WO2012131501A1 - Composés benzimidazole substitués en tant qu'inhibiteurs de la kinase cot - Google Patents

Composés benzimidazole substitués en tant qu'inhibiteurs de la kinase cot Download PDF

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WO2012131501A1
WO2012131501A1 PCT/IB2012/050756 IB2012050756W WO2012131501A1 WO 2012131501 A1 WO2012131501 A1 WO 2012131501A1 IB 2012050756 W IB2012050756 W IB 2012050756W WO 2012131501 A1 WO2012131501 A1 WO 2012131501A1
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benzimidazole
carboxylic acid
biphenyl
substituted
unsubstituted
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Sanjib Das
Abraham Thomas
Neelima Khairatkar-Joshi
Malini Bajpai
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Ichnos Sciences SA
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Glenmark Pharmaceuticals SA
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present patent application relates to substituted benzimidazole compounds and their use in treating or preventing diseases, conditions and/or disorders by inhibiting Cancer Osaka Thyroid kinase (COT-kinase).
  • COT-kinase Cancer Osaka Thyroid kinase
  • Cancer Osaka Thyroid (COT) kinase is a protein serine/threonine kinase which phosphorylates the OH group of serine or threonine. It is classified as mitogen- activated protein (MAP) kinase kinase kinase 8 belonging to the MAP kinase kinase kinase family of enzymes. In humans it is encoded by the MAP3K8 gene. COT was originally identified as an oncogene during SHOK cell transfection of human genomic DNA [Proc. Natl. Acad. Sci. U. S. A. (1990), 87, 2409-2413 and Mol. Cell. Biol. (1991), 11, 4088-4096].
  • MAP mitogen- activated protein
  • Tpl2 Tumor Progression Locus
  • ERK extracellular signal-regulated kinase
  • JNK c-jun N-terminal kinase
  • COT/Tpl2 is expressed primarily in spleen, thymus, and lung tissue and is a key component in activation of T cells and macrophages, resulting in TNF-a production from these cell types.
  • COT/Tpl-27 macrophages have a specific defect in LPS stimulated activation of the ERK1/2 mitogen activated protein kinase (MAPK) pathway that affects TNF-a production.
  • MAPK mitogen activated protein kinase
  • COT/Tpl-2 knockout animals are resistant to LPS/D-Galactosamine-Induced Endotoxin Shock [Cell (2000), 103. 1071 - 10831.
  • COT/Tpl-2 modulates cyclooxygenase-2 expression and the production of IL-6, IL-8, and the matrix metalloproteinases MMP- 1 and MMP-3. Inhibition of COT/Tpl2 in primary human cell types can decrease the production of TNF-a and other pro-inflammatory mediators during inflammatory events [J. Biol. Chem. (2007), 282. pp. 33295-33304]
  • TNF-a is believed to be responsible for initiation of inflammation and maintenance of the disease development through induction of effector proteins such as adhesion molecules and matrix metalloproteinases (MMPs) that contributes to cartilage breakdown and bone erosion.
  • MMPs matrix metalloproteinases
  • COT/tpl-2 is considered to be a promising target to develop new and improved anti-inflammatory drugs [Curr Opin Cell Biol. (2009), 21, 317-324, and Curr Med Chem (2007), 14, 2214-2234].
  • TNF-a adalimumab
  • Enbrel etanercept
  • infliximab Remicade
  • Identification of an inhibitor for COT kinase which would potentially alter the production of pro-inflammatory cytokines for example TNF-a, have a potential to be a novel and effective small molecule therapy for the treatment of various inflammatory diseases.
  • PCT publication numbers WO20051 10410, WO2006124692, WO2006124944 & WO20071 17465 disclose various classes of heterocyclic compounds which are shown to be COT kinase inhibitors and may be useful for the treatment of various diseases such as rheumatoid arthritis.
  • the present invention relates to compound of formula (I): ( *) ⁇ L -®- (R3)n
  • A is aryl, heteroaryl, cycloalkyl or heterocyclyl
  • 'L' is a bond or selected from -0-, -C(O)-, -0-(CH 2 ) p -, -(CH 2 ) p -0-, and -(CH 2 ) p -;
  • R 1 is selected from hydrogen, halogen, nitro, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, -C(0)R a , - C(0)NR a R b , -C(0)OR a , -NR a R b , -NR a C(0)R b , -NR a C(0)NR b R c , -NR a C(0)OR b , - N(R a )S0 2 R b , -OC(0)R a , -OC(0)OR a and
  • R 2 at each occurrence, is independently selected from cyano, halogen, - COOH, -C(0)NR a R b , -C(0)N(R a )S0 2 R b , -N(R a )S0 2 R b , substituted or unsubstituted heterocyclic ring, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
  • R 3 is independently selected from halogen, nitro, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, -C(0)R a , -C(0)NR a R b , -C(0)OR a , -NR a R b , - NR a C(0)R b , -NR a C(0)NR b R
  • R 4 at each occurrence, is independently selected from halogen, nitro, cyano, hydroxyl and substituted or unsubstituted alkyl;
  • R a , R b and R c which may be the same or different, are independently selected from hydrogen, halogen, hydroxyl, cyano, amino, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocyclyl; or R a and R b or R b and R c together with the atom to which they are attached, may form cyclic ring, which may be monocyclic, bicyclic or tricyclic rings; substituted or unsubstituted; the cyclic ring may optionally contain one or more hetero atoms selected from O, N or S;
  • 'm' is an integer ranging from 1 to 4, both inclusive;
  • 'n' is an integer ranging from 0 to 5, both inclusive;
  • 'p' is an integer ranging from 1 to 2, both inclusive;
  • 'q' is an integer ranging from 0 to 4, both inclusive.
  • the compounds of formula (I) may involve one or more embodiments.
  • Embodiments of formula (I) include compounds of formula (II), as described hereinafter. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition, claim or any other embodiment defined herein. Thus the invention contemplates all possible combinations and permutations of the various independently described embodiments.
  • R 2 is -C(0)N(R a )S0 2 R b , wherein R a is hydrogen and R b is alkyl (e.g. methyl), haloalkyl (e.g. trifluoromethyl) or aryl (e.g. phenyl).
  • R 2 is N(R a )S0 2 R b , wherein R a is hydrogen and R b is Ci -8 alkyl (e.g. methyl or isopropyl).
  • R 2 is substituted aryl, preferably hydroxyl substituted phenyl.
  • R 2 is halogen, preferably fluorine.
  • R 3 is same or different at each occurrence and independently selected from halogen (e.g. F, CI, Br or I), cyano, CONH 2 , COCH 3 , S0 2 NH 2 , alkyl (e.g. methyl), alkoxy (e.g. methoxy, ehthoxy, propran-2-yloxy), haloalkyl ( e.g. trifluoromethyl), and haloalkoxy (e.g. trifluoromethoxy).
  • halogen e.g. F, CI, Br or I
  • cyano CONH 2 , COCH 3
  • S0 2 NH 2 alkyl (e.g. methyl), alkoxy (e.g. methoxy, ehthoxy, propran-2-yloxy), haloalkyl (e.g. trifluoromethyl), and haloalkoxy (e.g. trifluoromethoxy).
  • R 3 is OR a , wherein R a is hydrogen or cycloalkyl (e.g. cyclopentyl).
  • R 4 is selected from halogen (e.g. F, CI, Br or I).
  • the invention also provides a compound of formula (II), which is an embodiment of a compound of formula (I).
  • 'A' is C6-i 4 aryl, 5- 14 membered heteroaryl or 3-15 membered heterocyclyl; 'L' is a bond or selected from -O- and -C(O)-;
  • R 2a is independently selected from -COOH, -C(0)NR a R b , -C(0)N(R a )S0 2 R b , - N(R a )S02R b , substituted or unsubstituted C6-i 4 aryl, substituted or unsubstituted 3- 15 membered heterocyclyl ring and substituted or unsubstituted 5-14 membered heteroaryl;
  • R 2b is selected from hydrogen, halogen, nitro, cyano, hydroxyl and substituted or unsubstituted Ci-salkyl;
  • R 3 is independently selected from halogen, cyano, hydroxyl, -C(0)R a , -C(0)NR a R b , -C(0)OR a , -NR a R b , -NR a C(0)R b , N(R a )S0 2 R b , - OR a , and S0 2 NR a R b , substituted or unsubstituted Ci-salkyl, substituted or unsubstituted Ci-salkoxy, substituted or unsubstituted haloCi-salkyl, substituted or unsubstituted haloCi-salkoxy and substituted or unsubstituted C3-i2cycloalkyl;
  • R 4 at each occurrence, is independently selected from halogen, cyano, hydroxyl and substituted or unsubstituted Ci-salkyl;
  • R a and R b which may be the same or different, are independently selected from hydrogen, hydroxyl, substituted or unsubstituted Ci-salkyl, substituted or unsubstituted Ci-salkoxy, substituted or unsubstituted haloCi-salkyl, substituted or unsubstituted haloCi-salkoxy, substituted or unsubstituted C3_i2cycloalkyl, substituted or unsubstituted C6-i4aryl, substituted or unsubstituted 3-15 membered heterocyclyl, substituted or unsubstituted 5-14 membered heteroaryl and; or R a and R b together with the atom to which they are attached, may form cyclic ring, which may be monocyclic, bicyclic or tricyclic rings; substituted or unsubstituted; the cyclic ring may optionally contain one or more hetero atoms selected from O, N or S;
  • 'n' is an integer ranging from 0 to 5, both inclusive;
  • 'q' is an integer ranging from 0 to 4, both inclusive.
  • the compound of formula (II) may involve one or more embodiments. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified.
  • R 2a is -C(0)NR a R b , wherein R a is hydrogen and R b is hydrogen or hydroxyl.
  • R 2a is -C(0)N(R a )S0 2 R b , wherein R a is hydrogen and R b is Ci_ 8 alkyl (e.g. methyl), halo Ci-salkyl (e.g. trifluoromethyl) or C6-i 4 aryl (e.g. phenyl).
  • R 2a is N(R a )S0 2 R b , wherein R a is hydrogen and R b is d_ 8 alkyl (e.g. methyl or isopropyl).
  • R 2a is substituted C6-i 4 aryl, preferably hydroxyl substituted phenyl.
  • R 2a is substituted or unsubstituted 5-14 membered heteroaryl or 3 - 15 membered heterocyclic ring wherein heterocyclic or heteroaryl ring is selected
  • R 2b is halogen, preferably fluorine.
  • R 3 is same or different at each occurrence and independently selected from halogen (e.g. F, CI, Br or I), cyano, CONH 2 , COCH 3 , S0 2 NH 2 , Ci_ salkyl (e.g. methyl), Ci-salkoxy (e.g. methoxy, ehthoxy, propran-2-yloxy), haloCi- salkyl ( e.g. trifluoromethyl), and haloCi_ 8 alkoxy (e.g. trifluoromethoxy).
  • halogen e.g. F, CI, Br or I
  • cyano CONH 2 , COCH 3 , S0 2 NH 2
  • Ci_ salkyl e.g. methyl
  • Ci-salkoxy e.g. methoxy, ehthoxy, propran-2-yloxy
  • haloCi- salkyl e.g. trifluoromethyl
  • R 3 is OR a , wherein R a is hydrogen or C3_i 2 cycloalkyl (e.g. cyclopentyl).
  • R 4 is selected from halogen (e.g. F, CI, Br or I).
  • compounds of formula (I) and/or (II) with an IC 50 value of less than 1000 nM, preferably, less than 500 nM, with respect to COT kinase activity as measured by method described in the present patent application.
  • the present invention also provides a pharmaceutical composition that includes at least one compound described herein and at least one pharmaceutically acceptable excipient, such as a pharmaceutically acceptable carrier or diluent.
  • the pharmaceutical composition comprises a therapeutically effective amount of at least one compound described herein.
  • the compounds described in the present patent application may be associated with a pharmaceutically acceptable excipient, such as a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.
  • the compounds and pharmaceutical compositions of the present invention are useful for inhibiting COT kinase, which is related to a variety of disease states.
  • the present invention further provides a method of inhibiting COT kinase receptors in a subject in need thereof by administering to the subject one or more compounds described herein in an amount effective to cause inhibition of such receptor.
  • halogen or halo means fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo).
  • alkyl refers to a hydrocarbon chain radical that includes solely carbon and hydrogen atoms in the backbone, containing no unsaturation, having from one to eight carbon atoms (i.e. Ci_ 8 alkyl), and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n- butyl, n-pentyl, and 1 , 1 -dimethylethyl (t-butyl).
  • Ci_ 8 alkyl refers to an alkyl chain having 1 to 6 carbon atoms.
  • Ci_ 4 alkyl refers to an alkyl chain having 1 to 4 carbon atoms. Unless set forth or recited to the contrary, all alkyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.
  • alkenyl refers to a hydrocarbon chain containing from 2 to 10 carbon atoms (i.e. C2-ioalkenyl) and including at least one carbon-carbon double bond.
  • alkenyl groups include ethenyl, 1-propenyl, 2-propenyl (allyl), /so-propenyl, 2-methyl- 1 -propenyl, 1 -butenyl, and 2-butenyl. Unless set forth or recited to the contrary, all alkenyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.
  • alkynyl refers to a hydrocarbyl radical having at least one carbon- carbon triple bond, and having 2 to about 12 carbon atoms (with radicals having 2 to about 10 carbon atoms being preferred i.e. C2-ioalkynyl).
  • Non- limiting examples of alkynyl groups include ethynyl, propynyl, and butynyl. Unless set forth or recited to the contrary, all alkynyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.
  • alkoxy denotes an alkyl group attached via an oxygen linkage to the rest of the molecule (i.e. Ci -8 alkoxy). Representative examples of such groups are -OCH 3 and -OC2H 5 . Unless set forth or recited to the contrary, all alkoxy groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.
  • alkoxyalkyl or “alkyloxyalkyl” refers to an alkoxy or alkyloxy group as defined above directly bonded to an alkyl group as defined above (i.e. Ci- 8 alkoxyCi- 8 alkyl or Ci-salkyloxyCi-salkyl).
  • alkoxyalkyl moiety includes, but are not limited to, -CH2OCH 3 and -CH2OC2H 5 . Unless set forth or recited to the contrary, all alkoxyalkyl groups described herein may be straight chain or branched, substituted or unsubstituted.
  • haloalkyl refers to at least one halo group (selected from F, CI, Br or I), linked to an alkyl group as defined above (i.e.haloCi-salkyl).
  • haloalkyl moiety include, but are not limited to, trifluoromethyl, difluoromethyl and fluoromethyl groups. Unless set forth or recited to the contrary, all haloalkyl groups described herein may be straight chain or branched, substituted or unsubstituted.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogen atoms (i.e.haloCi-salkoxy).
  • haloalkoxy include but are not limited to fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, pentachloroethoxy, chloromethoxy, dichlorormethoxy, trichloromethoxy and 1 -bromoethoxy.
  • all haloalkoxy groups described herein may be straight chain or branched, substituted or unsubstituted.
  • hydroxyalkyl refers to an alkyl group as defined above wherein one to three hydrogen atoms on different carbon atoms is/are replaced by hydroxyl groups (i.e. hydroxyCi-salkyl).
  • hydroxyalkyl moiety include, but are not limited to -CH 2 OH, -C 2 H 4 OH and -CH(OH)C 2 H 4 OH.
  • cycloalkyl denotes a non-aromatic mono or multicyclic ring system of 3 to about 12 carbon atoms, for example C 3 _i2cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • multicyclic cycloalkyl groups include, but are not limited to, perhydronapththyl, adamantyl and norbornyl groups, bridged cyclic groups or spirobicyclic groups, e.g., spiro(4,4)non-2- yl.
  • C 3 _6 cycloalkyl refers to the cyclic ring having 3 to 6 carbon atoms. Unless set forth or recited to the contrary, all cycloalkyl groups described or claimed herein may be substituted or unsubstituted.
  • cycloalkylalkyl refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms directly attached to an alkyl group, for example C 3 _ 8 CycloalkylCi_ 8 alkyl.
  • the cycloalkylalkyl group may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
  • Non-limiting examples of such groups include cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl. Unless set forth or recited to the contrary, all cycloalkylalkyl groups described or claimed herein may be substituted or unsubstituted.
  • cycloalkenyl refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms with at least one carbon-carbon double bond, for example C3_ 8 Cycloalkenyl, such as cyclopropenyl, cyclobutenyl, and cyclopentenyl. Unless set forth or recited to the contrary, all cycloalkenyl groups described or claimed herein may be substituted or unsubstituted.
  • cycloalkenylalkyl refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms with at least one carbon-carbon double bond, directly attached to an alkyl group, for example C3_ 8 CycloalkenylCi_ 8 alkyl.
  • the cycloalkenylalkyl group may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure. Unless set forth or recited to the contrary, all cycloalkenylalkyl groups described or claimed herein may be substituted or unsubstituted.
  • aryl refers to an aromatic radical having 6 to 14 carbon atoms (i.e. C6-i 4 aryl), including monocyclic, bicyclic and tricyclic aromatic systems, such as phenyl, naphthyl, tetrahydronapthyl, indanyl, and biphenyl. Unless set forth or recited to the contrary, all aryl groups described or claimed herein may be substituted or unsubstituted.
  • aryloxy refers to an aryl group as defined above attached via an oxygen linkage to the rest of the molecule (i.e. C6-i4aryloxy).
  • aryloxy moiety include, but are not limited to phenoxy and naphthoxy. Unless set forth or recited to the contrary, all aryloxy groups described herein may be substituted or unsubstituted.
  • arylalkyl refers to an aryl group as defined above directly bonded to an alkyl group as defined above, i.e. C6-i 4 arylCi_ 8 alkyl, such as -CH2C 6 H 5 and - C2H4C 6 H 5 . Unless set forth or recited to the contrary, all arylalkyl groups described or claimed herein may be substituted or unsubstituted.
  • heterocyclic ring or “heterocyclyl” unless otherwise specified refers to substituted or unsubstituted non-aromatic 3 to 15 membered ring radical which consists of carbon atoms and from one to five hetero atoms selected from nitrogen, phosphorus, oxygen and sulfur.
  • the heterocyclic ring radical may be a mono-, bi- or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states.
  • heterocyclic ring or heterocyclyl may optionally contain one or more olefinic bond(s).
  • heterocyclic ring radicals include, but are not limited to azepinyl, azetidinyl, benzodioxolyl, benzodioxanyl, chromanyl, dioxolanyl, dioxaphospholanyl, decahydroisoquinolyl, indanyl, indolinyl, isoindolinyl, isochromanyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, oxadiazolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2- oxoazepinyl,
  • heterocyclic ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure. Unless set forth or recited to the contrary, all heterocyclyl groups described or claimed herein may be substituted or unsubstituted.
  • heterocyclylalkyl refers to a heterocyclic ring radical directly bonded to an alkyl group (i.e. heterocyclylCi_ 8 alkyl).
  • the heterocyclylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure. Unless set forth or recited to the contrary, all heterocyclylalkyl groups described or claimed herein may be substituted or unsubstituted.
  • heteroaryl refers to substituted or unsubstituted 5 to 14 membered aromatic heterocyclic ring radical with one or more heteroatom(s) independently selected from N, O or S.
  • the heteroaryl may be a mono-, bi- or tricyclic ring system.
  • the heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
  • heteroaryl ring radicals include, but are not limited to oxazolyl, isoxazolyl, imidazolyl, furyl, indolyl, isoindolyl, pyrrolyl, triazolyl, triazinyl, tetrazoyl, thienyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, benzopyranyl, carbazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl, quinoxalinyl, quinolyl, isoquinolyl, thiadiazolyl, indoli
  • heteroarylalkyl refers to a heteroaryl ring radical directly bonded to an alkyl group (i.e. heterarylCi_ 8 alkyl).
  • the heteroarylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure. Unless set forth or recited to the contrary, all heteroarylalkyl groups described or claimed herein may be substituted or unsubstituted.
  • salts prepared from pharmaceutically acceptable bases or acids including inorganic or organic bases and inorganic or organic acids include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulf
  • treating or “treatment” of a state, disorder or condition includes: (a) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; (b) inhibiting the state, disorder or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof; or (c) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.
  • subject includes mammals (especially humans) and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non- domestic animals (such as wildlife).
  • domestic animals e.g., household pets including cats and dogs
  • non- domestic animals such as wildlife.
  • a “therapeutically effective amount” means the amount of a compound that, when administered to a subject for treating a state, disorder or condition, is sufficient to effect such treatment.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the subject to be treated.
  • the term "acute pain” is usually self-limiting. The sensation of pain can be triggered by any number of physical or chemical stimuli and the sensory neurons which mediate the response to this harmful stimulus are termed as “nociceptors”.
  • Nociceptors are primary sensory afferent (C and ⁇ fibers) neurons that are activated by a wide variety of noxious stimuli including chemical, mechanical, thermal, and proton (pH ⁇ 6) modalities.
  • Nociceptors are the nerves which sense and respond to parts of the body which suffer from damage. They signal tissue irritation, impending injury, or actual injury. When activated, they transmit pain signals (via the peripheral nerves as well as the spinal cord) to the brain.
  • chronic pain usually refers to pain which persists for 3 months or longer and can lead to significant changes in a patient's personality; lifestyle, functional ability and overall quality of life.
  • Chronic pain can be classified as either nociceptive or neuropathic.
  • Nociceptive pain includes tissue injury-induced pain and inflammatory pain such as that associated with arthritis.
  • Neuropathic pain is caused by damage to the sensory nerves of the peripheral or central nervous system and is maintained by aberrant somatosensory processing. The pain is typically well localized, constant, and often with an aching or throbbing quality.
  • Visceral pain is the subtype of nociceptive pain that involves the internal organs. It tends to be episodic and poorly localized.
  • Nociceptive pain is usually time limited, meaning when the tissue damage heals, the pain typically resolves (arthritis is a notable exception in that it is not time limited).
  • the compound described in the present patent application may form salts.
  • Non-limiting examples of pharmaceutically acceptable salts forming part of this patent application include salts derived from inorganic bases salts of organic bases salts of chiral bases, salts of natural amino acids and salts of non-natural amino acids.
  • Certain compounds of present patent application are capable of existing in stereoisomeric forms (e.g. diastereomers and enantiomers). With respect to the overall compounds described by the general formula (I) the present patent application extends to these stereoisomeric forms and to mixtures thereof.
  • the present invention also relates to a pharmaceutical composition that comprises one or more compounds described herein and one or more pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients are approved by regulatory authorities or are generally regarded as safe for human or animal use.
  • the pharmaceutically acceptable excipients include, but are not limited to, diluents, glidants and lubricants, preservatives, buffering agents, chelating agents, polymers, gelling agents, viscosifying agents, solvents and the like.
  • compositions may be in conventional forms, for example, capsules, tablets, aerosols, solutions, suspensions, injectables or products for topical application. Further, the pharmaceutical composition of the present invention may be formulated so as to provide desired release profile.
  • compositions can be suitable for administration by various routes, which include, but are not limited to, oral, pulmonary, buccal, intradermal, transdermal, parenteral, rectal, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic or topical.
  • compositions of the present invention may be prepared by conventional techniques, e.g., as described in Remington: The Science and Practice of Pharmacy, 20 th Ed., 2003 (Lippincott Williams & Wilkins).
  • Compounds of the present invention are particularly useful because they may selectively inhibit the activity of COT kinase, i.e. they prevent the action of COT kinase or a complex of which the COT kinase forms a part, and/or may elicit COT kinase modulating effect. Compounds of the invention may thus be useful in the treatment of those conditions in which inhibition of COT kinase is required.
  • inflammation will be understood by those skilled in the art to include any condition characterized by a localized or a systemic protective response, which may be elicited by physical trauma, infection, chronic diseases, such as those mentioned hereinbefore, and/or chemical and/or physiological reactions to external stimuli (e.g. as part of an allergic response). Any such response, which may serve to destroy, dilute or sequester both the injurious agent and the injured tissue, may be manifest by, for example, heat, swelling, pain, redness, dilation of blood vessels and/or increased blood flow, invasion of the affected area by white blood cells.
  • inflammation is also understood to include any inflammatory disease, disorder or condition per se, any condition that has an inflammatory component associated with it, and/or any condition characterized by inflammation as a symptom, including inter alia acute, chronic, ulcerative, specific, allergic, infection by pathogens, immune reactions due to hypersensitivity, autoimmune response, entering foreign bodies, physical injury, and necrotic inflammation, and other forms of inflammation known to those skilled in the art.
  • the term thus also includes, for the purposes of this invention, inflammatory pain, pain generally and/or fever.
  • the compounds of the present invention may also be useful in the treatment of asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, inflammatory bowel disease, irritable bowel syndrome, inflammatory pain, chronic pain, acute pain, neuropathic pain, bone cancer pain and pain due to endometriosis, fever, migraine, headache, low back pain, fibromyalgia, myofascial disorders, viral infections ⁇ e.g. influenza, common cold, herpes zoster, hepatitis C and AIDS), bacterial infections, fungal infections, dysmenorrhea, endometriosis, burns, surgical or dental procedures, malignancies ⁇ e.g.
  • hyperprostaglandin E syndrome classic Bartter syndrome, atherosclerosis, gout, arthritis, osteoarthritis, juvenile arthritis, rheumatoid arthritis, juvenile onset rheumatoid arthritis, rheumatic fever, ankylosing spondylitis, Hodgkin's disease, systemic lupus erythematosus, vasculitis, pancreatitis, nephritis, bursitis, conjunctivitis, ulceris, scleritis, uveitis, wound healing, dermatitis, eczema, psoriasis, stroke, diabetes mellitus, neurodegenerative and neuroinflammatory disorders such as Alzheimer's disease Parkinson's, Huntington's, Amyotrophic lateral sclerosis (ALS) and multiple sclerosis, autoimmune diseases, allergic disorders, rhinitis, ulcers, mild to moderately active ulcerative colitis, familial adenomato
  • Compounds of the invention may also have effects that are not linked to inflammatory mechanisms, such as in the reduction of bone loss in a subject.
  • Conditions that may be mentioned in this regard include osteoporosis, osteoarthritis, Paget's disease and/or periodontal diseases.
  • the compounds of Formula I are useful for the relief of pain, fever and inflammation of a variety of conditions including rheumatic fever, symptoms associated with influenza or other viral infections, common cold, low back and neck pain, dysmenorrhea, headache, migraine (acute and prophylactic treatment), toothache, sprains and strains, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis, juvenile rheumatoid arthritis, degenerative joint diseases (osteoarthritis), acute gout and ankylosing spondylitis, acute, subacute and chronic musculoskeletal pain syndromes such as bursitis, burns, injuries, and pain following surgical and dental procedures as well as the preemptive treatment of surgical pain.
  • Such a compound may inhibit cellular neoplastic transformations and metastic tumor growth and hence can be used in the treatment of cancer.
  • Compounds of Formula I may also be useful for the treatment or prevention of endometriosis, hemophilic arthropathy and Parkinson's disease.
  • Treatment refers to either reducing the risk of mortality, improving the quality of life or retarding the progression of the cancer.
  • Cancers include but not limited to lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head and neck, cancers of the tongue, mouth, pharynx, and oral cavity, melanoma, cutaneous or intraocular melanoma, BRAF resistant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, gynecologic tumors (e.g., uterine sarcomas, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina or carcinoma of the vulva), Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system (e.g., cancer of the thyroid, parathyroid or adrenal glands), sarcomas of soft tissues, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, solid
  • the compounds described represented by the general formula (I) and (II) can be prepared by methods depicted in the Schemes provided below as well as by other methods. Furthermore, in the following schemes, where specific acids, bases, reagents, coupling agents, solvents, etc. are mentioned, it is understood that other suitable acids, bases, reagents, coupling agents etc. may be used and are included within the scope of the present invention. Modifications to reaction conditions, for example, temperature, duration of the reaction or combinations thereof are envisioned as a part of the present invention. The compounds obtained by using the general reaction schemes may be of insufficient purity. These compounds can be purified by any of the methods for purification of organic compounds known in the art, for example, crystallization or silica gel or alumina column chromatography using different solvents in suitable ratios.
  • the benzimidazole derivatives of the general formula (I), wherein A, L, R 1 , R 2 , R 3 , 'm', 'n' and 'q' are as defined above, can be prepared as per the process outlined in Scheme 1.
  • Coupling reaction of substituted o-fluoronitrobenzene of general formula (1) with an aromatic amine of the formula (2) in presence of suitable base such as sodium hydride in a polar aprotic solvent such as N,N-dimethylacetamide affords the o-nitroaniline derivative (3).
  • Palladium catalyzed reduction of nitro group affords the diamine derivative (4).
  • the coupling reaction of 3-fluoro-4-nitrobenzoic acid (5) with substituted aromatic amine of formula (2) gives the nitroaniline derivative of formula (6).
  • reaction of intermediate (14) with hydroxylamine hydrochloride in presence of suitable base gives the N-hydroxy aryl imidamide, which on reaction with 1 , l'-carbonyldiimidazole (CDI) furnishes the benzimidazoles of formula (Ilb-B) bearing an oxadiazolone group.
  • CDI l'-carbonyldiimidazole
  • ketoester undergoes reaction with hydroxylamine hydrochloride to afford the 1,2- oxazol-3-ol derivative of formula (46).
  • Intermediate (46) undergoes Suzuki coupling reaction with substituted phenylboronic acid (12) using palladium catalyst in presence of suitable base and solvent to furnish compounds of the formula (Ilh).
  • work-up includes distribution of the reaction mixture between the organic and aqueous phase indicated within parentheses, separation of layers and drying the organic layer over sodium sulphate, filtration and evaporation of the solvent.
  • Purification includes purification by silica gel chromatographic techniques, generally using ethyl acetate/petroleum ether mixture of a suitable polarity as the mobile phase. Use of a different eluent system is indicated within parentheses.
  • IPA isopropanol
  • BOP Benzotriazole-l-yl-oxy- tris-(dimethylamino)-phosphonium hexafluorophosphate
  • TFA trifluoroacetic acid
  • DIPEA ⁇ , ⁇ -diisopropylethylamine
  • DMAP ⁇ , ⁇ -dimethylaminopyridine
  • DCC ⁇ , ⁇ '-Dicyclohexylcarbodiimide
  • EDCI isopropanol
  • IPA isopropanol
  • BOP Benzotriazole-l-yl-oxy- tris-(dimethylamino)-phosphonium hexafluorophosphate
  • TFA trifluoroacetic acid
  • DIPEA ⁇ , ⁇ -diisopropylethylamine
  • DMAP ⁇ , ⁇ -dimethylaminopyridine
  • DCC ⁇ , ⁇ '-Dicyclohexylcarbod
  • HC1 N-(3-Dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride
  • CDI 1 , l '-carbonyldiimidazole
  • HOBt hydroxybenzotriazole
  • THF tetrahydrofuran
  • TEA triethylamine
  • Step 1 3-(Biphenyl-2-ylamino)-4-nitrobenzoic acid: To a well-stirred solution of biphenyl-2-amine (200 mg, 1.18 mmol) in anhydrous DMSO (3 ml) was added sodium hydride (1 10 mg, 2.67 mmol) in portions for 15 min at room temperature and stirred for further 30 min at room temperature. The reaction mixture was cooled to 0 °C and solution of 3-fluoro-4-nitrobenzoic acid (200 mg, 1.07 mmol) in anhydrous DMSO (3 ml) was added drop-wise over 30 min. The resultant mixture was stirred at 50 °C for 18 h.
  • reaction mixture was cooled to room temperature and quenched with saturated aqueous solution of NH4CI (20 ml). The mixture was extracted with 20% IPA in CHCI 3 (2 x 100 ml). The combined organic layer was washed with brine (50 ml), dried (Na 2 S0 4 ) and concentrated under reduced pressure to yield crude residue, which was purified by column chromatography to yield 180 mg of product as an orange solid.
  • Step 2 4-Amino-3-(biphenyl-2-ylamino)benzoic acid: To a stirred solution of Step 1 intermediate (175 mg, 0.284 mmol) in methanol (6 ml) was added 10 % Pd/C (50 mg) and stirred at room temperature under hydrogen atmosphere for 2 h. The reaction mixture was filtered through celite bed and washed with methanol (10 ml). The filtrate was evaporated under reduced pressure and triturated with diethyl ether (50 ml) to give 1 15 mg of product as an off- white solid.
  • Step 3 To a well stirred mixture of Step 2 intermediate (200 mg, 0.60 mmol) and sulphamic acid (6 mg, 0.06 mmol) in methanol (8 ml) was added triethyl orthoformate (0.2 ml, 1.20 mmol) and stirred at room temperature under nitrogen atmosphere overnight. The reaction mixture was concentrated under reduced pressure to give crude solid. The crude residue was purified by column chromatography to yield 80 mg of product. !
  • Examples 2-32 described below were prepared in three steps as described in Example 1 using 3-fluoro-4-nitrobenzoic acid and appropriate aryl amines.
  • Examples 34-39 given below were prepared from the corresponding nitriles by partial hydrolysis of the cyano group using TFA and H2SO4 as described above.
  • Example 2 To a well stirred solution of Example 2 (25 mg, 0.0796 mmol), N,N- diisopropylethylamine (40 ⁇ , 0.2388 mmol) and ammonium chloride (12.77 mg, 0.2388 mmol) in DMSO (5 ml), was added BOP reagent (53.0 mg, 3.182 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with water (50 ml). The aqueous layer was separated and extracted with ethyl acetate (2 x 50 ml). The combined organic layer was washed with water (25 ml), brine (25 ml), dried (Na2S0 4 ) and concentrated under reduced pressure to yield 22 mg of product.
  • BOP reagent 53.0 mg, 3.182 mmol
  • reaction mixture was stirred at room temperature overnight.
  • the reaction mixture was diluted with water (20 ml).
  • the product was extracted with ethyl acetate (2 x 25 ml).
  • the combined organic layer was washed with brine (25 ml), dried (Na2S0 4 ) and concentrated under reduced pressure.
  • Step 1 l -(3-Bromo-5-fluorophenyl)- lH-benzimidazole-6-carboxylic acid: This intermediate was prepared by reacting 3-bromo-5-fluoroaniline (276 mg, 1.491 mmol) and 3-fluoro-4-nitrobenzoic acid (276 mg, 1.789 mmol) which yielded the amino nitro intermediate, which on further reduction followed by cyclization using triethyl orthoformate as described in Example 1 afforded 140 mg of the product; ! H NMR (300 MHz, DMSO-ife) ⁇ 7.76-7.83 (m, 2H), 7.86-7.95 (m, 1H), 8.14 (s, 1H), 8.77 (s, 1H).
  • Step 2 To the well stirred solution of Step 1 intermediate (70 mg, 0.208 mmol) in DMF (4 ml) were added 4-(trifluoromethoxy)phenylboronic acid (52 mg, 0.242 mmol) and 1 M aqueous solution of potassium carbonate (56 mg, 0.405 mmol). The reaction mixture was purged with nitrogen for 30 min. Tetrakis(triphenylphosphine) Pd(0) (12 mg, 0.010 mmol) was added to the reaction mixture and it was heated to 80- 90 °C for 16 h. The reaction mixture was cooled to room temperature. The reaction was diluted with water (20 ml) and extracted with ethyl acetate (25 ml x 2).
  • Examples 43 and 44 were prepared as described in Example 42 using appropriate aryl halide and substituted phenylboronic acid via Suzuki coupling reaction
  • Examples 46 and 47 were prepared by coupling appropriate sulphonamide with Example 43 as described above using DCC as coupling agent.
  • Step 1 tert-Buiyl [l-(3-bromophenyl)-lH-benzimidazol-6-yl]carbamate: To a well- stirred solution of l-(3-Bromophenyl)- lH-benzimidazole-6-carboxylic acid (1.5 g, 4.731 mmol) and triethylamine (0.9 ml, 6.623 mmol) in teri-butanol (15 ml), was added diphenylphosphoryl azide (1.2 ml, 5.678 mmol) drop-wise over 5 min and was heated at 100 °C for 2 h.
  • Step 2 tert-butyl ⁇ 1 -[4'-(Trifluoromethoxy)biphenyl-3-yl]- lH-benzimidazol-6- yl ⁇ carbamate:
  • This intermediate was prepared by Suzuki coupling reaction of Step 1 intermediate (900 mg, 2.319 mmol) with 4-trifluoromethoxyphenyl boronic acid (717 mg, 3.479 mmol) using Tetrakis(triphenylphosphine) Pd(0) (134 mg, 0.1 15 mmol) in presence of 1 M aqueous solution of potassium carbonate (3.5 ml, 3.479 mmol) in dry DMF (10 ml) as described in step 2 of Example 42 to yield 907 mg of product; !
  • Step 3 l-[4'-(Trifluoromethoxy)biphenyl-3-yl]- lH-benzimidazol-6-amine: To the Step 2 intermediate (900 mg, 1.918 mmol) was added a solution of TFA (2 ml) in dichloromethane (8 ml) at 0 °C and the reaction mixture was stirred at room temperature for 2 h. The excess of solvent was distilled under reduced pressure and the residue obtained was diluted with saturated sodium bicarbonate solution (25 ml).
  • Step 4 To a stirred mixture of Step 3 intermediate (100 mg, 0.271 mmol), in dichloromethane (2 ml) were sequentially added triethylamine (0.07 ml, 0.542 mmol) and methanesulphonyl chloride (0.02 ml, 0.298 mmol) at 0 °C and the resulting mixture was stirred at the same temperature for 1 h. The mixture was diluted with water (20 ml) and extracted with ethyl acetate (2 x 25 ml).
  • Step 1 3-(Biphenyl-3-ylamino)-4-nitrobenzonitrile: This intermediate was prepared by coupling reaction of 3-fluoro-4-nitrobenzonitrile (0.5 g, 3.012 mmol) with biphenyl-3-amine (0.560 g, 3.313 mmol) using sodium hydride (0.180 g, 4.518 mmol) in DMSO (10 ml) as described in Step 1 of Example 1 to yield 0.175 g of product, !
  • Step 2 N-[2-Nitro-5-(lH-tetrazol-5-yl)phenyl]biphenyl-3-amine: To a well stirred solution of Step 1 intermediate (170 mg, 0.539 mmol) in DMF (2 ml), was added ammonium chloride (37.52 mg 0.701 mmol) and sodium azide (46 mg, 0.701 mmol) and stirred at 80 °C at inert atmosphere overnight. The solvent was distilled out under reduced pressure and the residue obtained was diluted with water (50 ml). The product was extracted with ethyl acetate (3 x 75 ml).
  • Step 3 N 2 -(Biphenyl-3-yl)-4-(lH-tetrazol-5-yl)benzene- 1,2-diamine: This intermediate was prepared by catalytic reduction of nitro group of Step 2 intermediate (0.125 g, 0.349 mmol) using 3 ⁇ 4, Pd/C (0.040 g) in methanol (10 ml) as described in procedure of step 2 of Example 1 to yield 0.102 g of product. !
  • Step 4 This title compound was prepared by reaction of Step 3 intermediate (0.125 g, 0.381 mmol) with triethyl orthoformate (0.095 ml, 0.572 mmol) and sulphamic acid (3.70 mg, 0.038 mmol) in methanol (2 ml) as described in step 3 of Example 1 to yield 80 mg of product. !
  • Step 1 3-[(3-Iodophenyl)amino]-4-nitrobenzonitrile: To a well-stirred solution 3- fluoro-4-nitrobenzonitrile (3.5 g, 21.084 mmol) in DMF were added 3-iodoaniline (6.9 g, 31.624 mmol) and DIPEA (54 ml, 42.168 mmol) and the reaction mixture was heated to 80 °C for 16 h. The reaction mixture was quenched with water (150 ml), diluted with methanol (50 ml) and stirred for 30 min.
  • 3-fluoro-4-nitrobenzonitrile 3.5 g, 21.084 mmol
  • DIPEA 54 ml, 42.168 mmol
  • Step 3 N 2 -(3-Iodophenyl)-4-(2H-tetrazol-5-yl)benzene- l ,2-diamine: To the well stirred solution of Step 2 intermediate (3.6 g, 8.823 mmol) in ethanol (36 ml) was added aqueous ammonium chloride solution (4.72 g, 88.255 mmol) and the reaction mixture was refluxed. At the reflux temperature, iron powder (1.47 g, 26.47 mmol) was added portion- wise to the reaction mixture and it was further refluxed for 0.5 h. The reaction mixture was diluted with ethyl acetate (500 ml) and filtered.
  • Step 4 l -(3-Iodophenyl)-6-(2H-tetrazol-5-yl)- lH-benzimidazole:
  • This intermediate was prepared by reaction of Step 3 intermediate (2.2 g, 5.820 mmol) with triethyl orthoformate (1.6 ml, 8.730 mmol) and sulphamic acid (57 mg, 0.582 mmol) in methanol (100 ml) as described in Step 3 of Example 1 to yield 2 g of product; !
  • Step 5 The title compound was prepared by Suzuki coupling reaction of Step 4 intermediate (70 mg, 0.179 mmol) with 4-chlorophenylboronic acid (37 mg, 0.236 mmol) using Tetrakis(triphenylphosphine) Pd(0) (10 mg, 0.0089 mmol) in presence of 1 M aqueous solution of potassium carbonate (50 mg, 0.361 mmol) in DMF (5 ml) as described in step 2 of Example 42 to yield 30 mg of the product; !
  • Example 63 To 4-(cyclopentyloxy)-3'-[6-(2H-tetrazol-5-yl)- IH-benzimidazol- 1 -yl]biphenyl-3- carbonitrile (Example 63) (60 mg, 0.134 mmol) was added a solution of sulphuric acid (0.2 ml) in TFA (0.6 ml) and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was quenched with ice cold water (25 ml) and was extracted with chloroform (2 x 25 ml).
  • Step 1 l -(Biphenyl-3-yl)- lH-benzimidazole-6-carbonitrile:
  • the title compound was prepared by coupling 3-fluoro-4-nitrobenzonitrile (360 mg, 2.168 mmol) and biphenyl-3 -amine (400 mg, 2.366 mmol) followed by reduction and cyclization as described in Example 1 to yield 250 mg of the product; !
  • Step 2 l -(Biphenyl-3-yl)-N-hydroxy- lH-benzimidazole-6-carboximidamide: To the well stirred solution of Step 1 intermediate (250 mg, 0.847 mmol) in DMF (6 ml) was added hydroxylamine.hydrochloride (220 mg, 3.165 mmol) followed by DIPEA (0.53 ml, 3.120 mmol) and the reaction mixture was stirred at 60-70 °C for 18 h. The reaction mixture was diluted with water and stirred for 30 min. The precipitate obtained was filtered, washed with water and dried to yield 220 mg of the product; !
  • Step 3 To the well stirred solution of Step 2 intermediate (220 mg, 0.670 mmol) in DMF (6 ml) was added CDI ( ⁇ , ⁇ -carbonyldiimidazole; 1 10 mg, 0.670 mmol) and the reaction mixture was heated at 100°C for 8 h.
  • Step 1 4-Amino-3-[(3-bromophenyl)amino]benzonitrile: The title compound was prepared by coupling 3-fluoro-4-nitrobenzonitrile (5 g, 30.12 mmol) and 3- bromoaniline (5.7 g, 33.132 mmol) followed by reduction and cyclization as described in Example 1 to yield 4.6 g of the product; !
  • Step 2 1 -(3-Bromophenyl)-N-hydroxy- lH-benzimidazole-6-carboximidamide: This intermediate was prepared by reaction of Step 1 intermediate (1.5 g, 5.033 mmol) with hydroxylamine.hydrochloride (1.3 g, 18.624 mmol) in DMSO (20 ml) using DIPEA (3.2 ml, 18.624 mmol) as described in procedure of step 2 of Example 67 to yield 1.56 g of product; !
  • Step 3 3-[l -(3-Bromophenyl)- lH-benzimidazol-6-yl]- l ,2,4-oxadiazol-5(2H)-one:
  • This intermediate was prepared by reaction of Step 2 intermediate (1.5 g, 4.53 1 mmol) with CDI ( ⁇ , ⁇ -carbonyldiimidazole; 810 mg, 4.90 mmol) in DMF (15 ml) as described in procedure of step 3 of Example 67 to yield 1.3 g of the product; !
  • Step 4 The title compound was prepared by Suzuki coupling reaction of Step 3 intermediate (100 mg, 0.280 mmol) with 4-fluorophenylboronic acid (45 mg, 0.336 mmol) using Tetrakis(triphenylphosphine) Pd(0) (17 mg, 0.014 mmol) in presence of 1 M aqueous solution of potassium carbonate (0.6 ml, 0.57 mmol) in dry DMF (5 ml) as described in procedure in step 2 of Example 42 to yield 50 mg of product, !
  • Examples 70-83 were prepared by Suzuki coupling reaction of 3-[l -(3-bromophenyl)- lH-benzimidazol-6-yl]- l ,2,4-oxadiazol-5(2H)-one with substituted phenylboronic acids as described in Example 69.
  • Step 1 l -(3-Bromophenyl)- lH-benzimidazole-6-carboxylic acid:
  • This intermediate was prepared by coupling reaction of 3-fluoro-4-nitrobenzoic acid (5 g, 27.01 1 mmol) with 3-bromoaniline (3.529 ml, 32.413 mmol) furnished the amino nitro intermediate, which upon reduction to diamine and cyclisation to the corresponding benzimidazole using triethyl orthoformate as described in Example 1 affords 4.5 g of product.
  • Step 2 1 -(3-Bromophenyl)-N-methoxy-N-methyl- lH-benzimidazole-6-carboxamide: N,0-dimethylhydroxylamine hydrochloride (0.692 g, 7.098 mmol) was added to a stirred mixture of Step 1 intermediate (1.50 g, 4.732 mmol), hydroxybenzotriazole (0.959 g, 7.098 mmol) and l -ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (1.36 g, 7.098 mmol) in dry DMF (20 ml) at 0 °C and the suspension was stirred for 15 min.
  • Step 3 l -[l -(3-Bromophenyl)- lH-benzimidazol-6-yl]ethanone: To a cooled solution of Step 2 intermediate (1.1 g, 3.055 mmol) in dry THF (20 ml), methyl magnesium bromide (2.55 ml, 7.638 mmol) was drop wise added and the resulting mixture was stirred at 0 °C for 2 h. The reaction mixture was slightly warmed to room temperature and was quenched with saturated solution of ammonium chloride (50 ml). The mixture was extracted with ethyl acetate (3 x 50 ml).
  • Step 4 Methyl 3-[ l-(3-bromophenyl)- lH-benzimidazol-6-yl]-3-oxopropanoate: To a cooled solution of Step 3 intermediate (700 mg, 2.220 mmol) in dry THF (20 ml), was added sodium hydride (355 mg, 8.888 mmol) and the resulting suspension was stirred at 0 °C for 20 min. To this suspension dimethyl carbonate (0.281 ml, 3.330 mmol) was drop wise added and the reaction mixture was gradually heated to 85 °C for 4 h. The reaction mixture was cooled to room temperature and quenched with saturated solution of ammonium chloride (25 ml).
  • Step 5 5-[l -(3-Bromophenyl)- lH-benzimidazol-6-yl]- l ,2-oxazol-3-ol: To a cooled solution of sodium hydroxide (142 mg, 3.547 mmol) in methanol (2 ml) and water (2 ml), was drop wise added suspension of Step 4 intermediate (630 mg, 1.689 mmol) in methanol (2 ml) at -20 °C. The reaction mixture was stirred for 20 min at 0 °C, then freshly prepared hydroxylamine (235 mg, 3.378 mmol) was added at -30 °C and was stirred for 2 h at same temperature.
  • Step 6 The title compound was prepared by Suzuki coupling reaction of Step 5 intermediate (50 mg, 0.140 mmol) with 4-trifluoromethoxyphenylboronic acid (43 mg, 0.21 1 mmol) using Tetrakis(triphenylphosphine) Pd(0) (24 mg, 0.021 mmol) in presence of 1 M aqueous solution of potassium carbonate (0.7 ml, 0.702 mmol) in dry DMF (2 ml) as described in procedure in step 2 of Example 42 to yield 15 mg of product; !
  • Step 1 N-(5-Bromo-2-nitrophenyl)biphenyl-3-amine: This intermediate was prepared by coupling reaction of 4-bromo-2-fluoro- 1 -nitrobenzene (1 g, 4.545 mmol) with 3- phenylaniline (840 mg, 4.97 mmol) using sodium hydride (290 mg, 7.272 mmol) in DMSO (20 ml) as described in procedure of step 1 of Example 1 to yield 500 mg of the product.
  • Step 2 3'-(Biphenyl-3-ylamino)-4'-nitrobiphenyl-3-ol:
  • This intermediate was prepared by Suzuki coupling reaction of Step 1 intermediate (200 mg, 0.909 mmol) with 3- hydroxyphenylboronic acid (140 mg, 0.99 mmol) using Tetrakis(triphenylphosphine) Pd(0) (52 mg, 0.045 mmol) in presence of 1 M aqueous solution of potassium carbonate (1.8 ml, 1.80 mmol) in dry DMF (5 ml) as described in procedure in step 2 of Example 42 to yield 87 mg of product; !
  • Step 3 4'-Amino-3'-(biphenyl-3-ylamino)biphenyl-3-ol: This intermediate was prepared by nitro group reduction of Step 2 intermediate (85 mg) using Pd/C (20 mg) in methanol (7 ml) as described in Step 2 of Example 1 to yield 63 mg of product.
  • Step 4 The title compound was prepared by reaction of Step 3 intermediate (60, 0.170 mmol) with triethyl orthoformate (50 ⁇ , 0.255 mmol) using sulfamic acid (2 mg, 0.018 mmol) in methanol (4 ml) as described in step 3 of Example 1 to yield 10 mg of product; !
  • Step 1 5-Fluoro- 1 -(4'-methoxybiphenyl-3-yl)- lH-benzimidazole-6-carboxylic acid:
  • the title compound was prepared by Suzuki coupling reaction of l -(3-bromophenyl)- 5-fluoro- lH-benzimidazole-6-carboxylic acid (215 mg, 0.642 mmol) with 4- methoxyphenylboronic acid (1 17 mg, 0.770 mmol) in 1 ,4-dioxane (5 ml) using Tetrakis(triphenylphosphine) Pd(0) (74 mg, 0.064 mmol) in presence of 1 M aqueous solution of potassium carbonate (177 mg, 1.284 mmol) as described in procedure in Step 2 of example 42 to yield 215 mg of the product; !
  • Step 2 5-Fluoro- 1 -(4'-methoxybiphenyl-3-yl)- lH-benzimidazole-6-carboxamide:
  • the title compound was prepared by reaction of Step 1 intermediate (200 mg, 0.580 mmol) with ammonium chloride (95 mg, 1.740 mmol) using BOP reagent (310 mg, 0.696 mmol) in presence of DIPEA (290 ⁇ , 1.70 mmol) in DMSO (5 ml) as described in Example 40 to yield 143 mg of the product. !
  • Step 3 5-Fluoro- l -(4'-methoxybiphenyl-3-yl)- lH-benzimidazole-6-carbonitrile: To a stirred solution of Step 2 intermediate (140 mg, 0.385 mmol) in dichloromethane (5 ml) was added triethylamine (160 ⁇ , 1.157 mmol) at 0-5 °C followed by drop wise addition of trifluoroacetic anhydride (0.1 ml, 0.577 mmol) and the resultant mixture was stirred for 1 h. The reaction mixture was diluted with water (15 ml) and stirred for 10 min. The reaction mixture was extracted with ethyl acetate (2 x 50 ml). The combined organic layer was washed with water (100 ml), brine (75 ml), dried (Na2S0 4 ) and concentrated under reduced pressure to yield 80 mg of product. ! H
  • Step 4 The title compound was prepared by reaction of Step 3 intermediate (75 mg, 0.218 mmol) with sodium azide (50 mg, 0.76 mmol) using ammonium chloride (41 mg, 0.76 mmol) in DMF (5 ml) as described in step 2 of Example 50 to yield 7 mg of product; !
  • the illustrative examples of the present invention are screened for COT kinase activity according to procedure described in Jia Y et al., Analytical Biochemistry. 350 (12), pp. 268-276, 2006 using the non-radioactive method by homogeneous time resolved fluorescence (HTRF) with the Cisbio assay kit.
  • HTRF time resolved fluorescence
  • COT kinase catalyzes the inactive biotin-MEKl/2 causing its phosphorylation at Ser217 and S221 sites in presence of ATP that is detected by a detection complex that contains the donor molecule Europium cryptate molecule complex by anti-phospho- MEKl/2-specific antibody that recognizes the phosphorylation sites on the MEKl/2 peptide and an acceptor molecule XL-665 complex by streptavadin that binds to the biotin tag on the N-terminal region of MEKl/2 peptide.
  • On excitation of the donor molecule at 337nm causes a resonance energy transfer to the acceptor molecule at 620nm that emits at 665nm and can be recorded as an HTRF signal.
  • the signal obtained is proportional to the extent of substrate phosphorylation (MEKl/2) by COT kinase. Inhibition of COT kinase enzyme activity produces a low level of this energy transfer as compared to the control determining the percentage of inhibition of the respective inhibitor.
  • Test or reference compounds were dissolved in dimethylsulfoxide (DMSO) to prepare 10 mM stock solution and diluted suitably to get the desired concentration.
  • Final concentration of DMSO in the reaction was 5 % (v/v).
  • Substrate mixture was prepared by mixing ImM ATP (Sigma) and 5 ⁇ Biotin-MEKl/2 (American Peptide Company) in order to get ⁇ and 500nM final concentrations of each respectively in the assay buffer containing 50 mM Tris -HCL (pH 7.5), 10 mM MgCl 2 , ImM EGTA, 2mM DTT, 0.01% Brij, and 5mM ⁇ -phosphoglycerate.
  • Streptavidin- XL (Cisbio) and anti-Phospho MEKl/2(Ser217/221)-cryptate (Cisbio) were prepared in the Revelation buffer containing 30mM HEPES, pH 7.0, 0.06% BSA, 0.006% Tween 20, 0.24M Potassium Fluoride.
  • the assay was carried out using suitably dilution of COT kinase enzyme (BPS Biosciences) to get around 2.5 fold conversion of MEK1/2 to Phospho-MEKl/2 to ensure linear reaction kinetics.
  • COT kinase assay was carried out in 40 ⁇ ⁇ reaction volume by addition of assay buffer containing test compound and substrate mixture and initiated with the required concentration of the enzyme. Reaction mixture was incubated at room temperature for 60 min with constant shaking. The reaction was stopped by adding ⁇ of 500mM EDTA to get final concentration of lOOmM in the reaction mixture. This was followed by addition of 25 ⁇ ⁇ of each detection reagents Streptavidin- XL and anti- Phospho MEKl/2(Ser217/221)-cryptate to the reaction mixture. The reaction mixture was kept in cold over night after 10 mins shaking and read the emission (665/620) in the HTRF instrument the next day.
  • Reaction was measured based on the signal to background ratio of the phosphorylated and non-phosphorylated biotinylated MEK1/2 substrate using the Artemis instrument reader. An enzyme control without test compounds was run to quantitate maximum COT kinase reaction. Inhibition of enzyme activity was calculated as a percent of control reaction. IC 50 values were calculated from dose response curve by nonlinear regression analysis using GraphPad Prism software.

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Abstract

L'invention concerne des composés benzimidazole substitués ou des sels pharmaceutiquement acceptables de ceux-ci, qui sont utiles pour le traitement ou la prévention de maladies, d'états et/ou de troubles, tels que l'asthme, l'arthrose, la polyarthrite rhumatoïde, la douleur et des maladies neurodégénératives, par l'inhibition de la kinase du cancer de la Thyroïde d'Osaka.
PCT/IB2012/050756 2011-03-28 2012-02-20 Composés benzimidazole substitués en tant qu'inhibiteurs de la kinase cot Ceased WO2012131501A1 (fr)

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Cited By (8)

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Publication number Priority date Publication date Assignee Title
CN103864753A (zh) * 2014-02-27 2014-06-18 华东师范大学 含有五元芳杂环结构的抗丙肝化合物及制备方法和用途
US20150011548A1 (en) * 2011-10-10 2015-01-08 Orion Corporation Protein kinase inhibitors
WO2015052675A1 (fr) * 2013-10-10 2015-04-16 Glenmark Pharmaceuticals S.A. Utilisation de composés substitués dihydro-benzimidazole comme modulateurs du ror gamma
CN104926733A (zh) * 2014-03-18 2015-09-23 北京韩美药品有限公司 作为RORγ调节剂的化合物
CN111518031A (zh) * 2020-05-29 2020-08-11 中国药科大学 一种含有异羟肟酸的化合物及其制备方法、应用
US11352328B2 (en) 2016-07-12 2022-06-07 Arisan Therapeutics Inc. Heterocyclic compounds for the treatment of arenavirus
EP4434972A1 (fr) * 2023-03-22 2024-09-25 Eberhard-Karls-Universität Tübingen Inhibiteurs de l'atm kinase
US12419865B2 (en) 2018-12-06 2025-09-23 Arisan Therapeutics Inc. Compounds for the treatment of arenavirus infection

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EP0563001A1 (fr) * 1992-03-26 1993-09-29 Neurosearch A/S Dérivés de l'imidazole, leur préparation et leur utilisation
CN101193867A (zh) * 2004-12-01 2008-06-04 Osi医药有限公司 N取代的苯并咪唑基c-Kit抑制剂和苯并咪唑组合库

Patent Citations (2)

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EP0563001A1 (fr) * 1992-03-26 1993-09-29 Neurosearch A/S Dérivés de l'imidazole, leur préparation et leur utilisation
CN101193867A (zh) * 2004-12-01 2008-06-04 Osi医药有限公司 N取代的苯并咪唑基c-Kit抑制剂和苯并咪唑组合库

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9447091B2 (en) * 2011-10-10 2016-09-20 Orion Corporation Protein kinase inhibitors
US20150011548A1 (en) * 2011-10-10 2015-01-08 Orion Corporation Protein kinase inhibitors
US10391082B2 (en) 2011-10-10 2019-08-27 Orion Corporation Protein kinase inhibitors
WO2015052675A1 (fr) * 2013-10-10 2015-04-16 Glenmark Pharmaceuticals S.A. Utilisation de composés substitués dihydro-benzimidazole comme modulateurs du ror gamma
CN103864753A (zh) * 2014-02-27 2014-06-18 华东师范大学 含有五元芳杂环结构的抗丙肝化合物及制备方法和用途
CN103864753B (zh) * 2014-02-27 2016-01-20 华东师范大学 含有五元芳杂环结构的抗丙肝化合物及制备方法和用途
CN104926733A (zh) * 2014-03-18 2015-09-23 北京韩美药品有限公司 作为RORγ调节剂的化合物
CN104926733B (zh) * 2014-03-18 2019-05-10 北京韩美药品有限公司 作为RORγ调节剂的化合物
WO2015139619A1 (fr) * 2014-03-18 2015-09-24 北京韩美药品有限公司 Composé servant de modulateur rorγ
US11352328B2 (en) 2016-07-12 2022-06-07 Arisan Therapeutics Inc. Heterocyclic compounds for the treatment of arenavirus
US12419865B2 (en) 2018-12-06 2025-09-23 Arisan Therapeutics Inc. Compounds for the treatment of arenavirus infection
CN111518031A (zh) * 2020-05-29 2020-08-11 中国药科大学 一种含有异羟肟酸的化合物及其制备方法、应用
CN111518031B (zh) * 2020-05-29 2023-01-17 中国药科大学 一种含有异羟肟酸的化合物及其制备方法、应用
EP4434972A1 (fr) * 2023-03-22 2024-09-25 Eberhard-Karls-Universität Tübingen Inhibiteurs de l'atm kinase

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