l -sulfonamide (434 mg, 73 %), which was used in Step A without purification.
Example 69
4-{[{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5- yl}(methyl)amino]sulfonyl}-N-methylpiperazine-1-carboxamide
Following the procedure in Step A of Example 68, N- {2-tert-butyl- 1- [(4,4- difluorocyclohexyl)methyl]- lijT-benzimidazol-5-yl} -N-methylpiperazine- 1 - sulfonamide (56 mg, 0.116 mmol) was reacted with methyl isocyanate (57 mg, 1.0 mmol), after being purified by silica gel chromatography, to provide 4- {[{2-tert- butyl- 1 - [(4,4-difluorocy clohexyl)methyl] - 1H-benzimidazol-5 - yl}(methyl)amino]sulfonyl} -N-methylpiperazine- 1-carboxamide (TFA salt, 49 mg, 64 %). 1H ΝMR (400 MHz, CDCl3) δ 1.46 (m, 3H), 1.50 (s, 9H), 1.67 (m, 3H), 2.10 (m, 3H), 2.71 (m, 3H), 3.14 (m, 4H), 3.23 (s, 3H), 3.31 (m, 4H), 4.16 (d, J = 7.4 Hz, 2H), 4.68 (m, 1H), 7.22 (d, J = 8.6 Hz, 1H), 7.25 (d, J = 8.6 Hz, 1H), 7.65 (s, 1H); MS (ESI) (M+H)+ 541.0.
Example 70
4-{[{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5- yl}(methyl)amino]sulfonyl}-N-cyclopropylpiperazine-1-carboxamide
Step A. 4-{[{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5- yl}(methyl)amino]sulfonyl}-N-cyclopropylpiperazine-1-carboxamide
Following the procedure in Step A of Example 68, N-{2-tert-butyl-1-[(4,4- difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}-N-methylpiperazine-1- sulfonamide (54 mg, 0.112 mmol) was reacted with cyclopropyl isocyanate (1.0 mmol), after being purified by silica gel chromatography, to provide 4-{[{2-tert- butyl-1-[(4,4-difiuorocyclohexyl)methyl]-1H-benzimidazol-5- yl}(methyl)amino]sulfonyl}-N-cyclopropylpiperazme-1-carboxamide (TFA salt, 48 mg, 63 %). 1H NMR (400 MHz, CDCl3) δ 0.45 (m, 1H), 0.54 (m, 1H), 0.72 (m, 2H), 1.54 (m, 2H), 1.56 (s, 9H), 1.72 (m, 3H), 2.14 (m, 3H), 2.50 (m, 1H), 2.60 (m, 1H), 3.18 (m, 4H), 3.29 (s, 3H), 3.34 (m, 4H), 4.22 (d, J = 7.4 Hz, 2H), 5.01 (m, 1H), 7.28 (d, J = 8.6 Hz, 1H), 7.32 (d, J = 8.6 Hz, 1H), 7.71 (s, 1H); MS (ESI) (M+H)+ 567.0.
Step B. Cyclopropyl isocyanate
A solution of cyclopropylamine (57 mg, 1.0 mmol) and DEPEA (3.0 mmol) in 5 mL THF was slowly added to a solution of triphosgene (105 mg, 0.35 mmol) in 10 mL THF at 0°C. After 30 min, the cyclopropyl isocyanate solution was used directly in Step A.
Example 71
4-{[{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5- yl} (methyl)amino]sulfonyl}-N-cyclobutylpiperazine-1-carboxamide
Step A. 4-{[{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5- yl}(methyl)amino]sulfonyl}-N-cyclobutylpiperazme-1-carboxaniide
Following the procedure in Step A of Example 68, N-{2-tert-butyl-1-[(4,4- difluorocyclohexy^methyy-1H-benzimidazol-5-yll-N-methylpiperazine-1- sulfonamide (58 mg, 0.12 mmol) was reacted with cyclobutyl isocyanate (1.0 rnmol), after being purified by silica gel chromatography, to provide 4-{[{2-tert-butyl-1- [(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl} (methyl)amino]sulfonyl} -N- cyclobutylpiperazine-1-carboxamide (TFA salt, 39 mg, 47 %). 1HNMR (400 MHz, CDCl3) δ 1.52 (m, 2H), 1.56 (s, 9H), 1.72 (m, 8H), 2.04 (m, 3H), 2.32 (m, 2H), 3.19 (m, 4H)5 3.30 (s, 3H), 3.34 (m, 4H), 4.21 (m, 2H), 4.25 (m, 1H), 4.65 (m, 1H), 7.27 (d, J = 8.6 Hz, 1H), 7.32 (d, J = 8.6 Hz, 1H), 7.72 (s, 1H); MS (ESI) (M+H)+ 581.0.
Step B: Cyclobutyl isocyanate
A solution of cyclobutylamine (71 mg, 1.0 mmol) and DIPEA (3.0 mmol) in 5 mL THF was slowly added to a solution of triphosgene (105 mg, 0.35 mmol) in 10 mL
THF at O0C. After 30 min, the cyclopropyl isocyanate solution was used directly in Step A.
Example 72 N-{2-ferf-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-lJHr-benziinidazol-5-yl}-N- methyl-4-{[(methylamino)carbonyI]amino}piperidine-1-sulfonamide
Following the procedure in Step A of Example 68, 4-amino-N-{2-tert-butyl-1-[(4,4- difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl} -N-methylpiperidine- 1 - sulfonamide (50 mg, 0.1 mmol) was reacted with methyl isocyanate (57 mg, 1.0 mmol), after being purified by silica gel chromatography, to provide N-{2-tert-butyl- l-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}-N-methyl-4- {[(methylamino)carbonyl]amino}piperidine-1-sulfonamide (TFA salt, 49 mg, 73 %). 1H NMR (400 MHz, CDCl3) δ 1.39 (m, 2H), 1.52 (m, 3H), 1.56 (s, 9H), 1.72 (m, 3H), 1.89 (m, 2H), 2.15 (m, 3H), 2.72 (s, 3H), 2.83 (m, 2H), 3.27 (s, 3H), 3.63 (m, 3H), 4.22 (d, J = 8.0 Hz, 2H), 5.15 (m, 1H), 7.30 (m, 2H), 7.71 (s, 1H); MS (ESI) ■ (M+H)+ 555.0.
Example 73 N-[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benziinidazol-5-yl]-N- methylisoxazolidine-2-sulfonamide
Following the procedure in Step C of Example 60, ^{[p-tert-butyl-1-^etrahydro-ZH- pyran-4-ylmethyl)-1H-benzimidazol-5-yl](methyl)amino]sulfonyl}-3-methyl-1H- imidazol-3-ium triflate (500 mg, 0.84 mmol) was reacted with fert-butyl piperazine-1- carboxylate (558 mg, 3.0 mmol), after being purified by silica gel chromatography, to provide tert-butyl 4- { [ [2-tert-butyl- 1 -(tetrahydro-2H-pyran-4-ylmethyl)- IH- benzimidazol-5-yl](methyl)amino]sulfonyl}piperazine-1-carboxylate (460 mg, 100 %). MS (ESI) (M+H)
+ 550.0.
Example 74 4-Acetyl-N-[2-tert-butyl-1-(tetrahydro-2Jfir-pyran-4-ylinethyl)-1H-benziinidazol- 5-yl]-N-methylpiperazine-l -sulfonamide
Step A. 4-Acetyl-Λr-[2-tert-butyl-1-(tetrahydro-2JHr-pyran-4-ylmethyl)-1H- benzimidazol-5-yl]-N-methylpiperazine-l -sulfonamide
Following the procedure in Step A of Example 60, N-[2-fert-butyl-1-(tetrahydro-2H- pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-N-methylpiperazme- 1 -sulfonamide trifluoroacetate (100 mg, 0.18 mmol) was reacted with acetyl chloride (79 mg, 1.0 mmol), after being purified by reverse phase ΗPLC, to provide 4-acetyl-N-[2-tert- butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-N- methylpiperazine-1-sulfonamide (TFA salt, 58 mg, 53 %). 1HNMR (400 MHz, CD3OD5 TFA salt) δ 1.54 (m, 4H), 1.66 (s, 9H), 2.07 (s, 3H), 2.36 (m, 1H), 3.20 (m, 2H), 3.33 (s, 3H), 3.34 (m, 4H), 3.55 (m, 4H), 3.91 (m, 2H), 4.51 (d, J = 7.6 Hz, 2H), 7.65 (d, J=9.0 Hz, 1H)5 7.79 (s5 1H)5 7.92 (d, J=9.0 Hz, 1H); MS (ESI) (M+H)+ 492.0.
Step B: N-[2-tert-Butyl-.l-(tetrahydro-2H-pyran-4-ylmethyl)-lJΪ-benzimidazol-5- yl]-N-methylpiperazine-1-sulfonamide
A solution of tert-butyl 4-{[[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylnietliyl)-lHr- benzimidazol-5-yl](methyl)amino]sulfonyl}piperazine-1-carboxylate (460 mg, 0.84 mmol) in 10 mL CH2Cl2 was treated with 10 mL TFA at room temperature. After being stirred at room temperature for 1 hr, the reaction mixture was concentrated under reduced pressure to provide N-[2-tert-butyl-1-(tetrahydro-2H-pyran-4- ylmethyl)-1H-benzimidazol-5-yl]-N-methylpiperazine-l -sulfonamide (TFA salt, 100 %), which was used in Step A without purification.
Example 75 N-[2-tert-Butyl-1-(tetrahydro-2JHr-pyran-4-ylmethyl)-lJΪ-benziinidazol-5-yl]-4- (2,2-dimethylpropanoyl)-Λ'-methylpiperazine-l -sulfonamide
Following the procedure in Step A of Example 60, N-[2-tert-butyl-1-(tetrahydro-2H- pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-N-methylpiperazine- 1 -sulfonamide trifluoroacetate (100 mg, 0.18 mmol) was reacted with 2,2-dimethylpropanoyl chloride (120 mg, 1.0 mmol), after being purified by reverse phase HPLC, to provide N-[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-berizimidazol-5-yl]-4-(2,2- dimethylpropanoyl)-N-methylpiperazine-l -sulfonamide (TFA salt, 24 mg, 21 %). 1H ΝMR (400 MHz, CD3OD3 TFA salt) δ 1.23 (s, 9H), 1.56 (m, 4H), 1.66 (s, 9H), 2.36 (m, 1H), 3.23 (m, 4H), 3.33 (s, 3H), 3.36 (m, 2H), 3.66 (m, 4H), 3.91 (m, 2H), 4.51
(d, J = 7.6 Hz, 2H), 7.65 (d, J=9.2 Hz, 1H), 7.79 (s, 1H), 7.92 (d, J=9.2 Hz, 1H); MS (ESI) (M+H)+ 534.0.
Example 76
4-Benzoyl-N-[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-
5-yl]~N-methylpiperazine-1-sulfonamide
Following the procedure in Step A of Example 60, N-[2-tert-butyl-1-(tetrahydro-2H- pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-N-methylpiperazme-1-sulfonamide (45 mg, 0.10 mmol) was reacted with benzoyl chloride (28 mg, 0.2 mmol), after being purified by reverse phase HPLC, to provide 4-benzoyl-ΛL[2-terϊ-butyl-1-(tetrahydro- 2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-N-methylpiperazine-1-sulfonamide (TFA salt, 64 mg, 96 %). 1H ΝMR (400 MHz, CD3OD, TFA salt) δ 1.58 (m, 4H), 1.67 (s, 9H), 2.36 (m, 1H), 3.28 (m, 6H), 3.33 (s, 3H), 3.47 (m, 2H), 3.74 (m, 2H), 3.92 (m, 2H), 4.52 (d, J = 7.6 Hz, 2H), 7.40 (m, 2H), 7.46 (m, 3H), 7.68 (d, J=9.0 Hz, 1H), 7.80 (s, 1H), 7.95 (d, J=9.0 Hz, 1H); MS (ESI) (M+H)+ 554.0.
Example 77 N-[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-N- methyl-4-(3-methylbutanoyl)piperazine-l -sulfonamide
Following the procedure in Step A of Example 60, N-[2-tert-butyl-1-(tetrahydro-2H- pyran-4-ylmethyl)- lif-benzimidazol-S-yy-N-methylpiperazine- 1 -sulfonamide (45 mg, 0.10 mmol) was reacted with 3-methylbutanoyl chloride (24 mg, 0.2 mmol), after
being purified by reverse phase HPLC, to provide N-[2-tert-butyl-1-(tetrab.ydro-2H- pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-N-methyl-4-(3-me11iylbutanoyl)piperazme- 1 -sulfonamide (TFA salt, 63 mg, 97 %). 1H NMR (400 MHz, CD3OD, TFA salt) δ 0.87 (d, J=7.4 Hz, 6H), 1.45 (m, 4H), 1.49 (s, 9H), 2.00 (m, 1H), 2.09 (d, J=6.9 Hz, 2H), 2.22 (m, 1H), 3.06 (m, 2H), 3.16 (m, 2H), 3.22 (s, 3H), 3.23 (m, 2H), 3.39 (m, 2H), 3.52 (m, 2H), 3.91 (m, 2H), 4.12 (d, J = 7.6 Hz, 2H), 4.83 (m, 1H), 7.23 (m, 2H), 7.64 (s, 1H); MS (ESI) (M+H)+ 534.0.
Example 78 N-[2-to'-'-Butyl-1-(tetrahydro-2fl-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-4- (cyclopropylcarbonyl)~JV~methylpiperazine-l -sulfonamide
Following the procedure in Step A of Example 60, N-[2-tert-butyl-1-(tetrahydro-2H- pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-N-methylpiperazine-1-sulfonamide (50 mg, 0.11 mmol) was reacted with cyclopropanecarbonyl chloride (21 mg, 0.2 mmol), after being purified by reverse phase HPLC, to provide N-[2-tert-butyl-1-(tetrahydro- 2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-4-(cyclopropylcarbonyl)-N- methylpiperazine-1-sulfonamide (TFA salt, 45 mg, 71 %). 1H NMR (400 MHz, CDCl3) δ 0.76 (m, 2H), 0.95 (m, 2H), 1.53 (m, 4H), 1.57 (s, 9H), 1.69 (m, 1H), 2.32 (m, 1H), 3.21 (m, 2H), 3.28 (m, 2H), 3.30 (s, 3H), 3.33 (m, 2H), 3.60 (m, 2H), 3.70 (m, 2H), 3.98 (m, 2H), 4.20 (d, J = 7.6 Hz, 2H), 7.31 (m, 2H), 7.72 (s, 1H); MS (ESI) (M+H)+518.0.
Example 79 N-[2-rer^Butyl-1-(tetrahydro-2Jϊ-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-N- methyl-4-propionylpiperazme-1-sulfonamide
Following the procedure in Step A of Example 60, N-[2-tert-butyl-1-(tetrahydro-2H- pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-N-methylpiperazine-1-sulfonamide (60 mg, 0.13 mmol) was reacted with propanoic anhydride (26 mg, 0.2 mmol), after being purified by reverse phase HPLC, to provide N-[2-tert-butyl-1-(tetrahydro-2H- pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-N-methyl-4-propionylpiperazine-1- sulfonamide (TFA salt, 28 mg, 35 %). 1HNMR (400 MHz, CDCl3) δ 1.13 (t, J=7.4 Hz, 3H), 1.53 (m, 4H), 1.57 (s, 9H)3 2.32 (m, 3H), 3.14 (m, 2H), 3.25 (m, 2H), 3.30 (s, 3H), 3.33 (m, 2H), 3.45 (m, 2H), 3.60 (m, 2H), 3.98 (m, 2H), 4.20 (d, J = 7.6 Hz, 2H), 7.31 (m, 2H), 7.72 (s, 1H); MS (ESI) (M+H)+ 506.0.
Example 80 N-[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-4- isobutyryl-N-methylpiperazine-1 -sulfonamide
Following the procedure in Step A of Example 60, N-[2-tert-butyl-1-(tetrahydro-2H- pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-7Y-methylpiperazine-1-sulfonamide (50 mg, 0.11 mmol) was reacted with 2-methylρropanoyl chloride (22 mg, 0.2 mmol), after being purified by reverse phase ΗPLC, to provide N-[2-tert-butyl-1-(tetrahydro- 2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-4-isobutyryl-7Y-methylpiperazine-1- sulfonamide (TFA salt, 35 mg, 50 %). 1H NMR (400 MHz, CDCl3) δ 1.10 (d, J=6.6 Hz, 6H), 1.53 (m, 4H), 1.57 (s, 9H), 2.30 (m, 1H), 2.73 (m, 1H), 3.15 (m, 2H), 3.30 (m, 2H), 3.31 (s, 3H), 3.33 (m, 2H), 3.50 (m, 2H), 3.60 (m, 2H), 3.99 (m, 2H), 4.20 (d, J = 7.6 Hz, 2H), 7.31 (m, 2H), 7.72 (s, 1H); MS (ESI) (M+H)+ 520.0.
Example 81 N-[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-4- (cyclobutylcarbonyl)-N-methylpiperazine-l -sulfonamide
Following the procedure in Step A of Example 60, N-[2-tert-butyl-1-(tetrahydro-2H- pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-N-methylpiperazine-l -sulfonamide (50 mg, 0.11 mmol) was reacted with cyclobutanecarbonyl chloride (24 mg, 0.2 mmol), after being purified by reverse phase HPLC5 to provide N-[2-ter^-butyl-1-(tetrahydro- 2Jf-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-4-(cyclobutylcarbonyl)-N- methylpiperazine-1-sulfonamide (TFA salt, 34 mg, 48 %). 1HNMR (400 MHz, CDCl3) δ 1.53 (m, 4H), 1.57 (s, 9H), 1.80 -2.00 (m, 2H), 2.13 (m, 2H), 2.31 (m, 3H), 3.14 (m, 2H), 3.20 (m, 3H), 3.30 (s, 3H), 3.32 (m, 4H), 3.35 (m, 2H), 3.91 (m, 2H), 4.20 (d, J = 7.6 Hz, 2H), 7.31 (m, 2H), 7.72 (s, 1H); MS (ESI) (M+H)+ 532.0.
Example 82
Λr-[2-2'eri'-Butyl-1-(tetrahydro-2JHr-pyran-4-ylmethyl)-lJ7-benzimidazol-5-yl]-4- butyryl-N-methylpiperazine-1-sulfonamide
Following the procedure in Step A of Example 60, N-p-tert-butyl-1-^etrahydro^H- pyran-4-yrmethyl)-1H-benzimidazol-5-yl]-N-methylpiperazine-1-sulfonamide (50 mg, 0.11 mmol) was reacted with butanoyl chloride (21 mg, 0.2 mmol), after being purified by reverse phase HPLC, to provide N-[2-tert-butyl-1-(tetrahydro-2H-pyran-4- ylmethyl)- li-r-benzimidazol-5-yl]-4-butyryl-Λ/r-methylpiperazine-l -sulfonamide (TFA
salt, 28 mg, 40 %). 1HNMR (400 MHz, CDCl3) δ 0.96 (t, J=7.4 Hz, 3H), 1.53 (m, 4H), 1.57 (s, 9H), 1.65 (m, 2H), 2.27 (t, J=7.4 Hz, 2H), 2.30 (m, 1H), 3.14 (m, 2H), 3.24 (m, 2H), 3.30 (s, 3H), 3.33 (m, 2H), 3.45 (m, 2H), 3.60 (m, 2H), 3.98 (m, 2H), 4.20 (d, J = 7.6 Hz, 2H), 7.32 (m, 2H), 7.72 (s, 1H); MS (ESI) (M+H)+ 520.0.
Example 83
4-{[[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-lJΪ-benzimidazol-5- yl](methyl)amino]sulfonyl}-i\yV-dimethylpiperazine-1-carboxamide
Following the procedure in Step A of Example 60, N-[2-tert-butyl-1-(tetrahydro-2H- pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-N-metriylpiperazine-1-sulfonamide (45 mg, 0.1 mmol) was reacted with dimethylcarbamoyl chloride (22 mg, 0.2 mmol), after being purified by reverse phase HPLC, to provide 4-{[[2-tert-butyl-1-(tetrahydro-2H- pyran-4-ylmethyl)-1H-benzimidazol-5 -yl] (methyl)amino]sulfonyl} -N,N- dimethylpiperazine-1-carboxamide (TFA salt, 56 mg, 88 %).
1H NMR (400 MHz, CD
3OD, TFA salt) δ 1.54 (m, 4H), 1.67 (s, 9H), 2.37 (m, 1H), 2.82 (s, 6H), 3.23 (m, 6H), 3.33 (s, 3H), 3.36 (m, 4H), 3.91 (m, 2H), 4.53 (d, J = 7.6 Hz, 2H), 7.68 (d, J=9.2 Hz, 1H), 7.81 (s, 1H), 7.96 (d, JN9.2 Hz, 1H); MS (ESI) (M+H)
+ 521.0.
Example 84
4-{[[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino]sulfonyl}-N-isopropylpiperazine-1-carboxamide
Following the procedure in Step A of Example 68, N-[2-tert-butyl-1-(tetrahydro-2i?- pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-N-methylpiperazine- 1 -sulfonamide (45 mg, 0.1 mmol) was reacted with isopropyl isocyanate (17 mg, 0.2 mmol), after being purified by reverse phase HPLC, to provide 4-{[[2-tert-butyl-1-(tetrahydro-2H-pyran- 4-ylmethyl)-1H-benzimidazol-5-yl](methyl)amino]sulfonyl}-N-isopropylpiperazine- 1-carboxamide (TFA salt, 64 mg, 98 %).
1H NMR (400 MHz, CD
3OD, TFA salt) δ 1.10 (d, J=6.4 Hz, 6H), 1.58 (m, 4H), 1.67 (s, 9H), 2.35 (m, 1H), 3.20 (m, 4H), 3.33 (s, 3H), 3.37 (m, 6H), 3.85 (m, 1H), 3.91 (m, 2H), 4.53 (d, J = 7.6 Hz, 2H), 7.67 (d, J=9.2 Hz, 1H), 7.81 (s, 1H), 7.96 (d, J=9.2 Hz, 1H); MS (ESI) (M+H)
+ 535.0.
Example 85
4-{[[2-ter^-Butyl-1-(tetrahydro-2J3r-pyran-4-ylmethyl)-ljHr-benzimidazol-5- yll^ethy^aminolsulfonyll-N-cyclopentylpiperazine-1-carboxamide
Following the procedure in Step A of Example 68, N-[2-tert-butyl-1-(tetrahydro-2H- pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-N-methylpiperazme-1-sulfonamide (90 mg, 0.2 mmol) was reacted with isocyanatocyclopentane (44 mg, 0.4 mmol), after being purified by reverse phase HPLC, to provide 4-{[[2-tert-butyl-1-(tetrahydro-2H- pyran-4-ylmethyl)-1H-benzimidazol-5-yl](methyl)amino]sulfonyl}-N- cyclopentylpiperazine-1-carboxamide (TFA salt, 135 mg, 100 %).
1H NMR (400
MHz, CDCl3) δ 1.28 (m, 2H), 1.54 (m, 4H), 1.57 (s, 9H), 1.59 (m, 4H), 1.97 (m, 2H), 2.30 (m, 1H), 3.19 (m, 4H), 3.30 (s, 3H), 3.33 (m, 6H), 4.02 (m, 2H), 4.07 (m, 1H), 4.20 (d, J = 7.6 Hz, 2H), 4.38 (m, 1H), 7.31 (m, 2H), 7.72 (s, 1H); MS (ESI) (M+H)+ 561.0.
Example 86
4-{[[2-te/Y-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-lN-benzimidazol-5- yl](methyl)amino]sulfonyl}-N-methylpiperazine-1-carboxamide
Following the procedure in Step A of Example 68, N-[2-tert-butyl-1-(tetrahydro-2H- pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-N-methylpiperazine- 1 -sulfonamide (60 mg, 0.13 mmol) was reacted with methyl isocyanate (17 mg, 0.3 mmol), after being purified by reverse phase ΗPLC, to provide 4-{[[2-tert-butyl-1-(tetrahydro-2H-pyran- 4-ylmethyl)-1H-benzimidazol-5-yl](methyl)amino]sulfonyl}-N-methylpiperazine-1- carboxamide (TFA salt, 75 mg, 93 %). 1H NMR (400 MHz, CDCl3) δ 1.45 (m, 4H), 1.48 (s, 9H)3 2.21 (m, 1H), 2.68 (m, 3H), 3.10 (m, 4H)3 3.21 (s, 3H), 3.28 (m, 6H), 3.91 (m, 2H), 4.12 (d, J = 7.6 Hz, 2H), 4.78 (m, 1H), 7.23 (m, 2H), 7.62 (s3 1H); MS (ESI) (M+H)+ 507.0.
Example 87
4-{[[2-ter^-Butyl-1-(tetrahydro-2JH-pyran-4-ylmethyl)-lJHr-benzimidazol-5- yl](methyl)amino]sulfonyl}-N-cyclopropylpiperazine-1-carboxamide
Following the procedure in Step A of Example 68, N-[2-tert-butyl-1-(tetrahydro-2H- pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-N-methylpiperazine- 1 -sulfonamide (50 mg, 0.11 mmol) was reacted with cyclopropyl isocyanate (25 mg, 0.3 mmol), after being purified by reverse phase ΗPLC, to provide 4-{[[2-tert-butyl-1-(tetrahydro-2H- pyran-4-ylmethyl)-1H-benzimidazol-5-yl](methyl)amino]sulfonyl}-N- cyclopropylρiperazine-1-carboxamide (TFA salt, 56 mg, 78 %). 1H NMR (400 MHz, CDCl3) δ 0.53 (m, 2H), 0.68 (m, 2H), 1.53 (m3 4H)3 1.57 (s, 9H), 2.30 (m, 1H), 2.61 (m, 1H), 3.18 (m, 4H), 3.30 (s, 3H), 3.33 (m, 6H), 3.99 (m, 2H), 4.20 (d, J = 7.6 Hz, 2H), 5.01 (s, 1H), 7.31 (m3 2H), 7.70 (s3 1H); MS (ESI) (M+H)+ 533.0.
- Il l -
Example 88
4-{[[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino lsulfonyl}-N-cyclobutylpiperazine-1-carboxamide
Following the procedure in Step A of Example 68, N-[2-tert-butyl-1-(tetrahydro-2H- pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-N-methylpiperazine-1-sulfonarnide (50 mg, 0.11 mmol) was reacted with cyclobutyl isocyanate (29 mg, 0.3 mmol), after being purified by reverse phase HPLC, to provide 4-{[[2-tert-butyl-1-(tetrahydro-2H- pyran-4-ylmethyl)-1H-benzimidazol-5-yl](methyl)amino]sulfonyl}-N- cyclobutylpiperazine-1-carboxamide (TFA salt, 39 mg, 54 %). 1H ΝMR (400 MHz, CDCl3) δ 1.53 (m, 4H), 1.57 (s, 9H), 1.69 (m, 2H), 1.79 (m, 2H), 2.30 (m, 3H), 3.19 (m, 4H), 3.30 (s, 3H), 3.34 (m, 6H), 3.98 (m, 2H), 4.20 (d, J = 7.6 Hz, 2H), 4.23 (m, 1H), 7.31 (m, 2H), 7.72 (s, 1H); MS (ESI) (M+H)+ 547.0.
Example 89
N-(tert-Butyl)-4-{[[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H- benzimidazol-5-yl] (methyl) amino] sulfonyl} piperazine-1-carboxamide
Following the procedure in Step A of Example 68, N-[2-tert-butyl-1-(tetrahydro-2H- pyran-4-ylmethyl)- 1 H-benzimidazol-5 -yl] - N-methylpiperazine- 1 -sulfonamide (50 mg, 0.11 mmol) was reacted with tert-butyl isocyanate (29 mg, 0.3 mmol), after being purified by reverse phase HPLC, to provide N-(tert-butyl)-4-{[[2-tert-butyl-l- (tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-
yl](methyl)amino]sulfonyl}piperazine-1-carboxamide (TFA salt, 29 mg, 40 %). 1H NMR (400 MHz, CDCl3) δ 1.33 (s, 9H), 1.53 (m, 4H), 1.57 (s, 9H), 2.30 (m, 1H)5 3.20 (m, 4H), 3.30 (s, 3H), 3.33 (m, 6H), 3.98 (m, 2H), 4.20 (d, J = 7.6 Hz, 2H), 7.31 (m, 2H), 7.72 (s, 1H); MS (ESI) (M+H)+ 549.0.
Example 90 N-Butyl-4-{[[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-lir-benzimidazol-
5-yl](raethyl)amino]sulfonyl}piperazine-1-carboxamide
Following the procedure in Step A of Example 68, N-[2-fert-butyl-1-(tetrahydro-2H- pyran-4-ylmethyl)-1H-benzimidazol-5 -yl] -N-methylpiperazine- 1 -sulfonamide (50 mg, 0.11 mmol) was reacted with butyl isocyanate (29 mg, 0.3 mmol), after being purified by reverse phase ΗPLC, to provide N-butyl-4-{[[2-tert-butyl-1-(tetrahydro- 2H-pyran-4-ylmethyl)-li/-benzimidazol-5-yl](methyl)amino]sulfonyl}piperazine-1- carboxamide (TFA salt, 26 mg, 36 %).
1H NMR (400 MHz, CDCl
3) δ 0.90 (t, J=7.2 Hz, 3H), 1.33 (m, 2H), 1.46 (m, 2H), 1.53 (m, 4H), 1.57 (s, 9H), 2.30 (m, 1H), 3.16 (m, 6H), 3.30 (s, 3H), 3.35 (m, 4H), 3.99 (m, 2H), 4.20 (d, J = 7.6 Hz, 2H), 7.31 (m, 2H), 7.72 (s, 1H); MS (ESI) (M+H)
+ 549.0.
Example 91 N-Allyl-4-{[[2-ter^-butyl-1-(tetrahydro-2fl-pyran-4-ylmethyl)-1H-benzimidazol- 5-yl](methyl)amino]sulfonyl}piperazine-1-carboxamide
Following the procedure in Step A of Example 68, N-[2-tert-butyl-1-(tetrahydro-2i-
r- pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-N-methylpiperazine- 1 -sulfonamide (50 mg, 0.11 mmol) was reacted with 3-isocyanatoprop-1-ene (25 mg, 0.3 mmol), after being purified by reverse phase HPLC, to provide N-allyl-4-{[[2-tert-butyl-1- (tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino]sulfonyl}piperazine-1-carboxamide (TFA salt, 29 mg, 41 %).
1H NMR (400 MHz, CDCl
3) δ 1.54 (m, 4H), 1.57 (s, 9H), 2.30 (m, 1H)
5 3.21 (m, 4H), 3.30 (s, 3H)
5 3.37 (m, 6H)
5 3.84 (m, 2H), 3.98 (m, 2H), 4.20 (d, J = 7.6 Hz, 2H), 5.11 (m, 1H)
5 5.17 (m, 1H), 5.85 (m, 1H)
5 7.31 (m, 2H), 7.73 (s, 1H); MS (ESI) (M+H)
+ 533.0.
Example 92
4-{[[2-ter^-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-lJfiT-benzimidazol-5- yl](methyl)amino]sulfonyl}-N-ethylpiperazine-1-carboxamide
Following the procedure in Step A of Example 68, N-[2-tert-butyl-1-(tetrahydro-2H- pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-N-methylpiperazine-1-sulfonamide (50 mg5 0.11 mmol) was reacted with isocyanatoethane (21 mg, 0.3 mrnol), after being purified by reverse phase HPLC5 to provide 4-{[[2-tert-butyl-1-(tetrahydro-2H-pyran- 4-ylmethyl)-1H-benzimidazol-5-yl](methyl)amino]sulfonyl}-N-ethylpiperazine-1- carboxamide (TFA salt, 13 mg, 19 %). 1HNMR (400 MHz, CDCl3) δ 1.13 (t, J=7.2 Hz, 3H)5 1.53 (m, 4H)5 1.57 (s, 9H)5 2.30 (m, 1H), 3.20 (m, 6H), 3.30 (s, 3H)5 3.33 (m, 4H)5 3.98 (m, 2H), 4.20 (d, J = 7.6 Hz, 2H), 7.31 (m, 2H), 7.72 (s, 1H); MS (ESI) (M+H)+ 521.0.
Example 93
4-{[[2-terf-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl] (methyl)amino] sulfonyl}-N-propylpiperazme-1-carboxamide
Following the procedure in Step A of Example 68, N-[2-tert-butyl-1-(tetrahydro-2i-7- pyran-4-ylme1hyl)-1H-benzimidazol-5-yl]-N:-rriethylpiperazme-1-sulfonarnide (50 mg, 0.11 mmol) was reacted with 1-isocyanatopropane (25 mg, 0.3 mmol), after being purified by reverse phase HPLC, to provide 4-{[[2-tert-buryl-1-(tetrahydro-2/i'- pyran-4-ylmethyl)-1H-benzimidazol-5-yl](methyl)amino]sulfonyl}-7V'- propylpiperazine-1-carboxamide (TFA salt, 24 mg, 34 %). 1H NMR (400 MHz, CDCl3) δ 0.91 (t, J=7.6 Hz, 3H), 1.53 (m, 6H), 1.57 (s, 9H), 2.33 (m, 1H), 3.20 (m, 6H), 3.30 (s, 3H), 3.33 (m, 4H), 3.98 (m, 2H), 4.20 (d, J = 7.6 Hz, 2H), 7.31 (m, 2H), 7.72 (s, 1H); MS (ESI) (M+H)+ 535.0.
Example 94
4-{[[2-tert-ButyI-1-(tetrahydro-2H-pyran-4-ylmethyl)-li?-benzimidazol-5- yl](methyl)amino]sulfonyl}-N-(cyclopropylmethyl)piperazine-1-carboxamide
Following the procedure in Step A of Example 68, N-[2-te^butyl-1-(tetrahydro-2H- pyran-4-ylmethyl)- lu/-benzimidazol-5-yl]-N-methylpiperazine- 1 -sulfonamide (50 mg, 0.11 mmol) was reacted with (isocyanatomethytycyclopropane (28 mg, 0.3 mmol), after being purified by reverse phase HPLC, to provide 4-{[[2-tert-butyl-1- (tetrahydro-2/i'-pyran-4-ylmethyl)-li-r-benzimidazol-5-yl](methyl)amino]sulfonyl}-N- (cyclopropylmethy^piperazine-1-carboxamide (TFA salt, 35 mg, 48 %). 1H NMR (400 MHz, CDCl3) δ 0.17 (m, 2H), 0.50 (m, 2H), 0.94 (m, 1H), 1.54 (m, 4H), lr57 (s, 9H), 2.30 (m, 1H), 3.06 (m, 2H), 3.20 (m, 4H), 3.30 (s, 3H), 3.37 (m, 6H), 3.99 (m, 2H), 4.20 (d, J = 7.6 Hz, 2H), 7.31 (m, 2H), 7.72 (s, 1H); MS (ESI) (M+H)+ 547.0.
Example 95
N-[2-tert-Butyl-1-(tetrahydro-2fir-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-4-
(liϊ-imidazol-1-ylcarbonyl)-N-methylpiperazme-1-sulfonamide
A solution of N-[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol- 5-yl]-N-methylpiperazme-l -sulfonamide (2.25 g, 5.0 mmol) and l,l'-biscarbonyl-1H- imidazole (0.97 g, 6.0 mmol) in THF (40 mL) was heated at 650C for two days. The reaction mixture was concentrated under reduced pressure. The residue was then dissolved in AcOEt (60 mL), washed with brine, and dried over Na2SO4. Removal of solvents provided N-[2-t ert-butyl- 1 -(tetrahy&o-2H-pyτan-4-ylmethyl)- IH- benzimidazol-5 -yl] -4-( 1H-imidazol- 1 -ylcarbonyl)-N-methylpiperazine- 1 -sulfonamide (2.6 g, 96 %), 1H NMR (400 MHz, CD3OD, TFA salt) δ 1.54 (m, 4H), 1.68 (s, 9H), 2.37 (m, 1H), 3.32 (m, 2H), 3.34 (s, 3H), 3.42 (m, 4H), 3.65 (m, 4H), 3.92 (m, 2H), 4.54 (d, J = 7.6 Hz, 2H), 7.67 (m, 2H), 7.84 (s, 1H), 7.90 (s, 1H), 7.97 (d, J=8.8 Hz, 1H), 9.32 (s, 1H); MS (ESI) (M+H)+ 543.8.
Example 96
Isopropyl 4-{ [ p-terf-butyl-1-^etrahydro^H-pyran^-ylmethy^-1H- benzimidazol-5-yl](methyl)amino]sulfonyl}piperazine-1-carboxylate
Following the procedure in Step A of Example 60, N-[2-tert-butyl-1-(tetrahydro-2H- pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-N-methylpiperazine-1-sulfonamide (45 mg, 0.10 mmol) was reacted with isopropyl chloroformate (25 mg, 0.2 mmol), after
being purified by reverse phase HPLC, to isopropyl 4-{[[2-tert-butyl-1-(tetrahydro- 2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl](methyl)amino]sulfonyl}piperazine-1- carboxylate (TFA salt, 62 mg, 94 %). 1H NMR (400 MHz, CDCl3) δ 1.16 (d, J=6.3 Hz, 6H), 1.47 (m, 4H), 1.49 (s, 9H), 2.22 (m, 1H)5 3.10 (m, 4H), 3.23 (s, 3H)5 3.23 (m, 2H), 3.37 (m5 4H), 3.91 (m, 2H), 4.13 (d, J = 7.6 Hz, 2H), 4.83 (m, 1H), 7.23 (m, 2H), 7.64 (S5 1H); MS (ESI) (M+H)+ 536.0.
Example 97 N-(1-{[[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benziinidazol-5- yl] (methyl)amino] sulfonyl}pyrrolidin-3-yl)acetamide
Step A. -V-(1-{ [ [2-ter^-Butyl-1-(tetrahydro-2J3r-pyran-4-ylmethyl)-lJff- benzimidazol-5-yl](methyl)amino]sulfonyl}pyrrolidin-3-yl)acetamide
Following the procedure in Step A of Example 60, 3-amino-N-[2-tert-butyl-1-
(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-N-methylpyrrolidine-1- sulfonamide trifluoroacetate (100 mg, 0.18 mmol) was reacted with acetyl chloride (79 mg3 1.0 mmol), after being purified by reverse phase HPLC5 to provide 2V-(I- { [[2-tert-butyl- 1 -(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino]sulfonyl}pyrrolidin-3-yl)acetamide (TFA salt, 25 mg, 23 %). 1H NMR (400 MHz, CD3OD5 TFA salt) δ 1.54 (m, 4H), 1.67 (s, 9H)3 1.85 (m, 1H), 1.89 (s, 3H)5 2.13 (m, 1H), 2.36 (m, 1H)5 3.10 (m, 1H)5 3.31 (s, 3H), 3.33 (m, 3H)5 3.48 (m, 2H), 3.91 (m, 2H), 4.20 (m, 1H)5 4.52 (d, J = 7.6 Hz, 2H), 7.65 (d5 J=9.0 Hz, 1H)5 7.79 (S5 1H)5 7.93 (d, J=9.0 Hz, 1H); MS (ESI) (M+H)+492.0.
Step B. tert-Butyl (1-{[[2-tert-butyl-1-(tetrahydro-2Jff-pyran-4-ylmethyl)-lJ3- benzimidazol-5-yl](methyl)amino]sulfonyl}pyrroIidin-3-yl)carbamate
Following the procedure in Step C of Example 60, 1-{[[2-tert-butyl-1-(tetrahydxo-2H- pyran-4-ylmethyl)-1H-benzimidazol-5-yl](methyl)amino]sulfonyl}-3-methyl-li/- imidazol-3-ium triflate (460 mg, 0.77 mrαol) was reacted with tert-butyl pyrrolidin-3- ylcarbamate (558 mg, 3.0 mmol), after being purified by silica gel chromatography, to provide tert-hutyl (1-{[[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-lJf- benzimidazol-5-yl](methyl)amino]sulfonyl}pyrrolidin-3-yl)carbamate (385 mg, 91 %). MS (ESI) (M+H)
+ 550.0.
Step C : 3-Amino-Λ^-[2-tert-butyl-1-(tetrahydro-2H-pyran-4-yImethyl)-1H- benzimidazol-5-yl]-N-methylpyrroHdine-1-sulfonamide
A solution of tert-butyl (1-{[[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H- benzimidazol-5-yl](methyl)amino]sulfonyl}pyrrolidin-3-yl)carbamate (385 mg, 0.7 mmol) in 10 mL CH2Cl2 was treated with 10 mL TFA at room temperature. After being stirred at room temperature for 1 hr, the reaction mixture was concentrated under reduced pressure to provide 3-amino-N-[2-tert-butyl- 1 -(tetrahydro-2H-pyran-4- ylmethyO-1H-benzimidazol-5-ylJ-N-methylpyrrolidme-1-sulfonamide (TFA salt, 100 %), which was used in Step A without purification.
Example 98 N-(l-{[[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino]sulfonyl}pyrrolidin-3-yl)-2,2-dimethylpropanamide
Following the procedure in Step A of Example 60, 3-amino-N-[2-tert-butyl-1- (tetrahydro-2H-pyran-4-ylmethyl)-l//-benzimidazol-5-yl]-N-methylpyrrolidme-1- sulfonamide trifluoroacetate (100 mg, 0.18 mmol) was reacted with 2,2- dimethylpropanoyl chloride (60 mg, 0.5 mmol), after being purified by reverse phase HPLC, to provide N-(1-{[[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H- benzimidazol-5-yl](methyl)amino]sulfonyl}pyrrolidin-3-yl)-2,2- dimethylpropanamide (TFA salt, 39 mg, 33 %).
1H NMR (400 MHz, CD
3OD
5 TFA salt) δ 1.12 (s, 9H), 1.57 (m, 4H), 1.67 (s, 9H), 1.96 (m, 1H), 2.11 (m, 1H), 2.36 (m, 1H), 3.10 (m, 1H), 3.31 (s, 3H), 3.33 (m, 3H), 3.48 (m, 2H), 3.91 (m, 2H), 3.94 (m, 1H), 4.52 (d, J = 7.6 Hz, 2H), 7.65 (d, J=9.0 Hz, 1H), 7.79 (s, 1H), 7.94 (d, J=9.0 Hz, 1H); MS (ESI) (M+H)
+ 534.0.
Example 99 N-(1-{[[2-tert-Butyl-1-(tetrahydro-2JHr-pyran-4-ylmethyl)-ljEr-benzimidazol-5- yl] (methyl)amino] sulfonyl} azetidin-3-yl)acetamide
Following the procedure in Step A of Example 60, 3-amino-N-[2-tert-butyl-1- (tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-N-methylazetidme- 1 - sulfonamide (20 mg, 0.046 mmol) was reacted with acetic anhydride (51 mg, 0.5 mmol), after being purified by reverse phase HPLC, to provide N-(I- {[[2-tert-butyl-
l-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino]sulfonyl}azetidin-3-yl)acetamide (TFA salt, 9 mg, 33 %). 1H NMR (400 MHz, CD3OD5 TFA salt) δ 1.58 (m, 4H), 1.67 (s, 9H), 1.91 (s, 3H), 2.32 (m, 1H), 3.28 (s, 3H), 3.33 (m, 2H), 3.80 (m, 2H), 3.91 (m, 2H), 3.99 (m, 2H), 4.50 (m, 1H), 4.53 (d, J = 7.6 Hz, 2H), 7.65 (d, J=9.2 Hz, 1H), 7.78 (s, 1H), 7.95 (d, J=9.2 Hz, 1H); MS (ESI) (M+H)+ 478.0.
Example 100 N-{2-fert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-lJ9r-benzimidazol-5-yl}-N- methyl-1H-imidazole-1-sulfonamide
3-(Imidazole-1-sulfonyl)-1-methyl-3H-imidazol-1-ium triflate (xx mg; 1.5 mmol) was added into a solution of 2-tert -butyl- l-[(4,4-difluorocyclohexyl)methyl]-N-inethyl- 1H-benzimidazol-5-amine (335 mg, 1.0 mmol) in acetonitrile (15 mL). After being stirred at room temperature overnight, the reaction mixture was concentrated under reduced pressure to give a residue, which was purified by HPLC to provide N-{2-tert- butyl- 1 - [(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl} -N-methyl- IH- imidazole-1 -sulfonamide (295 mg, 51 %). MS (ESI) (M+H)+ 466.0.
Example 101 N-{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-lj9r-benzimidazol-5-yl}--V- methyl-1H-l,2,4-triazole-1-sulfonamide
Following the procedure in Step C of Example 60, 1-{[{2-tert-butyl-1-[(4,4- difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}(methyl)amino]sulfonyl}-3- methyl-1H-imidazol-3-ium triflate (50 rag, 0.08 mmol) was reacted with 1H-1,2,4- triazole (69 mg, 1.0 mmol), after being purified by reverse phase HPLC, to provide N-{2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}-N- memyl-1H-l,2,4-triazole-1-sulfonamide (TFA salt, 15 mg, 32 %).
1H NMR (400 MHz, CD
3OD, TFA salt) δ 1.40-1.76 (m, 6H), 1.62 (s, 9H), 2.03 (m, 2H), 2.20 (m, 1H), 3.55 (s, 3H), 4.48(d, J = 7.4 Hz, 2H), 7.36(d, J=9.0 Hz, 1H), 7.60 (s, 1H), 7.86(d, J=9.0 Hz, 1H), 8.28 (s, 1H), 8.72(s, 1H); MS (ESI) (M+H)
+ 467.0.
Example 102 N-{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}-N- methyl-1H-l,2,3-triazole-1-sulfonamide
Following the procedure in Step C of Example 60, 1-{[{2-tert-butyl-1-[(4,4- difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}(methyl)amino]sulfonyl}-3- methyl-1H-imidazol-3-ium triflate (50 mg, 0.08 mmol) was reacted with 1H-1,2,3- triazole (69 mg, 1.0 mmol), after being purified by reverse phase ΗPLC, to provide N-{2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}-N- methyl-1H-l,2,3-triazole-1-sulfonamide (TFA salt, 14 mg, 30 %).
1H NMR (400 MHz, CD
3OD, TFA salt) δ 1.40-1.76 (m, 6H), 1.59 (s, 9H), 2.03 (m, 2H), 2.20 (m, 1H), 3.56 (s, 3H), 4.42 (d, J = 7.4 Hz, 2H), 7.22(d, J=9.0 Hz, 1H), 7.47 (s, 1H), 7.75(d, J=9.0 Hz, 1H), 7.82 (d, J=1.1 Hz, 1H), 8.21 (d, J=Ll Hz, 1H); MS (ESI) (M+H)
+ 467.0.
Example 103 N-[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benziinidazol-5-yl]-4- formyl-N-methyl-1H-pyrazole-1-sulfonamide
Following the procedure in Step C of Example 60, 1-{[2-tert-butyl-1-(tetrahydro-1H- pyran-4-ylmethyl)-1H-benzimidazol-5-yl](methyl)amino]sulfonyl}-3-methyl-1H- imidazol-3-ium triflate (1.89 g, 3.0 mmol) was reacted with 1H-pyrazole-4- carbaldehyde (576 mg, 6.0 mmol), after being purified by silica gel chromatography, to provide N-[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl]-4-formyl-N-methyl-1H-pyrazole-l -sulfonamide (586 mg, 43 %). 1H NMR (400 MHz, CDCl3) δ 1.48 (m, 4H), 1.50 (s, 9H), 2.22 (m, 1H), 3.27 (m, 2H), 3.55 (s, 3H), 3.91 (m, 2H), 4.14 (d, J = 7.2 Hz, 2H), 6.98 (dd, J = 8.8, 2.0 Hz, 1H), 7.925 (d, J = 8.8 Hz, 1H), 7.37 (s, 1H), 8.14 (s, 1H), 8.18 (s, 1H), 9.81 (s, 1H); MS (ESI) (M+H)+ 460.0.
Example 104 1-{[[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino]sulfonyl}-N-cyclopropyl-1H-pyrazole-4-carboxaraide
Step A. 1-{ [ [2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol- 5-yl](methyl)amino]sulfonyl}-N-cyclopropyl-1H-pyrazole-4-carboxamide
HATU (150 mg, 0.4 mmol) was added to a solution of 1-{[[2-tert-butyl-1-(tetrahydro- 2/f-pyran-4-ylmethyl)- li7-benzimidazol-5-yl](methyl)amino]sulfonyl} -1H-pyrazole- 4-carboxylic acid (100 mg, 0.21 mmol), cyclopropylamine (57 mg, 1.0 mmol) and DIPEA (0.2 mL) in DMF (3.0 mL) at r.t. After 30 min, the reaction mixture was condensed to give a residue, which was purified by reverse phase HPLC to provide 1- { [[2-tert-butyl-l -(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino]sulfonyl}-N-cyclopropyl-1H-pyrazole-4-carboxamide (TFA salt, 29 mg, 22 %). 1H NMR (400 MHz, CDCl3) δ 0.59 (m, 2H), 0.80 (m, 2H), 1.54 (m, 4H), 1.56 (s, 9H), 2.33 (m, 1H), 2.82 (m, 1H), 3.33 (m, 2H), 3.55 (s, 3H), 3.99 (m, 2H), 4.20 (d, J = 7.6 Hz, 2H), 6.40 (s, 1H), 7.06 (dd, J = 9.0, 2.0 Hz, 1H), 7.28 (d, J = 9.0 Hz, 1H), 7.38 (s, 1H), 8.02 (s, 1H), 8.05 (d, J=3.5 Hz, 1H); MS (ESI) (M+H)+515.0.
Step B. 1-{[[2-tert-Butyl-1-(tetrahydro-2JHr-pyran-4-ylmethyl)-lJH-benzimidazol- 5-yl] (methyl) amino] sulfonyl} -1H-pyrazole-4-carboxylic acid
N-[2-ført-butyl-1-(tetrahydro-2H-pyran-4-ylmemyl)-1H-benzimidazol-5-yl]-4-formyl- ΛT-methyl-1H-pyrazole-1 -sulfonamide (460 mg, 1.0 mmol) and ozone (1.0 g, 1.6 mmol) was heated in DMF (15 mL) at 50
0C for 2 hr. The resulting 1-{[[2-fert-butyl- 1 -(tetrahydro-2H-pyran-4-ylmethyl)-1H-berizimidazol-5-yl](me&yl)amino]sulfonyl} - 1H-pyrazole-4-carboxylic acid solution in DMF was used directly in Step A. MS (ESI) (M+H)
+ 476.0.
Example 105 1-{[[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylraethyl)-1H-benzimidazol-5- yl](methyl)amino]sulfonyl}-N-ethyl-1H
r-pyrazole-4-carboxamide
Following the procedure in Step A of Example 104, 1-{[[2-tert-butyl-1-(tetrahydro- 2H-pyran-4-ylmethyl)-li/-benzimidazol-5-yl](methyl)amino]sulfonyl}-1H-pyrazole- 4-carboxylic acid (96 mg, 0.20 mmol) was reacted with ethylamine (90 mg, 2.0 mmol), after being purified by reverse phase HPLC, to provide 1-{[[2-føt-butyl-1- (tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5 -yl] (methyl)amino] sulfonyl} -N- ethyl-1H-pyrazole-4-carboxamide (TFA salt, 33 mg, 27 %).
1H NMR (400 MHz, CD
3OD
5 TFA salt) δ 1.14 (d, J = 7.4 Hz, 3H), 1.52 (m, 4H), 1.65 (s, 9H), 2.33 (m, 1H), 3.32 (m, 4H)
3 3.51 (s, 3H), 3.91 (m, 2H), 4.51 (d, J = 7.6 Hz, 2H), 7.42 (dd, J = 9.0, 2.0 Hz, 1H), 7.66 (d, J = 2.0 Hz, 1H), 7.95 (d, J = 9.0 Hz, 1H), 8.18 (s, 1H), 8.30 (s, 1H); MS (ESI) (M+H)
+502.8.
Example 106 N-Allyl-1-{[[2-tert-butyl-1-(tetrahydro-2J9r-pyran-4-yImethyl)-1H-benzimidazol- 5-yl] (methyl) amino] sulfonyl} -lIZ-pyrazole-4-carb oxamide
Following the procedure in Step A of Example 104, 1 - { [[2-tert-butyl- 1 -(tetrahydro- 2H-pyran-4-ylmeώyl)-1H-benzimidazol-5-yl](methyl)amino]sulfonyl}-1H-pyrazole- 4-carboxylic acid (96 mg, 0.20 mmol) was reacted with allylamine (114 mg, 2.0
mmol), after being purified by reverse phase HPLC, to provide N-allyl-1-{[[2-tert- butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)ainino]sulfonyl}-1H-pyrazole-4-carboxamide (TFA salt, 38 mg, 30 %).
1H NMR (400 MHz, CD
3OD, TFA salt) δ 1.52 (m, 4H), 1.65 (s, 9H), 2.33 (m, 1H), 3.32 (m, 4H), 3.52 (s, 3H), 3.91 (m, 4H), 4.51 (d, J = 7.6 Hz, 2H), 5.09 (m, 1H), 5.17 (m, 1H), 5.85 (m, 1H), 7.42 (dd, J = 9.0, 2.0 Hz, 1H), 7.67 (d, J = 2.0 Hz, 1H), 7.95 (d, J = 9.0 Hz, 1H), 8.20 (s, 1H), 8.32 (s, 1H); MS (ESI) (M+H)
+515.0.
Example 107 1-{ [[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino]sulfonyl}-N-propyl-1H-pyrazole-4-carboxamide
Following the procedure in Step A of Example 104, 1-{[[2-tert-butyl-1-(tetrahydro- 2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl](methyl)amino]sulfonyl} -1H-pyrazole- 4-carboxylic acid (96 mg, 0.20 mmol) was reacted with propylamine (118 mg, 2.0 mmol), after being purified by reverse phase HPLC, to provide 1-{[[2-tert-butyl-1- (tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl](methyl)amino]sulfonyl}-N- propyl-1H-ρyrazole-4-carboxamide (TFA salt, 44 mg, 35 %). 1H NMR (400 MHz, CD3OD, TFA salt) δ 0.91 (d, J = 7.4 Hz, 3H), 1.52 (m, 6H), 1.65 (s, 9H), 2.33 (m, 1H), 3.23 (t, J=7.2 Hz, 2H), 3.32 (m, 2H), 3.52 (s, 3H), 3.91 (m, 2H), 4.51 (d, J = 7.6 Hz, 2H), 7.41 (dd, J = 9.0, 2.0 Hz, 1H), 7.66 (d, J = 2.0 Hz, 1H), 7.95 (d, J = 9.0 Hz, 1H), 8.19 (s, 1H), 8.31 (s, 1H); MS (ESI) (M+H)+516.8.
Example 108 1-{[[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino]suIfonyl}-N^V-dimethyl-1H-pyrazole-4-carboxamide
Following the procedure in Step A of Example 104, 1-{[[2-tert-butyl-1-(tetrahydro- 2H-pyran-4-ylmethyl)-liif-benzimidazol-5-yl](methyl)amino]sulfonyl}-l//'-pyrazole- 4-carboxylic acid (96 mg, 0.20 mmol) was reacted with dimethylamine (90 mg, 2.0 mmol), after being purified by reverse phase HPLC, to provide 1-{[[2-tert-butyl-1- (tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl](methyl)amino]sulfonyl}- N,N-dimethyl-1H-ρyrazole-4-carboxamide (TFA salt, 79 mg, 64 %). 1H NMR (400 MHz, CD3OD, TFA salt) δ 1.53 (m, 4H), 1.66 (s, 9H), 2.33 (m, 1H), 3.02 (s, 3H), 3.12 (s, 3H), 3.32 (m, 2H), 3.51 (s, 3H), 3.89 (m, 2H), 4.52 (d, J = 7.6 Hz, 2H), 7.41 (dd, J = 9.0, 2.0 Hz, 1H), 7.61 (d, J = 2.0 Hz, 1H), 7.95 (d, J = 9.0 Hz, 1H), 8.09 (s, 1H), 8.16 (s, 1H); MS (ESI) (M+H)+502.8.
Example 109 1-{[[2-tert-Butyl-1-(tetrahydro-2i?-pyran-4-ylmethyl)-lJ3-benzimidazol-5- yl] (methyl)amino] sulfonyl}-N-methyl-l£?-pyrazole-4-carboxaraide
Following the procedure in Step A of Example 104, 1-{[[2-tert-butyl-1-(tetrahydro-
2#-pyran-4-ylmethyl)-1H-berizm
4-carboxylic acid (96 mg, 0.20 mmol) was reacted with methylamine (31 mg, 1.0 mmol), after being purified by reverse phase HPLC, to provide 1-{[[2-tert-butyl-1-
(tetrahydro-2H-pyran-4-ylmethyl)-1H-berizimidazol-5-yl](methyl)amino]sulfonyl}-N- methyl-1H-ρyrazole-4-carboxamide (TFA salt, 24 mg, 20 %). 1H NMR (400 MHz,
CD3OD, TFA salt) δ 1.52 (m, 4H), 1.65 (s, 9H), .2.33 (m, 1H), 2.81 (s, 3H), 3.32 (m,
2H), 3.52 (s, 3H), 3.91 (m, 2H), 4.51 (d, J = 7.6 Hz, 2H), 7.41 (dd, J = 9.0, 2.0 Hz, 1H), 7.66 (d, J = 2.0 Hz, 1H), 7.95 (d, J = 9.0 Hz, 1H), 8.17 (s, 1H), 8.27 (s, 1H); MS (ESI) (M+H)+488.7.
Example 110 N-(tert-Butyl)-1-{[[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H- benzimidazol-5-yl}(methyl)amino ]sulfonyl}-1H-pyrazole-4-carboxamide
Following the procedure in Step A of Example 104, 1-{[[2-tert-butyl-1-(tetrahydro- 2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl](methyl)amino]sulfonyl}-1H-pyrazole- 4-carboxylic acid (96 mg, 0.20 mmol) was reacted with t-butylamine (73 mg, 1.0 mmol), after being purified by reverse phase HPLC, to provide N-(tert-butyl)-1-{[[2- tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino]sulfonyl}-1H-pyrazole-4-carboxamide (TFA salt, 26 mg, 20 %). 1H NMR (400 MHz, CD3OD, TFA salt) δ 1.37 (s, 9H), 1.52 (m, 4H), 1.66 (s, 9H), 2.33 (m, 1H), 3.32 (m, 2H), 3.51 (s, 3H), 3.91 (m, 2H), 4.51 (d, J = 7.6 Hz, 2H), 7.44 (dd, J = 9.0, 2.0 Hz, 1H), 7.66 (d, J = 2.0 Hz, 1H), 7.96 (d, J = 9.0 Hz, 1H), 8.17 (s, 1H), 8.36 (s, 1H); MS (ESI) (M+H)+530.8.
Example 111 N-(1-{[[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl] (methyl)amino] sulfonyl}-1H-pyrazol-3-yl)acetamide
Step A. N-(1-{[[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H- benzimidazol-5-yl](methyl)amino]sulfonyl}-1H-pyrazoI-3-yl)acetamide
Following the procedure in Step A of Example 60, 3-amino-N-[2-tert-butyl-1- (tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-N-methyl-1H-pyrazole-1- sulfonamide (from Step B) was reacted with acetic anhydride (530 mg, 5.0 mmol), after being purified by silica gel chromatography, to provide N-(1-{[[2-tert-butyl-1- (tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl](methyl)amino]sulfonyl}- 1H-pyrazol-3-yl)acetamide (3 mg, 2 %). 1H NMR (400 MHz, CD3OD, TFA salt) δ 1.52 (m, 4H), 1.66 (s, 9H), 2.14 (s, 3H), 2.34 (m, 1H), 3.32 (m, 2H), 3.51 (s, 3H), 3.91 (m, 2H), 4.51 (d, J = 7.6 Hz, 2H), 6.75 (d, J = 2.8 Hz, 1H), 7.41 (dd, J = 9.0, 2.2 Hz, 1H), 7.54 (s, 1H), 7.68 (d, J = 2.8 Hz, 1H), 7.93 (d, J = 9.0 Hz, 1H); MS (ESI) (M+H)+489.0.
Step B. 3-Amino-N-[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H- benzimidazol-5-yl]-N-methyI-1H-pyrazole-1-sulfonamide
Following the procedure in Step C of Example 60, 1-{[[2-tert-butyl-1-(tetrahydro-2H- pyran-4-yrmethyl)-1H-benzimidazol-5-yl](methyl)amino]sulfonyl}-3-methyl-1H- imidazol-3-ium triflate (189 mg, 0.3 mmol) was reacted with 1H-pyrazol-3-amine (83 mg, 1.0 mmol), after being purified by silica gel chromatography, to provide crude 3- amino-N-[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-N- methyl-1H-pyrazole-l -sulfonamide, which was used in Step A without further purification.
Example 112 N-[2-fer/-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-4- formyl-N-methyl-llZ-imidazole-1-sulfonamide
Following the procedure in Step C of Example 60, 1-{[[2-fert-butyl-1-(tetrahydro-2if- pyran-4-ylmethyl)-1H-benzimidazol-5-yl](methyl)amino]sulfonyl}-3-methyl-1H- imidazol-3-ium triflate (630 g, 1.0 mmol) was reacted with lϋ/'-imidazole-4- carbaldehyde (288 mg, 3.0 mmol), after being purified by silica gel chromatography, to provide N-[2-tert-butyl-1-(tetrahydro-2/i'-pyran-4-ylmethyl)-1H-benzimidazol-5- yl]-4-formyl-N-methyl-1H-imidazole-1-sulfonarnide (335 mg, 73 %). 1H NMR (400 MHz, CDCl3) δ 1.52 (m, 4H), 1.54 (s, 9H), 2.25 (m, 1H), 3.32 (m, 2H), 3.60 (s, 3H), 3.98 (m, 2H), 4.19 (d, J = 7.6 Hz, 2H), 6.81 (s, 1H), 7.01 (dd, J = 8.6, 1.9 Hz, 1H), 7.32 (d, J = 8.6 Hz, 1H)5 7.41 (s, 1H), 7.74 (s, 1H), 10.12 (s, 1H); MS (ESI) (M+H)+ 460.0.
Example 113 1-{[[2-terf-Butyl-1-(tetrahydro-2i?-pyran-4-ylmethyl)-l/ir-benzimidazol-5- yl](methyl)amino]sulfonyl}-N-cyclopropyl-ljH-imidazole-4-carboxamide
Step A. l-{[[2-ter^-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol- 5-yl](methyl)amino]sulfonyl}-N-cyclopropyl-1H-imidazole-4-carboxamide
HATU (15 mg, 0.04 mmol) was added to a solution of 1-{[[2-tert-butyl-1-(tetrahydro- 2/i-pyran-4-ylmethyl)-1H-benzimidazol-5-yl](methyl)amino]sulfonyl}-li/- imidazole-4-carboxylic acid (10 mg, 0.02 mmol), cyclopropylamine (6 mg, 0.1 mmol) and DIPEA (0.1 niL) in DMF (1.0 mL) at r.t. After 30 min, the reaction mixture was condensed to give a residue, which was purified by reverse phase HPLC to provide 1- {[[2-tert-butyl-1-(tetrahydro-2Jc-r-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino]sulfonyl}-N-cyclopropyl-li/-imidazole-4-carboxamide (TFA salt, 2 mg, 15 %). 1H NMR (400 MHz, CDCl3) δ 0.61 (m, 2H), 0.80 (m, 2H), 1.54 (m, 4H), 1.68 (s, 9H), 2.35 (m, 1H), 2.80 (m, 1H), 3.33 (m, 2H), 3.46 (s, 3H), 3.93 (m, 2H), 4.54 (d, J - 7.6 Hz, 2H), 7.37 (dd, J = 9.0, 1.9 Hz, 1H), 7.56 (d, J = 1.9 Hz, 1H), 7.72 (s, 1H), 7.91 (s, 1H), 7.99 (d, J = 9.0 Hz, 1H); MS (ESI) (M+H)+514.8.
Step B. 1-{[[2-tert-Butyl-1-(tetrahydro-2JY-pyran-4-yImethyl)-1H-benzimidazol- 5-yl](methyl)amino]sulfonyl}-ljHr-imidazole-4-carboxylic acid
N-[2-tert-Butyl- 1 -(tetrahydro-2H-pyran-4-ylmethyl)- l#-benzimidazol-5-yl]-4- formyl-N-methyl-1H-imidazole-1-sulfonainide (320 mg, 0.7 mmol) and ozone (650 mg, 1.1 mmol) was heated in DMF (6 mL) at r.t for 24 hr. The resulting \-{[[2-tert- butyl- 1 -(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](memyl)amino]sulfonyl}-1H-imidazole-4-carboxylic acid solution in DMF was used directly in Step A. MS (ESI) (M+H)+ 476.0.
Example 114 1-{[[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino ]sulfonyl}-N-cyclopropyl-1H-pyrazole-3-carboxamide
Step A. 1-{[[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol- 5-yl](methyl)amino]sulfonyl}-N-cyclopropyl-1H-pyrazole-3-carboxamide
HATU (250 mg, 0.66 mmol) was added to a solution of 1-[[[2-tert-butyl-1- (tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino](methylene)oxido-λ4-sulfanyl]-1H-pyrazole-3-carboxylic acid (65 mg, 0.14 mmol), cyclopropylamine (57 mg, 1.0 mmol) and DIPEA (0.4 mL) in DMF (1.0 mL) at r.t. After 30 min, the reaction mixture was condensed to give a residue, which was purified by reverse phase HPLC to provide 1-{[[2-tert-butyl-1-(tetrahydro- 2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl](methyl)amino]sulfonyl} -N- cycloρropyl-1H-pyrazole-3-carboxamide (TFA salt, 19 mg, 22 %). 1HNMR (400 MHz, CDCl3) δ 0.64 (m, 2H), 0.81 (m, 2H), 1.52 (m, 4H), 1.65 (s, 9H), 2.33 (m, 1H), 2.84 (m, 1H), 3.33 (m, 2H), 3.56 (s, 3H), 3.91 (m, 2H), 4.51 (d, J = 7.6 Hz, 2H), 6.80 (d, J = 2.8 Hz, 1H), 7.39 (dd, J = 9.0, 2.0 Hz, 1H), 7.52 (s, 1H), 7.88 (d, J = 2.8 Hz, 1H), 7.95 (d, J = 9.0 Hz, 1H); MS (ESI) (M+H)+514.8.
Step B. N-[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl]-3-formyl-N-methyl-1H-pyrazole-1-sulfonamide
Following the procedure in Step C of Example 60, 1-{[[2-tert-butyl-1-(tetrahydro-2H- pyran-4-ylmethyl)-1H-benzimidazol-5-yl](methyl)amino]sulfonyl}-3-methyl-l//- imidazol-3-ium triflate (630 g, 1.0 mmol) was reacted with 1H-pyrazole-3- carbaldehyde (288 mg, 3.0 mmol), after being purified by silica gel chromatography, to provide Λr-[2-tert-butyl-1-(tetrahydro-2/i-pyran-4-ylmethyl)-l/i'-benzimidazol-5- yl]-3-formyl-N-methyl-1H-pyrazole-1-sulfonamide (320 mg, 70 %). MS (ESI) (M+H)+ 460.0.
Step C. l-[[[2-tert-Butyl-1-(tetrahydro-2Jfir-pyran-4-ylmethyl)-1Hr-benzimidazol- 5-yl](methyl)amino](methylene)oxido-λ4-sulfanyl]-1H-pyrazole-3-carboxylic acid
N-[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-3- formyl-N-methyl-1H-pyrazole-1-sulfonamide (320 mg, 0.7 mmol) and ozone (615 mg, 1.0 mmol) was heated in DMF (6 mL) at 50
0C for 4 hr. The resulting 1 -[[[2-tert- butyl- 1 -(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino](methylene)oxido-λ
4-sulfanyl]-1H-pyrazole-3-carboxylic acid solution in DMF was used directly in Step A. MS (ESI) (M+H)
+ 476.0.
Example 115 l-{[[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-lIf-benzimidazol-5- yl](raethyl)amino]sulfonyl}-Λ'-isopropyl-ljH
r-pyrazole-3-carboxamide
Following the procedure in Step A of Example 114, l-[[[2-tert-butyl-1-(tetrahydro- 2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl](methyl)arniB.o](methylene)oxido-λ4- sulfanylJ-1H-pyrazole-S-carboxylic acid (65 mg, 0.14 mmol) was reacted with isopropylamine (59 mg, 1.0 mmol), after being purified by reverse phase HPLC to provide 1-{[[2-tert-butyl-1-(tetrahydro-2Ii-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino]sulfonyl}-N-isopropyl-li/-pyrazole-3-carboxamide (TFA salt, 31 mg, 36 %). 1H NMR (400 MHz, CDCl3) δ 1.24 (d, J = 6.6 Hz, 6H), 1.52 (m, 4H), 1.65 (s, 9H), 2.33 (m, 1H), 3.33 (m, 2H), 3.56 (s, 3H), 3.91 (m, 2H), 4.20 (m, 1H), 4.51 (d, J = 7.6 Hz, 2H), 6.80 (d, J = 2.8 Hz, 1H), 7.40 (dd, J = 9.0, 2.0 Hz, 1H), 7.53 (s, 1H), 7.88 (d, J = 2.8 Hz, 1H), 7.95 (d, J = 9.0 Hz, 1H); MS (ESI) (M+H)+516.8.
Example 116 1-{[[2-terr-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl] (methyl)amino] sulfonyl}-N-propyl-1H-pyrazole-3-carboxamide
Following the procedure in Step A of Example 114, l-[[[2-tert-butyl-1-(tetrahydro- 2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl](methyl)amino](methylene)oxido-λ4- sulfanyl]-1H~-pyrazole-3-carboxylic acid (65 mg, 0.14 mmol) was reacted with propylamine (59 mg, 1.0 mmol), after being purified by reverse phase HPLC to provide 1 - { [[2-tert-butyl- 1 -(tetrahydro-2H-pyran-4-ylmethyl)- 1H-benzimidazol-5- yl](methyl)amino]sulfonyl}-N-propyl-1H-pyrazole-3-carboxamide (TFA salt, 26 mg,
30 %). 1HNMR (400 MHz, CDCl3) δ 0.95 (t, J = 7.4 Hz, 3H), 1.52 (m, 4H), 1.62 (m, 2H), 1.65 (s, 9H), 2.33 (m, 1H), 3.28 (m, 2H), 3.33 (m, 2H), 3.58 (s, 3H), 3.91 (m, 2H), 4.51 (d, J = 7.6 Hz, 2H), 6.80 (d, J = 2.8 Hz, 1H), 7.39 (dd, J = 9.0, 2.0 Hz, 1H), 7.53 (s, 1H), 7.88 (d, J = 2.8 Hz, 1H), 7.95 (d, J = 9.0 Hz, 1H); MS (ESI) (M+H)+516.8.
Example 117
N-Allyl-1-{[[2-ter^-butyl-1-(tetrahydro-2JHr-pyran-4-ylmethyl)-1H-benzimidazol-
5-yl](methyl)amino]sulfonyl}-1H-pyrazole-3-carboxamide
Following the procedure in Step A of Example 114, l-[[[2-tert-butyl-1-(tetrahydro- 2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl](methyl)amino](methylene)oxido-λ4- sulfanyl]-1H-pyrazole-3-carboxylic acid (65 mg, 0.14 mmol) was reacted with allylamine (57 mg, 1.0 mmol), after being purified by reverse phase HPLC to provide N-allyl- 1 -{[[2-tert-butyl- 1 -(tetrahydro-2H-pyran-4-ylmethyl)- 1H-benzimidazol-5- yl](methyl)amino]sulfonyl}-1H-pyrazole-3-carboxamide (TFA salt, 18 mg, 21 %). 1H NMR (400 MHz, CDCl3) δ 1.50 (m, 4H), 1.62 (m, 2H), 1.64 (s, 9H), 2.32 (m, 1H), 3.31 (m, 2H), 3.57 (s, 3H), 3.91 (m, 2H), 3.97 (d, J=5.3 Hz, 2H), (m, 1H), 4.49 (d, J = 7.6 Hz, 2H), 5.11 (m, 1H), 5.21 (m, 1H), 5,88 (m, 1H), 6.80 (d, J = 2.8 Hz, 1H), 7.39 (dd, J = 9.0, 2.0 Hz, 1H), 7.52 (s, 1H), 7.88 (d, J = 2.8 Hz, 1H), 7.94 (d, J = 9.0 Hz, 1H); MS (ESI) (M+H)+514.8.
Example 118 1-{[[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-li3-benzimidazol-5- yl](methyl)amino]sulfonyl}-N-ethyl-lJ3-pyrazole-3-carboxamide
Following the procedure in Step A of Example 114, l-[[[2-tert-butyl-1-(tetrahydro- 2H-pyran-4-ylmethyl)-lH-benzimidazol-5-yl](methyl)amino](methylene)oxido-λ4- sulfanyl]-li/-pyrazole-3-carboxylic acid (65 mg, 0.14 mmol) was reacted with ethylamine (45 mg, 1.0 mmol), after being purified by reverse phase HPLC to provide 1 - { [[2-tert-butyl- 1 -(tetr ahy dro-2H-pyran-4-y lmethyl)- 1H-benzimidazol-5 - yl](methyl)amino]sulfonyl}-N-ethyl-1H-pyrazole-3-carboxamide (TFA salt, 30 mg, 36 %). 1H NMR (400 MHz, CDCl3) δ 1.21 (d, J = 7.4 Hz, 3H), 1.52 (m, 4H), 1.65 (s, 9H), 2.33 (m, 1H), 3.32 (m, 2H), 3.40 (q, J =7.4 Hz, 2H), 3.58 (s, 3H), 3.91 (m, 2H), 4.51 (d, J = 7.6 Hz, 2H), 6.80 (d, J = 2.8 Hz, 1H), 7.40 (dd, J = 9.0, 2.0 Hz, 1H)5 7.53 (s, 1H), 7.88 (d, J = 2.8 Hz, 1H), 7.95 (d, J = 9.0 Hz, 1H); MS (ESI) (M+H)+502.8.
Example 119 N-[2-tert-ButyI-1-(tetrahydro-2iar-pyran-4-ylmethyl)-1H-benzimidazol-S-yl]-7Λ'- methyl-4-(morpholm-4-ylcarbonyl)piperazme-l -sulfonamide
Step A. 7Λ
ir-[2-tert-Butyl-1-(tetrahydro-2iϊ-pyran-4-ylmethyl)-l
JH
r-benzimidazol-5- yl]-/y-methyl-4-(morpholin-4-ylcarbonyl)piperazine-1-sulfonamide
A solution of l-[(4-{[[2-terf-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H- benzimidazol-5-yl](methyl)amino]sulfonyl}piperazin-1-yl)carbonyl]-3-methyl-l/i:- imidazol-3-ium triflate (20 mg, 0.03 mmol), morpholine (87 mg, 1 mmol), and Hunig's base (0.2 mL) in MeCN (2 mL) was stirred overnight at r.t. The reaction mixture was then condensed to give a residue, which was purified by reverse phase HPLC to provide N-[2-tert-butyl-1-(tetrahydro-2/J-pyran-4-ylmethyl)-1H- benzimidazol-5-yl]-N-methyl-4-(morpholm-4-ylcarbonyl)piperazine-1-sulfonamide (TFA salt, 5 mg, 26 %). 1H NMR (400 MHz, CDCl3) δ 1.55 (m, 4H), 1.68 (s, 9H)5 1.83 (m, 4H), 2.37 (m, 1H), 3.25 (m, 8H), 3.29 (m, 6H), 3.33 (s, 3H), 3.62 (m, 4H), 3.93 (m, 2H), 4.54 (d, J = 7.6 Hz, 2H), 7.69 (d, J=9.2 Hz, 1H), 7.81 (s, 1H), 7.97 (d, J=9.2 Hz, 1H); MS (ESI) (M+H)+562.8.
Step B. l-[(4-{[[2-tert-Butyl-1-(tetrahydro-2J3-pyran-4-ylmethyl)-lJfiT- benzimidazol-S-yl}(methyl)amino lsulfonyl}piperazin-1-yl)carbonyy-S-methyl- 1H-imidazol-3-ium triflate
N-[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-lHr-benzimidazol-5-yl]-4-(li7- imidazol-1-ylcarbonyl)-N-methylpiperazine-l -sulfonamide (1.09 g, 2.0 mmol) in acetonitrile (20 mL) was treated with methyl trifluoromethanesulfonate (1.0 g, 6.0 mmol) at r.t for 0.5 hr. The resulting l-[(4-{[[2-tert-butyl-1-(tetrahydro-2H-pyran-4- ylmethyl)-1H-benzimidazol-5-yl](methyl)amino]sulfonyl}piperazin- 1 -yl)carbonyl]-3- methyl- li7-imidazol-3-ium triflate solution in MeCN was used in the step A directly.
Example 120
4-{[[2-fe^-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-lJET-benzimidazoI-5- yl](methyl)amino]sulfonyl}-Λr-(2-hydroxyethyl)piperazine-1-carboxamide
Following the procedure in Step A of Example 119, l-[(4-{[[2-tert-butyl-1-
(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl] (methyl)amino] sulfonyl} piperazin- 1 -yl)carbonyl]-3-methyl- 1H-imidazol-3-ium triflate (40 mg, 0.06 mmol) was reacted with 2-aminoethanol (61 mg, 1.0 mmol), after being purified by reverse phase HPLC to provide 4-{[[2-ter^-butyl-1-(tetrahydro-2H- pyran-4-yhτiethyl)-1H-benzimidazol-5-yl](methyl)amino]sulfonyl}-N-(2- hydroxyethyl)piρerazine-1-carboxamide (TFA salt, 19 mg, 52 %). 1H NMR (400 MHz, CDCl3) δ 1.55 (m, 4H), 1.68 (s, 9H), 2.37 (m, 1H), 3.24 (m, 8H), 3.33 (s, 3H), 3.40 (m, 4H), 3.55 (m, 2H), 3.93 (m, 2H), 4.54 (d, J = 7.6 Hz, 2H), 7.69 (d, J=9.2 Hz, 1H), 7.82 (s, 1H), 7.97 (d, J=9.2 Hz, 1H); MS (ESI) (M+H)+536.8.
Example 121 N-[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-Λr- methyl-4-(liϊ-pyrazol-1-ylcarbonyl)piperazine-1-sulfonamide
Following the procedure in Step A of Example 119, l-[(4-{[[2-ter?-butyl-1- (tetrahydro-2H:-pyran-4-ylmethyl)-liJ-benzimidazol-5- yl](methyl)amino]sulfonyl}piperazin-1-yl)carbonyl]-3-methyl-1H-imidazol-3-ium triflate (40 mg, 0.06 mmol) was reacted with 1H-pyrazole (68 mg, 1.0 mmol), after
being purified by reverse phase HPLC to provide N-[2-tert-butyl-1-(tetrahydro-2H- pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-N-methyl-4-(1H-pyrazol-1- ylcarbonyl)ρiρerazine-l -sulfonamide (TFA salt, 29 mg, 78 %). 1H ΝMR (400 MHz, CDCl3) δ 1.56 (m, 4H), 1.68 (s, 9H), 2.37 (m, 1H), 3.35 (m, 9H)5 3.81 (m, 4H), 3.93 (m, 2H), 4.54 (d, J = 7.6 Hz, 2H), 6.44 (m, 1H), 7.68 (s, 1H), 7.69 (d, J=9.2 Hz, 1H), 7.84 (s, 1H), 7.97 (d, J=9.2 Hz, 1H), 8.11 (s, 1H); MS (ESI) (M+H)+543.8.
Example 122
N-[2-tert-Butyl-1-(tetrahydro-2Hr-pyran-4-ylraethyl)-lJ9r-benziraidazol-5-yl]-N- methyl-4-(pyrrolidin-1-ylcarbonyl)piper azine-1-sulf bnamide
Following the procedure in Step A of Example 119, l-[(4-{[[2-tert-butyl-1- (tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino]sulfonyl}piperazin-1-yl)carbonyl]-3-methyl-1H-imidazol-3-ium triflate (40 mg, 0.06 mmol) was reacted with pyrrolidine (71 mg, 1.0 mmol), after being purified by reverse phase HPLC to provide AT-[2-tert-butyl-1-(tetrahydro-2H- pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-N-methyl-4-(pyrrolidin-1- ylcarbonyl)piperazine-l -sulfonamide (TFA salt, 26 mg, 70 %). 1H NMR (400 MHz, CDCl3) δ 1.58 (m, 4H)5 1.68 (s, 9H)5 1.83 (m, 4H)5 2.37 (m, 1H), 3.25 (m, 8H)5 3.34 (m, 9H)5 3.93 (m, 2H), 4.54 (d, J = 7.6 Hz, 2H), 7.69 (d, J=9.2 Hz, 1H), 7.82 (s, 1H)5 7.97 (d, JM9.2 Hz, 1H); MS (ESI) (M+H)+547.0.