WO2015162452A1 - Substituted pyrazole compounds as cb1 receptor antagonists and uses thereof - Google Patents

Substituted pyrazole compounds as cb1 receptor antagonists and uses thereof Download PDF

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WO2015162452A1
WO2015162452A1 PCT/IB2014/060920 IB2014060920W WO2015162452A1 WO 2015162452 A1 WO2015162452 A1 WO 2015162452A1 IB 2014060920 W IB2014060920 W IB 2014060920W WO 2015162452 A1 WO2015162452 A1 WO 2015162452A1
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chlorophenyl
pyrazole
dichlorophenyl
cyano
carboximidamide
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PCT/IB2014/060920
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French (fr)
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Sumit Mukherjee
Rajiv Sharma
Nauzer DUBASH
Pravin SHELKAR
Valmik Aware
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Piramal Enterprises Limited
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Priority to PCT/IB2014/060920 priority Critical patent/WO2015162452A1/en
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    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • 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
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D487/18—Bridged systems

Definitions

  • the present invention relates to substituted pyrazole compounds (the compounds of formula 1 as described herein), processes for their preparation, pharmaceutical compositions comprising the compounds of formula 1 , their use as cannabinoid 1 (CB1 ) receptor antagonists and methods of using said compounds in the treatment of diseases mediated by CB1 receptors (CB1 R).
  • CB1 cannabinoid 1
  • Endocannabinoid system is a unique neuromodulatory system in mammalian physiology which is primarily responsible for maintaining homeostasis in all body systems including the central and peripheral nervous system, all organ systems, somatic tissues, metabolic systems and the immune system (G. Marsicano et al., J. Endocrinol. Invest, 2006, 29, 27-46).
  • the endocannabinoid system consists of transporters, endocannabinoids, enzymes involved in the synthesis and degradation of endocannabinoids and G protein-coupled receptors.
  • CB1 receptor cannabinoid 1 receptor
  • CB2 receptor cannabinoid 2 receptor
  • CB1 receptor is prominently expressed in the central nervous system (CNS) and peripheral tissues, including thyroid gland, adrenal gland, reproductive organs, adipose tissue, liver, muscle, pancreas and gastrointestinal tract.
  • the CB2 receptor is mainly expressed in immune cells and hematopoietic cells and to a lesser extent in the myocardium, coronary endothelial cells and smooth muscle cells.
  • CB1 receptor plays a pivotal role in regulating energy balance, food intake, and metabolism of lipids and glucose. It has been observed that exogenous cannabinoids and endocannabinoids increase food intake and promote weight gain in animals by activating CB1 receptor (Stefan Engeli et al., Diabetes, 2005, 54, 2838-2843).
  • CB1 receptor From among the diseases or disorders implicated by CB1 receptor, obesity is the one which is most prevalent globally. In the United States (the US) alone, obesity is estimated to cause 18 % of deaths per year. WHO has estimated that, yearly, obesity affects at least about 400 million people worldwide. An over activated endocannabinoid system is known to contribute to obesity through central and peripheral mechanism, thereby having a role in obesity and associated disorders. A CB1 receptor knockout mouse has shown resistance to diet induced obesity. It has also been observed that blockage of CB1 receptor with a CB1 receptor antagonist or a CB1 receptor inverse agonist reduces food intake and body weight in rodents (Stefan Engeli et al., Diabetes, 2005, 54, 2838-2843). Inhibition of central and peripheral CB1 receptor would therefore be a useful approach in the treatment of obesity and related metabolic disorders.
  • Type 2 diabetes is a serious life-threatening disorder with growing prevalence in both adult and childhood populations. According to American Medical Association Type 2 diabetes is currently the 7 th leading cause of death in the US. It has been reported that endocannabinoid levels are enhanced in the plasma and adipose tissue of type 2 diabetic patients. Studies on CB1 receptors revealed that activation of the CB1 receptor with a CB1 receptor agonist reduces glucose tolerance and insulin release from pancreatic beta cells, whereas CB1 receptor antagonists reverse this effect by elevating the levels of adiponectin protein.
  • CB1 receptors undergo increased expression during inflammatory conditions.
  • CB1 receptor antagonists have demonstrated antiinflammatory effect in rodent models of inflammatory disease.
  • Studies have also reported a significant reduction in LPS-induced production of pro-inflammatory cytokine TNF-a in animals treated with a CB1 receptor antagonist (Stephen J et al. Journal of Pharmacology and Experimental Therapeutics, 2010, 333, 445-453).
  • the CB1 receptor also plays a pivotal role in cardiovascular regulation. Recently it has been reported that CB1 receptor blockage improves systolic and diastolic heart function, decreases cardiac collagen and hydroxyproline content (Svetiana Slavic et al., J. Mol. Med., 2013, 91 , 81 1-823). Inhibition of the CB1 receptor with a CB1 receptor antagonist exerts cardio-protective effect in rats with metabolic syndrome. This renders inhibition of the CB1 receptor as a potential pharmacological tool in the treatment of cardiovascular diseases.
  • CB1 receptor antagonists have been reported to have utility in the treatment of several other diseases and disorders such as cancer, atherosclerosis, psychosis, schizophrenia, epilepsy, Parkinson's disease, amnesia, cognitive disorders, dyslipidemias, dyslipoproteinemia, hepatic lipidosis, liver fibrosis, cirrhosis, fatty liver disease, neuroinflammatory disorders, gastrointestinal disorders, urinary disorders and infertility disorders.
  • Rimonabant a central CB1 receptor antagonist, which is selective for CB1 receptor, was the first drug that was developed for therapeutic use. Rimonabant was developed for treating obesity and other related disorders.
  • peripheral CB1 receptor Studies on the peripheral CB1 receptor have led to selection of the peripheral CB1 receptor as a promising molecular target for the treatment of diseases or disorders mediated by CB1 receptor.
  • TM38837 (7TM Pharma) a peripheral CB1 receptor antagonist, is in phase I clinical development for the treatment of obesity and type 2 diabetes.
  • PCT patent publication WO2003026647A1 discloses novel 4,5-dihydro-1 H- pyrazole derivatives having CB1 antagonistic activity for the treatment of diseases or disorders of the cannabinoid system.
  • PCT patent publication WO2009130234A1 discloses (5R)-1 ,5-diaryl-4,5-dihydro- 1 H-pyrazole-s-carboxamidine derivatives for the treatment of psychiatric and neurological disorders involving cannabinoid receptors.
  • the present invention relates to a compound of formula 1 (as described herein), or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a polymorph, a prodrug, S-oxide or N-oxide thereof.
  • processes for the preparation of the compounds of formula 1 , or pharmaceutically acceptable salts thereof are provided.
  • a pharmaceutical composition comprising one or more compounds of formula 1 , or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof; and at least one pharmaceutically acceptable carrier or excipient.
  • a compound of formula 1 or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof; for use as a CB1 receptor (CB1 R) antagonist.
  • a compound of formula 1 or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof; for use in the treatment of a disease or a disorder mediated by CB1 receptors (CB1 R).
  • CB1 R CB1 receptors
  • a method for the treatment of a disease or disorder mediated by CB1 receptor comprising administering to a subject in need thereof; a therapeutically effective amount of the compound of formula 1 , or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof.
  • a compound of formula 1 or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof; for the manufacture of a medicament for the treatment of a disease or a disorder mediated by CB1 receptors.
  • the present invention relates to use of a compound of formula 1 , or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof; in combination with at least one further therapeutically active agent for the treatment of a disease or a disorder mediated by CB1 receptors.
  • the present invention relates to a compound of formula 1
  • Ri and R 2 are independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, (CrC 8 )-alkyl, (CrC 8 )-alkoxy, halo(CrC 8 )-alkyl, (C 3 -Ci 2 )-cycloalkyl, C(O)R a , CO 2 R a and NR a R b ;
  • X is hydrogen, halogen, hydroxy, (Ci-C 8 )-alkyl, halo(CrC8)-alkyl, or (Ci-C 8 )-alkoxy;
  • Q is:
  • R 3 is hydrogen, cyano, (CrC 8 )-alkyl, halo(CrC 8 )-alkyl, (C 3 -Ci 2 )-cycloalkyl, heterocyclyl, heteroaryl, C(O)R a , CO 2 R a , CONR a R b , S(O) q R c or S(O) q NR a R b ;
  • R 4 is cyano, (Ci-C 8 )-alkyl, halo(Ci-C8)-alkyl, (C3-Ci 2 )-cycloalkyl, (C5-C 8 )-cycloalkenyl, (C 6 -Ci 4 )-aryl, (C 6 -Ci 4 )ar-(Ci-C 8 )-alkyl, heterocyclyl, heteroaryl, COR a , CO 2 R a , CONR a R b , S(O) q R c or S(O) q NR a R b ;
  • R 5 is hydrogen, cyano, (d-C 8 )-alkyl, halo(CrC 8 )-alkyl, (C 3 -d 2 )-cycloalkyl, (C 5 -C 8 )- cycloalkenyl, (C6-C )-aryl, (C6-Ci 4 )ar-(Ci-C 8 )-alkyl, heterocyclyl, heteroaryl, COR a , CO 2 R a , CONR a R b , S(O) q Rc or S(O) q NR a R b ; or
  • R 3 and R 5 can join together to form a 3-12 membered saturated or unsaturated monocyclic or bicyclic ring system, optionally containing one to three heteroatoms independently selected from the group consisting of O, N and S; or R 4 and R 5 can join together to form a 3-12 membered saturated or unsaturated, monocyclic or bicyclic ring system including spiro ring systems, optionally containing one to three heteroatoms independently selected from the group consisting of O, N and S;
  • each of the said 3-12 membered rings can be unsubstituted or substituted with one or more groups selected from the group consisting of halogen, hydroxy, oxo, cyano, (C C 8 )-alkyl, halo(C C 8 )-alkyl, (C C 8 )-alkoxy, halo(C C 8 )-alkoxy, (C 3 -Ci 2 )- cycloalkyl-(R d )o-2, O-(C 3 -Ci 2 )-cycloalkyl-(R d ) 0 - 2 , (C 6 -Ci 4 )-aryl-(R d ) 0 -2, O-(C 6 -Ci 4 )-aryl- (Rd)o-2, heterocyclyl-(R d )o-2, O-heterocyclyl-(R d ) 0 - 2 , heteroaryl-(R d ) )
  • R a and R b are independently selected from the group consisting of hydrogen, hydroxy, (CrCs)-alkyl, (C C 8 )-alkoxy, (C 3 -Ci 2 )-cycloalkyl, (C 5 -C 8 )-cycloalkenyl, (C 6 -Ci 4 )-aryl, heterocyclyl and heteroaryl; or
  • R a and R b together with the nitrogen atom can form a 3-12 membered ring system, optionally containing one to three heteroatoms independently selected from the group consisting of O, N and S;
  • Rc is (CrCs)-alkyl, (C 3 -Ci 2 )-cycloalkyl, (C 6 -Ci 4 )-aryl, (C 6 -Ci 4 )ar-(Ci-C 8 )-alkyl, heterocyclyl or heteroaryl;
  • n and n are integers selected from 0, 1 or 2;
  • q is an integer 1 or 2; wherein each of the (CrC 8 )-alkyl and (CrC 8 )-alkoxy group can be unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, oxo, cyano, (CrC 8 )-alkoxy, halo(CrC 8 )-alkoxy, (C 3 -C-i 2 )-cycloalkyl- (Rd)o-2, O-(C 3 -Ci 2 )-cycloalkyl-(R d )o- 2 , (C 6 -Ci 4 )-aryl-(R d ) 0 - 2 , O-(C 6 -Ci 4 )-aryl-(R d ) 0 - 2 , heterocyclyl-(R d )o- 2 , O-heterocyclyl-(R d ) 0 - 2 ,
  • each of the (C 3 -Ci 2 )-cycloalkyl, (C 5 -C 8 )-cycloalkenyl and (C 6 -Ci 4 )-aryl can be unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, oxo, cyano, (CrC 8 )-alkyl, halo(CrC 8 )-alkyl, (d- C 8 )-alkoxy, halo(CrC 8 )-alkoxy, (C 3 -Ci 2 )-cycloalkyl-(R d ) 0 - 2 , O-(C 3 -Ci 2 )-cycloalkyl-(R d ) 0 - 2 , (C 6 -Ci 4 )-aryl-(Rd)o-2.
  • heterocyclyl is a 3-12 membered saturated or partially unsaturated, monocyclic or bicyclic ring system, including spiro ring systems, containing one to four heteroatoms independently selected from the group consisting of O, N and S; wherein the heterocyclyl can be un
  • the heteroaryl is a 5-10 membered monocyclic or bicyclic aromatic ring system containing one to four heteroatoms independently selected from O, N or S, wherein the heteroaryl can be unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, oxo, cyano, (CrC 8 )-alkyl, halo(C C 8 )-alkyl, (C C 8 )-alkoxy, halo(C C 8 )-alkoxy, (C 3 -C 12 )-cycloalkyl-(R d )o- 2 , O-(C 3 - Ci 2 )-cycloalkyl-(R d )o-2, (C 6 -Ci 4 )-aryl-(R d ) 0 -2, O-(C 6 -Ci 4 )-aryl-(R d ) 0 -2, heterocyclyl-(R d )
  • R d at each occurrence is independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, (CrC 8 )-alkyl, halo(CrC 8 )alkyl, (C 3 -Ci 2 )-cycloalkyl, (C 6 -C-
  • substitution means that one or more hydrogens of the specified moiety are replaced with a suitable substituent and includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and results in a stable compound.
  • alkyl or "(CrC 8 )-alkyl” whether used alone or as part of a substituent group, refers to the radical of saturated aliphatic groups, including straight or branched-chain alkyl groups. If the number of carbon atoms is not specified, “alkyl” refers to alkyl group having 1 -8 (both inclusive) carbon atoms. Accordingly, a straight-chain or branched chain alkyl has eight or fewer carbon atoms in its backbone, for instance, CrC 8 for straight- chain and C 3 -C 8 for branched chain.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, iso-butyl, sec-butyl, n-pentyl, isopentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl, isohexyl, 2-hexyl, 3-hexyl and the like.
  • alkyl groups can be unsubstituted or substituted with one or more substituents.
  • a substituted alkyl refers to a (CrC 8 )-alkyl substituted preferably with 1 -7 groups, more preferably 1 -3 groups independently selected from the group consisting of halogen, hydroxy, oxo, cyano, (CrC 8 )-alkoxy, halo(C C 8 )-alkoxy, (C 3 -C 12 )-cycloalkyl-(R d ) 0 - 2 , O-(C 3 -C 12 )-cycloalkyl-(R d ) 0 - 2 , (C 6 -C 14 )- aryl-(R d )o-2, O-(C 6 -Ci 4 )-aryl-(R d ) 0 -2, heterocyclyl-(R d ) 0 - 2 , O-heterocycly
  • substituted alkyls include, but are not limited to, trifluoromethyl, hydroxymethyl, hydroxyethyl, 1 - aminoethyl, benzyl, N-morpholino methyl, N-indolomethyl, and N-piperidinylmethyl.
  • halogen refers to a fluorine, chlorine, bromine, or iodine atom.
  • halo(C C 8 )-alkyl When the alkyl group is substituted with one or more halogens, it is specifically referred to as "halo(C C 8 )-alkyl" or "haloalkyl".
  • a monohalo(C C 8 )-alkyl radical for example, can have a chlorine, bromine, iodine or fluorine atom.
  • Dihalo and polyhalo(Cr C 8 )-alkyl radicals may have two or more of the same or different halogen atoms.
  • halo(CrC 8 )-alkyl include, but are not limited to, chloromethyl, dichloromethyl, trichloromethyl, dichloroethyl, dichloropropyl, fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl or the like groups.
  • alkoxy refers to a (CrC 8 )-alkyl having an oxygen radical attached thereto.
  • the terms "(CrC 8 )-alkoxy” or O-(CrC 6 )alkyl wherever used in this specification have the same meaning.
  • Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy and t-butoxy.
  • halo(CrC 6 )alkoxy refers to the radical wherein one or more of the hydrogen atoms of the alkoxy group are substituted with one or more halogens.
  • Representative examples of "haloalkoxy” or “halo(CrC 6 )alkoxy” groups include, but not limited to, difluoromethoxy (OCHF 2 ), trifluoromethoxy (OCF 3 ) or trifluorethoxy (OCH 2 CF 3 ).
  • An alkoxy group can be unsubstituted or substituted with one or more substituents.
  • a substituted alkoxy refers to an (CrC 8 )-alkoxy group in which the alkyl is substituted with one or more groups as explained in the definition of 'substituted alkyl' herein above.
  • Representative examples of substituted (CrC 8 )-alkoxy include, but are not limited to, 2-cyanoethoxy and benzyloxy group.
  • a benzyloxy group refers to a benzyl having an oxygen radical attached thereto.
  • cycloalkyl or "(C3-Ci2)-cycloalkyl” whether used alone or as part of a substituent group, refers to a saturated cyclic hydrocarbon radical including 1 , 2 or 3 rings and including a total of 3-12 carbon atoms forming the rings.
  • the term cycloalkyl includes bridged, fused and spiro ring systems.
  • (C3-Ci2)-cycloalkyl refers to a cycloalkyl group having 3-12 (both inclusive) carbon atoms.
  • cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, norbornyl, bicyclo[2.1 .0]pentane, bicyclo[2.2.1 ]heptyl, bicyclo[2.2.1 ]hept-2-ene, spiro[3.3]heptane and 1 ,2,3,3a-tetrahydropentalene.
  • cycloalkenyl or "(Cs-CsJ-cycloalkenyl” refers to a non-aromatic monocyclic carbocyclic ring having from 5 to 8 carbon atoms and up to 3 carbon-carbon double bonds.
  • Representative examples of cycloalkenyl include, but are not limited to, cyclopentenyl and cyclohexenyl.
  • cycloalkyl and “cycloalkenyl” can be unsubstituted or substituted with 1 -7, preferably 1 -3 groups independently selected from the group consisting of halogen, hydroxy, oxo, cyano, (d-CsJ-alkyl, halo(CrC8)-alkyl, (d-Cs)- alkoxy, halo(CrC 8 )-alkoxy, (C 3 -C-i2)-cycloalkyl-(R d ) 0 -2, O-(C 3 -C-i2)-cycloalkyl-(R d ) 0 -2, (C 6 -Ci 4 )-aryl-(R d )o-2, O-(C 6 -Ci 4 )-aryl-(R d ) 0 -2, heterocyclyl-(R d ) 0 - 2 , O-heterocyclyl-(R d ) 0 -
  • aryl or "(C 6 -Ci 4 )-aryl” as used herein refers to monocyclic or polycyclic hydrocarbon groups having 6-14 ring carbon atoms in which the carbocyclic ring(s) present have a conjugated pi electron system.
  • Representative examples of ⁇ CQ- C )-aryl residues include, but are not limited to, phenyl, naphthyl, fluorenyl or anthracenyl.
  • Aryl groups can be unsubstituted or substituted with one or more substituents, for example 1 -5 substituents independently selected from the group consisting of halogen, hydroxy, oxo, cyano, (d-CsJ-alkyl, halo(Ci-C8)-alkyl, (d-Cs)- alkoxy, halo(d-C 8 )-alkoxy, (C 3 -Ci2)-cycloalkyl-(R d ) 0 -2, O-(C 3 -Ci2)-cycloalkyl-(R d ) 0 -2, (C 6 -Ci 4 )-aryl-(R d ) 0 -2, O-(C 6 -Ci 4 )-aryl-(R d ) 0 -2, heterocyclyl-(R d ) 0 - 2 , O-heterocyclyl-(R d ) 0 - 2 , heteroaryl
  • the substituent can be located in the 2- position, the 3-position or the 4-position. If the phenyl carries two substituents, they can be located in 2, 3-position, 2, 4-position, 2, 5-position, 2, 6-position, 3, 4-position or 3, 5- position.
  • monosubstituted phenyl groups include, but are not limited to, 3-trifluoromethylphenyl, 4-chlorophenyl and 4-cyanophenyl.
  • disubstituted phenyl groups include, but are not limited to,
  • aryloxy or "O-(C6-Ci 4 )-aryl” refers to an "(C6-Ci 4 )-aryl” group having an oxygen radical attached thereto.
  • the aryl of aryloxy group may be unsubstituted or substituted as indicated in the definition of (C 6 -Ci 4 )-aryl herein above.
  • aryloxy groups include, but are not limited to, phenoxy, 4- chlorophenoxy, and 3, 4-dimethoxyphenoxy.
  • aralkyl or "(C6-Ci 4 )ar-(Ci-C 8 )-alkyl” refers to an alkyl group substituted with an (C 6 -Ci 4 )-aryl group, wherein the terms alkyl and aryl are as defined above.
  • Representative examples of aralkyl groups include (CH 2 ) p -phenyl, wherein p is an integer selected from 1 -6, such as benzyl wherein p is 1 .
  • (C6-Ci 4 )-aralkyl group can be unsubstituted or substituted as indicated in the definition of aryl herein above.
  • heteroatom as used herein, includes nitrogen (N), oxygen (O) and sulfur (S). Any heteroatom with unsatisfied valency is assumed to have a hydrogen atom to satisfy the valency.
  • heterocyclyl or “heterocyclic” whether used alone is a 3-12 membered saturated or partially unsaturated, monocyclic or bicyclic ring system, including spiro ring systems, containing one to four heteroatoms independently selected from the group consisting of O, N and S.
  • heterocyclyls include, but are not limited to, pyrrolyl, pyrrolidinyl, pyrazolyl, imidazolyl, pyrazinyl, piperazinyl, oxazolyl, oxadiazolyl, isoxazolyl, triaziolyl, thiazolyl, tetrazolyl, furyl, thienyl, purinyl, pyridinyl, pyridazinyl, pyrimidinyl, piperidyl, benzoxazolyl, benzothiazolyl, benzofuranyl, purinyl, benzimidazolyl, benzoxazolyl, indolyl, indazolyl, isoindolyl, isothiazolyl, isoquinolyl, isoquinolyl, morpholinyl, thiomorpholinyl, thiomorpholinyl-1 , 1 - dioxide, quinoxalinyl,
  • heterocyclyl having an aromatic ring containing heteroatoms are herein referred to by the customary term "heteroaryl".
  • heteroaryl refers to a 5-10 membered aromatic monocyclic or bicyclic ring system containing one to four heteroatoms independently selected from: nitrogen, sulphur and oxygen.
  • heteroaryls include, but are not limited to, pyrrole, pyrazole, imidazole, pyrazine, furan, thiophene, oxazole, thiazole, benzimidazole, benzoxazole, benzothiazole, benzofuran, indole, indazole, isoindole, isoquinoline, isooxazole, triazine, purine, pyridine, quinoline, oxadiazole, thiene, pyridazine, pyrimidine, isothiazole, quinoxaline (benzopyrine) and tetrazole.
  • the nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S, S-dioxide.
  • a heterocyclyl or heteroaryl group can be unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, oxo, cyano, (CrC 8 )-alkyl, halo(CrC 8 )-alkyl, (CrC 8 )-alkoxy, halo(CrC 8 )-alkoxy, (C 3 - Ci 2 )-cycloalkyl-(R d )o-2, O-(C 3 -Ci 2 )-cycloalkyl-(R d ) 0 -2, (C 6 -Ci 4 )-aryl-(R d ) 0 -2, O-(C 6 -C )- aryl-(R d )o-2, heterocyclyl-(R d )o-2, O-heterocyclyl-(R d )o-2, heteroaryl-(R d ) 0 -2
  • isotopic forms or “isotopically labeled forms” is a general term used for isotopic forms of the compounds of formula 1 , wherein one or more atoms of the compounds of formula 1 are replaced by their respective isotopes. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the present invention.
  • isotopes that can be incorporated into the compounds disclosed herein include, but are not limited to, isotopes of hydrogen such as 2 H (deuterium or D) and 3 H (tritium or T), carbon such as 11 C, 13 C and 14 C, nitrogen such as 13 N and 15 N, oxygen such as 15 0, 17 O and 18 O, chlorine such as 36 CI, fluorine such as 18 F and sulphur such as 35 S.
  • isotopes of hydrogen such as 2 H (deuterium or D) and 3 H (tritium or T)
  • carbon such as 11 C, 13 C and 14 C
  • nitrogen such as 13 N and 15 N
  • oxygen such as 15 0, 17 O and 18 O
  • chlorine such as 36 CI
  • fluorine such as 18 F
  • sulphur such as 35 S.
  • Substitution with heavier isotopes, for example, replacing one or more key carbon-hydrogen bonds with carbon-deuterium bond may show certain therapeutic advantages, resulting from longer metabolism cycles, (e.g., increased
  • isotopic forms of the compounds of formula 1 can include, without limitation, deuterated compounds of formula 1 .
  • deuterated as used herein, by itself or used to modify a compound or group, refers to replacement of one or more hydrogen atom(s), which is attached to carbon(s), with a deuterium atom.
  • the compounds of formula 1 can include in the definitions of one or more of its various variables, wherever applicable, deuterium, deuterated-alkyl, deuterated-alkoxy, deuterated-cycloalkyl, deuterated-heterocyclyl, deuterated-aryl, deuterated-heteroaryl and the like.
  • deuterated-alkyl refers to an (d-CsJ-alkyl group as defined herein, wherein at least one hydrogen atom bound to carbon is replaced by a deuterium, i.e., in a deuterated alkyl group, at least one carbon atom is bound to a deuterium.
  • a deuterated alkyl group it is possible for a carbon atom to be bound to more than one deuterium; it is also possible that more than one carbon atom in the alkyl group is bound to a deuterium.
  • deuterated and the terms deuterated- heterocyclyl, deuterated-heteroaryl, deuterated-cycloalkyl, deuterated-aryl, deuterated- alkoxy each refer to the corresponding chemical moiety wherein at least one carbon is bound to a deuterium.
  • solvate(s) refers to an aggregate of a molecule (in the present invention, a compound of formula 1 or a pharmaceutically acceptable salt thereof) with one or more solvent molecules.
  • solvents for the purpose of the invention may not interfere with the biological activity of the molecule.
  • the solvent used is a pharmaceutically acceptable solvent.
  • suitable pharmaceutically acceptable solvents include, without limitation, water, ethanol and acetic acid.
  • the solvent used is water and the solvates obtained are referred to as hydrates.
  • suitable solvates are the mono- or di-hydrates or alcoholates of the compounds of the present invention.
  • stereoisomer or “stereoisomeric form” is a general term used for all isomers of individual compounds (in the present invention, a compound of formula 1 or a pharmaceutically acceptable salt thereof) that differ only in the orientation of their atoms in space.
  • stereoisomer includes mirror image isomers (enantiomers), mixtures of mirror image isomers (racemates, racemic mixtures), geometric (cis/trans or E/Z) isomers, and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereoisomers).
  • tautomer refers to the coexistence of two (or more) compounds that differ from each other only in the position of one (or more) mobile atoms and in electron distribution, for example, keto-enol tautomers or amide-imidic acid tautomers.
  • the term "pharmaceutically acceptable” means that the carrier, diluent, excipients, and/or salt must be compatible with the other ingredients of the formulation (composition), and not deleterious to the recipient thereof.
  • pharmaceutically acceptable salts or “pharmaceutically acceptable salt” as used herein includes salts of the active compound i.e. the compound of formula 1 , which retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects; and are prepared with suitable acids or bases, depending on the particular substituents found on the compounds described herein.
  • polymorph(s) or “pharmaceutically acceptable polymorph” or “polymorphic form” refers to crystals of the same compound (in the present invention, a compound of formula 1 ) that differs only in the arrangement and/or conformation of the molecule in the crystal lattice.
  • N-oxide refers to an oxide of the nitrogen atom of a nitrogen-containing heteroaryl or heterocycle.
  • N- oxide can be formed in the presence of an oxidizing agent such as m-chloro-perbenzoic acid or hydrogen peroxide.
  • N-oxide refers to an amine oxide, also known as amine-N- oxide, and is a chemical compound that contains N->O bond.
  • S-oxide refers to the oxide of the sulfur atom (S-oxide) or dioxide of the sulfur atom (S, S-dioxide) of a sulfur-containing heteroaryl or heterocycle.
  • S-oxide and S, S-dioxides can be formed in the presence of an oxidizing agent such as m-chloro-perbenzoic acid or oxone (potassium peroxymonosulfate).
  • a prodrug or
  • prodrugs refers to a compound, which is a derivative of a parent compound (in the present invention, a compound of formula 1 or a pharmaceutically acceptable salt thereof), which following administration, releases the parent compound in vivo via a chemical or physiological process, e.g., a prodrug on being brought to the physiological pH or through enzyme action is converted to the parent compound.
  • the terms “compound of formula 1 ", “compounds of formula 1 ", and “compounds of the present invention” include all the isotopic forms, stereoisomeric and tautomeric forms and mixtures thereof in all ratios, and the pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, pharmaceutically acceptable polymorphs, N- oxides and S-oxides thereof.
  • the compound(s) of the present invention can also be referred to herein as "the active compound” or "the active ingredient”.
  • CB1 receptor antagonist refers to a compound which is capable of binding to the CB1 receptor (CB1 R), or in its vicinity, and lacks any substantial ability to activate the receptor itself.
  • a CB1 receptor antagonist prevents or reduces the functional activation or occupation of the receptor by a CB1 receptor agonist such as for example the endogenous agonist, N- Arachidonylethanolamine (anandamide).
  • CB1 receptor inverse agonist refers to a compound which binds to the CB1 receptor and exerts the opposite pharmacological effect as a CB1 receptor agonist does upon binding to the CB1 receptor.
  • disease or disorder mediated by CB1 receptor(s) refers to a disease or condition which is mediated by CB1 receptor signaling activity.
  • the disease or disorder mediated by CB1 receptors can be selected from gastrointestinal disorder; inflammatory disease or disorder; cardiovascular disease; cancer; obesity and metabolic disorder; osteoporosis; nephropathy; glaucoma; psychiatric disorder, neurological disorder; autoimmune hepatitis and encephalitis; pain; reproductive disorder; skin inflammatory disease or fibrotic disease.
  • therapeutically effective amount means an amount of the compound of formula 1 or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof or a composition comprising a compound of formula 1 , or a pharmaceutically acceptable salt thereof, effective in producing the desired therapeutic response in a particular patient (subject) suffering from a disease or disorder to be treated.
  • therapeutically effective amount includes the amount of the compound of the present invention, when administered, that induces a positive modification in the condition (a disease or a disorder) to be treated or is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disease or disorder being treated in a patient (subject).
  • the amount of the compound used for the treatment of a subject is low enough to avoid undue or severe side effects, within the scope of sound medical judgment.
  • the therapeutically effective amount of the compound or composition will vary with the particular condition being treated, the age and physical condition of the patient (subject in need of the treatment), the severity of the condition being treated/prevented, the duration of the treatment, the nature of concurrent therapy, the specific compound or composition employed and the particular pharmaceutically acceptable carrier utilized.
  • the term "pharmaceutically acceptable carrier” refers to a material that is non-toxic, inert, solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type which is compatible with a subject, preferably a mammal, more preferably a human, and is suitable for delivering an active agent (in the present invention, a compound of formula 1 or a pharmaceutically acceptable salt thereof or any other form recited herein), to the target site without adversely affecting activity of the agent.
  • an active agent in the present invention, a compound of formula 1 or a pharmaceutically acceptable salt thereof or any other form recited herein
  • subject refers to an animal, preferably a mammal, and most preferably a human.
  • mammal refers to warm-blooded vertebrate animals of the class mammalia, including humans, characterized by a covering of hair on the skin and, in the female, milk-producing mammary glands for nourishing the young.
  • mammal includes animals such as cat, dog, rabbit, bear, fox, wolf, monkey, deer, mouse, pig as well as human.
  • subject may be used interchangeably with the term patient.
  • the phrase "a subject in need thereof” means a subject in need of the treatment for the disease or disorder that is mediated by CB1 receptors.
  • the phrase "a subject in need thereof” means a subject (patient) diagnosed having a disease or disorder that is mediated by CB1 receptors.
  • treatment refers to alleviate, slow the progression, attenuation or cure of existing disease or condition (e.g. obesity and metabolic disorder). Treatment also includes treating, preventing development of, or alleviating to some extent, one or more of the symptoms of the disease or condition.
  • the present invention relates to a compound of formula 1 : wherein,
  • Ri and R2 are halogen
  • the present invention relates to a compound of formula 1 : wherein,
  • Ri and R 2 are halogen
  • the present invention relates to a compound of formula 1 : wherein,
  • Ri and R2 are halogen
  • the present invention relates to a compound of formula 1 : wherein,
  • Ri and R 2 are independently selected from the group consisting of hydrogen, halogen, (CrC 8 )-alkyl, halo-(C C 8 )-alkyl and (C C 8 )-alkoxy;
  • n 1 ;
  • n 1 or 2;
  • X is hydrogen, halogen or (CrC 8 )-alkyl
  • R 3 is hydrogen, cyano, (C C 8 )-alkyl, halo(C C 8 )-alkyl, (C 3 -Ci 2 )-cycloalkyl, C(O)R a , C(O) 2 R a or S(O) q Rc; and
  • R 4 , R 5 , R a , R c and q are as defined in the first aspect
  • the present invention relates to a compound of formula
  • Ri and R 2 are halogen
  • n 1 ;
  • n 1 or 2;
  • X is hydrogen, halogen or (CrC 8 )-alkyl
  • R 3 is hydrogen, cyano, (CrC 8 )-alkyl, (C 3 -Ci 2 )-cycloalkyl or S(O) q R c ;
  • R 4 , R5, R c , and q are as defined in the first aspect
  • the present invention relates to a compound of formula
  • Ri and R 2 are halogen
  • n 1 ;
  • n 1 or 2;
  • X is hydrogen, halogen or (C-i-C 8 )-alkyl
  • R3 and R5 can join together to form a 3-12 membered saturated or unsaturated monocyclic or bicyclic ring system, optionally containing one to three heteroatoms independently selected from the group consisting of O, N and S;
  • the said 3-12 membered ring can be unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, oxo, cyano, (CrC 8 )-alkyl, halo(CrC 8 )-alkyl, (CrC 8 )-alkoxy, halo(CrC 8 )-alkoxy, (C 3 - C 12 )-cycloalkyl-(R d )o- 2 , O-(C 3 -C 12 )-cycloalkyl-(R d ) 0 - 2 , (C 6 -C 14 )-aryl-(R d ) 0 - 2 , O-(C 6 -C 14 )- aryl-(R d )o-2, heterocyclyl-(R d )o-2, O-heterocyclyl-(R d )o-2, heteroaryl-(R d )
  • R 4 , R a , R b , R c , R d and q are as defined in the first aspect
  • the present invention relates to a compound of formula
  • Ri and R2 are halogen
  • n 1 ;
  • n 1 or 2;
  • X is hydrogen, halogen or (Ci-C 8 )-alkyl
  • R 3 is hydrogen, cyano, (CrC 8 )-alkyl, (C 3 -Ci 2 )-cycloalkyl or S(O) q R c ;
  • R 4 and R5 can join together to form a 3-12 membered saturated or unsaturated, monocyclic or bicyclic ring system including spiro ring systems, optionally containing one to three heteroatoms independently selected from the group consisting of O, N and S;
  • the said 3-12 membered ring can be unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, oxo, cyano, (Ci-C 8 )-alkyl, halo(d-C8)-alkyl, (Ci-C 8 )-alkoxy, halo(Ci-C8)-alkoxy, (C3- Ci 2 )-cycloalkyl-(Rd)o-2, O-(C 3 -Ci 2 )-cycloalkyl-( R d )o-2, (C 6 -Ci 4 )-aryl-( R d )o-2, O-(C 6 -d 4 )- aryl-(Rd)o-2, heterocyclyl-(Rd)o-2, O-heterocyclyl-(Rd)o-2, heteroaryl-( R d )o-2, C(O) R a , CO 2 R a
  • Ra, Rb, Rc, Rd and q are as defined in the first aspect
  • the present invention relates to a compound of formula 1 , wherein,
  • Ri and R 2 are independently selected from the group consisting of hydrogen, halogen, (d-C 8 )-alkyl, halo (d-C 8 )-alkyl and (d-C 8 )-alkoxy;
  • n 1 ;
  • n 1 or 2;
  • X is hydrogen, halogen or (Ci-C 8 )-alkyl;
  • Q is:
  • R3 is hydrogen, cyano, (d-CsJ-alkyl, halo(CrC8)-alkyl, (C3-Ci2)-cycloalkyl, C(O)R a , C(O) 2 R a or S(O) q R c ;
  • R 4 , R 5 , R c and q are as defined in the first aspect
  • the present invention relates to a compound of formula 1 ,
  • Ri and R2 are halogen
  • X is hydrogen, halogen or (d-CsJ-alkyl
  • R 3 is hydrogen, cyano, (d-C 8 )-alkyl, (C 3 -Ci 2 )-cycloalkyl or S(O) q R c ;
  • R 4 , R5, R c , and q are as defined in the first aspect
  • the present invention relates to a compound of formula
  • Ri and R 2 are halogen
  • X is hydrogen, halogen or (CrC 8 )-alkyl;
  • R3 and R5 can join together to form a 3-12 membered saturated or unsaturated monocyclic or bicyclic ring system, optionally containing one to three heteroatoms independently selected from the group consisting of O, N and S;
  • the said 3-12 membered ring can be unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, oxo, cyano, (d-CsJ-alkyl, halo(CrC8)-alkyl, (Ci-Cs)-alkoxy, halo(CrC8)-alkoxy, (C3- C 12 )-cycloalkyl-(R d )o- 2 , O-(C 3 -C 12 )-cycloalkyl-(R d ) 0 - 2 , (C 6 -C 14 )-aryl-(R d ) 0 - 2 , O-(C 6 -C 14 )- aryl-(R d )o-2, heterocyclyl-(R d ) 0 - 2 , O-heterocyclyl-(R d ) 0 - 2 , heteroaryl-(R d
  • R 4 , R a , R b , R Cl R d and q are as defined in the first aspect
  • the present invention relates to a compound of formula
  • Ri and R 2 are halogen
  • X is hydrogen, halogen or (CrC 8 )-alkyl
  • R 3 is hydrogen, cyano, (CrC 8 )-alkyl, (C 3 -Ci 2 )-cycloalkyl or S(O) q R c ; and R 4 and R 5 can join together to form a 3-12 membered saturated or unsaturated, monocyclic or bicyclic ring system including spiro ring systems, optionally containing one to three heteroatoms independently selected from the group consisting of O, N and S;
  • the said 3-12 membered ring can be unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, oxo, cyano, (C-i-C 8 )-alkyl, halo(CrC8)-alkyl, (C-i-C 8 )-alkoxy, halo(CrC8)-alkoxy, (C3- Ci 2 )-cycloalkyl-(R d )o-2, O-(C 3 -Ci 2 )-cycloalkyl-(R d ) 0 - 2 , (C 6 -Ci 4 )-aryl-(R d ) 0 -2, 0-(C 6 -Ci 4 )- aryl-(R d )o-2, heterocyclyl-(R d ) 0 - 2 , O-heterocyclyl-(R d ) 0 - 2 , heteroaryl
  • Ra, Rb, Rc, Rd and q are as defined in the first aspect
  • the present invention relates to a compound of formula 1 , wherein,
  • Ri and R 2 are independently selected from the group consisting of hydrogen, halogen,
  • n 1 ;
  • n 1 or 2;
  • X is hydrogen, halogen or (CrC 8 )-alkyl
  • R3 is hydrogen, cyano, (CrC 8 )-alkyl, halo(CrC 8 )-alkyl, (C3-Ci 2 )-cycloalkyl, C(O)R a , C(O) 2 R a or S(O) q R c ;
  • R 4 , R 5 , R c and q are as defined in the first aspect
  • the present invention relates to a compound of formula 1 , wherein,
  • Ri and R 2 are halogen
  • n 1 ;
  • n 1 or 2;
  • X is hydrogen, halogen or (CrC 8 )-alkyl
  • R3 is hydrogen, cyano, (d-CsJ-alkyl, (C3-Ci 2)-cycloalkyl or S(O) q R c ;
  • R 4 , R 5 , R c , and q are as defined in the first aspect
  • the present invention relates to a compound of formula
  • Ri and R 2 are halogen
  • n 1 ;
  • n 1 or 2;
  • X is hydrogen, halogen or (d-CsJ-alkyl
  • R 3 and R 5 can join together to form a 3-12 membered saturated or unsaturated monocyclic or bicyclic ring system, optionally containing one to three heteroatoms independently selected from the group consisting of O, N and S; wherein the said 3-12 membered ring can be unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, oxo, cyano, (d-CsJ-alkyl, halo(CrC8)-alkyl, (Ci-Cs)-alkoxy, halo(CrC8)-alkoxy, (C 3 - Ci 2 )-cycloalkyl-(R d )o-2, O-(C 3 -Ci 2 )-cycloalkyl-(R d ) 0 - 2 , (C 6 -d 4 )-aryl-(R d ) 0 - 2 , O-(C 6 -d 4 )- ary
  • R 4 , R a , R b , R c , R d and q are as defined in the first aspect
  • the present invention relates to a compound of formula
  • Ri and R 2 are halogen
  • n 1 ;
  • n 1 or 2;
  • X is hydrogen, halogen or (d-CsJ-alkyl
  • R 3 is hydrogen, cyano, (d-C 8 )-alkyl, (C 3 -d 2 )-cycloalkyl or S(O) q R c ;
  • R 4 and R 5 can join together to form a 3-12 membered saturated or unsaturated, monocyclic or bicyclic ring system including spiro ring systems, optionally containing one to three heteroatoms independently selected from the group consisting of O, N and S;
  • the said 3-12 membered ring can be unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, oxo, cyano, (d-CsJ-alkyl, halo(Ci-C8)-alkyl, (d-CsJ-alkoxy, halo(Ci-C8)-alkoxy, (C 3 - Ci 2 )-cycloalkyl-(R d ) 0 - 2 , O-(C 3 -d 2 )-cycloalkyl-(R d ) 0 - 2 , (C 6 -d 4 )-aryl-(R d ) 0 - 2 , O-(C 6 -d 4 )- aryl-(Rd)o-2.
  • heterocyclyl-(R d ) 0 - 2 O-heterocyclyl-(R d ) 0 - 2 , heteroaryl-(R d ) 0 - 2 , C(O)R a , CO 2 R a , C(O)NR a R b , NR a R b , NR a C(O)R b , S(O) q R c and S(O) q NR a R b ; and R a> Rb > Rc > Rd and q are as defined in the first aspect;
  • the present invention relates to a compound of formula 1 , wherein,
  • Ri and R 2 are halogen
  • n 1 ;
  • n 1 or 2;
  • X is hydrogen, halogen or (CrC 8 )-alkyl
  • R3 is hydrogen, cyano, (d-CsJ-alkyl, (C3-Ci2)-cycloalkyl or S(O) q R c ;
  • R 4 is (d-CsJ-alkyl, (C3-Ci2)-cycloalkyl, (C6-d 4 )-aryl, heterocyclyl or heteroaryl;
  • R 5 is hydrogen, (d-C 8 )-alkyl, (C 3 -Ci 2 )-cycloalkyl, (C 6 -C )-aryl, heterocyclyl or heteroaryl; or
  • R3 and R5 can join together to form a 3-12 membered saturated or unsaturated monocyclic or bicyclic ring system, optionally containing one to three heteroatoms independently selected from the group consisting of O, N and S; or
  • R 4 and R 5 can join together to form a 3-12 membered saturated or unsaturated, monocyclic or bicyclic ring system including spiro ring systems, optionally containing one to three heteroatoms independently selected from the group consisting of O, N and S;
  • the said 3-12 membered ring can be unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, oxo, cyano, (d-CsJ-alkyl, halo(d-C8)-alkyl, (Ci-Cs)-alkoxy, halo(Ci-C8)-alkoxy, (C3- Ci 2 )-cycloalkyl-(Rd)o-2, O-(C 3 -d 2 )-cycloalkyl-(R d ) 0 - 2 , (C 6 -Ci 4 )-aryl-(R d )o-2, O-(C 6 -d 4 )- aryl-(R d )o-2, heterocyclyl-(R d ) 0 - 2 , O-heterocyclyl-(R d ) 0 - 2 , heteroaryl-(R d ) 0 -
  • R a , R b , R c , R d and q are as defined in the first aspect; or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.
  • Representative compounds of the present invention include:
  • the compounds of the present invention include:
  • the compounds of the present invention include all isotopic forms, stereoisomeric and tautomeric forms and mixtures thereof in all ratios and their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, prodrugs, N- oxides, S-oxides and polymorphs.
  • processes for the preparation of the compounds of formula 1 can be prepared using various methods including the methods well known to a person skilled in the art. Representative processes to prepare the compounds of the present invention are described below, and are particularly illustrated in Schemes 1 -5, but are not limited thereto. It will be appreciated by persons skilled in the art that within certain of the processes described herein, the order of the reaction steps employed can be varied and will depend inter alia on factors such as the nature of functional groups present in a particular substrate (starting compound or an intermediate) and the protecting group strategy (if any) to be adopted. Clearly, such factors will also influence the choice of reagent to be used in the reaction steps.
  • Scheme 1 depicts a process for the preparation of the compound of formula 1 , wherein, Q is:
  • a coupling reagent such as O- (benzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) and an amine such as diisopropyl ethylamine at room temperature and the mixture is stirred for 4-6 h, to yield the compound of formula 5 (wherein Ri , R 2 , R3, m, n and X are as defined in the first aspect of the invention).
  • TBTU benzotriazol-1 -yl
  • amine such as diisopropyl ethylamine
  • R-i , R2, R3, R4, R5, X, m and n are as defined in the first aspect of the invention).
  • Scheme 2 depicts a process for the preparation of the compound of formula 1 , wherein, Q is:
  • R 3 , R 4 and R 5 are as defined in the first aspect of the present invention.
  • a solution of the compound of formula 4 (wherein Ri , R 2 , X, m and n are as defined in the first aspect of the invention), coupling reagent such as N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC), and a base such as N,N-dimethylpyridin-4-amine (DMAP) are added to a solvent such as dichloromethane (CH 2 CI 2 ). The resulting mixture is stirred at room temperature for 0.5-1 h.
  • EDC N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride
  • DMAP N,N-dimethylpyridin-4-amine
  • R-i , 2, R3, R4, R5, X, rn and n are as defined in the first aspect of the invention).
  • R 3 , R 4 and R 5 are as defined in the first aspect of the present invention.
  • reaction mixture is quenched with a saturated solution of a salt such as NaHCO 3 at 0-2 °C, which results in the formation of the compound of formula 10 (wherein R ; R 2 , X, m and n are as defined in the first aspect of the invention).
  • a salt such as NaHCO 3
  • R-i, R 2 , X, m and n are as defined in the first aspect of the invention.
  • Scheme 4 depicts a process for the preparation of the compound of formula 1 , wherein, Q is:
  • R 3 , R 4 and R 5 are as defined in the first aspect of the present invention.
  • a solution of the compound of formula 15 (wherein R-i , R 2 , R3, X, m and n are as defined in the first aspect of the invention), in a reagent such as phosphoryl chloride, is refluxed at 1 10-130 °C for 1 -3 h. Excess reagent is distilled off, and the residue is dissolved in a solvent such as dichloromethane, followed by addition of of a base such as triethylamine and the compound of formula B (as described in step I d of the scheme 1 ) at room temperature, to yield the compound of formula 1 (wherein R-i , R 2 , Q, X, m and n are as defined in the first aspect of the invention).
  • the compound of formula 1 can be prepared from compound of formula 14 using the procedure described below:
  • R-i , R 2 , X, m and n are as defined in the first aspect of the invention.
  • Scheme 5 depicts a process for the preparation of the compound of formula 1 , wherein, Q is:
  • R3, R 4 and R5 are as defined in the first aspect of the present invention.
  • a solution of the compound of formula 16 (wherein R-i , R 2 , R 3 , X, m and n are as defined in the first aspect of the invention) in a solvent such as chlorobenzene is heated at 105-1 15 °C in the presence of a reagent such as phosphorous pentachloride for 1 -3 h. After evaporation of the solvent, the residue is dissolved in a solvent such as dichloromethane and treated with a base such as triethylamine and the compound of formula B (as described in step d of the scheme 1 ), to yield the compound of formula 1 (wherein Q is:
  • R-i, R 2 , X, m and n are as defined in the first aspect of the invention.
  • pharmaceutically acceptable salt(s) means those salts of compounds of the formula 1 which retain the efficacy and the biological properties of the free bases or of the free acids and are safe for use in mammals.
  • pharmaceutically acceptable salts include organic and inorganic salts of the compounds of the invention (the compounds of formula 1 ) depending on the particular group (acidic or basic group) present in the said compounds.
  • acid addition salts can be obtained.
  • the pharmaceutically acceptable acid addition salts include those derived from inorganic acids, which are not limited to, such as hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, mono-hydrogensulfuric or hydroiodic acids and the like; as well as the salts derived from organic acids such as acetic, ascorbic, benzenesulfonic, benzoic, citric, ethanesulfonic, formic, fumaric, galacturonic, gluconic, glucuronic, glutamic, isobutyric, isonicotinic, lactic, maleic, malonic, mandelic, methanesulfonic, 4-methylbenzenesulfonic, nicotinic, oxalic, pantothenic, phthalic, propionic, saccharic, succinic,
  • base addition salts can be obtained.
  • examples of pharmaceutically acceptable organic base addition salts of the compounds of the present invention include those derived from organic bases such as lysine, arginine, guanidine, diethanolamine, choline, tromethamine, metformin and the like.
  • examples of pharmaceutically acceptable base addition salts of the compounds of the present invention include their alkali metal salts. Suitable alkali metal salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, or zinc salts.
  • the pharmaceutically acceptable salts of the compounds of formula 1 can be synthesized from the compound of formula 1 , which contains a basic or an acidic group, by using conventional chemical methods. Generally, the salts are prepared by treating the compound of formula 1 which may be a free base or an acid with a suitable salt- forming inorganic or an organic acid or a base in a suitable solvent or dispersant or from another salt by cation or anion exchange.
  • suitable solvents that can be used for the preparation of pharmaceutically acceptable salts include, but are not limited to, ethyl acetate, diethyl ether, methanol, ethanol, acetone, tetrahydrofuran, dioxane or mixtures of these solvents.
  • the compounds of formula 1 can be regenerated by contacting the salt with a base or an acid depending on the type of salt and isolating the parent compound in the conventional manner.
  • the present invention also encompasses within its scope the solvates of the compounds of formula 1 .
  • Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. Certain compounds of the present invention can exist in multiple crystalline or amorphous forms. In general, all physical forms are suitable for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
  • polymorphs of the compound of formula 1 can be prepared by crystallization of the compound under different conditions.
  • the different conditions are, for example, using different solvents or their mixtures for carrying out crystallization; crystallization at different temperatures; various modes of cooling, ranging from very fast to very slow cooling during crystallization or by heating or melting the compound followed by gradual or fast cooling.
  • the presence of polymorphs can be determined by IR (Infra-red) spectroscopy, solid probe NMR (Nuclear Magnetic Resonance) spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques.
  • the present invention includes all possible stereoisomers and geometric isomers of the compound of formula 1 and includes not only racemic compounds but also the optically active isomers as well.
  • a compound of formula 1 When a compound of formula 1 is desired as a single enantiomer, it can be obtained either by resolution of the final product or by stereospecific synthesis from either isomerically pure starting material or an appropriate intermediate. Resolution of the final product, an intermediate or a starting material may be effected by any suitable method known in the art, for example, Chiral reagents for asymmetric synthesis by Leo A. Paquette; John Wiley & Sons Ltd (2003).
  • the present invention is intended to include all tautomeric forms of the compounds.
  • prodrugs of the compound of formula 1 are those compounds that are converted to their parent compound intracellular ⁇ , where the cellular converting location is the site of therapeutic action.
  • the prodrugs of the compounds of the present invention are derivatives, particularly simple derivatives of the said compounds which upon administration to a subject in need thereof undergoes conversion by metabolic or chemical processes to release the parent drug (e.g. the compound of formula 1 ) in vivo from which the prodrug is derived.
  • the preferred prodrugs are pharmaceutically acceptable ester derivatives e.g., alkyl esters, cycloalkyl esters, alkenyl esters, benzyl esters, mono- or di-substituted alkyl esters that are convertible by solvolysis under physiological conditions to the parent carboxylic acid (e.g. the compound of formula 1 containing the carboxylic acid group), and those conventionally known in the art (An introduction to Medicinal Chemistry, Graham. L. Patrick, Second Edition, Oxford University Press, pg 239-248; Prodrugs: Challenges and Rewards, Part 1 and Part 2, AAPS Press, Edited by Valentino J. Stella, Renald T. Borchardt, Michael J. Hagemon, Reza Oliyai, Hans Maag, Jefferson W. Tilley).
  • ester derivatives e.g., alkyl esters, cycloalkyl esters, alkenyl esters, benzyl esters, mono- or di-substitute
  • the present invention relates to a method for the treatment of a disease or a disorder mediated by CB1 receptors, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula 1 , a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof.
  • the present invention provides a compound of formula 1 or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof; for use as a CB1 receptor antagonist.
  • the compound of formula 1 of the present invention or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof; can be used as CB1 receptor inverse agonist.
  • a compound of formula 1 or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof for use in the treatment of a disease or a disorder mediated by CB1 receptors.
  • the present invention provides use of a compound of formula 1 or a pharmaceutically acceptable salt thereof; for the manufacture of a medicament for the treatment of a disease or a disorder mediated by CB1 receptors.
  • the present invention encompasses within its scope all the diseases or disorders wherein CB1 receptors are implicated.
  • the disease or disorder mediated by CB1 receptors is gastrointestinal disorder; inflammatory disease or disorder; cardiovascular disease; cancer; metabolic disorder (e.g. obesity); osteoporosis; nephropathy; glaucoma; psychiatric disorder; neurological disorder; autoimmune hepatitis and encephalitis; pain; reproductive disorder; skin inflammatory disease or fibrotic disease.
  • metabolic disorder e.g. obesity
  • osteoporosis nephropathy
  • glaucoma psychiatric disorder
  • neurological disorder autoimmune hepatitis and encephalitis
  • pain reproductive disorder
  • skin inflammatory disease or fibrotic disease is gastrointestinal disorder; inflammatory disease or disorder; cardiovascular disease; cancer; metabolic disorder (e.g. obesity); osteoporosis; nephropathy; glaucoma; psychiatric disorder; neurological disorder; autoimmune hepatitis and encephalitis; pain; reproductive disorder; skin inflammatory disease or fibrotic disease.
  • the disease or disorder mediated by CB1 receptor is gastrointestinal disorder; inflammatory disease or disorder; cardiovascular disease; cancer; metabolic disorder (e.g. obesity); psychiatric disorder or neurological disorder.
  • the disease or disorder mediated by CB1 receptor is gastrointestinal disorder.
  • gastrointestinal disorder that can be treated by the compound of formula 1 or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof or pharmaceutical compositions containing the said compounds; is selected from functional bowel disease, gastro-esophagael reflux condition, secretory diarrhea, gastric ulcer, paralytic ileus, cholelithiasis or hernia.
  • the disease or disorder mediated by CB1 receptor is an inflammatory disease or disorder.
  • the inflammatory disease or disorder that can be treated by the compound of formula 1 or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or solvate thereof or pharmaceutical compositions containing the said compounds is selected from: arthritis, hepatitis, inflammatory bowel disease, ulcerative colitis, Crohn's disease or congestive obstructive pulmonary disorder.
  • CB1 receptor is a cardiovascular disease.
  • cardiovascular disease that can be treated by the compound of formula 1 or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof or pharmaceutical compositions containing the said compounds; is selected from aneurysm, angina, arrhythmia, atherosclerosis, cardiomyopathy, cerebrovascular accident (stroke), cerebrovascular disease, congenital heart disease, congestive heart failure, myocarditis, valve disease, coronary artery disease, dilated cardiomyopathy, diastolic dysfunction, endocarditis, high blood pressure (hypertension), hypertrophic cardiomyopathy and its associated arrhythmia and dizziness, mitral valve prolapse, myocardial infarction (heart attack), venous thromboembolism, varicose veins or pulmonary embolism.
  • aneurysm angina, arrhythmia, atherosclerosis, cardiomyopathy, cerebrovascular accident (stroke), cerebrovascular disease, congenital heart disease, congestive heart failure, myocarditis, valve disease,
  • the disease or disorder mediated by CB1 receptor is cancer.
  • Cancer can include metastatic or malignant tumors.
  • cancer that can be treated by the compound of formula 1 or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof or pharmaceutical compositions containing the said compounds is selected from thyroid carcinoma, cardiac sarcoma, lung carcinoma, gastrointestinal carcinoma, genitourinary tract carcinoma, liver carcinoma, mantle cell lymphoma, bone sarcoma, sarcoma of the nervous system, gynaecological carcinoma, haematological cancer, adrenal gland neuroblastoma, skin cancer, astrocytic cancer, breast cancer, colorectal cancer, endometrial cancer, head and neck cancer or oral cancer.
  • cancer examples include squamous cell cancer (e.g. epithelial squamous cell cancer), lung cancer including small-cell lung cancer, non- small cell lung cancer, adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, blood cancer, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, as well as head and neck cancer.
  • lung cancer including small-cell lung cancer, non- small cell lung cancer, adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach
  • the disease or disorder mediated by CB1 receptor is a metabolic disorder.
  • the metabolic disorder that can be treated by the compound of formula 1 or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof or pharmaceutical compositions containing the said compounds is selected from obesity, dyslipidemia, hyperlipidemia, low HDL (high density lipoprotein) and/or high LDL (low density lipoprotein) cholesterol level, hypertriglyceridemia, low adiponectin level, dyslipoproteinemia, impaired glucose tolerance, insulin resistance, increase in HbA1 c (glycosylated haemoglobin) level, type 2 diabetes, reduced metabolic activity, hypertension or non-alcoholic fatty liver disease.
  • metabolic disorder that can be treated by the compound of formula 1 or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof or pharmaceutical compositions containing the said compounds is selected from obesity, low HDL cholesterol level, high LDL cholesterol level, impaired glucose tolerance, insulin resistance, type 2 diabetes, reduced metabolic activity, hypertension or non-alcoholic fatty liver disease.
  • metabolic disorder that can be treated by the compound of formula 1 or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof or pharmaceutical compositions containing the said compounds is obesity.
  • the metabolic disorder that can be treated by the compound of formula 1 or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof or pharmaceutical compositions containing the said compounds is type 2 diabetes, insulin resistance, impaired glucose or reduced metabolic activity.
  • the metabolic disorder that can be treated by the compound of formula 1 or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof or pharmaceutical compositions containing the said compounds is type 2 diabetes.
  • the disease or disorder mediated by CB1 receptor is a psychiatric disorder or a neurological disorder.
  • the psychiatric disorder or neurological disorder that can be treated by the compound of formula 1 of the invention or pharmaceutical compositions containing the said compounds is selected from psychosis, anxiety, depression, attention deficits, dementia, distonia, Parkinson's disease, Alzheimer's disease, schizophrenia, epilepsy, Huntington's disease, Tourette's syndrome or cerebral ischaemia.
  • the present invention also encompasses within its scope the use of a compound of formula 1 or its pharmaceutically acceptable salt or a solvate in combination, with other therapeutically active agents; wherein the compound of formula 1 and the further therapeutic agent are administered either simultaneously or sequentially.
  • the present invention furthermore relates to pharmaceutical compositions containing a therapeutically effective amount of at least one compound of formula 1 or a stereoisomer, a tautomer or a pharmaceutically acceptable salt or a solvate thereof in addition to a customary pharmaceutically acceptable carrier or excipient.
  • the present invention also relates to a process for the production of a pharmaceutical composition, which includes bringing at least one compound of formula 1 , into a suitable administration form using a pharmaceutically acceptable excipient and, if appropriate, further suitable additives or auxiliaries.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound of formula 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition(s) of the present invention can be administered orally, for example in the form of pills, tablets, coated tablets, capsules, granules or elixirs.
  • Administration can also be carried out rectally, for example in the form of suppositories, or parenterally, for example intravenously, intramuscularly or subcutaneously, in the form of injectable sterile solutions or suspensions, or topically, for example in the form of ointments or creams or transdermally, in the form of patches, or in other ways, for example in the form of aerosols or nasal sprays.
  • composition(s) according to the invention are prepared in a manner known and familiar to one skilled in the art.
  • Pharmaceutically acceptable inert inorganic and/or organic carriers and/or additives can be used in addition to the compound of formula 1 , or a pharmaceutically acceptable salt for the production of oral dosage forms of compounds of formula 1 such as pills, tablets, coated tablets and hard gelatin capsules. It is possible to use, for example, lactose, corn starch or derivatives thereof, gum arabica, magnesia or glucose, etc.
  • Carriers for soft gelatin capsules and suppositories are, for example, fats, waxes, natural or hardened oils, etc.
  • Suitable carriers for the production of solutions for example injection solutions, or of emulsions or syrups are, for example, water, physiological sodium chloride solution or alcohols, for example, ethanol, propanol or glycerol, sugar solutions, such as glucose solutions or mannitol solutions, or a mixture of the said solvents.
  • the pharmaceutical compositions normally contain from about 1 -99 %, for example, from about 5-70 %, or from about 10-30 % by weight of the compound of formula 1 or its pharmaceutically acceptable salt.
  • the amount of the compound of formulal or its pharmaceutically acceptable salt in the pharmaceutical compositions normally ranges from about 0.01 -1000 mg, preferably 0.5-500 mg.
  • the dose of the compounds of formula 1 of the present invention, which is to be administered, can cover a wide range depending on the type of disease or disorder to be treated.
  • the dose to be administered daily is to be selected to suit the desired effect.
  • a suitable dosage can be from about 0.01 -100 mg/kg of the compound of formula 1 or its pharmaceutically acceptable salt depending on the body weight of the recipient (subject) per day, for example, from about 0.1 -50 mg/kg/day of a compound of formula 1 or its pharmaceutically acceptable salt. If required, higher or lower daily doses can also be administered.
  • the selected dosage level will depend upon a variety of factors including the activity of a compound of the present invention employed, or its pharmaceutically acceptable salt, the route of administration, the time of administration, the rate of excretion of the particular compound being administered, the duration of the treatment, other concurrently administered drugs, compounds and/or materials, the age, sex, weight, condition, general health and prior medical history of the patient (subject) being treated, and like factors well known in the medical arts.
  • the pharmaceutical compositions of the present invention can contain additives such as, for example, fillers, antioxidants, dispersants, emulsifiers, defoamers, flavors, preservatives, solubilizers or colorants. They can also contain more than one compound of formula 1 or their pharmaceutically acceptable salts. Furthermore, in addition to at least one compound of formula 1 or its pharmaceutically acceptable salt, the pharmaceutical compositions can also contain one or more other therapeutically or prophylactically active agents.
  • the present invention also encompasses within its scope use of a compound of formula 1 or its pharmaceutically acceptable salt in combination with other therapeutically active agents.
  • the compound of formula 1 or its pharmaceutically acceptable salt can be administered either simultaneously or sequentially in combination with the further therapeutically active agents.
  • the therapeutically active agents that can be used in combination with one or more compounds of formula I or its pharmaceutically acceptable salt can be selected from: CB1 receptor antagonists such as AM-6545 (National Inst. Alcohol Abuse Alcoholism, Northeastern University) LY-320135 (Lilly), Otenabant (Pfizer) and Rosonabant (Esteve); anti-inflammatory agents such as COX-2 inhibitors (e.g., VioxxTM, CelebrexTM and BextraTM); non-selective anti-inflammatory agents (ibuprofen, naproxen), acetaminophen, and steroids such as prednisolone, and budesonide; serotonin reuptake inhibitors (SSRIs, also known as serotonin boosters), such as CipramilTM or CelexaTM (citalopram), EffexorTM (venlafaxine HCI), ElavilTM (amitriptyline), fluvoxamine maleate, Lexapro ® (escitalopram o
  • the reaction mixture was quenched with water, extracted with dichloromethane, washed with water and brine, dried (anhydrous Na 2 SO 4 ) and concentrated.
  • the crude material was purified by column chromatography (silica gel, 0 - 1 1 % MeOH in dichloromethane) to obtain the title compound.
  • the compound of example 7 was prepared analogous to the compound of example 4, using the procedure described for the preparation of the compound of example 4, wherein, 2,4-dichlorophenylhydrazine hydrochloride was replaced with 2- chlorophenylhydrazine hydrochloride.
  • Triethylamine (1 .028 g, 7.38 mmol) was added, followed by cyclopropanamine or its hydrochloride (8.0 equivalents), and the mixture was stirred at room temperature for 14 h.
  • the reaction mixture was quenched with water, extracted with dichloromethane, washed with water and brine, dried (anhydrous Na 2 SO 4 ) and concentrated.
  • the crude material obtained was purified by column chromatography (silica gel, 0 - 10 % MeOH in dichloromethane) to obtain the title compound.
  • the compound of example 1 5 was prepared analogous to the compound of example 1 1 , using the procedure comprised in preparation of the compound of example 1 1 , wherein, 2,4-dichlorophenylhydrazine hydrochloride was replaced with 2- chlorophenylhydrazine hydrochloride.
  • the compound of example 16 was prepared analogous to the compound of example 15, using the procedure comprised in the preparation of the compound of example 15, wherein 4-aminothiomorpholine 1 ,1 -dioxide was replaced with cyclohexyl amine.
  • the compound of example 17 was prepared analogous to the compound of example 12, using the procedure comprised in the preparation of the compound of example 12, wherein cyclopropanamine was replaced with methanamine.
  • the compound of example 18 was prepared analogous to the compound of example 13, using the procedure comprised in the preparation of the compound of example 13, wherein cyclopropanamine was replaced with ethanamine.
  • the compound of example 19 was prepared analogous to the compound of example 15, using the procedure comprised in the preparation of the compound of example 15, wherein cyclopropanamine was replaced with ethanamine.
  • the sodium salt sodium (Z)-1 -ethoxy-4-(4-methoxyphenyl)-1 ,4-dioxobut-2-en-2- olate [synthesized as described in European Journal of Medicinal Chemistry 45 (2010) 4720-4725] (4.75 g, 19.45 mmol) was suspended in ethanol and (2- methoxyphenyl)hydrazine hydrochloride (3.74 g, 21 .39 mmol) was added. The slurry was refluxed for 16 h. After evaporation of solvent in vacuum, the crude solid was dissolved in acetic acid and refluxed for 18 h. The mixture was allowed to cool and then poured over ice.
  • Compound of example 41 was prepared by the deprotection of the t-butyloxy carbonyl group of the compound of example 40 with dioxane-HCI.
  • the compound of example 42 was prepared analogous to the compound of example 13, using the procedure comprised in preparation of the compound of example 13, wherein, 2,4-dichlorophenylhydrazine hydrochloride was replaced with 2- chlorophenylhydrazine hydrochloride.
  • the compound of example 68 was prepared analogous to the compound of example 51 , using the procedure comprised in the preparation of the compound of example 51 , wherein ethyl 5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboxylate was replaced with 5-(4-chlorophenyl)-1 -(2-chlorophenyl)-1 H-pyrazole-3- carboxylate.
  • the compound of example 69 was prepared analogous to the compound of example 52, using the procedure comprised in the preparation of the compound of example 52, wherein ethyl 5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboxylate was replaced with 5-(4-chlorophenyl)-1 -(2-chlorophenyl)-1 H-pyrazole-3- carboxylate.
  • the compound of example 70 was prepared analogous to the compound of example 53, using the procedure comprised in the preparation of the compound of example 53, wherein ethyl 5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboxylate was replaced with 5-(4-chlorophenyl)-1 -(2-chlorophenyl)-1 H-pyrazole-3- carboxylate.
  • the compound of example 71 was prepared analogous to the compound of example 54, using the procedure comprised in the preparation of the compound of example 54, wherein ethyl 5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboxylate was replaced with 5-(4-chlorophenyl)-1 -(2-chlorophenyl)-1 H-pyrazole-3- carboxylate.
  • the compound of example 72 was prepared analogous to the compound of example 55, using the procedure comprised in the preparation of the compound of example 55, wherein ethyl 5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboxylate was replaced with 5-(4-chlorophenyl)-1 -(2-chlorophenyl)-1 H-pyrazole-3- carboxylate.
  • the compound of example 73 was prepared analogous to the compound of example 56, using the procedure comprised in the preparation of the compound of example 56, wherein ethyl 5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboxylate was replaced with 5-(4-chlorophenyl)-1 -(2-chlorophenyl)-1 H-pyrazole-3- carboxylate.
  • the compound of example 74 was prepared analogous to the compound of example 59, using the procedure comprised in the preparation of the compound of example 59, wherein ethyl 5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboxylate was replaced with 5-(4-chlorophenyl)-1 -(2-chlorophenyl)-1 H-pyrazole-3- carboxylate.
  • the compound of example 76 was prepared analogous to the compound of example 61 , using the procedure comprised in the preparation of the compound of example 61 , wherein ethyl 5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboxylate was replaced with 5-(4-chlorophenyl)-1 -(2-chlorophenyl)-1 H-pyrazole-3- carboxylate.
  • the compound of example 77 was prepared analogous to the compound of example 62, using the procedure comprised in the preparation of the compound of example 62, wherein ethyl 5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboxylate was replaced with 5-(4-chlorophenyl)-1 -(2-chlorophenyl)-1 H-pyrazole-3- carboxylate.
  • the compound of example 78 was prepared analogous to the compound of example 76, using the procedure comprised in the preparation of the compound of example 76, wherein (S)-2-aminopropanamide was replaced with (S)-2-amino-3- methylbutanamide.
  • the compound of example 79 was prepared analogous to the compound of example 64, using the procedure comprised in the preparation of the compound of example 64, wherein ethyl 5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboxylate was replaced with 5-(4-chlorophenyl)-1 -(2-chlorophenyl)-1 H-pyrazole-3- carboxylate.
  • the compound of example 82 was prepared by the deprotection of the t-butyl oxy carbonyl group of the compound of example 81 using dioxane-HCI.
  • the compound of example 83 was prepared by the deprotection of the t-butyl oxy carbonyl group of the compound of example 58 using dioxane-HCI.
  • the compound of example 91 was prepared analogous to the compound of example 80, using the procedure comprised in the preparation of the compound of example 80, wherein ethyl 5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboxylate was replaced with 5-(4-chlorophenyl)-1 -(2-chlorophenyl)-1 H-pyrazole-3- carboxylate.

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Abstract

The present invention relates to compounds of formula 1, or isotopic forms, stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, polymorphs, prodrugs, S-oxides or N-oxides thereof, and processes for their preparation. The invention further relates to pharmaceutical compositions containing the compounds; and use of the compounds of formula 1 and the pharmaceutical compositions comprising the compounds in the treatment of diseases or disorders mediated by cannabinoid 1 (CB1) receptors.

Description

SUBSTITUTED PYRAZOLE COMPOUNDS AS CB1 RECEPTOR ANTAGONISTS
AND USES THEREOF
FIELD OF THE INVENTION
The present invention relates to substituted pyrazole compounds (the compounds of formula 1 as described herein), processes for their preparation, pharmaceutical compositions comprising the compounds of formula 1 , their use as cannabinoid 1 (CB1 ) receptor antagonists and methods of using said compounds in the treatment of diseases mediated by CB1 receptors (CB1 R).
BACKGROUND OF THE INVENTION
Endocannabinoid system (ECS) is a unique neuromodulatory system in mammalian physiology which is primarily responsible for maintaining homeostasis in all body systems including the central and peripheral nervous system, all organ systems, somatic tissues, metabolic systems and the immune system (G. Marsicano et al., J. Endocrinol. Invest, 2006, 29, 27-46). The endocannabinoid system consists of transporters, endocannabinoids, enzymes involved in the synthesis and degradation of endocannabinoids and G protein-coupled receptors. To date, two different G protein- coupled cannabinoid (CB) receptors namely cannabinoid 1 (CB1 ) receptor and cannabinoid 2 (CB2) receptor, have been identified. The CB1 receptor is prominently expressed in the central nervous system (CNS) and peripheral tissues, including thyroid gland, adrenal gland, reproductive organs, adipose tissue, liver, muscle, pancreas and gastrointestinal tract. The CB2 receptor is mainly expressed in immune cells and hematopoietic cells and to a lesser extent in the myocardium, coronary endothelial cells and smooth muscle cells. CB1 receptor plays a pivotal role in regulating energy balance, food intake, and metabolism of lipids and glucose. It has been observed that exogenous cannabinoids and endocannabinoids increase food intake and promote weight gain in animals by activating CB1 receptor (Stefan Engeli et al., Diabetes, 2005, 54, 2838-2843).
From among the diseases or disorders implicated by CB1 receptor, obesity is the one which is most prevalent globally. In the United States (the US) alone, obesity is estimated to cause 18 % of deaths per year. WHO has estimated that, yearly, obesity affects at least about 400 million people worldwide. An over activated endocannabinoid system is known to contribute to obesity through central and peripheral mechanism, thereby having a role in obesity and associated disorders. A CB1 receptor knockout mouse has shown resistance to diet induced obesity. It has also been observed that blockage of CB1 receptor with a CB1 receptor antagonist or a CB1 receptor inverse agonist reduces food intake and body weight in rodents (Stefan Engeli et al., Diabetes, 2005, 54, 2838-2843). Inhibition of central and peripheral CB1 receptor would therefore be a useful approach in the treatment of obesity and related metabolic disorders.
Type 2 diabetes is a serious life-threatening disorder with growing prevalence in both adult and childhood populations. According to American Medical Association Type 2 diabetes is currently the 7th leading cause of death in the US. It has been reported that endocannabinoid levels are enhanced in the plasma and adipose tissue of type 2 diabetic patients. Studies on CB1 receptors revealed that activation of the CB1 receptor with a CB1 receptor agonist reduces glucose tolerance and insulin release from pancreatic beta cells, whereas CB1 receptor antagonists reverse this effect by elevating the levels of adiponectin protein.
It has further been reported that CB1 receptors undergo increased expression during inflammatory conditions. CB1 receptor antagonists have demonstrated antiinflammatory effect in rodent models of inflammatory disease. Studies have also reported a significant reduction in LPS-induced production of pro-inflammatory cytokine TNF-a in animals treated with a CB1 receptor antagonist (Stephen J et al. Journal of Pharmacology and Experimental Therapeutics, 2010, 333, 445-453).
The CB1 receptor also plays a pivotal role in cardiovascular regulation. Recently it has been reported that CB1 receptor blockage improves systolic and diastolic heart function, decreases cardiac collagen and hydroxyproline content (Svetiana Slavic et al., J. Mol. Med., 2013, 91 , 81 1-823). Inhibition of the CB1 receptor with a CB1 receptor antagonist exerts cardio-protective effect in rats with metabolic syndrome. This renders inhibition of the CB1 receptor as a potential pharmacological tool in the treatment of cardiovascular diseases.
CB1 receptor antagonists have been reported to have utility in the treatment of several other diseases and disorders such as cancer, atherosclerosis, psychosis, schizophrenia, epilepsy, Parkinson's disease, amnesia, cognitive disorders, dyslipidemias, dyslipoproteinemia, hepatic lipidosis, liver fibrosis, cirrhosis, fatty liver disease, neuroinflammatory disorders, gastrointestinal disorders, urinary disorders and infertility disorders. Rimonabant, a central CB1 receptor antagonist, which is selective for CB1 receptor, was the first drug that was developed for therapeutic use. Rimonabant was developed for treating obesity and other related disorders. However, it was withdrawn from the European markets, and was denied FDA approval in the US due to its CNS- related side effects including anxiety, depression and suicidal ideation. Subsequently developed compounds namely ibipinabant, taranabant and otenabant, which belonged to the same class as rimonabant, were also terminated due to similar side effects. Failure with central CB1 receptor antagonists has diverted the attention of researchers towards peripheral CB1 receptor antagonists. In diet-induced obese mice, use of a peripheral CB1 receptor antagonist has shown weight loss and significant reduction in insulin and triglyceride level. Studies on the peripheral CB1 receptor have led to selection of the peripheral CB1 receptor as a promising molecular target for the treatment of diseases or disorders mediated by CB1 receptor. Currently, TM38837 (7TM Pharma), a peripheral CB1 receptor antagonist, is in phase I clinical development for the treatment of obesity and type 2 diabetes.
PCT patent publication WO2003026647A1 discloses novel 4,5-dihydro-1 H- pyrazole derivatives having CB1 antagonistic activity for the treatment of diseases or disorders of the cannabinoid system.
PCT patent publication WO2009130234A1 discloses (5R)-1 ,5-diaryl-4,5-dihydro- 1 H-pyrazole-s-carboxamidine derivatives for the treatment of psychiatric and neurological disorders involving cannabinoid receptors.
Mark D. Black et al; Psychopharmacology, 201 1 , 215, 149-163, discloses AVE1625, a cannabinoid CB1 receptor antagonist, as a co-treatment with antipsychotics for schizophrenia.
Thus, it is evident from the above discussion that since the CB1 receptor is implicated in obesity and associated diseases or disorders as well as several other diseases and conditions, it is highly desirable to find effective and highly selective peripheral CB1 receptor blockers with limited or no central nervous system related adverse side effects.
SUMMARY OF THE INVENTION
In one aspect, the present invention, relates to a compound of formula 1 (as described herein), or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a polymorph, a prodrug, S-oxide or N-oxide thereof. According to yet another aspect of the present invention, there are provided processes for the preparation of the compounds of formula 1 , or pharmaceutically acceptable salts thereof.
According to another aspect of the present invention, there is provided a pharmaceutical composition comprising one or more compounds of formula 1 , or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof; and at least one pharmaceutically acceptable carrier or excipient.
According to a further aspect of the present invention, there is provided a compound of formula 1 , or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof; for use as a CB1 receptor (CB1 R) antagonist.
According to a yet another aspect of the present invention, there is provided a compound of formula 1 , or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof; for use in the treatment of a disease or a disorder mediated by CB1 receptors (CB1 R).
According to a further aspect of the present invention, there is provided a method for the treatment of a disease or disorder mediated by CB1 receptor, comprising administering to a subject in need thereof; a therapeutically effective amount of the compound of formula 1 , or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof.
According to yet another aspect of the present invention, there is provided use of a compound of formula 1 , or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof; for the manufacture of a medicament for the treatment of a disease or a disorder mediated by CB1 receptors.
In a further aspect, the present invention relates to use of a compound of formula 1 , or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof; in combination with at least one further therapeutically active agent for the treatment of a disease or a disorder mediated by CB1 receptors.
One or more further aspects of the present invention are discussed in detail herein below. These and other aspects and objectives of the present invention will be apparent to those skilled in the art from the following description. DETAILED DESCRIPTION OF THE INVENTION
In a first aspect, the present invention relates to a compound of formula 1
Figure imgf000006_0001
Formula 1
wherein,
Ri and R2 are independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, (CrC8)-alkyl, (CrC8)-alkoxy, halo(CrC8)-alkyl, (C3-Ci2)-cycloalkyl, C(O)Ra, CO2Ra and NRaRb;
X is hydrogen, halogen, hydroxy, (Ci-C8)-alkyl, halo(CrC8)-alkyl, or (Ci-C8)-alkoxy; Q is:
Figure imgf000006_0002
wherein (*) indicates the point of attachment;
R3 is hydrogen, cyano, (CrC8)-alkyl, halo(CrC8)-alkyl, (C3-Ci2)-cycloalkyl, heterocyclyl, heteroaryl, C(O)Ra, CO2Ra, CONRaRb, S(O)qRc or S(O)qNRaRb;
R4 is cyano, (Ci-C8)-alkyl, halo(Ci-C8)-alkyl, (C3-Ci2)-cycloalkyl, (C5-C8)-cycloalkenyl, (C6-Ci4)-aryl, (C6-Ci4)ar-(Ci-C8)-alkyl, heterocyclyl, heteroaryl, CORa, CO2Ra, CONRaRb, S(O)qRc or S(O)qNRaRb;
R5 is hydrogen, cyano, (d-C8)-alkyl, halo(CrC8)-alkyl, (C3-d2)-cycloalkyl, (C5-C8)- cycloalkenyl, (C6-C )-aryl, (C6-Ci4)ar-(Ci-C8)-alkyl, heterocyclyl, heteroaryl, CORa, CO2Ra, CONRaRb, S(O)qRc or S(O)qNRaRb; or
R3 and R5 can join together to form a 3-12 membered saturated or unsaturated monocyclic or bicyclic ring system, optionally containing one to three heteroatoms independently selected from the group consisting of O, N and S; or R4 and R5 can join together to form a 3-12 membered saturated or unsaturated, monocyclic or bicyclic ring system including spiro ring systems, optionally containing one to three heteroatoms independently selected from the group consisting of O, N and S;
wherein each of the said 3-12 membered rings can be unsubstituted or substituted with one or more groups selected from the group consisting of halogen, hydroxy, oxo, cyano, (C C8)-alkyl, halo(C C8)-alkyl, (C C8)-alkoxy, halo(C C8)-alkoxy, (C3-Ci2)- cycloalkyl-(Rd)o-2, O-(C3-Ci2)-cycloalkyl-(Rd)0-2, (C6-Ci4)-aryl-(Rd)0-2, O-(C6-Ci4)-aryl- (Rd)o-2, heterocyclyl-(Rd)o-2, O-heterocyclyl-(Rd)0-2, heteroaryl-(Rd)0-2, C(O)Ra, CO2Ra, C(O)NRaRb, NRaRb, N RaC(O)Rb, S(O)qRc and S(O)qNRaRb;
Ra and Rb are independently selected from the group consisting of hydrogen, hydroxy, (CrCs)-alkyl, (C C8)-alkoxy, (C3-Ci2)-cycloalkyl, (C5-C8)-cycloalkenyl, (C6-Ci4)-aryl, heterocyclyl and heteroaryl; or
Ra and Rb together with the nitrogen atom can form a 3-12 membered ring system, optionally containing one to three heteroatoms independently selected from the group consisting of O, N and S;
Rc is (CrCs)-alkyl, (C3-Ci2)-cycloalkyl, (C6-Ci4)-aryl, (C6-Ci4)ar-(Ci-C8)-alkyl, heterocyclyl or heteroaryl;
m and n are integers selected from 0, 1 or 2;
q is an integer 1 or 2; wherein each of the (CrC8)-alkyl and (CrC8)-alkoxy group can be unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, oxo, cyano, (CrC8)-alkoxy, halo(CrC8)-alkoxy, (C3-C-i2)-cycloalkyl- (Rd)o-2, O-(C3-Ci2)-cycloalkyl-(Rd)o-2, (C6-Ci4)-aryl-(Rd)0-2, O-(C6-Ci4)-aryl-(Rd)0-2, heterocyclyl-(Rd)o-2, O-heterocyclyl-(Rd)0-2, heteroaryl-(Rd)0-2, C(O)Ra, OC(O)Ra, CO2Ra, C(O)NRaRb, NRaRb, N RaC(O)Rb, NRaC(O)NRaRb, S(O)qRc and S(O)qNRaRb;
each of the (C3-Ci2)-cycloalkyl, (C5-C8)-cycloalkenyl and (C6-Ci4)-aryl can be unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, oxo, cyano, (CrC8)-alkyl, halo(CrC8)-alkyl, (d- C8)-alkoxy, halo(CrC8)-alkoxy, (C3-Ci2)-cycloalkyl-(Rd)0-2, O-(C3-Ci2)-cycloalkyl-(Rd)0-2, (C6-Ci4)-aryl-(Rd)o-2. O-(C6-Ci4)-aryl-(Rd)0-2, heterocyclyl-(Rd)0-2, O-heterocyclyl-(Rd)0-2, heteroaryl-(Rd)0-2, C(O)Ra, OC(O)Ra, CO2Ra, C(O)NRaRb, NRaRb, NRaC(O)Rb, NRaC(O)N RaRb, S(O)qRc and S(O)qNRaRb; the heterocyclyl is a 3-12 membered saturated or partially unsaturated, monocyclic or bicyclic ring system, including spiro ring systems, containing one to four heteroatoms independently selected from the group consisting of O, N and S; wherein the heterocyclyl can be unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, oxo, cyano, (CrC8)-alkyl, halo(C C8)-alkyl, (C C8)-alkoxy, halo(C C8)-alkoxy, (C3-C12)-cycloalkyl-(Rd)o-2, O-(C3- Ci2)-cycloalkyl-(Rd)o-2, (C6-Ci4)-aryl-(Rd)o-2, O-(C6-Ci4)-aryl-(Rd)o-2, heterocyclyl-(Rd)o-2, O-heterocyclyl-(Rd)o-2, heteroaryl-(Rd)0-2, C(O)Ra, OC(O)Ra, CO2Ra, C(O)NRaRb, NRaRb, NRaC(O)Rb, NRaC(O)NRaRb, S(O)qRc and S(O)qNRaRb;
the heteroaryl is a 5-10 membered monocyclic or bicyclic aromatic ring system containing one to four heteroatoms independently selected from O, N or S, wherein the heteroaryl can be unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, oxo, cyano, (CrC8)-alkyl, halo(C C8)-alkyl, (C C8)-alkoxy, halo(C C8)-alkoxy, (C3-C12)-cycloalkyl-(Rd)o-2, O-(C3- Ci2)-cycloalkyl-(Rd)o-2, (C6-Ci4)-aryl-(Rd)0-2, O-(C6-Ci4)-aryl-(Rd)0-2, heterocyclyl-(Rd)0-2, O-heterocyclyl-(Rd)o-2, heteroaryl-(Rd)0-2, C(O)Ra, OC(O)Ra, CO2Ra, C(O)NRaRb, NRaRb, NRaC(O)Rb, NRaC(O)NRaRb, S(O)qRc and S(O)qNRaRb; and
Rd at each occurrence is independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, (CrC8)-alkyl, halo(CrC8)alkyl, (C3-Ci2)-cycloalkyl, (C6-C-|4)- aryl, (C6-C14)-ar-(C C8)-alkyl, heteroaryl, heterocyclyl, CORa, CO2Ra, CONRaRb, CONRaNRaRb, S(O)qRc, S(O)qNRaRb, NRaRb, NRaC(O)Rb, NRaC(O)NRaRb, NRaC(O)ORb and NRaS(O)qNRaRb;
or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.
Definitions
Unless otherwise indicated, the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein and the appended claims. These definitions should not be interpreted in the literal sense as they are not general definitions and are relevant only for this application.
It will be understood that "substitution," "substituted" or "substituted with" means that one or more hydrogens of the specified moiety are replaced with a suitable substituent and includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and results in a stable compound.
The terms "a", "an" and "the" refers to "one or more" when used in the subject specification, including the claims. Thus, for example, reference to "a compound" may include a plurality of such compounds, or reference to "a disease" or "a condition" includes a plurality of diseases or disorders.
It should also be noted that the term "or" is generally employed in its sense including "and/or" unless the content clearly dictates otherwise.
Use of "(s)" as part of a term, includes reference to the term singly or in plurality, e.g. the term compound(s) may indicate a single compound or more compounds.
The term "independently" when used in the context of selection of substituents for a variable, it means that where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different.
As used herein, the term "alkyl" or "(CrC8)-alkyl" whether used alone or as part of a substituent group, refers to the radical of saturated aliphatic groups, including straight or branched-chain alkyl groups. If the number of carbon atoms is not specified, "alkyl" refers to alkyl group having 1 -8 (both inclusive) carbon atoms. Accordingly, a straight-chain or branched chain alkyl has eight or fewer carbon atoms in its backbone, for instance, CrC8 for straight- chain and C3-C8 for branched chain. Representative examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, iso-butyl, sec-butyl, n-pentyl, isopentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl, isohexyl, 2-hexyl, 3-hexyl and the like.
Furthermore, unless stated otherwise, the alkyl groups can be unsubstituted or substituted with one or more substituents. A substituted alkyl refers to a (CrC8)-alkyl substituted preferably with 1 -7 groups, more preferably 1 -3 groups independently selected from the group consisting of halogen, hydroxy, oxo, cyano, (CrC8)-alkoxy, halo(C C8)-alkoxy, (C3-C12)-cycloalkyl-(Rd)0-2, O-(C3-C12)-cycloalkyl-(Rd)0-2, (C6-C14)- aryl-(Rd)o-2, O-(C6-Ci4)-aryl-(Rd)0-2, heterocyclyl-(Rd)0-2, O-heterocyclyl-(Rd)0-2, heteroaryl-(Rd)0-2, C(O)Ra, OC(O)Ra, CO2Ra, C(O)NRaRb, NRaRb, NRaC(O)Rb, NRaC(O)NRaRb, S(O)qRc and S(O)qNRaRb; wherein Rd at each occurrence is independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, (C C8)-alkyl, halo(C C8)alkyl, (C3-C12)-cycloalkyl, (C6-C14)-aryl, (C6-C14)-ar-(C C8)-alkyl, heteroaryl, heterocyclyl, CORa, CO2Ra, CONRaRb, CONRaNRaRb, S(O)qRc, S(O)qNRaRb, NRaRb, NRaC(O)Rb, NRaC(O)NRaRb, NRaC(O)ORb and NRaS(O)qNRaRb; q is an integer 1 or 2; Ra and Rb are independently selected from the group consisting of hydrogen, hydroxy, (CrC8)-alkyl, (CrC8)-alkoxy, (C3-Ci2)-cycloalkyl, (C5-C8)- cycloalkenyl, (C6-Ci4)-aryl, heterocyclyl and heteroaryl; or Ra and Rb together with the nitrogen atom can form 3 to 12 membered saturated or unsaturated ring, optionally containing one to three identical or different heteroatom selected from the group consisting of O, N and S; and Rc is (CrC8)-alkyl, (C3-Ci2)-cycloalkyl, (C6-Ci4)-aryl, (C6- C )ar-(Ci-C8)-alkyl, heterocyclyl or heteroaryl. Representative examples of substituted alkyls include, but are not limited to, trifluoromethyl, hydroxymethyl, hydroxyethyl, 1 - aminoethyl, benzyl, N-morpholino methyl, N-indolomethyl, and N-piperidinylmethyl.
The term "halogen" or "halo" refers to a fluorine, chlorine, bromine, or iodine atom.
When the alkyl group is substituted with one or more halogens, it is specifically referred to as "halo(C C8)-alkyl" or "haloalkyl". A monohalo(C C8)-alkyl radical, for example, can have a chlorine, bromine, iodine or fluorine atom. Dihalo and polyhalo(Cr C8)-alkyl radicals may have two or more of the same or different halogen atoms. Representative examples of halo(CrC8)-alkyl include, but are not limited to, chloromethyl, dichloromethyl, trichloromethyl, dichloroethyl, dichloropropyl, fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl or the like groups.
As used herein, the term "alkoxy" or "(CrC8)-alkoxy" refers to a (CrC8)-alkyl having an oxygen radical attached thereto. The terms "(CrC8)-alkoxy" or O-(CrC6)alkyl wherever used in this specification have the same meaning. Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy and t-butoxy.
As used herein, the term "halo(CrC6)alkoxy" or "haloalkoxy" refers to the radical wherein one or more of the hydrogen atoms of the alkoxy group are substituted with one or more halogens. Representative examples of "haloalkoxy" or "halo(CrC6)alkoxy" groups include, but not limited to, difluoromethoxy (OCHF2), trifluoromethoxy (OCF3) or trifluorethoxy (OCH2CF3).
An alkoxy group can be unsubstituted or substituted with one or more substituents. A substituted alkoxy refers to an (CrC8)-alkoxy group in which the alkyl is substituted with one or more groups as explained in the definition of 'substituted alkyl' herein above. Representative examples of substituted (CrC8)-alkoxy include, but are not limited to, 2-cyanoethoxy and benzyloxy group. A benzyloxy group refers to a benzyl having an oxygen radical attached thereto.
As used herein, the term "cycloalkyl" or "(C3-Ci2)-cycloalkyl" whether used alone or as part of a substituent group, refers to a saturated cyclic hydrocarbon radical including 1 , 2 or 3 rings and including a total of 3-12 carbon atoms forming the rings. The term cycloalkyl includes bridged, fused and spiro ring systems. As used herein, (C3-Ci2)-cycloalkyl refers to a cycloalkyl group having 3-12 (both inclusive) carbon atoms. Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, norbornyl, bicyclo[2.1 .0]pentane, bicyclo[2.2.1 ]heptyl, bicyclo[2.2.1 ]hept-2-ene, spiro[3.3]heptane and 1 ,2,3,3a-tetrahydropentalene.
The term "cycloalkenyl" or "(Cs-CsJ-cycloalkenyl" refers to a non-aromatic monocyclic carbocyclic ring having from 5 to 8 carbon atoms and up to 3 carbon-carbon double bonds. Representative examples of cycloalkenyl include, but are not limited to, cyclopentenyl and cyclohexenyl.
Unless stated otherwise, the "cycloalkyl" and "cycloalkenyl" can be unsubstituted or substituted with 1 -7, preferably 1 -3 groups independently selected from the group consisting of halogen, hydroxy, oxo, cyano, (d-CsJ-alkyl, halo(CrC8)-alkyl, (d-Cs)- alkoxy, halo(CrC8)-alkoxy, (C3-C-i2)-cycloalkyl-(Rd)0-2, O-(C3-C-i2)-cycloalkyl-(Rd)0-2, (C6-Ci4)-aryl-(Rd)o-2, O-(C6-Ci4)-aryl-(Rd)0-2, heterocyclyl-(Rd)0-2, O-heterocyclyl-(Rd)0-2, heteroaryl-(Rd)0-2, C(0)Ra, OC(O)Ra, CO2Ra, C(O)NRaRb, NRaRb, NRaC(O)Rb, NRaC(O)NRaRb, S(O)qRc and S(O)qNRaRb; wherein Ra, Rb, Rc, Rd and q are as defined herein above.
The term "aryl" or "(C6-Ci4)-aryl" as used herein refers to monocyclic or polycyclic hydrocarbon groups having 6-14 ring carbon atoms in which the carbocyclic ring(s) present have a conjugated pi electron system. Representative examples of {CQ- C )-aryl residues include, but are not limited to, phenyl, naphthyl, fluorenyl or anthracenyl. Aryl groups can be unsubstituted or substituted with one or more substituents, for example 1 -5 substituents independently selected from the group consisting of halogen, hydroxy, oxo, cyano, (d-CsJ-alkyl, halo(Ci-C8)-alkyl, (d-Cs)- alkoxy, halo(d-C8)-alkoxy, (C3-Ci2)-cycloalkyl-(Rd)0-2, O-(C3-Ci2)-cycloalkyl-(Rd)0-2, (C6-Ci4)-aryl-(Rd)0-2, O-(C6-Ci4)-aryl-(Rd)0-2, heterocyclyl-(Rd)0-2, O-heterocyclyl-(Rd)0-2, heteroaryl-(Rd)0-2, C(O)Ra, OC(O)Ra, CO2Ra, C(O)NRaRb, NRaRb, NRaC(O)Rb, NRaC(O)NRaRb, S(O)qRc and S(O)qNRaRb; wherein Ra, Rb, Rc, Rd and q are as defined herein above. In monosubstituted phenyl, the substituent can be located in the 2- position, the 3-position or the 4-position. If the phenyl carries two substituents, they can be located in 2, 3-position, 2, 4-position, 2, 5-position, 2, 6-position, 3, 4-position or 3, 5- position. Representative examples of monosubstituted phenyl groups include, but are not limited to, 3-trifluoromethylphenyl, 4-chlorophenyl and 4-cyanophenyl.
Representative examples of disubstituted phenyl groups include, but are not limited to,
3, 5-difluorophenyl, and 3, 4-dimethoxyphenyl.
As used herein, the term "aryloxy" or "O-(C6-Ci4)-aryl" refers to an "(C6-Ci4)-aryl" group having an oxygen radical attached thereto. The aryl of aryloxy group may be unsubstituted or substituted as indicated in the definition of (C6-Ci4)-aryl herein above.
Representative examples of aryloxy groups include, but are not limited to, phenoxy, 4- chlorophenoxy, and 3, 4-dimethoxyphenoxy.
As used herein, the term "aralkyl" or "(C6-Ci4)ar-(Ci-C8)-alkyl" refers to an alkyl group substituted with an (C6-Ci4)-aryl group, wherein the terms alkyl and aryl are as defined above. Representative examples of aralkyl groups include (CH2)p-phenyl, wherein p is an integer selected from 1 -6, such as benzyl wherein p is 1 . The aryl of the
(C6-Ci4)-aralkyl group can be unsubstituted or substituted as indicated in the definition of aryl herein above.
The term "heteroatom" as used herein, includes nitrogen (N), oxygen (O) and sulfur (S). Any heteroatom with unsatisfied valency is assumed to have a hydrogen atom to satisfy the valency.
As used herein, the terms "heterocyclyl" or "heterocyclic" whether used alone is a 3-12 membered saturated or partially unsaturated, monocyclic or bicyclic ring system, including spiro ring systems, containing one to four heteroatoms independently selected from the group consisting of O, N and S. Representative examples of heterocyclyls include, but are not limited to, pyrrolyl, pyrrolidinyl, pyrazolyl, imidazolyl, pyrazinyl, piperazinyl, oxazolyl, oxadiazolyl, isoxazolyl, triaziolyl, thiazolyl, tetrazolyl, furyl, thienyl, purinyl, pyridinyl, pyridazinyl, pyrimidinyl, piperidyl, benzoxazolyl, benzothiazolyl, benzofuranyl, purinyl, benzimidazolyl, benzoxazolyl, indolyl, indazolyl, isoindolyl, isothiazolyl, isoquinolyl, isoquinolyl, morpholinyl, thiomorpholinyl, thiomorpholinyl-1 , 1 - dioxide, quinoxalinyl, quinolinyl and thiophenyl. The nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S, S- dioxide. Heterocyclyl having an aromatic ring containing heteroatoms are herein referred to by the customary term "heteroaryl". Within the context of the present invention and as used herein, the term "heteroaryl" refers to a 5-10 membered aromatic monocyclic or bicyclic ring system containing one to four heteroatoms independently selected from: nitrogen, sulphur and oxygen. Representative examples of heteroaryls include, but are not limited to, pyrrole, pyrazole, imidazole, pyrazine, furan, thiophene, oxazole, thiazole, benzimidazole, benzoxazole, benzothiazole, benzofuran, indole, indazole, isoindole, isoquinoline, isooxazole, triazine, purine, pyridine, quinoline, oxadiazole, thiene, pyridazine, pyrimidine, isothiazole, quinoxaline (benzopyrine) and tetrazole. The nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S, S-dioxide.
A heterocyclyl or heteroaryl group can be unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, oxo, cyano, (CrC8)-alkyl, halo(CrC8)-alkyl, (CrC8)-alkoxy, halo(CrC8)-alkoxy, (C3- Ci2)-cycloalkyl-(Rd)o-2, O-(C3-Ci2)-cycloalkyl-(Rd)0-2, (C6-Ci4)-aryl-(Rd)0-2, O-(C6-C )- aryl-(Rd)o-2, heterocyclyl-(Rd)o-2, O-heterocyclyl-(Rd)o-2, heteroaryl-(Rd)0-2, C(O)Ra, OC(O)Ra, CO2Ra, C(O)NRaRb, NRaRb, NRaC(O)Rb, NRaC(O)NRaRb, S(O)qRc and S(O)qNRaRb; wherein Ra, Rb, Rc, Rd and q are as defined herein above. The substituents can be present on either the ring carbon or the ring nitrogen atom(s). The substituents can be present at one or more positions provided that a stable molecule results.
As used herein, the term "carbonyl" or "oxo" whether used alone or as part of a substituent group, refers to a group of formula (=O).
Within the context of this present invention and as used herein the term "isotopic forms" or "isotopically labeled forms" is a general term used for isotopic forms of the compounds of formula 1 , wherein one or more atoms of the compounds of formula 1 are replaced by their respective isotopes. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the present invention. Representative examples of isotopes that can be incorporated into the compounds disclosed herein include, but are not limited to, isotopes of hydrogen such as 2H (deuterium or D) and 3H (tritium or T), carbon such as 11C, 13C and 14C, nitrogen such as 13N and 15N, oxygen such as 150, 17O and 18O, chlorine such as 36CI, fluorine such as 18F and sulphur such as 35S. Substitution with heavier isotopes, for example, replacing one or more key carbon-hydrogen bonds with carbon-deuterium bond may show certain therapeutic advantages, resulting from longer metabolism cycles, (e.g., increased in vivo half life or reduced dosage requirements), improved safety or greater effectiveness and hence, may be preferred in certain circumstances.
Representative examples of isotopic forms of the compounds of formula 1 can include, without limitation, deuterated compounds of formula 1 . The term "deuterated" as used herein, by itself or used to modify a compound or group, refers to replacement of one or more hydrogen atom(s), which is attached to carbon(s), with a deuterium atom. For example, the compounds of formula 1 can include in the definitions of one or more of its various variables, wherever applicable, deuterium, deuterated-alkyl, deuterated-alkoxy, deuterated-cycloalkyl, deuterated-heterocyclyl, deuterated-aryl, deuterated-heteroaryl and the like.
The term "deuterated-alkyl" refers to an (d-CsJ-alkyl group as defined herein, wherein at least one hydrogen atom bound to carbon is replaced by a deuterium, i.e., in a deuterated alkyl group, at least one carbon atom is bound to a deuterium. In a deuterated alkyl group, it is possible for a carbon atom to be bound to more than one deuterium; it is also possible that more than one carbon atom in the alkyl group is bound to a deuterium. Analogously, the term "deuterated" and the terms deuterated- heterocyclyl, deuterated-heteroaryl, deuterated-cycloalkyl, deuterated-aryl, deuterated- alkoxy each refer to the corresponding chemical moiety wherein at least one carbon is bound to a deuterium.
The term "pharmaceutically acceptable solvate(s)" or "solvate(s)" as used herein refers to an aggregate of a molecule (in the present invention, a compound of formula 1 or a pharmaceutically acceptable salt thereof) with one or more solvent molecules. Such solvents for the purpose of the invention may not interfere with the biological activity of the molecule. Preferably, the solvent used is a pharmaceutically acceptable solvent. Examples of suitable pharmaceutically acceptable solvents include, without limitation, water, ethanol and acetic acid. Preferably, the solvent used is water and the solvates obtained are referred to as hydrates. Examples for suitable solvates are the mono- or di-hydrates or alcoholates of the compounds of the present invention.
Within the context of the present invention and as used herein, the term
"stereoisomer" or "stereoisomeric form" is a general term used for all isomers of individual compounds (in the present invention, a compound of formula 1 or a pharmaceutically acceptable salt thereof) that differ only in the orientation of their atoms in space. The term stereoisomer includes mirror image isomers (enantiomers), mixtures of mirror image isomers (racemates, racemic mixtures), geometric (cis/trans or E/Z) isomers, and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereoisomers).
The term "tautomer" refers to the coexistence of two (or more) compounds that differ from each other only in the position of one (or more) mobile atoms and in electron distribution, for example, keto-enol tautomers or amide-imidic acid tautomers.
As used herein, the term "pharmaceutically acceptable" means that the carrier, diluent, excipients, and/or salt must be compatible with the other ingredients of the formulation (composition), and not deleterious to the recipient thereof.
The term "pharmaceutically acceptable salts" or "pharmaceutically acceptable salt" as used herein includes salts of the active compound i.e. the compound of formula 1 , which retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects; and are prepared with suitable acids or bases, depending on the particular substituents found on the compounds described herein.
Within the context of the present invention and as used herein the term
"polymorph(s)" or "pharmaceutically acceptable polymorph" or "polymorphic form" refers to crystals of the same compound (in the present invention, a compound of formula 1 ) that differs only in the arrangement and/or conformation of the molecule in the crystal lattice.
Within the context of the present invention and as used herein, "N-oxide" refers to an oxide of the nitrogen atom of a nitrogen-containing heteroaryl or heterocycle. N- oxide can be formed in the presence of an oxidizing agent such as m-chloro-perbenzoic acid or hydrogen peroxide. N-oxide refers to an amine oxide, also known as amine-N- oxide, and is a chemical compound that contains N->O bond.
Within the context of the present invention and as used herein "S-oxide" refers to the oxide of the sulfur atom (S-oxide) or dioxide of the sulfur atom (S, S-dioxide) of a sulfur-containing heteroaryl or heterocycle. S-oxide and S, S-dioxides can be formed in the presence of an oxidizing agent such as m-chloro-perbenzoic acid or oxone (potassium peroxymonosulfate).
Within the context of the present invention and as used herein, "a prodrug" or
"prodrugs" refers to a compound, which is a derivative of a parent compound (in the present invention, a compound of formula 1 or a pharmaceutically acceptable salt thereof), which following administration, releases the parent compound in vivo via a chemical or physiological process, e.g., a prodrug on being brought to the physiological pH or through enzyme action is converted to the parent compound.
Within the context of the present invention and as used herein interchangeably throughout this application, the terms "compound of formula 1 ", "compounds of formula 1 ", and "compounds of the present invention" include all the isotopic forms, stereoisomeric and tautomeric forms and mixtures thereof in all ratios, and the pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, pharmaceutically acceptable polymorphs, N- oxides and S-oxides thereof. The compound(s) of the present invention can also be referred to herein as "the active compound" or "the active ingredient".
The term "CB1 receptor antagonist" refers to a compound which is capable of binding to the CB1 receptor (CB1 R), or in its vicinity, and lacks any substantial ability to activate the receptor itself. By binding to the CB1 receptor, a CB1 receptor antagonist prevents or reduces the functional activation or occupation of the receptor by a CB1 receptor agonist such as for example the endogenous agonist, N- Arachidonylethanolamine (anandamide).
The term "CB1 receptor inverse agonist" refers to a compound which binds to the CB1 receptor and exerts the opposite pharmacological effect as a CB1 receptor agonist does upon binding to the CB1 receptor.
The term "disease or disorder mediated by CB1 receptor(s)" refers to a disease or condition which is mediated by CB1 receptor signaling activity.
The disease or disorder mediated by CB1 receptors can be selected from gastrointestinal disorder; inflammatory disease or disorder; cardiovascular disease; cancer; obesity and metabolic disorder; osteoporosis; nephropathy; glaucoma; psychiatric disorder, neurological disorder; autoimmune hepatitis and encephalitis; pain; reproductive disorder; skin inflammatory disease or fibrotic disease.
The term, "therapeutically effective amount" as used herein means an amount of the compound of formula 1 or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof or a composition comprising a compound of formula 1 , or a pharmaceutically acceptable salt thereof, effective in producing the desired therapeutic response in a particular patient (subject) suffering from a disease or disorder to be treated. Particularly, the term "therapeutically effective amount" includes the amount of the compound of the present invention, when administered, that induces a positive modification in the condition (a disease or a disorder) to be treated or is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disease or disorder being treated in a patient (subject). In respect of the therapeutic amount of the compound, consideration is also given that the amount of the compound used for the treatment of a subject is low enough to avoid undue or severe side effects, within the scope of sound medical judgment. The therapeutically effective amount of the compound or composition will vary with the particular condition being treated, the age and physical condition of the patient (subject in need of the treatment), the severity of the condition being treated/prevented, the duration of the treatment, the nature of concurrent therapy, the specific compound or composition employed and the particular pharmaceutically acceptable carrier utilized.
As used herein, the term "pharmaceutically acceptable carrier" refers to a material that is non-toxic, inert, solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type which is compatible with a subject, preferably a mammal, more preferably a human, and is suitable for delivering an active agent (in the present invention, a compound of formula 1 or a pharmaceutically acceptable salt thereof or any other form recited herein), to the target site without adversely affecting activity of the agent.
The term "subject" as used herein refers to an animal, preferably a mammal, and most preferably a human. The term "mammal" as used herein refers to warm-blooded vertebrate animals of the class mammalia, including humans, characterized by a covering of hair on the skin and, in the female, milk-producing mammary glands for nourishing the young. The term mammal includes animals such as cat, dog, rabbit, bear, fox, wolf, monkey, deer, mouse, pig as well as human. The term "subject" may be used interchangeably with the term patient. In the context of the present invention the phrase "a subject in need thereof" means a subject in need of the treatment for the disease or disorder that is mediated by CB1 receptors. Alternatively, the phrase "a subject in need thereof" means a subject (patient) diagnosed having a disease or disorder that is mediated by CB1 receptors.
As used herein, the terms "treatment" "treat" and "therapy" and the like; refer to alleviate, slow the progression, attenuation or cure of existing disease or condition (e.g. obesity and metabolic disorder). Treatment also includes treating, preventing development of, or alleviating to some extent, one or more of the symptoms of the disease or condition. Embodiments
The invention encompasses all the compounds described by the formula 1 without limitation, however, for the purposes of further illustrations, preferred aspects and elements of the invention are discussed herein in the form of the following embodiments.
In an embodiment, the present invention relates to a compound of formula 1 : wherein,
Ri and R2 are halogen;
Q is:
Figure imgf000018_0001
wherein * indicates the point of attachment; and m, n, X, R3, R4, and R5 are as defined; or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.
In an embodiment, the present invention relates to a compound of formula 1 : wherein,
Ri and R2 are halogen;
Q is:
Figure imgf000018_0002
wherein * indicates the point of attachment; and m, n, X, R3, R4, and R5 are as defined; or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.
In an embodiment, the present invention relates to a compound of formula 1 : wherein,
Ri and R2 are halogen;
Q is:
Figure imgf000019_0001
wherein * indicates the point of attachment; and m, n, X, R3, R4, and R5 are as defined; or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.
In an embodiment, the present invention relates to a compound of formula 1 : wherein,
Ri and R2 are independently selected from the group consisting of hydrogen, halogen, (CrC8)-alkyl, halo-(C C8)-alkyl and (C C8)-alkoxy;
n is 1 ;
m is 1 or 2;
X is hydrogen, halogen or (CrC8)-alkyl;
Q is:
Figure imgf000019_0002
wherein * indicates the point of attachment;
R3 is hydrogen, cyano, (C C8)-alkyl, halo(C C8)-alkyl, (C3-Ci2)-cycloalkyl, C(O)Ra, C(O)2Ra or S(O)qRc; and
R4, R5, Ra, Rc and q are as defined in the first aspect;
or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.
In another embodiment, the present invention relates to a compound of formula
1 ,
wherein,
Ri and R2 are halogen;
n is 1 ;
m is 1 or 2;
X is hydrogen, halogen or (CrC8)-alkyl;
Q is:
Figure imgf000020_0001
wherein * indicates the point of attachment;
R3 is hydrogen, cyano, (CrC8)-alkyl, (C3-Ci2)-cycloalkyl or S(O)qRc; and
R4, R5, Rc, and q are as defined in the first aspect;
or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.
In another embodiment, the present invention relates to a compound of formula
1 ,
wherein,
Ri and R2 are halogen;
n is 1 ;
m is 1 or 2;
X is hydrogen, halogen or (C-i-C8)-alkyl;
Q is:
Figure imgf000020_0002
wherein * indicates the point of attachment;
R3 and R5 can join together to form a 3-12 membered saturated or unsaturated monocyclic or bicyclic ring system, optionally containing one to three heteroatoms independently selected from the group consisting of O, N and S;
wherein the said 3-12 membered ring can be unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, oxo, cyano, (CrC8)-alkyl, halo(CrC8)-alkyl, (CrC8)-alkoxy, halo(CrC8)-alkoxy, (C3- C12)-cycloalkyl-(Rd)o-2, O-(C3-C12)-cycloalkyl-(Rd)0-2, (C6-C14)-aryl-(Rd)0-2, O-(C6-C14)- aryl-(Rd)o-2, heterocyclyl-(Rd)o-2, O-heterocyclyl-(Rd)o-2, heteroaryl-(Rd)0-2, C(0)Ra, CO2Ra, C(O)NRaRb, NRaRb, NRaC(O)Rb, S(O)qRc and S(O)qNRaRb; and
R4, Ra, Rb, Rc, Rd and q are as defined in the first aspect;
or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof. In another embodiment, the present invention relates to a compound of formula
1 ,
wherein,
Ri and R2 are halogen;
n is 1 ;
m is 1 or 2;
X is hydrogen, halogen or (Ci-C8)-alkyl;
Q is:
Figure imgf000021_0001
wherein * indicates the point of attachment;
R3 is hydrogen, cyano, (CrC8)-alkyl, (C3-Ci2)-cycloalkyl or S(O)qRc; and
R4 and R5 can join together to form a 3-12 membered saturated or unsaturated, monocyclic or bicyclic ring system including spiro ring systems, optionally containing one to three heteroatoms independently selected from the group consisting of O, N and S;
wherein the said 3-12 membered ring can be unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, oxo, cyano, (Ci-C8)-alkyl, halo(d-C8)-alkyl, (Ci-C8)-alkoxy, halo(Ci-C8)-alkoxy, (C3- Ci2)-cycloalkyl-(Rd)o-2, O-(C3-Ci2)-cycloalkyl-( Rd)o-2, (C6-Ci4)-aryl-( Rd)o-2, O-(C6-d4)- aryl-(Rd)o-2, heterocyclyl-(Rd)o-2, O-heterocyclyl-(Rd)o-2, heteroaryl-( Rd)o-2, C(O) Ra, CO2Ra, C(O) N RaRb, N RaRb, N RaC(O) Rb, S(O)qRc and S(O)qN RaRb; and
Ra, Rb, Rc, Rd and q are as defined in the first aspect;
or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.
In an embodiment, the present invention relates to a compound of formula 1 , wherein,
Ri and R2 are independently selected from the group consisting of hydrogen, halogen, (d-C8)-alkyl, halo (d-C8)-alkyl and (d-C8)-alkoxy;
n is 1 ;
m is 1 or 2;
X is hydrogen, halogen or (Ci-C8)-alkyl; Q is:
Figure imgf000022_0001
wherein * indicates the point of attachment;
R3 is hydrogen, cyano, (d-CsJ-alkyl, halo(CrC8)-alkyl, (C3-Ci2)-cycloalkyl, C(O)Ra, C(O)2Raor S(O)qRc; and
R4, R5, Rc and q are as defined in the first aspect;
or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.
In another embodiment, the present invention relates to a compound of formula 1 ,
wherein,
Ri and R2 are halogen;
n is 1 ; and m is 1 or 2;
X is hydrogen, halogen or (d-CsJ-alkyl;
Q is:
Figure imgf000022_0002
wherein * indicates the point of attachment;
R3 is hydrogen, cyano, (d-C8)-alkyl, (C3-Ci2)-cycloalkyl or S(O)qRc; and
R4, R5, Rc, and q are as defined in the first aspect;
or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.
In another embodiment, the present invention relates to a compound of formula
1 ,
wherein,
Ri and R2 are halogen;
n is 1 ; and m is 1 or 2; X is hydrogen, halogen or (CrC8)-alkyl;
Q is:
Figure imgf000023_0001
wherein * indicates the point of attachment;
R3 and R5 can join together to form a 3-12 membered saturated or unsaturated monocyclic or bicyclic ring system, optionally containing one to three heteroatoms independently selected from the group consisting of O, N and S;
wherein the said 3-12 membered ring can be unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, oxo, cyano, (d-CsJ-alkyl, halo(CrC8)-alkyl, (Ci-Cs)-alkoxy, halo(CrC8)-alkoxy, (C3- C12)-cycloalkyl-(Rd)o-2, O-(C3-C12)-cycloalkyl-(Rd)0-2, (C6-C14)-aryl-(Rd)0-2, O-(C6-C14)- aryl-(Rd)o-2, heterocyclyl-(Rd)0-2, O-heterocyclyl-(Rd)0-2, heteroaryl-(Rd)0-2, C(O)Ra, CO2Ra, C(O)NRaRb, NRaRb, NRaC(O)Rb, S(O)qRc and S(O)qNRaRb; and
R4, Ra, Rb, RCl Rd and q are as defined in the first aspect;
or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.
In another embodiment, the present invention relates to a compound of formula
1 ,
wherein,
Ri and R2 are halogen;
n is 1 ; and m is 1 or 2;
X is hydrogen, halogen or (CrC8)-alkyl;
Q is:
Figure imgf000023_0002
wherein * indicates the point of attachment;
R3 is hydrogen, cyano, (CrC8)-alkyl, (C3-Ci2)-cycloalkyl or S(O)qRc; and R4 and R5 can join together to form a 3-12 membered saturated or unsaturated, monocyclic or bicyclic ring system including spiro ring systems, optionally containing one to three heteroatoms independently selected from the group consisting of O, N and S;
wherein the said 3-12 membered ring can be unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, oxo, cyano, (C-i-C8)-alkyl, halo(CrC8)-alkyl, (C-i-C8)-alkoxy, halo(CrC8)-alkoxy, (C3- Ci2)-cycloalkyl-(Rd)o-2, O-(C3-Ci2)-cycloalkyl-(Rd)0-2, (C6-Ci4)-aryl-(Rd)0-2, 0-(C6-Ci4)- aryl-(Rd)o-2, heterocyclyl-(Rd)0-2, O-heterocyclyl-(Rd)0-2, heteroaryl-(Rd)0-2, C(0)Ra, CO2Ra, C(O)NRaRb, NRaRb, NRaC(O)Rb, S(O)qRc and S(O)qNRaRb; and
Ra, Rb, Rc, Rd and q are as defined in the first aspect;
or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.
In an embodiment, the present invention relates to a compound of formula 1 , wherein,
Ri and R2 are independently selected from the group consisting of hydrogen, halogen,
(CrC8)-alkyl, halo (C C8)-alkyl and (C C8)-alkoxy;
n is 1 ;
m is 1 or 2;
X is hydrogen, halogen or (CrC8)-alkyl;
Q is:
Figure imgf000024_0001
wherein Indicates the point of attachment;
R3 is hydrogen, cyano, (CrC8)-alkyl, halo(CrC8)-alkyl, (C3-Ci2)-cycloalkyl, C(O)Ra, C(O)2Ra or S(O)qRc; and
R4, R5, Rc and q are as defined in the first aspect;
or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.
In another embodiment, the present invention relates to a compound of formula 1 , wherein,
Ri and R2 are halogen;
n is 1 ;
m is 1 or 2;
X is hydrogen, halogen or (CrC8)-alkyl;
Q is:
Figure imgf000025_0001
wherein * indicates the point of attachment;
R3 is hydrogen, cyano, (d-CsJ-alkyl, (C3-Ci 2)-cycloalkyl or S(O)qRc; and
R4, R5, Rc, and q are as defined in the first aspect;
or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.
In another embodiment, the present invention relates to a compound of formula
1 ,
wherein,
Ri and R2 are halogen;
n is 1 ;
m is 1 or 2;
X is hydrogen, halogen or (d-CsJ-alkyl;
Q is:
Figure imgf000025_0002
wherein * indicates the point of attachment;
R3 and R5 can join together to form a 3-12 membered saturated or unsaturated monocyclic or bicyclic ring system, optionally containing one to three heteroatoms independently selected from the group consisting of O, N and S; wherein the said 3-12 membered ring can be unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, oxo, cyano, (d-CsJ-alkyl, halo(CrC8)-alkyl, (Ci-Cs)-alkoxy, halo(CrC8)-alkoxy, (C3- Ci2)-cycloalkyl-(Rd)o-2, O-(C3-Ci2)-cycloalkyl-(Rd)0-2, (C6-d4)-aryl-(Rd)0-2, O-(C6-d4)- aryl-(Rd)o-2, heterocyclyl-(Rd)0-2, O-heterocyclyl-(Rd)0-2, heteroaryl-(Rd)0-2, C(0)Ra, CO2Ra, C(O)NRaRb, NRaRb, NRaC(O)Rb, S(O)qRc and S(O)qNRaRb; and
R4, Ra, Rb, Rc, Rd and q are as defined in the first aspect;
or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.
In another embodiment, the present invention relates to a compound of formula
1 ,
wherein,
Ri and R2 are halogen;
n is 1 ;
m is 1 or 2;
X is hydrogen, halogen or (d-CsJ-alkyl;
Q is:
Figure imgf000026_0001
wherein * indicates the point of attachment;
R3 is hydrogen, cyano, (d-C8)-alkyl, (C3-d2)-cycloalkyl or S(O)qRc; and
R4 and R5 can join together to form a 3-12 membered saturated or unsaturated, monocyclic or bicyclic ring system including spiro ring systems, optionally containing one to three heteroatoms independently selected from the group consisting of O, N and S;
wherein the said 3-12 membered ring can be unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, oxo, cyano, (d-CsJ-alkyl, halo(Ci-C8)-alkyl, (d-CsJ-alkoxy, halo(Ci-C8)-alkoxy, (C3- Ci2)-cycloalkyl-(Rd)0-2, O-(C3-d2)-cycloalkyl-(Rd)0-2, (C6-d4)-aryl-(Rd)0-2, O-(C6-d4)- aryl-(Rd)o-2. heterocyclyl-(Rd)0-2, O-heterocyclyl-(Rd)0-2, heteroaryl-(Rd)0-2, C(O)Ra, CO2Ra, C(O)NRaRb, NRaRb, NRaC(O)Rb, S(O)qRc and S(O)qNRaRb; and Ra> Rb> Rc> Rd and q are as defined in the first aspect;
or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.
In an embodiment, the present invention relates to a compound of formula 1 , wherein,
Ri and R2 are halogen;
n is 1 ;
m is 1 or 2;
X is hydrogen, halogen or (CrC8)-alkyl;
Q is:
Figure imgf000027_0001
wherein * indicates the point of attachment;
R3 is hydrogen, cyano, (d-CsJ-alkyl, (C3-Ci2)-cycloalkyl or S(O)qRc;
R4 is (d-CsJ-alkyl, (C3-Ci2)-cycloalkyl, (C6-d4)-aryl, heterocyclyl or heteroaryl;
R5 is hydrogen, (d-C8)-alkyl, (C3-Ci2)-cycloalkyl, (C6-C )-aryl, heterocyclyl or heteroaryl; or
R3 and R5 can join together to form a 3-12 membered saturated or unsaturated monocyclic or bicyclic ring system, optionally containing one to three heteroatoms independently selected from the group consisting of O, N and S; or
R4 and R5 can join together to form a 3-12 membered saturated or unsaturated, monocyclic or bicyclic ring system including spiro ring systems, optionally containing one to three heteroatoms independently selected from the group consisting of O, N and S;
wherein the said 3-12 membered ring can be unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, oxo, cyano, (d-CsJ-alkyl, halo(d-C8)-alkyl, (Ci-Cs)-alkoxy, halo(Ci-C8)-alkoxy, (C3- Ci2)-cycloalkyl-(Rd)o-2, O-(C3-d2)-cycloalkyl-(Rd)0-2, (C6-Ci4)-aryl-(Rd)o-2, O-(C6-d4)- aryl-(Rd)o-2, heterocyclyl-(Rd)0-2, O-heterocyclyl-(Rd)0-2, heteroaryl-(Rd)0-2, C(0)Ra, CO2Ra, C(O)NRaRb, NRaRb, NRaC(O)Rb, S(O)qRc and S(O)qNRaRb; and
Ra, Rb, Rc, Rd and q are as defined in the first aspect; or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.
Representative compounds of the present invention include:
4-Chloro-5-(4-chlorophenyl)-N,N'-dicyclopropyl-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboximidamide;
N-((1 S,3R,5S)-Adamantan-1 -yl)-4-chloro-5-(4-chlorophenyl)-N'-cyclopropyl-1 -(2,4- dichlorophenyl)-1 H-pyrazole-3-carboximidamide;
4-Chloro-5-(4-chlorophenyl)-N'-cyclopropyl-1 -(2,4-dichlorophenyl)-N-(1 ,1 - dioxidothiomorpholino)-1 H-pyrazole-3-carboximidamide;
4- Chloro-1 -(2-chlorophenyl)-5-(4-chlorophenyl)-N'-cyclopropyl-N-(1 ,1 -dioxidothio morpholino)-1 H-pyrazole-3-carboximidamide;
5- (4-Chlorophenyl)-N,N'-dicyclopropyl-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboximidamide;
N-((1 S,3R,5S)-Adamantan-1 -yl)-5-(4-chlorophenyl)-N'-cyclopropyl-1 -(2,4- dichlorophenyl)-1 H-pyrazole-3-carboximidamide;
N-((2R)-Adamantan-2-yl)-5-(4-chlorophenyl)-N'-cyclopropyl-1 -(2,4-dichlorophenyl)-1 H- pyrazole-3-carboximidamide;
5-(4-Chlorophenyl)-N'-cyclopropyl-1 -(2,4-dichlorophenyl)-N-(1 ,1 -dioxidothiomorpholino) 1 H-pyrazole-3-carboximidamide;
4- ((5-(4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol3-yl)(cyclopropylimino) methyl)thiomorpholine 1 ,1 -dioxide;
5- (4-Chlorophenyl)-N'-cyclopropyl-1 -(2,4-dichlorophenyl)-N-morpholino-1 H-pyrazole-3- carboximidamide;
2-(5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3-yl)-1 -cyclopropyl-4-isopropyl- 1 H-imidazol-5(4H)-one;
1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyclopropyl-N-(1 ,1 -dioxidothiomorpholino)-1 H pyrazole-3-carboximidamide;
1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N-cyclohexyl-N'-cyclopropyl-1 H-pyrazole-3- carboximidamide;
4- ((5-(4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3-yl)(methylimino)methyl) thiomorpholine 1 ,1 -dioxide;
5- (4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-N'-ethyl-N-morpholino-1 H-pyrazole-3- carboximidamide; 4- ((5-(4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3-yl)(ethylimino)methyl) thiomorpholine 1 ,1 -dioxide;
5- (4-Chlorophenyl)-N,N'-dicyclopropyl-1 -(2,4-dichlorophenyl)-4-methyl-1 H-pyrazole-3- carboximidamide;
5-(4-Chlorophenyl)-N'-cyclopropyl-1 -(2,4-dichlorophenyl)-N-(1 ,1 -dioxidothiomorpholino) 4-methyl-1 H-pyrazole-3-carboximidamide;
4- ((5-(4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-4-methyl-1 H-pyrazol-3-yl)
(cyclopropylimino)methyl)thiomorpholine 1 ,1 -dioxide;
5- (4-Chlorophenyl)-N'-cyclopropyl-1 -(2,4-dichlorophenyl)-4-methyl-N-morpholino-1 H- pyrazole-3-carboximidamide;
N-((5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-4-methyl-1 H-pyrazol-3-yl)(morpholino) methylene)cyclopropanamine;
1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N,N'-dicyclopropyl-4-methyl-1 H-pyrazole-3- carboximidamide;
N-((1 S,3R,5S)-Adamantan-1 -yl)-1 -(2-chlorophenyl)-5-(4-chlorophenyl)-N'-cyclopropyl-4 methyl-1 H-pyrazole-3-carboximidamide;
1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyclopropyl-N-(1 ,1 -dioxidothiomorpholino)-4- methyl-1 H-pyrazole-3-carboximidamide;
1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyclopropyl-4-methyl-N-morpholino-1 H- pyrazole-3-carboximidamide;
1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyclopropyl-4-methyl-N-(oxetan-3-yl)-1 H- pyrazole-3-carboximidamide;
N-Cyclohexyl-N'-cyclopropyl-1 -(2-methoxyphenyl)-5-(4-methoxyphenyl)-1 H-pyrazole-3- carboximidamide;
te/t-Butyl 4-((5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-4-methyl-1 H-pyrazol-3-yl) (cyclopropylimino)methyl)piperazine-1 -carboxylate;
N-((5-(4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-4-methyl-1 H-pyrazol-3-yl)(piperazin-1 - yl)methylene)cyclopropanamine hydrochloride;
N-((5-(4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-4-methyl-1 H-pyrazol-3-yl)(morpholino) methylene)cyclopropanamine;
N,N'-Dicyclopropyl-1 -(2-methoxyphenyl)-5-(4-methoxyphenyl)-1 H-pyrazole-3- carboximidamide;
N'-Cyclopropyl-N-(1 ,1 -dioxidothiomorpholino)-1 -(2-methoxyphenyl)-5-(4- methoxyphenyl)-1 H-pyrazole-3-carboximidamide; 5-(4-Chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-N-methyl-1 H-pyrazole-3- carboximidamide;
5-(4-Chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-N-ethyl-1 H-pyrazole-3- carboximidamide;
5-(4-Chlorophenyl)-N'-cyano-N-cyclopropyl-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboximidamide;
5-(4-Chlorophenyl)-N'-cyano-N-cyclohexyl-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboximidamide;
5-(4-Chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-N-(oxetan-3-yl)-1 H-pyrazole-3- carboximidamide;
N-((5-(4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3-yl)(4-(oxetan-3-yl) piperidin 1 -yl)methylene)cyanamide;
5-(4-Chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-N-(1 -(oxetan-3-yl)piperidin-4-yl)-1 H pyrazole-3-carboximidamide;
N-((4-Acetylpiperazin-1 -yl)(5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3- yl)methylene)cyanamide;
te/t-Butyl 4-((5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3-yl)(cyanoimino) methyl)piperazine-1 -carboxylate;
N-((1 S,3R,5S)-Adamantan-1 -yl)-5-(4-chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-1 H pyrazole-3-carboximidamide;
N-((1 s,3s,5s)-1 ,3,5-Triazaadamantan-7-yl)-5-(4-chlorophenyl)-N'-cyano-1 -(2,4- dichlorophenyl)-1 H-pyrazole-3-carboximidamide;
(S)-2-(5-(4-Chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboximidamido)propanamide;
(S)-Methyl 2-(5-(4-chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboximidamido)-3-methylbutanoate;
N-((5-(4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3-yl)(1 ,1 -dioxidothio morpholino)methylene)cyanamide;
5-(4-Chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-N-(1 ,1 -dioxidothiomorpholino)-1 H- pyrazole-3-carboximidamide;
N-((5-(4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3-yl) (morpholino)
methylene)cyanamide;
5-(4-Chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-N-morpholino-1 H-pyrazole-3- carboximidamide; 5-(4-Chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-N-(4-methoxybenzyl)-1 H-pyrazole- 3-carboximidamide;
1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-N-ethyl-1 H-pyrazole-3- carboximidamide;
1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-N-cyclopropyl-1 H-pyrazole-3- carboximidamide;
1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-N-cyclohexyl-1 H-pyrazole-3- carboximidamide;
1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-N-(oxetan-3-yl)-1 H-pyrazole-3- carboximidamide;
N-((1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl)(4-(oxetan-3-yl)piperidin-1 - yl)methylene)cyanamide;
1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-N-(1 -(oxetan-3-yl)piperidin-4-yl)-1 H- pyrazole-3-carboximidamide;
N-((1 S,3R,5S)-Adamantan-1 -yl)-1 -(2-chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-1 H- pyrazole-3-carboximidamide;
N-((1 s,3s,5s)-1 ,3,5-Triazaadamantan-7-yl)-1 -(2-chlorophenyl)-5-(4-chlorophenyl)-N'- cyano-1 H-pyrazole-3-carboximidamide;
(S)-2-(1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-1 H-pyrazole-3- carboximidamido)propanamide;
(S)-Methyl 2-(1 -(2-chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-1 H-pyrazole-3- carboximidamido)-3-methylbutanoate;
(S)-2-(1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-1 H-pyrazole-3- carboximidamido)-3-methylbutanamide;
1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-N-(1 ,1 -dioxidothiomorpholino)-1 H- pyrazole-3-carboximidamide;
N-((5-(4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3-yl)(piperidin-1 -yl) methylene)cyanamide;
tert-Butyl (1 -((5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3-yl)
(cyanoimino)methyl)piperidin-4-yl)carbamate;
N-((4-Aminopiperidin-1 -yl)(5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3-yl) methylene)cyanamide hydrochloride;
N-((5-(4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3-yl)(piperazin-1 -yl) methylene)cyanamide hydrochloride; 2- (5-(4-Chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboximidamido)-2-methylpropanamide;
1 -(5-(4-Chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboximidamido)cyclopropanecarboxamide;
1 -(5-(4-Chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboximidamido)cyclopentanecarboxamide;
(S)-2-(5-(4-Chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboximidamido)-3-methylbutanoic acid;
(S)-2-(5-(4-Chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboximidamido)-3-methylbutanamide;
te/t-Butyl 9-((5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3-yl)(cyanoimino) methyl)-2,9-diazaspiro[5.5]undecane-2-carboxylate;
N-((5-(4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3-yl)(2,9-diazaspiro[5.5] undecan-9-yl)methylene)cyanamide hydrochloride;
N-((1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl)(piperidin-1 -yl) methylene) cyanamide;
N-((4-Acetylpiperazin-1 -yl) ( 1 -(2-chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl) methylene)cyanamide;
1 -(1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-1 H-pyrazole-3-carboximidamido) cyclopentanecarboxamide;
te/t-Butyl 9-((1 -(2-chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl)(cyanoimino) methyl)-2,9-diazaspiro[5.5]undecane-2-carboxylate;
5-(4-Chlorophenyl)-N'-cyano-N-cyclohexyl-1 -(2,4-dichlorophenyl)-4-methyl-1 H-pyrazole-
3- carboximidamide;
( )-2-(5-(4-Chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-4-methyl-1 H-pyrazole-3- carboximidamido)propanamide;
2-(5-(4-Chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-4-methyl-1 H-pyrazole-3- carboximidamido)-2-methylpropanamide;
1 -(5-(4-Chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-4-methyl-1 H-pyrazole-3- carboximidamido)cyclopropanecarboxamide;
1 -(5-(4-Chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-4-methyl-1 H-pyrazole-3- carboximidamido)cyclopentanecarboxamide;
2-(5-(4-Chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-4-methyl-1 H-pyrazole-3- carboximidamido)-3-methylbutanamide; 1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-N-cyclopropyl-4-methyl-1 H-pyrazole-3 carboximidamide;
1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-N-cyclohexyl-4-methyl-1 H-pyrazole-3- carboximidamide;
(S)-2-(1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-4-methyl-1 H-pyrazole-3- carboximidamido)propanamide;
1 -(1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-4-methyl-1 H-pyrazole-3- carboximidamido)cyclopropanecarboxamide;
1 -(1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-4-methyl-1 H-pyrazole-3- carboximidamido)cyclopentanecarboxamide;
(S)-2-(5-(4-chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-4-methyl-1 H-pyrazole-3- carboximidamido)-3-methylbutanamide;
te/t-Butyl 9-((1 -(2-chlorophenyl)-5-(4-chlorophenyl)-4-methyl-1 H-pyrazol-3-yl)
(cyanoimino)methyl)-2,9-diazaspiro[5.5]undecane-2-carboxylate;
tert-Butyl 4-((1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-4-methyl-1 H-pyrazol-3-yl)
(cyanoimino)methyl)-1 -oxa-4,8-diazaspiro[5.5]undecane-8-carboxylate;
1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-4-methyl-N-(quinuclidin-3-yl)-1 H- pyrazole-3-carboximidamide;
N-((1 S,2R,4S)-Bicyclo[2.2.1 ]hept-5-en-2-ylmethyl)-1 -(2-chlorophenyl)-5-(4- chlorophenyl)-N'-cyano-4-methyl-1 H-pyrazole-3-carboximidamide;
1 -(1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl)-2-cyclopropyl-3- ethylguanidine;
1 -(1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl)-2,3-dicyclopropylguanidine; 1 -Benzyl-3-(1 -(2-chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl)-2-cyclopropyl guanidine;
N-(1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl)-N'-cyclopropyl
thiomorpholine-4-carboximidamide 1 ,1 -dioxide;
N-(1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl)-N'-cyclopropylmorpholine-4- carboximidamide;
1 -(1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl)-2-cyclopropyl-3- morpholinoguanidine;
1 -((1 r,3r,5r,7r)-Adamantan-2-yl)-3-(1 -(2-chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3 yl)-2-cyclopropylguanidine; 1 -(1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl)-2-cyano-3-cyclopropyl guanidine;
4- (((1 -(2-chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl)imino)(cyclopropyl) methyl)thiomorpholine 1 ,1 -dioxide;
1 -(1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl)-3-cyclohexyl-2- cyclopropylguanidine;
N'-(1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl)-N-(1 ,1 -dioxidothio
morpholino)cyclopropanecarboximidamide;
N-Benzyl-N'-(1 -(2-chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl)cyclopropane carboximidamide;
5- (4-Chlorophenyl)-N-cyclohexyl-1 -(2,4-dichlorophenyl)-N'-(methylsulfonyl)-1 H- pyrazole-3-carboximidamide;
N-Benzyl-5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-N'-(methylsulfonyl)-1 H-pyrazole-3- carboximidamide;
N-((5-(4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3-yl)(4-ethylpiperazin-1 -yl) methylene)methanesulfonamide;
N-((4-Benzylpiperazin-1 -yl)(5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3- yl)methylene)methanesulfonamide;
N-((5-(4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3-yl)(1 ,1 -dioxido
thiomorpholino)methylene)methanesulfonamide;
N-((5-(4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3-yl)(morpholino)
methylene)methanesulfonamide; or
N-((5-(4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3-yl)(4-(oxetan-3-yl) piperidin- 1 -yl)methylene)methanesulfonamide;
or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.
In an embodiment, the compounds of the present invention include:
4-Chloro-5-(4-chlorophenyl)-N,N'-dicyclopropyl-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboximidamide;
N-((1 S,3R,5S)-Adamantan-1 -yl)-4-chloro-5-(4-chlorophenyl)-N'-cyclopropyl-1 -(2,4- dichlorophenyl)-1 H-pyrazole-3-carboximidamide;
4-Chloro-5-(4-chlorophenyl)-N'-cyclopropyl-1 -(2,4-dichlorophenyl)-N-(1 ,1 - dioxidothiomorpholino)-1 H-pyrazole-3-carboximidamide;
4-Chloro-1 -(2-chlorophenyl)-5-(4-chlorophenyl)-N'-cyclopropyl-N-(1 ,1 -dioxidothio morpholino)-1 H-pyrazole-3-carboximidamide; 5-(4-Chlorophenyl)-N,N'-dicyclopropyl-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboximidamide;
N-((1 S,3R,5S)-Adamantan-1 -yl)-5-(4-chlorophenyl)-N'-cyclopropyl-1 -(2,4- dichlorophenyl)-1 H-pyrazole-3-carboximidamide;
N-((2R)-Adamantan-2-yl)-5-(4-chlorophenyl)-N'-cyclopropyl-1 -(2,4-dichlorophenyl)-1 H- pyrazole-3-carboximidamide;
5-(4-Chlorophenyl)-N'-cyclopropyl-1 -(2,4-dichlorophenyl)-N-(1 ,1 -dioxidothiomorpholino) 1 H-pyrazole-3-carboximidamide;
4- ((5-(4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol3-yl)(cyclopropylimino) methyl)thiomorpholine 1 ,1 -dioxide;
5- (4-Chlorophenyl)-N'-cyclopropyl-1 -(2,4-dichlorophenyl)-N-morpholino-1 H-pyrazole-3- carboximidamide;
2-(5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3-yl)-1 -cyclopropyl-4-isopropyl- 1 H-imidazol-5(4H)-one;
1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyclopropyl-N-(1 ,1 -dioxidothiomorpholino)-1 H pyrazole-3-carboximidamide;
1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N-cyclohexyl-N'-cyclopropyl-1 H-pyrazole-3- carboximidamide;
4- ((5-(4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3-yl)(methylimino)methyl) thiomorpholine 1 ,1 -dioxide;
5- (4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-N'-ethyl-N-morpholino-1 H-pyrazole-3- carboximidamide;
4- ((5-(4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3-yl)(ethylimino)methyl) thiomorpholine 1 ,1 -dioxide;
5- (4-Chlorophenyl)-N,N'-dicyclopropyl-1 -(2,4-dichlorophenyl)-4-methyl-1 H-pyrazole-3- carboximidamide;
5-(4-Chlorophenyl)-N'-cyclopropyl-1 -(2,4-dichlorophenyl)-N-(1 ,1 -dioxido
thiomorpholino)-4-methyl-1 H-pyrazole-3-carboximidamide;
4- ((5-(4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-4-methyl-1 H-pyrazol-3-yl)
(cyclopropylimino)methyl)thiomorpholine 1 ,1 -dioxide;
5- (4-Chlorophenyl)-N'-cyclopropyl-1 -(2,4-dichlorophenyl)-4-methyl-N-morpholino-1 H- pyrazole-3-carboximidamide;
N-((5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-4-methyl-1 H-pyrazol-3-yl)(morpholino) methylene)cyclopropanamine; 1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N,N'-dicyclopropyl-4-methyl-1 H-pyrazole-3- carboximidamide;
N-((1 S,3R,5S)-Adamantan-1 -yl)-1 -(2-chlorophenyl)-5-(4-chlorophenyl)-N'-cyclopropyl-4 methyl-1 H-pyrazole-3-carboximidamide;
1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyclopropyl-N-(1 ,1 -dioxidothiomorpholino)-4- methyl-1 H-pyrazole-3-carboximidamide;
1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyclopropyl-4-methyl-N-morpholino-1 H- pyrazole-3-carboximidamide;
1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyclopropyl-4-methyl-N-(oxetan-3-yl)-1 H- pyrazole-3-carboximidamide;
N-Cyclohexyl-N'-cyclopropyl-1 -(2-methoxyphenyl)-5-(4-methoxyphenyl)-1 H-pyrazole-3- carboximidamide;
5-(4-Chlorophenyl)-N' -cyano-1 -(2,4-dichlorophenyl)-N-methyl-1 H-pyrazole-3- carboximidamide;
5-(4-Chlorophenyl)-N' -cyano-1 -(2,4-dichlorophenyl)-N-ethyl-1 H-pyrazole-3- carboximidamide;
5-(4-Chlorophenyl)-N' -cyano-N-cyclopropyl-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboximidamide;
5-(4-Chlorophenyl)-N' -cyano-N-cyclohexyl-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboximidamide;
5-(4-Chlorophenyl)-N' -cyano-1 -(2,4-dichlorophenyl)-N-(oxetan-3-yl)-1 H-pyrazole-3- carboximidamide;
N-((5-(4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3-yl)(4-(oxetan-3-yl) piperidin 1 -yl)methylene)cyanamide;
5-(4-Chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-N-(1 -(oxetan-3-yl)piperidin-4-yl)-1 H pyrazole-3-carboximidamide;
N-((4-Acetylpiperazin-1 -yl)(5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3- yl)methylene)cyanamide;
te/t-Butyl 4-((5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3-yl)(cyanoimino) methyl)piperazine-1 -carboxylate;
N-((1 S,3R,5S)-Adamantan-1 -yl)-5-(4-chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-1 H pyrazole-3-carboximidamide;
N-((1 s,3s,5s)-1 ,3,5-Triazaadamantan-7-yl)-5-(4-chlorophenyl)-N'-cyano-1 -(2,4- dichlorophenyl)-1 H-pyrazole-3-carboximidamide; (S)-2-(5-(4-Chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboximidamido)propanamide;
(S)-Methyl 2-(5-(4-chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboximidamido)-3-methylbutanoate;
N-((5-(4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3-yl)(1 ,1 -dioxidothio morpholino)methylene)cyanamide;
5-(4-Chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-N-(1 ,1 -dioxidothiomorpholino)-1 H- pyrazole-3-carboximidamide;
N-((5-(4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3-yl) (morpholino)
methylene)cyanamide;
5-(4-Chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-N-morpholino-1 H-pyrazole-3- carboximidamide;
5-(4-Chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-N-(4-methoxybenzyl)-1 H-pyrazole- 3-carboximidamide;
1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-N-ethyl-1 H-pyrazole-3- carboximidamide;
1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-N-cyclopropyl-1 H-pyrazole-3- carboximidamide;
1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-N-cyclohexyl-1 H-pyrazole-3- carboximidamide;
1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-N-(oxetan-3-yl)-1 H-pyrazole-3- carboximidamide;
N-((1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl)(4-(oxetan-3-yl)piperidin-1 - yl)methylene)cyanamide;
1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-N-(1 -(oxetan-3-yl)piperidin-4-yl)-1 H- pyrazole-3-carboximidamide;
N-((1 S,3R,5S)-Adamantan-1 -yl)-1 -(2-chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-1 H- pyrazole-3-carboximidamide;
N-((1 s,3s,5s)-1 ,3,5-Triazaadamantan-7-yl)-1 -(2-chlorophenyl)-5-(4-chlorophenyl)-N'- cyano-1 H-pyrazole-3-carboximidamide;
(S)-2-(1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-1 H-pyrazole-3- carboximidamido)propanamide;
(S)-Methyl 2-(1 -(2-chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-1 H-pyrazole-3- carboximidamido)-3-methylbutanoate; (S)-2-(1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-1 H-pyrazole-3- carboximidamido)-3-methylbutanamide;
1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-N-(1 ,1 -dioxidothiomorpholino)-1 H- pyrazole-3-carboximidamide;
N-((5-(4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3-yl)(piperidin-1 -yl)
methylene)cyanamide;
1 -(1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl)-2-cyclopropyl-3- ethylguanidine;
1 -(1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl)-2,3-dicyclopropylguanidine; 1 -Benzyl-3-(1 -(2-chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl)-2-cyclopropyl guanidine;
N-(1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl)-N'-cyclopropyl
thiomorpholine-4-carboximidamide 1 ,1 -dioxide;
N-(1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl)-N'-cyclopropylmorpholine-4- carboximidamide;
1 -(1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl)-2-cyclopropyl-3- morpholinoguanidine;
1 -((1 r,3r,5r,7r)-Adamantan-2-yl)-3-(1 -(2-chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3- yl)-2-cyclopropylguanidine;
1 -(1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl)-2-cyano-3-cyclopropyl guanidine; or
4-(((1 -(2-chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl)imino)(cyclopropyl) methyl)thiomorpholine 1 ,1 -dioxide;
or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.
The compounds of the present invention include all isotopic forms, stereoisomeric and tautomeric forms and mixtures thereof in all ratios and their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, prodrugs, N- oxides, S-oxides and polymorphs.
According to another aspect of the present invention, there are provided processes for the preparation of the compounds of formula 1 . The compounds of formula 1 can be prepared using various methods including the methods well known to a person skilled in the art. Representative processes to prepare the compounds of the present invention are described below, and are particularly illustrated in Schemes 1 -5, but are not limited thereto. It will be appreciated by persons skilled in the art that within certain of the processes described herein, the order of the reaction steps employed can be varied and will depend inter alia on factors such as the nature of functional groups present in a particular substrate (starting compound or an intermediate) and the protecting group strategy (if any) to be adopted. Clearly, such factors will also influence the choice of reagent to be used in the reaction steps.
The reagents, reactants and intermediates used in the following processes are either commercially available or can be prepared according to standard procedures known in the art, for instance those reported in the literature references. In the following schemes and the description of the processes for the synthesis of the compounds of formula 1 , the starting compounds and the intermediates that are used for the synthesis of the compounds of the present invention, are designated as compounds 2-16, for ease of reference. Unless stated otherwise, throughout the process description, the corresponding substituent groups in the various formulae representing starting compounds and intermediates have the same meaning as that for the compound(s) of formula 1 as indicated in one or more embodiments described above, unless stated otherwise.
Processes for the preparation of the compounds of formula 1 of the present invention are depicted in schemes 1 , 2, 3, 4 and 5 presented below. For ease of reference, the reaction steps shown in the schemes, are referred to as steps 1 a, 1 b, 1 c and 1 d in scheme 1 ; steps 2a, 2b, 2c and 2d in scheme 2; steps 3a, 3b, 3c, 3d, 3e and 3f in scheme 3; steps 4a, 4b 4c and 4d in scheme 4; and steps 5a and 5b in scheme 5 respectively.
Scheme 1 depicts a process for the preparation of the compound of formula 1 , wherein, Q is:
Figure imgf000039_0001
wherein * indicates the point of attachment;
R3, R4 and R5 are as defined in the first aspect of the present invention. Scheme 1
Figure imgf000040_0001
(compound of formula 1 )
Reaction step 1a:
Preparation of the compound of formula 3:
To a stirred solution of the compound of formula 2 (wherein Ri, n and X are as defined in the first aspect of the invention) in a solvent selected from diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diisopropyl ether, hexane, toluene or N,N- dimethylacetamide; a solution of lithium bis(trimethylsilyl)amide (LiHMDS) is slowly added at 10-80 °C over 1 -2 h. After stirring for 0-12 h, diethyl oxalate in solvent such as diethyl ether is added over 25-35 min at the same temperature and the resulting reaction mixture is maintained for 1 -3 h at -78 °C. The reaction mixture is stirred for 14- 16 h at 25-30 °C, to yield an intermediate compound Y:
Figure imgf000041_0001
(wherein R and n are as defined in the first aspect of the invention).
A stirred solution of the compound of formula Y in a solvent such as ethanol, methanol or tetrahydrofuran (THF) is reacted with a compound of formula G:
Figure imgf000041_0002
(wherein R2 and m are as defined in the first aspect of the invention) and the mixture is refluxed for 2-16 h, to yield the compound of formula 3 (wherein R-i, R2, m, n and X are as defined in the first aspect of the invention).
Reaction step 1 b:
Preparation of the compound of formula 4:
To a stirred solution of the compound of formula 3 (wherein Ri, R2, m, n and X are as defined in the first aspect of the invention) in a mixture of solvents such as THF, methanol and water; a base such as lithium hydroxide hydrate (LiOH.H2O) is added and the resulting mixture is heated for 2-4 h at 70-90 °C, to yield the compound of formula 4 (wherein R-i, R2, m, n and X are as defined in the first aspect of the invention). Reaction step 1 c:
Preparation of the compound of formula 5:
To a stirred solution of the compound of formula 4 (wherein Ri, R2, m, n and X are as defined in the first aspect of the invention) in a solvent selected from dichloromethane, 1 ,2-dichloroethane, toluene, diethyl ether, cyclohexane or acetonitrile; is added the compound of formula A:
H2N R3
A (wherein R3 is as defined in the first aspect), a coupling reagent such as O- (benzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) and an amine such as diisopropyl ethylamine at room temperature and the mixture is stirred for 4-6 h, to yield the compound of formula 5 (wherein Ri , R2, R3, m, n and X are as defined in the first aspect of the invention).
Reaction step 1d:
Preparation of the compound of formula 1 :
To a stirred solution of the compound of formula 5 (wherein R-i , R2, R3, m, n and X are as defined in the first aspect of the invention) in a solvent such as chlorobenzene is added a reagent such as phosphorus pentachloride (PCI5) at room temperature and the reaction mixture is heated at 125-140 °C for 1 -3 h. The mixture is allowed to cool to room temperature. Triethylamine is added to the reaction mixture, followed by the compound of formula B:
Figure imgf000042_0001
(wherein R4 and R5 are as defined in the first aspect of the invention) or its hydrochloride and the resulting mixture is stirred at room temperature for 12-15 h, which results in the formation of the compound of formula 1 (wherein Q is:
Figure imgf000042_0002
R-i , R2, R3, R4, R5, X, m and n are as defined in the first aspect of the invention).
Scheme 2 depicts a process for the preparation of the compound of formula 1 , wherein, Q is:
Figure imgf000042_0003
R3, R4 and R5 are as defined in the first aspect of the present invention. Scheme 2
Figure imgf000043_0001
(compound of formula 1)
Reaction step 2a:
Preparation of compound of formula 7:
The compound of formula 6 (wherein R ; n and X are as defined in the first aspect of the invention) in a solvent selected from ethanol, methanol or tetrahydrofuran (THF); is treated with the compound of formula C:
Figure imgf000043_0002
C (wherein R2 and m are as defined in the first aspect of the invention). The resulting mixture is refluxed for 15-17 h. The solvent is evaporated, the crude solid obtained is dissolved in acetic acid and refluxed for 15-20 h, to yield the compound of formula 7 (wherein R-i, R2, X, m and n are as defined in the first aspect of the invention).
Reaction step 2b:
Preparation of the compound of formula 4:
A solution of the compound of formula 7 (wherein Ri , R2, X, m and n are as defined in the first aspect of the invention) and a base such as LiOH is refluxed for 12- 16 h in THF in water, to yield the compound of formula 4 (wherein R-i , R2, X, m and n are as defined in the first aspect of the invention).
Reaction step 2c:
Preparation of the compound of formula 8:
A solution of the compound of formula 4 (wherein Ri , R2, X, m and n are as defined in the first aspect of the invention), coupling reagent such as N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC), and a base such as N,N-dimethylpyridin-4-amine (DMAP) are added to a solvent such as dichloromethane (CH2CI2). The resulting mixture is stirred at room temperature for 0.5-1 h. A solution of the compound of formula A (as described in step 1 c of the scheme 1 ) in a solvent such as dichloromethane, 1 ,2-dichloroethane, toluene, diethyl ether, cyclohexane or acetonitrile is added dropwise to the above mixture. The resulting reaction mixture is stirred for 12-16 h at room temperature, to yield the compound of formula 8 (wherein R-i, R2, X, m and n are as defined in the first aspect of the invention).
Reaction step 2d:
Preparation of the compound of formula 1 :
Compound of formula 9 (wherein R-i, R2, X, m and n are as defined in the first aspect of the invention) is dissolved in a solvent such as chlorobenzene and is then heated at 100-120 °C in the presence of a reagent such as phosphorous pentachloride for 1 -3 h. After evaporation of the solvent, the residue is dissolved in a solvent such as dichloromethane and treated with an amine such as triethylamine and the compound of formula B (as described in step 1 d of the scheme 1 ) at room temperature, to yield the compound of formula 1 . wherein Q is:
Figure imgf000045_0001
R-i , 2, R3, R4, R5, X, rn and n are as defined in the first aspect of the invention).
Alternatively, the compounds of formula 1 can be prepared by the procedu depicted in the following scheme 3, wherein, Q is:
Figure imgf000045_0002
R3, R4 and R5 are as defined in the first aspect of the present invention.
Figure imgf000046_0001
(compound of formula 1)
Reaction step 3a:
Preparation of the compound of formula 9:
To a stirred solution of the compound of formula 3 (wherein Ri, R2, X, m and n are as defined in the first aspect of the invention) in a solvent such as THF is added a reducing agent such as LiBH4 at room temperature, followed by adding a solvent such as methanol at 0-2 °C and the reaction mixture is refluxed for 1 -2 h, to yield the compound of formula 9 (wherein R ; R2, X, m and n are as defined in the first aspect of the invention). Reaction step 3b:
Preparation of the compound of formula 10:
To a stirred solution of the compound of formula 9 (wherein Ri, R2, X, m and n are as defined in the first aspect of the invention) in a solvent such as dichloromethane is added a base such as DIPEA (Ν,Ν-Diisopropylethylamine) and DMSO (dimethyl sulfoxide) at 0-2 °C. After stirring for 10-20 min, a complex such as SO3-pyridine is added dropwise at 0-2 °C and the mixture is stirred for 40-50 min at 0-2 °C. The reaction mixture is quenched with a saturated solution of a salt such as NaHCO3 at 0-2 °C, which results in the formation of the compound of formula 10 (wherein R ; R2, X, m and n are as defined in the first aspect of the invention).
Reaction step 3c:
Preparation of the compound of formula 11 :
To a stirred solution of compound of formula 10 (wherein Ri , R2, X, m and n are as defined in the first aspect of the invention) in a solvent such as DMSO is added a base such as hydroxylamine or its hydrochloride salt at room temperature followed by heating at 90-95 °C for 4-8 h, to yield the compound of formula 1 1 (wherein R-i , R2, X, m and n are as defined in the first aspect of the invention).
Reaction step 3d:
Preparation of the compound of formula 12:
To a stirred solution of the compound of formula 1 1 (wherein R-i, R2, X, m and n are as defined in the first aspect of the invention) in a solvent such as methanol is added a reagent such as sodium methoxide slowly and is stirred for 12-16 h at room temperature under nitrogen atmosphere. The reaction mixture is neutralised with an acid such as acetic acid, which results in the formation of the compound of formula 12 (wherein R ; R2, X, m and n are as defined in the first aspect of the invention).
Reaction step 3e:
Preparation of the compound of formula 13: To a stirred solution of a reagent such as sodium phosphate monobasic monohydrate, sodium phosphate dibasic and the compound of formula A (as described in step 1 c of the scheme 1 ) in a solvent such as water, is added a solution of the compound of formula 12 (wherein Ri, R2, X, m and n are as defined in the first aspect of the invention) in a solvent such as THF and the mixture is heated for 12-16 h at 65-75 °C, to yield the compound of formula 13 (wherein R ; R2, R3, X, m and n are as defined in the first aspect of the invention).
Reaction step 3f :
Preparation of the compound of formula 1 :
To a stirred solution of the compound of formula 13 (wherein R-i, R2, R3, X, m and n are as defined in the first aspect of the invention) in anhydrous methanol is added to the compound of formula B (as described in step 1 d of the scheme 1 ) and a base such as triethylamine, and the mixture is stirred for 12-16 h at room temperature which results in the formation of the compound of formula 1 (wherein Q is:
Figure imgf000048_0001
5, ; and
R-i, R2, X, m and n are as defined in the first aspect of the invention).
Scheme 4 depicts a process for the preparation of the compound of formula 1 , wherein, Q is:
Figure imgf000048_0002
R3, R4 and R5 are as defined in the first aspect of the present invention. heme 4
Figure imgf000049_0001
(compound of formula 1)
Reaction step 4a:
Preparation of the compound of formula 14:
To a solution of the compound of formula 4 (prepared according to steps 1 a and
1 b as depicted in scheme 1 , wherein R-i , R2, X, m and n are as defined in the first aspect of the invention) in a solvent such as tert-butyl alcohol (t-BuOH) is added an organic compound such as diphenylphosphorylazide and a base such as triethylamine at room temperature. The reaction mixture is heated at 1 30-1 50 °C, to yield the compound of formula 14 (wherein Ri , R2, X, m and n are as defined in the first aspect of the invention). Reaction step 4b:
Preparation of the compound of formula 15:
To a solution of the compound of formula 14 (wherein R-i , R2, X, m and n are as defined in the first aspect of the invention) in a solvent such as THF is added a base such as sodium hydride at room temperature and the mixture is stirred for 0.5-1 .5 h. Reagent such as triphosgene is added at 0 °C and the reaction mixture is stirred at room temperature. After 0.5-1 .5 h, the compound of formula A (as described in step 1 c of the scheme 1 ) is added and the mixture is stirred for 12 -16 h, to yield the compound of formula 15 (wherein R-i , R2, R3, X, m and n are as defined in the first aspect of the invention).
Reaction step 4c:
Preparation of the compound of formula 1 :
A solution of the compound of formula 15 (wherein R-i , R2, R3, X, m and n are as defined in the first aspect of the invention), in a reagent such as phosphoryl chloride, is refluxed at 1 10-130 °C for 1 -3 h. Excess reagent is distilled off, and the residue is dissolved in a solvent such as dichloromethane, followed by addition of of a base such as triethylamine and the compound of formula B (as described in step I d of the scheme 1 ) at room temperature, to yield the compound of formula 1 (wherein R-i , R2, Q, X, m and n are as defined in the first aspect of the invention).
Reaction step 4d:
Preparation of the compound of formula 1 :
Alternative to the procedure as described in reaction step 4c, the compound of formula 1 can be prepared from compound of formula 14 using the procedure described below:
A solution of the compound of formula 14 (wherein R-i , R2, X, m and n are as defined in the first aspect of the invention) in a solvent such as dimethylformamide (DMF) is added to a base such as sodium hydride at 0-2 °C and the reaction mixture is stirred at room temperature. After 25-35 min, compound of formula K:
Figure imgf000050_0001
K (wherein R3 is as defined in the first aspect of the present invention) is added and the reaction mixture is stirred for about 25-35 min.The compound of formula B (as described in the scheme 1 ) is then added and the reaction mixture is stirred at room temperature for 2-4 h, to yield the compound of formula 1 (wherein Q is:
Figure imgf000051_0001
R-i , R2, X, m and n are as defined in the first aspect of the invention).
Scheme 5 depicts a process for the preparation of the compound of formula 1 , wherein, Q is:
Figure imgf000051_0002
R3, R4 and R5 are as defined in the first aspect of the present invention.
Figure imgf000051_0003
(compound of formula 1) Reaction step 5a:
Preparation of the compound of formula 16:
A solution of the compound of formula 14 (prepared according to step 4a depicted in scheme 4, wherein Ri, R2, X, m and n are as defined in the first aspect of the invention) in a base such as pyridine, is treated with the compound of formula D:
Figure imgf000052_0001
D
(wherein R3 is as defined in the first aspect of the invention) at room temperature, to yield the compound of formula 16 (wherein Ri , R2, R3, X, m and n are as defined in the first aspect of the invention).
Reaction step 5b:
Preparation of the compound of formula 1 :
A solution of the compound of formula 16 (wherein R-i , R2, R3, X, m and n are as defined in the first aspect of the invention) in a solvent such as chlorobenzene is heated at 105-1 15 °C in the presence of a reagent such as phosphorous pentachloride for 1 -3 h. After evaporation of the solvent, the residue is dissolved in a solvent such as dichloromethane and treated with a base such as triethylamine and the compound of formula B (as described in step d of the scheme 1 ), to yield the compound of formula 1 (wherein Q is:
Figure imgf000052_0002
R-i, R2, X, m and n are as defined in the first aspect of the invention).
The compounds of formula 1 , as obtained in Schemes 1 -5 above can be optionally converted into their corresponding pharmaceutically acceptable salts.
The term "pharmaceutically acceptable salt(s)", as used herein, means those salts of compounds of the formula 1 which retain the efficacy and the biological properties of the free bases or of the free acids and are safe for use in mammals. In the context of the present invention, the pharmaceutically acceptable salts include organic and inorganic salts of the compounds of the invention (the compounds of formula 1 ) depending on the particular group (acidic or basic group) present in the said compounds.
When compounds of the present invention contain relatively basic groups, acid addition salts can be obtained. The pharmaceutically acceptable acid addition salts include those derived from inorganic acids, which are not limited to, such as hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, mono-hydrogensulfuric or hydroiodic acids and the like; as well as the salts derived from organic acids such as acetic, ascorbic, benzenesulfonic, benzoic, citric, ethanesulfonic, formic, fumaric, galacturonic, gluconic, glucuronic, glutamic, isobutyric, isonicotinic, lactic, maleic, malonic, mandelic, methanesulfonic, 4-methylbenzenesulfonic, nicotinic, oxalic, pantothenic, phthalic, propionic, saccharic, succinic, suberic, p-tolylsulfonic, tartaric acids and the like. When compounds of the present invention contain relatively acidic groups, base addition salts can be obtained. Examples of pharmaceutically acceptable organic base addition salts of the compounds of the present invention include those derived from organic bases such as lysine, arginine, guanidine, diethanolamine, choline, tromethamine, metformin and the like. Examples of pharmaceutically acceptable base addition salts of the compounds of the present invention include their alkali metal salts. Suitable alkali metal salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, or zinc salts.
The pharmaceutically acceptable salts of the compounds of formula 1 can be synthesized from the compound of formula 1 , which contains a basic or an acidic group, by using conventional chemical methods. Generally, the salts are prepared by treating the compound of formula 1 which may be a free base or an acid with a suitable salt- forming inorganic or an organic acid or a base in a suitable solvent or dispersant or from another salt by cation or anion exchange. Suitable solvents that can be used for the preparation of pharmaceutically acceptable salts include, but are not limited to, ethyl acetate, diethyl ether, methanol, ethanol, acetone, tetrahydrofuran, dioxane or mixtures of these solvents.
The compounds of formula 1 can be regenerated by contacting the salt with a base or an acid depending on the type of salt and isolating the parent compound in the conventional manner. The present invention also encompasses within its scope the solvates of the compounds of formula 1 .
Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. Certain compounds of the present invention can exist in multiple crystalline or amorphous forms. In general, all physical forms are suitable for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
Various polymorphs of the compound of formula 1 can be prepared by crystallization of the compound under different conditions. The different conditions are, for example, using different solvents or their mixtures for carrying out crystallization; crystallization at different temperatures; various modes of cooling, ranging from very fast to very slow cooling during crystallization or by heating or melting the compound followed by gradual or fast cooling. The presence of polymorphs can be determined by IR (Infra-red) spectroscopy, solid probe NMR (Nuclear Magnetic Resonance) spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques.
Those skilled in the art will recognize that stereocentres exist in the compounds of formula 1 . Accordingly, the present invention includes all possible stereoisomers and geometric isomers of the compound of formula 1 and includes not only racemic compounds but also the optically active isomers as well. When a compound of formula 1 is desired as a single enantiomer, it can be obtained either by resolution of the final product or by stereospecific synthesis from either isomerically pure starting material or an appropriate intermediate. Resolution of the final product, an intermediate or a starting material may be effected by any suitable method known in the art, for example, Chiral reagents for asymmetric synthesis by Leo A. Paquette; John Wiley & Sons Ltd (2003).
Additionally, in situations wherein tautomers of the compounds of formula 1 are possible, the present invention is intended to include all tautomeric forms of the compounds.
The present invention also encompasses within its scope prodrugs of the compound of formula 1 . Preferably prodrugs are those compounds that are converted to their parent compound intracellular^, where the cellular converting location is the site of therapeutic action. The prodrugs of the compounds of the present invention are derivatives, particularly simple derivatives of the said compounds which upon administration to a subject in need thereof undergoes conversion by metabolic or chemical processes to release the parent drug (e.g. the compound of formula 1 ) in vivo from which the prodrug is derived. The preferred prodrugs are pharmaceutically acceptable ester derivatives e.g., alkyl esters, cycloalkyl esters, alkenyl esters, benzyl esters, mono- or di-substituted alkyl esters that are convertible by solvolysis under physiological conditions to the parent carboxylic acid (e.g. the compound of formula 1 containing the carboxylic acid group), and those conventionally known in the art (An introduction to Medicinal Chemistry, Graham. L. Patrick, Second Edition, Oxford University Press, pg 239-248; Prodrugs: Challenges and Rewards, Part 1 and Part 2, AAPS Press, Edited by Valentino J. Stella, Renald T. Borchardt, Michael J. Hagemon, Reza Oliyai, Hans Maag, Jefferson W. Tilley).
In one aspect, the present invention relates to a method for the treatment of a disease or a disorder mediated by CB1 receptors, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula 1 , a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof.
In another aspect, the present invention provides a compound of formula 1 or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof; for use as a CB1 receptor antagonist.
The compound of formula 1 of the present invention or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof; can be used as CB1 receptor inverse agonist.
According to yet another aspect of the present invention, there is provided a compound of formula 1 or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof; for use in the treatment of a disease or a disorder mediated by CB1 receptors.
In yet another aspect, the present invention provides use of a compound of formula 1 or a pharmaceutically acceptable salt thereof; for the manufacture of a medicament for the treatment of a disease or a disorder mediated by CB1 receptors.
In an embodiment of the present invention, the present invention encompasses within its scope all the diseases or disorders wherein CB1 receptors are implicated.
In an embodiment, the disease or disorder mediated by CB1 receptors is gastrointestinal disorder; inflammatory disease or disorder; cardiovascular disease; cancer; metabolic disorder (e.g. obesity); osteoporosis; nephropathy; glaucoma; psychiatric disorder; neurological disorder; autoimmune hepatitis and encephalitis; pain; reproductive disorder; skin inflammatory disease or fibrotic disease.
In an embodiment, the disease or disorder mediated by CB1 receptor is gastrointestinal disorder; inflammatory disease or disorder; cardiovascular disease; cancer; metabolic disorder (e.g. obesity); psychiatric disorder or neurological disorder.
In an embodiment of the present invention, the disease or disorder mediated by CB1 receptor is gastrointestinal disorder.
In an embodiment, gastrointestinal disorder that can be treated by the compound of formula 1 or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof or pharmaceutical compositions containing the said compounds; is selected from functional bowel disease, gastro-esophagael reflux condition, secretory diarrhea, gastric ulcer, paralytic ileus, cholelithiasis or hernia.
In an embodiment of the present invention, the disease or disorder mediated by CB1 receptor is an inflammatory disease or disorder.
In an embodiment, the inflammatory disease or disorder that can be treated by the compound of formula 1 or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or solvate thereof or pharmaceutical compositions containing the said compounds; is selected from: arthritis, hepatitis, inflammatory bowel disease, ulcerative colitis, Crohn's disease or congestive obstructive pulmonary disorder.
In an embodiment of the present invention, the disease or disorder mediated by
CB1 receptor is a cardiovascular disease.
In an embodiment, cardiovascular disease that can be treated by the compound of formula 1 or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof or pharmaceutical compositions containing the said compounds; is selected from aneurysm, angina, arrhythmia, atherosclerosis, cardiomyopathy, cerebrovascular accident (stroke), cerebrovascular disease, congenital heart disease, congestive heart failure, myocarditis, valve disease, coronary artery disease, dilated cardiomyopathy, diastolic dysfunction, endocarditis, high blood pressure (hypertension), hypertrophic cardiomyopathy and its associated arrhythmia and dizziness, mitral valve prolapse, myocardial infarction (heart attack), venous thromboembolism, varicose veins or pulmonary embolism.
In an embodiment of the present invention, the disease or disorder mediated by CB1 receptor is cancer. Cancer can include metastatic or malignant tumors. In an embodiment, cancer that can be treated by the compound of formula 1 or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof or pharmaceutical compositions containing the said compounds; is selected from thyroid carcinoma, cardiac sarcoma, lung carcinoma, gastrointestinal carcinoma, genitourinary tract carcinoma, liver carcinoma, mantle cell lymphoma, bone sarcoma, sarcoma of the nervous system, gynaecological carcinoma, haematological cancer, adrenal gland neuroblastoma, skin cancer, astrocytic cancer, breast cancer, colorectal cancer, endometrial cancer, head and neck cancer or oral cancer.
Examples of cancer include squamous cell cancer (e.g. epithelial squamous cell cancer), lung cancer including small-cell lung cancer, non- small cell lung cancer, adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, blood cancer, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, as well as head and neck cancer.
In an embodiment of the present invention, the disease or disorder mediated by CB1 receptor is a metabolic disorder.
In an embodiment, the metabolic disorder that can be treated by the compound of formula 1 or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof or pharmaceutical compositions containing the said compounds; is selected from obesity, dyslipidemia, hyperlipidemia, low HDL (high density lipoprotein) and/or high LDL (low density lipoprotein) cholesterol level, hypertriglyceridemia, low adiponectin level, dyslipoproteinemia, impaired glucose tolerance, insulin resistance, increase in HbA1 c (glycosylated haemoglobin) level, type 2 diabetes, reduced metabolic activity, hypertension or non-alcoholic fatty liver disease.
In an embodiment, metabolic disorder that can be treated by the compound of formula 1 or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof or pharmaceutical compositions containing the said compounds; is selected from obesity, low HDL cholesterol level, high LDL cholesterol level, impaired glucose tolerance, insulin resistance, type 2 diabetes, reduced metabolic activity, hypertension or non-alcoholic fatty liver disease. In an embodiment, metabolic disorder that can be treated by the compound of formula 1 or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof or pharmaceutical compositions containing the said compounds is obesity.
In an embodiment, the metabolic disorder that can be treated by the compound of formula 1 or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof or pharmaceutical compositions containing the said compounds is type 2 diabetes, insulin resistance, impaired glucose or reduced metabolic activity.
In an embodiment, the metabolic disorder that can be treated by the compound of formula 1 or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof or pharmaceutical compositions containing the said compounds is type 2 diabetes.
In an embodiment of the present invention, the disease or disorder mediated by CB1 receptor is a psychiatric disorder or a neurological disorder.
In an embodiment, the psychiatric disorder or neurological disorder that can be treated by the compound of formula 1 of the invention or pharmaceutical compositions containing the said compounds; is selected from psychosis, anxiety, depression, attention deficits, dementia, distonia, Parkinson's disease, Alzheimer's disease, schizophrenia, epilepsy, Huntington's disease, Tourette's syndrome or cerebral ischaemia.
The present invention also encompasses within its scope the use of a compound of formula 1 or its pharmaceutically acceptable salt or a solvate in combination, with other therapeutically active agents; wherein the compound of formula 1 and the further therapeutic agent are administered either simultaneously or sequentially.
In another aspect, the present invention furthermore relates to pharmaceutical compositions containing a therapeutically effective amount of at least one compound of formula 1 or a stereoisomer, a tautomer or a pharmaceutically acceptable salt or a solvate thereof in addition to a customary pharmaceutically acceptable carrier or excipient. The present invention also relates to a process for the production of a pharmaceutical composition, which includes bringing at least one compound of formula 1 , into a suitable administration form using a pharmaceutically acceptable excipient and, if appropriate, further suitable additives or auxiliaries.
Accordingly, in an aspect, the present invention relates to a pharmaceutical composition comprising at least one compound of formula 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. The pharmaceutical composition(s) of the present invention can be administered orally, for example in the form of pills, tablets, coated tablets, capsules, granules or elixirs. Administration, however, can also be carried out rectally, for example in the form of suppositories, or parenterally, for example intravenously, intramuscularly or subcutaneously, in the form of injectable sterile solutions or suspensions, or topically, for example in the form of ointments or creams or transdermally, in the form of patches, or in other ways, for example in the form of aerosols or nasal sprays.
The pharmaceutical composition(s) according to the invention are prepared in a manner known and familiar to one skilled in the art. Pharmaceutically acceptable inert inorganic and/or organic carriers and/or additives can be used in addition to the compound of formula 1 , or a pharmaceutically acceptable salt for the production of oral dosage forms of compounds of formula 1 such as pills, tablets, coated tablets and hard gelatin capsules. It is possible to use, for example, lactose, corn starch or derivatives thereof, gum arabica, magnesia or glucose, etc. Carriers for soft gelatin capsules and suppositories are, for example, fats, waxes, natural or hardened oils, etc. Suitable carriers for the production of solutions, for example injection solutions, or of emulsions or syrups are, for example, water, physiological sodium chloride solution or alcohols, for example, ethanol, propanol or glycerol, sugar solutions, such as glucose solutions or mannitol solutions, or a mixture of the said solvents.
The pharmaceutical compositions normally contain from about 1 -99 %, for example, from about 5-70 %, or from about 10-30 % by weight of the compound of formula 1 or its pharmaceutically acceptable salt. The amount of the compound of formulal or its pharmaceutically acceptable salt in the pharmaceutical compositions normally ranges from about 0.01 -1000 mg, preferably 0.5-500 mg. The dose of the compounds of formula 1 of the present invention, which is to be administered, can cover a wide range depending on the type of disease or disorder to be treated. The dose to be administered daily is to be selected to suit the desired effect. A suitable dosage can be from about 0.01 -100 mg/kg of the compound of formula 1 or its pharmaceutically acceptable salt depending on the body weight of the recipient (subject) per day, for example, from about 0.1 -50 mg/kg/day of a compound of formula 1 or its pharmaceutically acceptable salt. If required, higher or lower daily doses can also be administered.
The selected dosage level will depend upon a variety of factors including the activity of a compound of the present invention employed, or its pharmaceutically acceptable salt, the route of administration, the time of administration, the rate of excretion of the particular compound being administered, the duration of the treatment, other concurrently administered drugs, compounds and/or materials, the age, sex, weight, condition, general health and prior medical history of the patient (subject) being treated, and like factors well known in the medical arts.
In addition to the compound of formula 1 or its pharmaceutically acceptable salt and the pharmaceutically acceptable carrier substances, the pharmaceutical compositions of the present invention can contain additives such as, for example, fillers, antioxidants, dispersants, emulsifiers, defoamers, flavors, preservatives, solubilizers or colorants. They can also contain more than one compound of formula 1 or their pharmaceutically acceptable salts. Furthermore, in addition to at least one compound of formula 1 or its pharmaceutically acceptable salt, the pharmaceutical compositions can also contain one or more other therapeutically or prophylactically active agents.
The present invention also encompasses within its scope use of a compound of formula 1 or its pharmaceutically acceptable salt in combination with other therapeutically active agents. The compound of formula 1 or its pharmaceutically acceptable salt, can be administered either simultaneously or sequentially in combination with the further therapeutically active agents.
The therapeutically active agents that can be used in combination with one or more compounds of formula I or its pharmaceutically acceptable salt can be selected from: CB1 receptor antagonists such as AM-6545 (National Inst. Alcohol Abuse Alcoholism, Northeastern University) LY-320135 (Lilly), Otenabant (Pfizer) and Rosonabant (Esteve); anti-inflammatory agents such as COX-2 inhibitors (e.g., Vioxx™, Celebrex™ and Bextra™); non-selective anti-inflammatory agents (ibuprofen, naproxen), acetaminophen, and steroids such as prednisolone, and budesonide; serotonin reuptake inhibitors (SSRIs, also known as serotonin boosters), such as Cipramil™ or Celexa™ (citalopram), Effexor™ (venlafaxine HCI), Elavil™ (amitriptyline), fluvoxamine maleate, Lexapro® (escitalopram oxalate), Paxil™ or Aropax™ (paroxetine), Prozac™ (fluoxetine), Sarafem™ (fluoxetine HCI), Zyban™ or Welibutrin™ (bupropion HCI) and Zoioft™ (sertraline HCI); selective seritonin and noradrenaline reuptake inhibitors (SSNRIs), such as Cymbalta™ (duloxetine) and Effexor™ (venlafaxine); carbonic anhydrase inhibitors (CAIs) such as Diamox® (acetazolomide), Neptazane® (Methazolamide); statins such as Crestor® (rosuvastatin sodium), Lipitor® (atorvastatin calcium), Zocor® (simvastatin); niacin derivatives such as Ateromixol® (policonasol), and liver X receptor (LXR) agonists/antagonists such as hypocholamide; anti-obesity agents such as growth hormone secretagogue receptor (GHSR) antagonists (GHCP07CHis, Asterion), glucagon-like peptide-1 (GLP-1 ) agonists such as Byetta® (Exenatide), Victoza® (Liraglutide); corticotropin releasing factor (CRF) antagonists such as Antalarmin (Pfizer), Pexacerfont (Bristol-Myers Squibb); histamine receptor-3 (H3) modulators; beta-3 adrenergic agonists such as Myrbetriq® (Mirabegron), lubabegron (Lilly); lipase inhibitors such as Xenical® (orlistat), Cetilistat (Alizyme); anti-diabetic agents or antihyperglycemic agents including insulin secretagogues or insulin sensitizers biguanides (Metformin, (Glucophage®)), sulfonyl ureas (Orinase® (tolbutamide), Glucotrol® (glipizide)), glucosidase inhibitors (Glyset® (miglitol) and/or meglitinides (Prandin® (repaglinide), Starlix® (nateglinide)), as well as insulin; and anti-hypertensive agents, such as angiotensin- converting enzyme (ACE) inhibitors (Capoten® (captopril), Vasotec® (Enalapril)), angiotensin II receptor antagonists (Diovan® (Valsartan), Cozaar®(Losartan)), as well as calcium channel blockers (Norvasc® (Amlodipine), Procardia® (Nifedipine)), β-adrenergic blockers (Tenormin® (Atenolol), Lopressor® (Metoprolol)).
It is understood that modifications that do not substantially affect the activity of the various aspects of this invention are included. Accordingly, the following examples are intended to illustrate but not to limit the present invention.
EXAMPLES
The following abbreviations or terms are used herein:
ACN Acetonitrile
CDCI3 Deuterated chloroform
DIPEA N,N-Diisopropylethylamine
DMF N, N-dimethylformamide
DMSO Dimethylsulfoxide
D2O Deuterated water
g : Gram
h Hour
HCI Hydrochloric acid
LiOH Lithium hydroxide
UOH.H2O Lithium hydroxide monohydrate mg Milligram
min : Minute(s)
mL Millilitre
μΙ_ Microlitre
μΜ Micromolar
mmol Millimole
mM Millimolar
MeOH Methanol
MgCI2 Magnesium chloride
NaHCO3 Sodium bicarbonate
Na2SO4 Sodium sulphate
NH4CI Ammonium chloride
°C Degree Centigrade
PCI5 Phosphorus pentachloride
TBTU N,N,N',N'-Tetramethyl-O-(benzotriazol-1 -yl)uronium
tetrafluoroborate
THF Tetrahydrofuran
TFA Trifluoroacetic acid Example 1 :
Ethyl 5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3-carboxylate
To a stirred solution of 4-chloroacetophenone (20 g, 129 mmol) in diethyl ether (100 mL) was slowly added a solution of lithium bis(trimethylsilyl)amide (155 mL, 155 mmol) at -78 °C over 1 h. After stirring for 10 h, diethyl oxalate (21 .20 mL, 155 mmol) in diethyl ether (40 mL) was added over 30 min at the same temperature and maintained for 2 h at -78 °C. The reaction mixture was stirred for 15 h at 25-30 °C. The solid was filtered under nitrogen atmosphere, washed with diethyl ether and dried to give a yellow, moisture-sensitive solid which was poured in water and acidified with 1 N HCI (pH = 2). The resulting mixture was extracted with ethyl acetate, washed with water and brine, dried (anhydrous Na2SO4) and concentrated to give intermediate ethyl 4-(4- chlorophenyl)-2,4-dioxobutanoate as a light yellow solid.
A stirred solution of ethyl 4-(4-chlorophenyl)-2,4-dioxobutanoate (23 g, 90 mmol) and (2,4-dichlorophenyl)hydrazine hydrochloride (21 .21 g, 99 mmol) in ethanol (690 mL) was refluxed for 3 h. The reaction mixture was allow to cool to room temperature and solvent was removed to give a red-orange solid, which was purified by column chromatography (silica gel, 0 - 9 % ethyl acetate in petroleum ether) to obtain the title compound.
Yield: 49 %; 1 H NMR (300 MHz, DMSO-a^): δ 1 .29 (t, J = 7.0 Hz, 3H, COOCH2CH3), 4.40 (q, J = 7.2 Hz, 2H, COOCH2CH3), 7.21 - 7.31 (m, 3H, pyrazole and Ar-H), 7.44 (d, J = 8.7 Hz, Ar-H), 7.66 (dd, J = 2.1 Hz, 8.4 Hz, 1 H, Ar-H), 7.81 (d, J = 8.7 Hz, Ar-H), 7.88 (d, J = 2.1 Hz, Ar-H); MS: m/z 41 9.0 [M + Na]+.
Example 2:
5-(4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3-carboxylic acid
To a stirred solution of the compound of example 1 (2.5 g, 6.32 mmol) in 60 imL of THF:methanol:water (7:2:1 ) was added LiOH.H2O (1 .392 g, 33.20 mmol) and the mixture was heated for 3 h at 80 °C. The mixture was allowed to cool to room temperature and the solvent was removed to give a sticky solid. Water was added to the solid obtained and the resulting mixture was acidified with 1 N HCI (pH = 2), extracted with ethyl acetate, washed with water and brine, dried (anhydrous Na2SO4) and concentrated. The crude material obtained was purified by column chromatography (silica gel, 0-35 % ethyl acetate in petroleum ether) to obtain the title compound.
Yield: 95 %; 1H NMR (300 MHz, DMSO-a^): δ 7.1 8 (s, 1 H, pyrazole-H), 7.26 (d, J = 8.7 Hz, 2H, Ar-H), 7.44 (d, J = 8.4 Hz, 2H, Ar-H), 7.65 (dd, J = 2.1 Hz, 8.5 Hz, 1 H, Ar-H), 7.79 (d, J = 8.7 Hz, 1 H, Ar-H), 7.87 (d, J = 2.1 Hz, 1 H, Ar-H), 1 3.14 (brs, 1 H, exchangeable in D2O, COOH); MS: m/z 369.0 [M + H]+.
Example 3:
5-(4-Chlorophenyl)-N-cyclopropyl-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboxamide
To a stirred solution of the compound of example 2 (2.0 g, 5.44 mmol) in dichloromethane (55 imL) was added cyclopropanamine (0.422 imL, 5.98 mmol), TBTU (1 .922 g, 5.98 mmol) and diisopropyl ethylamine (1 .045 imL, 5.98 mmol) at room temperature and the mixture was stirred for 5 h. The reaction mixture was quenched with water, extracted with dichloromethane, washed with water and brine, dried (anhydrous Na2SO4) and concentrated. The crude material obtained was purified by column chromatography (silica gel, 0 - 20 % ethyl acetate in petroleum ether) to obtain the title compound. Yield: 77 %; 1H NMR (300 MHz, DMSO-a : δ 0.50 - 0.75 (m, 4H, cyclopropyl-CH2), 2.75 - 2.90 (m, 1 H, cyclopropyl-CH), 7.08 (s, 1 H, pyrazole-H), 7.23 (d, J = 8.4 Hz, 2H, Ar-H), 7.41 (d, J = 8.4 Hz, 2H, Ar-H), 7.58 - 7.66 (m, 1 H, Ar-H), 7.78 (d, J = 8.7 Hz, 1 H, Ar-H), 7.82 (d, J = 2.1 Hz, 1 H, Ar-H), 8.37 (d, J = 4.5 Hz, 1 H, exchangeable in D2O, NH); MS: m/z 408.0 [M + H]+.
Example 4:
4-Chloro-5-(4-chlorophenyl)-N,N'-dicyclopropyl-1-(2,4-dichlorophenyl)-1 H- pyrazole-3-carboximidamide
To a stirred solution of the compound of example 3 (0.150 g, 0.369 mmol) in chlorobenzene (5 mL) was added PCI5 (0.381 g, 1 .845 mmol) at room temperature and the reaction mixture was heated at 131 °C for 1 .5 h. The mixture was allowed to cool to room temperature, and the solvent was removed to give a yellow sticky solid, which was dissolved in dichloromethane (5 mL). Triethylamine (1 .028 mL, 7.38 mmol) was added, followed by cyclopropanamine or its hydrochloride (8.0 equivalents), and the mixture was stirred at room temperature for 14 h. The reaction mixture was quenched with water, extracted with dichloromethane, washed with water and brine, dried (anhydrous Na2SO4) and concentrated. The crude material was purified by column chromatography (silica gel, 0 - 1 1 % MeOH in dichloromethane) to obtain the title compound.
Yield: 42.3 %; 1 H NMR (300 MHz, DMSO-a : δ 0.65 - 0.10 (m, 8H, cyclopropyl-CH2), 2.85 - 3.0 (m, 2H, cyclopropyl-CH), 7.33 (d, J = 8.7 Hz, 2H, Ar-H), 7.57 (d, J = 8.4 Hz, 2H, Ar-H), 7.66 (dd, J = 2.1 Hz, 8.4 Hz, 1 H, Ar-H), 7.76 (d, J = 8.7 Hz, 1 H, Ar-H), 7.89 (d, J = 2.1 Hz, 1 H, Ar-H ), 10.2 (brs, 1 H, exchangeable in D2O, NH); MS: m/z 481 .1 [M + H]+.
Example 5:
N-((1 S,3R,5S)-Adamantan-1 -yl)-4-chloro-5-(4-chlorophenyl)-N'-cyclopropyl-1 -(2,4- dichlorophenyl)-1 H-pyrazole-3-carboximidamide
The compound of the example 3 (0.150 g, 0.369 mmol) in chlorobenzene (5 mL) was treated with (3s,5s,7s)-adamantan-1 -amine or its hydrochloride (8.0 equivalents) according to the procedure for the preparation of the compound of example 4 to obtain the title compound. Yield: 9.1 %; 1 H NMR (300 MHz, DMSO-a : δ 0.35 - 0.55 (m, 2H, cyclopropyl-CH2), 0.70 - 0.90 (m, 2H, cyclopropyl-CH2), 1 .40 - 1 .70 (m, 6H, adamantyl), 1 .75 - 2.1 0 (m, 9H, adamantyl), 2.65 - 2.80 (m, 1 H, cyclopropyl-CH), 5.47 (brs, 1 H, exchangeable in D2O, NH), 7.1 0 - 7.30 (m, 2H, Ar-H), 7.40 - 7.50 (m, 1 H, Ar-H), 7.55 - 7.65 (m, 1 H, Ar- H), 7.80 - 7.95 (m, 1 H, Ar-H); MS: m/z 575.0 [M + H]+.
Example 6:
4-Chloro-5-(4-chlorophenyl)-N'-cyclopropyl-1 -(2,4-dichlorophenyl)-N-(1 ,1 - dioxidothiomorpholino)-1 H-pyrazole-3-carboximidamide
The compound of the example 3 (0.1 50 g, 0.369 mmol) in chlorobenzene (5 imL) was treated with 4-aminothiomorpholine 1 ,1 -dioxide (8.0 equivalents) according to the procedure for the preparation of the compound of example 4 to obtain the title compound.
Yield: 28.4 %; 1 H NMR (300 MHz, DMSO-a : δ 0.30 - 0.60 (m, 4H, cyclopropyl-CH2), 2.48 - 2.70 (m, 1 H, cyclopropyl-CH), 2.90 - 3.25 (m, 8H, thiomorpholine), 7.04 (s, 1 H, exchangeable in D2O, NH), 7.31 (d, J = 8.1 Hz, 2H, Ar-H), 7.50 (d, J = 8.1 Hz, 2H, Ar- H), 7.57 - 7.64 (m, 1 H, Ar-H), 7.75 (d, J = 8.7 Hz, 1 H, Ar-H), 7.8 (brs, 1 H, Ar-H); MS: m/z 574.0 [M + H]+. Example 7:
4-Chloro-1 -(2-chlorophenyl)-5-(4-chlorophenyl)-N'-cyclopropyl-N-(1 ,1 -dioxidothio morpholino)-1 H-pyrazole-3-carboximidamide
The compound of example 7 was prepared analogous to the compound of example 4, using the procedure described for the preparation of the compound of example 4, wherein, 2,4-dichlorophenylhydrazine hydrochloride was replaced with 2- chlorophenylhydrazine hydrochloride.
Yield: 2.6 %; 1 H NMR (300 MHz, DMSO-a : δ 0.35 - 0.55 (m, 4H, cyclopropyl-CH2 ) 2.52 - 2.62 (m, 1 H, cyclopropyl-CH ), 3.1 0 (brs, 4H, thiomorpholine), 3.25 (brs, 4H, thiomorpholine), 7.04 (s, 1 H, exchangeable in D2O, NH), 7.30 {d, J = 8.4 Hz, 2H, Ar-H), 7.41 (m, 5H, Ar-H) 7.68 - 7.72 (m, 1 H, Ar-H); MS: m/z: 539.6 [M + H]+.
Example 8:
5-(4-Chlorophenyl)-N,N'-dicyclopropyl-1-(2,4-dichlorophenyl)-1 H-pyrazole-3- carboximidamide To a stirred solution of the compound of example 3 (0.150 g, 0.369 mmol) in chlorobenzene (5 mL) was added PCI5 (0.1 14 g, 0.553 mmol) at room temperature and the reaction mixture was heated at 131 °C for 1 .5 h. The mixture was allowed to cool to room temperature, and the solvent was removed to give a yellow sticky solid, which was dissolved in dichloromethane (5 mL). Triethylamine (1 .028 g, 7.38 mmol) was added, followed by cyclopropanamine or its hydrochloride (8.0 equivalents), and the mixture was stirred at room temperature for 14 h. The reaction mixture was quenched with water, extracted with dichloromethane, washed with water and brine, dried (anhydrous Na2SO4) and concentrated. The crude material obtained was purified by column chromatography (silica gel, 0 - 10 % MeOH in dichloromethane) to obtain the title compound.
Yield: 3.6 %; 1 H NMR (300 MHz, DMSO-a : δ 0.66 - 0.10 (m, 8H cyclopropyl-CH2), 2.65 - 2.95 (m, 2H, cyclopropyl-CH), 7.26 {d, J = 8.4 Hz, 2H, Ar-H), 7.42 - 7.55 (m, 3H, pyrazole- & Ar-H), 7.67 (d, J = 8.0 Hz, 1 H, Ar-H), 7.89 (d, J = 8.7 Hz, 1 H, Ar-H), 7.89 (s, 1 H, Ar-H), 10.04 (brs, 1 H, exchangeable in D2O, NH); MS: m/z 446.1 [M + H]+.
Example 9:
N-((1 S,3R,5S)-Adamantan-1 -yl)-5-(4-chlorophenyl)-N'-cyclopropyl-1 -(2,4- dichlorophenyl)-1 H-pyrazole-3-carboximidamide
The compound of the example 3 (0.150 g, 0.369 mmol) in chlorobenzene (5 mL) was treated with (3s,5s,7s)-adamantan-1 -amine or its hydrochloride (8.0 equivalents) according to the procedure described for the preparation of the compound of example 7 to obtain the title compound.
Yield: 10 %; 1 H NMR (300 MHz, DMSO-a : δ 0.35 - 0.45 (m, 2H, cyclopropyl-CH2), 0.55 - 0.62 (m, 2H, cyclopropyl-CH2), 1 .58 (brs, 6H, adamantyl), 1 .95 - 2.10 (m, 9H, adamantyl), 2.95 - 3.05 (m, 1 H, cyclopropyl-CH), 5.09 (s, 1 H, exchangeable in D2O, NH), 6.95 (s, 1 H, pyrazole-H), 7.24 (d, J = 8.4 Hz, 2H, Ar-H), 7.43 (d, J = 8.4 Hz, 2H, Ar-H), 7.58 - 7.65 (m, 1 H, Ar-H), 7.69 (d, J = 8.4 Hz, 1 H, Ar-H), 7.86 - 7.89 (m, 1 H, Ar- H); MS: m/z 540.6 [M + H]+.
Example 10:
N-((2R)-Adamantan-2-yl)-5-(4-chlorophenyl)-N'-cyclopropyl-1-(2,4-dichlorophenyl) -1 H-pyrazole-3-carboximidamide The compound of the example 3 (0.150 g, 0.369 mmol) in chlorobenzene (5 imL) was treated with (1 R,3S,5r,7r)-adamantan-2-amine or its hydrochloride (8.0 equivalents) according to the procedure described for the preparation of the compound of example 7 to obtain the title compound.
Yield: 20.1 %; 1 H NMR (300 MHz, DMSO-a : δ 0.30 - 0.50 (m, 2H, cyclopropyl-CH2), 0.52 - 0.70 (m, 2H, cyclopropyl-CH2), 1 .32 - 2.00 (m, 14H, adamantyl), 3.00 - 3.15 (m, 1 H, cyclopropyl-CH), 3.82 - 3.90 (m, 1 H, adamantyl), 5.61 (brs, 1 H, exchangeable in D2O, NH), 7.04 (s, 1 H, pyrazole-H), 7.20 - 7.35 (m, 2H, Ar-H), 7.40 - 7.50 (m, 2H, Ar- H), 7.56 - 7.68 (m, 1 H, Ar-H), 7.70 - 7.75 (m, 1 H, Ar-H), 7.85 - 7.90 (m, 1 H, Ar-H); MS: m/z 540.6 [M + H]+.
Example 11 :
5-(4-Chlorophenyl)-N'-cyclopropyl-1 -(2,4-dichlorophenyl)-N-(1 ,1 - dioxidothiomorpholino)-1 H-pyrazole-3-carboximidamide
The compound of the example 3 (0.150 g, 0.369 mmol) in chlorobenzene (5 imL) was treated with 4-aminothiomorpholine 1 ,1 -dioxide (8.0 equivalents) according to the procedure described for the preparation of the compound of example 7 to obtain the title compound.
Yield: 25.2 %; 1 H NMR (300 MHz, DMSO-d6): δ 0.40 - 0.60 (m, 4H, cyclopropyl-CH2 ), 2.80 - 3.00 (m, 1 H, cyclopropyl-CH ), 3.06 - 3.30 (m, 8H, thiomorpholine), 6.71 (s, 1 H, exchangeable in D2O, NH), 6.97 (s, 1 H, pyrazole-H), 7.24 (d, J = 8.4 Hz, 2H, Ar-H), 7.41 (d, J = 8.4 Hz, 2H, Ar-H), 7.57 - 7.64 (m, 1 H, Ar-H), 7.68 (d, J = 8.1 Hz, 1 H, Ar-H), 7.84 (d, J = 2.1 Hz,1 H, Ar-H); MS: m/z 539.2 [M + H]+. Example 12:
4-((5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-1 H-pyrazol3-yl)(cyclopropylimino) methyl)thiomorpholine 1 ,1 -dioxide
The compound of the example 3 (0.150 g, 0.369 mmol) in chlorobenzene (5 imL) was treated with thiomorpholine 1 ,1 -dioxide (8.0 equivalents) according to the procedure for the preparation of the compound of example 7 to obtain the title compound.
Yield: 38.8 %; 1 H NMR (300 MHz, DMSO-a^): δ 0.50 - 0.70 (m, 4H, cyclopropyl-CH2) 2.80 - 3.00 (m, 1 H, cyclopropyl-CH) 3.20 - 4.20 (m, 8H, thiomorpholine) 7.24 - 7.38 (m, 3H pyrazole & Ar-H) 7.5 (d, J = 8.4 Hz, 2 H, Ar-H), 7.64 - 7.20 (m, 1 H, Ar-H), 7.84 (d, J = 8.4 Hz, 1 H, Ar-H), 7.89 - 7.91 (brs, 1 H, Ar-H), 1 0.1 8 (s, 1 H, exchangeable in D2 NH); MS: m/z 525.1 [M + H]+.
Example 13:
5-(4-Chlorophenyl)-N'-cyclopropyl-1 -(2,4-dichlorophenyl)-N-morpholino-1 H- pyrazole-3-carboximidamide
The compound of the example 3 (0.1 50 g, 0.369 mmol) in chlorobenzene (5 imL) was treated with morpholin-4-amine or its hydrochloride (8.0 equivalents) according to the procedure for the preparation of the compound of example 7 to obtain the title compound.
Yield: 20.7 %; 1 H NMR (300 MHz, DMSO-a^): δ 0.30 - 0.60 (m, 4H, cyclopropyl-CH2) 2.56 (brs, 4H, morpholine), 2.80 - 3.00 (m, 1 H, cyclopropyl-CH), 3.68 (brs, 4H, morpholine), 6.40 (s, 1 H, exchangeable in D2O, NH), 6.89 (s, 1 H, pyrazole-H) 7.23 (d, J = 8.4 Hz, 2H, Ar-H), 7.41 (d, J = 8.4 Hz, 2H, Ar-H), 7.52 - 7.69 (m, 2H, Ar-H), 7.83 (brs, 1 H, Ar-H); MS: m/z 490.2 [M]+.
Example 14:
2-(5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3-yl)-1 -cyclopropyl-4- isopropyl-1 H-imidazol-5(4H)-one
The compound of the example 3 (0.1 50 g, 0.369 mmol) in chlorobenzene (5 imL) was treated with (R)-methyl 2-amino-3-methylbutanoate or its hydrochloride (8.0 equivalents) according to the procedure for the preparation of the compound of example 7 to obtain the title compound.
Yield: 4.8 %; 1 H NMR (300 MHz, DMSO-a : δ 0.62 (brs, 2H, cyclopropyl-CH2), 0.78 (d, 3H, isopropyl-CH3 ), 0.84 (d, 2H, cyclopropyl-CH2), 1 .03 (d, 3H, isopropyl-CH3), 2.1 0 - 2.30 (m, 1 H, isopropyl-CH), 7.07 (d, J = 4.2 Hz, 1 H, CH), 7.26 - 7.34 (m, 3H, Ar-H & pyrazole-H), 7.46 (d, J = 8.40 Hz, 1 H, Ar-H), 7.64 (dd, J = 2.1 Hz, 8.4 Hz,1 H, Ar-H), 7.79 (d, J = 8.7 Hz, 1 H, Ar-H), 7.88 (d, J = 2.1 Hz, Ar-Hj; MS: m/z 488.6 [M + H]+. Example 15:
1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyclopropyl-N-(1 ,1 -dioxidothio
morpholino)-1 H-pyrazole-3-carboximidamide
The compound of example 1 5 was prepared analogous to the compound of example 1 1 , using the procedure comprised in preparation of the compound of example 1 1 , wherein, 2,4-dichlorophenylhydrazine hydrochloride was replaced with 2- chlorophenylhydrazine hydrochloride.
Yield: 18.4 %; 1H NMR (300 MHz, DMSO-a^): δ 0.40 - 0.6 (m, 4H, cyclopropyl-CH2 ) 2.90 - 3.00 (m, 1 H, cyclopropyl-CH ), 3.05 - 3.20 (m, 4H, thiomorpholine), 3.21 - 3.31 (m, overlap with H2O in DMSO, 4H, thiomorpholine), 6.70 (s, 1 H, exchangeable in D2O, NH), 6.97 (s, 1 H, pyrazole-H), 7.23 (d, J = 8.4 Hz, 2H, Ar-H), 7.30 (d, J = 8.4 Hz, 2H, Ar-H), 7.45 - 7.68 (m, 4H, Ar-H); MS: m/z 505.3 [M + H]+.
Example 16:
1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N-cyclohexyl-N'-cyclopropyl-1 H-pyrazole- 3-carboximidamide
The compound of example 16 was prepared analogous to the compound of example 15, using the procedure comprised in the preparation of the compound of example 15, wherein 4-aminothiomorpholine 1 ,1 -dioxide was replaced with cyclohexyl amine.
Yield: 5.2 %; 1H NMR (300 MHz, DMSO-a^): δ 1 .28 - 1 .41 (m, 1 1 H, cyclopropyl and cyclohexyl- CH2), 1 .81 (m, 3H, cyclopropyl and cyclohexyl- CH2), 2.48 (m, 1 H, cyclohexyl- CH), 3.44 (m, 1 H, cyclopropyl- CH), 6.66 (s, 1 H, Ar-H), 7.24 (d, 2H, J = 8.4 Hz, Ar-H), 7.44 (d, 2H, J = 8.4 Hz, Ar-H), 7.53 - 7.59 (m, 3H, Ar-H), 7.68 (m, 1 H, Ar-H), 10.53 (brs, cyclohexylamine-NH, exchangeable in D2O); MS m/z: [M+H]+ = 454.6.
Example 17:
4-((5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-1 H-pyrazol-3-yl)(methylimino) methyl)thiomorpholine 1 ,1 -dioxide
The compound of example 17 was prepared analogous to the compound of example 12, using the procedure comprised in the preparation of the compound of example 12, wherein cyclopropanamine was replaced with methanamine.
Yield: 18.2 %; 1 H NMR (500 MHz, DMSO-a^): δ 1 .23 (s, 3H, -CH3), 3.20 - 3.40 (brs, overlap with H^O in DMSO, 4H, thiomorpholine), 4.06 (brs, 2H, thiomorpholine), 4.32 (brs, 2H, thiomorpholine), 7.12 (s, 1 H, pyrazole-H), 7.30 (d, J = 8.0 Hz, 2H, Ar-H), 7.26 (d, J = 8.0 Hz, 2H, Ar-H), 7.64 (d, J = 8.0 Hz, 1 H, Ar-H), 7.75 (d, J = 8.0 Hz, 1 H, Ar-H), 7.94 (s, 1 H, Ar-H) 1 1 .13 (s, 1 H, exchangeable in D2O, NH); MS: m/z 486.1 [M - CH3]+. Example 18:
5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-N'-ethyl-N-morpholino-1H-pyrazole-3- carboximidamide
The compound of example 18 was prepared analogous to the compound of example 13, using the procedure comprised in the preparation of the compound of example 13, wherein cyclopropanamine was replaced with ethanamine.
Yield: 27.5 %; 1H NMR (500 MHz, DMSO-a : δ 1.22 (t, J= 7.0 Hz, 3H, -CH3), 2.80 - 3.10 (m, 4H, morpholine-CH2), 3.30-4.0 (m, 6H, ethyl-CH2, & morpholine), 7.30 (d, J = 8.5 Hz, 2H, Ar-H), 7.40 (s, 1H, pyrazole-H), 7.52 (d, J= 8.5 Hz, 2H, Ar-H), 7.68 - 7.73 (m, 1H, Ar-H ), 7.83 (d, J = 8.5 Hz, 1H, Ar-H), 7.94 (s, 1H, Ar-H) 11.13 (s, 1H, exchangeable in D2O, NH); MS: m/z 479.6 [M + H]+.
Example 19:
4-((5-(4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3-yl) (ethylimino) methyl)thiomorpholine 1,1 -dioxide
The compound of example 19 was prepared analogous to the compound of example 15, using the procedure comprised in the preparation of the compound of example 15, wherein cyclopropanamine was replaced with ethanamine.
Yield: 12.6 %; 1H NMR (500 MHz, DMSO-a : δ 1.05 (t, J= 7.0 Hz, 3H, -CH3), 3.10 - 3.15 (brs, 4H, thiomorpholine ), 3.17 (q, J = 7.0 Hz, 2H, CH2), 3.70 - 3.80 (brs, 4H, thiomorpholine), 6.97 (s, 1 H, pyrazole-H), 7.26 (d, J = 8.0 Hz, 2H, Ar-H), 7.61 - 7.70 (m, 1 H, Ar-H), 7.74 {d, J = 8.5 Hz, 1 H, Ar-H), 7.88 (d, J = 2.0 Hz, 1 H, Ar-H); MS: m/z 512.7 [M + H]+. Example 20:
Ethyl 5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-4-methyl-1 H-pyrazole-3- carboxylate
To a stirred solution of 1-(4-chlorophenyl)propan-1-one (20 g, 119 mmol) in diisopropyl ether (150 mL) was slowly added a solution of lithium bis(trimethylsilyl)amide (119 mL, 119 mmol) at 14-28 °C. After stirring for 30 min, diethyl oxalate (21.06 mL, 154 mmol) was added over 30 min at the same temperature and the reaction mixture was stirred for 15 h at 25-30 °C. The solid was filtered under nitrogen atmosphere, washed with diethyl ether and dried to give a yellow, moisture- sensitive solid which was poured in water and acidified with 1N HCI (pH = 2). The resulting mixture was extracted with ethyl acetate, washed with water and brine, dried (anhydrous Na2SO4) and concentrated to give intermediate ethyl 4-(4-chlorophenyl)-3- methyl-2,4-dioxobutanoate (23 g) as a red oil.
A stirred solution of ethyl 4-(4-chlorophenyl)-3-methyl-2,4-dioxobutanoate (23 g, 86 mmol) and (2,4-chlorophenyl)hydrazine hydrochloride (20.10 g, 94 mmol) in ethanol (600 mL) was heated for 16 h. The mixture was allowed to cool to room temperature, and the solvent was removed, which was purified by column chromatography (silica gel, petroleum ether in ethyl acetate, 9:1 ) to obtain the title compound.
Yield: 35 %; 1H NMR (300 MHz, CDCI3): δ 1 .43 (t, J = 7.2 Hz, 3H, COOCH2CH3), 2.34 (s, 3H, pyrazole-CH3), 4.40 (q, J = 7.2 Hz, 2H, COOCH2CH3), 7.08 (d, J = 8.4 Hz, 2H, Ar-H), 7.27 - 7.39 (m, 5H, Ar-H); MS: m/z 41 1 .9 [M + H]+.
Example 21 :
5-(4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-4-methyl-1 H-pyrazole-3-carboxylic acid To a stirred solution of the compound of example 20 (5.0 g, 12.20 mmol) in 120 mL of THF:methanol:water (7:2:1 ) was added LiOH.H2O (2.69 g, 64.1 mmol) and refluxed for 3 h. The mixture was allowed to cool to room temperature, and solvent was removed to give a sticky solid. To the solid was added water and acidified using 1 N HCI (pH = 2), filtered, washed with water, diethyl ether and dried under vacuum to obtain the title compound.
Yield: 92 %; 1H NMR (300 MHz, DMSO-a : δ 2.22 (s, 3H, pyrazole-CH3), 7.22 (brd, J = 8.1 Hz, 2H, Ar-H), 7.46 (brd, J = 8.1 Hz, 2H, Ar-H), 7.57 (d, J = 8.4 Hz, 1 H, Ar-H), 7.36 (d, J = 8.4 Hz, 1 H, Ar-H), 7.78 (m, 1 H, Ar-H), 12.95 (brs, 1 H, exchangeable in D2O, COOH); MS: m/z 382.9 [M + H]+.
Example 22:
5-(4-Chlorophenyl)-N-cyclopropyl-1-(2,4-dichlorophenyl)-4-methyl-1 H-pyrazole-3- carboxamide
To a stirred solution of the compound of example 21 (2.0 g, 5.24 mmol) in dichloromethane (20 mL) were added cyclopropylamine (0.406 mL, 5.76 mmol), TBTU (1 .85 g, 5.76 mmol) and diisopropyl ethylamine (1 .007 mL, 5.76 mmol) and the reaction mixture was stirred at room temperature for 5 h. The reaction mixture was quenched with water, extracted with dichloromethane, washed with water and brine, dried (anhydrous Na2SO4) and concentrated. The crude material obtained was purified by column chromatography (silica gel, 50-60 % ethyl acetate in petroleum ether) to obtain the title compound.
Yield: 77 %; 1H NMR (300 MHz, CDCI3): δ 0.60 - 0.63 (m, 4H, cyclopropyl-CH2), 2.23 (s, 3H, pyrazole-CH3), 2.82 (m, 1 H, cyclopropyl-CH), 7.22 (d, J = 8.1 Hz, 2H, Ar-H), 7.45 (d, J = 8.1 Hz, 2H, Ar-H), 7.56 (d, J = 8.4 Hz, 1 H, Ar-H), 7.71 - 7.75 (m, 2H, Ar-H), 8.25 (m, 1 H, exchangeable in D2O, -NH); MS: 422.1 m/z [M + H]+.
Example 23:
5-(4-Chlorophenyl)-N,N'-dicyclopropyl-1-(2,4-dichlorophenyl)-4-methyl-1 H- pyrazole-3-carboximidamide
To a stirred solution of the compound of example 22 (0.150 g, 0.357 mmol) in chlorobenzene (5 imL) was added PCI5 (0.186 g, 0.891 mmol), and the reaction mixture was heated at 131 °C for 1 .5 h. The mixture was allowed to cool to room temperature and solvent was removed to give a yellow sticky solid. This solid was dissolved in dichloromethane (5 imL), cyclopropanamine or its hydrochloride (6.0 equivalents) was added, and the mixture was stirred at room temperature for 14 h. The reaction mixture was quenched with water, extracted with dichloromethane, washed with water and brine, dried (anhydrous Na2SO4) and concentrated. The crude material was purified by column chromatography (silica gel, 2-3 % methanol in dichloromethane) to obtain the title compound.
Yield: 6.1 %; 1H NMR (300 MHz, DMSO-a^): δ 0.24 - 0.42 (m, 8H, cyclopropyl-CH?), 2.10 (s, 3H, pyrazole-CH3), 3.14 - 3.34 (m, 2H, cyclopropyl-CH), 7.33 (d, J = 8.1 Hz, 2H, Ar-H), 7.51 (d, J = 8.4 Hz, 2H, Ar-H), 7.60 (d, J = 8.4 Hz, 2H, Ar-H) , 7.69 (d, J = 8.4 Hz, 2H, Ar-H), 7.84 (brs,1 H, Ar-H), 8.46 (brs, 1 H, exchangeable in D2O, NH); MS: m/z 459.3 [M]+.
Example 24:
5-(4-Chlorophenyl)-N'-cyclopropyl-1 -(2,4-dichlorophenyl)-N-(1 ,1 -dioxidothio morpholino)-4-methyl-1 H-pyrazole-3-carboximidamide
The compound of the example 22 (0.150 g, 0.357 mmol) in chlorobenzene (5 imL) was treated with 4-aminothiomorpholine 1 ,1 -dioxide (8 equivalents) according to the procedure for the preparation of the compound of example 23 to obtain the title compound. Yield: 8.6 %; 1H NMR (300 MHz, DMSO-a : δ 0.42 - 0.46 (m, 4H, cyclopropyl-CH2), 2.07 (s, 3H, pyrazole-CH3), 2.70 (m, 1 H, cyclopropyl-CH), 3.09 - 3.33 (m, 8H, thiomorpholine-CH2), 6.82 (s, 1 H, exchangeable in D2O, HH), 7.21 (d, J = 8.4 Hz, 2H, Ar-H), 7.45(d, J = 8.4 Hz, 2H, Ar-H), 7.55 - 7.61 (m, 2H, Ar-H), 7.77 (m, 1 H, Ar-H); MS: 553.9 m/z [M + H]+.
Example 25:
4- ((5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1 H-pyrazol-3-yl)
(cyclopropylimino)methyl)thiomorpholine 1 ,1 -dioxide
The compound of the example 22 (0.150 g, 0.357 mmol) in chlorobenzene (5 mL) was treated with thiomorpholine 1 ,1 -dioxide (8 equivalents) according to the procedure for the preparation of the compound of example 23 to obtain the title compound.
Yield: 9.3 %; 1H NMR (300 MHz, DMSO-a : δ 0.57 - 0.62 (m, 4H, cyclopropyl-CH2), 2.62 (m, 1 H, cyclopropyl-CHj, 2.73 (s, 3H, pyrazole-CH3), 3.03 - 3.13 (m, 4H, thiomorpholine-CH2), 3.52 - 3.70 (m, 4H, thiomorpholine-CH2), 7.32 (d, J = 8.1 Hz, 2H, Ar-H), 7.47 (d, J = 8.4 Hz, 2H, Ar-H), 7.56 - 7.61 (m, 1 H, Ar-H), 7.63 - 7.69 (m, 1 H, Ar- H), 7.80 - 7.82 (m, 1 H, Ar-H); MS: m/z 538.2 [M + H]+. Example 26:
5- (4-Chlorophenyl)-N'-cyclopropyl-1-(2,4-dichlorophenyl)-4-methyl-N-morpholino- 1 H-pyrazole-3-carboximidamide
The compound of the example 22 (0.150 g, 0.357 mmol) in chlorobenzene (5 mL) was treated with morpholin-4-amine or its hydrochloride (6.0 equivalents) according to the procedure described for the preparation of the compound of example 23 to obtain the title compound.
Yield: 7.7 %; 1H NMR (300 MHz, DMSO-a^): δ 0.39 - 0.47 (m, 4H, cyclopropyl- CH2), 2.07 (s, 3H, pyrazole-CH3), 2.49 - 2.68 (m, 5H, aminomorpholine-CH2 & cyclopropyl-CH), 3.70 (brs, 4H, aminomorpholine-C -/2), 6.50 (s, 1 H, exchangeable in D2O, HH), 7.21 (d, J = 8.4 Hz, 2H, Ar-H), 7.45 (d, J = 8.7 Hz, 2H, Ar-H), 7.50 - 7.60 (m, 2H, Ar-H), 7.78 (m, 1 H, Ar-H); MS: m/z 505.9 [M + H]+. Example 27:
N-((5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1 H-pyrazol-3-yl)
(morpholino)methylene)cyclopropanamine
The compound of the example 22 (0.150 g, 0.357 mmol) in chlorobenzene (5 mL) was treated with morpholine (6.0 equivalents) according to the procedure described for the preparation of the compound of example 23 to obtain the title compound.
Yield: 9.1 %; 1H NMR (300 MHz, DMSO-a^): δ 0.48 - 0.55 (m, 4H, cyclopropyl-CH2), 2.23 (s ,3H, pyrazole-CH3), 2.61 (m, 1 H, cyclopropyl-CHj, 3.13 (m, 4H, morpholine- CH2), 3.46 - 3.57 (m, 4H, morpholine-CH2), 7.33 (d, J = 8.4 Hz, 2H, Ar-H), 7.44 (d, J = 8.4 Hz, 2H, Ar-H), 7.55 (d, J = 8.7 Hz, 1 H, Ar-H), 7.69 (d, J = 8.7 Hz, 1 H, Ar-H), 7.77 - 7.79 (m, 1 H, Ar-H); MS: m/z 489.5 [M]+.
Example 28:
Ethyl 1 -(2-chlorophenyl)-5-(4-chlorophenyl)-4-methyl-1 H-pyrazole-3-carboxylate
To a stirred solution of 1 -(4-chlorophenyl)propan-1 -one ( 20 g, 1 19 mmol) in diisopropyl ether (150 mL) was slowly added a solution of lithium bis(trimethylsilyl)amide (1 19 mL, 1 19 mmol) at 14-28 °C. After stirring for 30 min, diethyl oxalate (21 .06 mL, 154 mmol) was added over 30 min at the same temperature and the reaction mixture was stirred for 15 h at 25-30 °C. The solid was filtered under nitrogen atmosphere, washed with diethyl ether and dried to give a yellow, moisture- sensitive solid which was poured in water and acidified with 1 N HCI (pH = 2). The resulting mixture was extracted with ethyl acetate, washed with water and brine, dried (anhydrous Na2SO4) and concentrated to give ethyl 4-(4-chlorophenyl)-3-methyl-2,4- dioxobutanoate (23.0 g) as a red oil.
A stirred solution of ethyl 4-(4-chlorophenyl)-3-methyl-2,4-dioxobutanoate (23.0 g, 86 mmol) and (2-chlorophenyl)hydrazine hydrochloride (16.86 g, 94 mmol) in ethanol (600 mL) was heated at reflux temperature for 16 h. The mixture was allowed to cool to room temperature and the solvent was removed to give a red-orange solid, which was purified by column chromatography (silica gel, petroleum ether/ethyl acetate, 9:1 ) to obtain the title compound.
Yield: 43 %; 1H NMR (300 MHz, CDCI3): δ 1 .42 (t, J = 7.2 Hz, 3H, COOCH2CH3), 2.35 (s, 3H, pyrazole-CH3), 4.40 (q, J = 7.2 Hz, 2H, COOCH2CH3), 7.08 (brd, J = 8.4 Hz, 2H, Ar-H), 7.27 (d, J = 8.4 Hz, 2H, Ar-H), 7.30 - 7.42 (m, 4H, Ar-H); MS: m/z 398.9 [M + Na]+.
Example 29:
1 -(2-chlorophenyl)-5-(4-chlorophenyl)-4-methyl-1 H-pyrazole-3-carboxylic acid
To a stirred solution of the compound of example 28 (4.50 g, 1 1 .99 mmol) in 240 mL of THF:methanol:water (7:2:1 ) was added LiOH.H2O (2.64 g, 63.0 mmol) and the mixture was refluxed for 3 h. The mixture was allowed to cool to room temperature, and solvent was removed to give a sticky solid. To the solid was added water and acidified using 1 N HCI (pH = 2), filtered, washed with water, diethyl ether and dried under vacuum to obtain the title compound.
Yield: 82 %; 1H NMR (300 MHz, DMSO-a^): δ 2.23 (s, 3H, pyrazole-CH3), 7.22 (brd, J = 8.4 Hz, 2H, Ar-H), 7.43 (d, J = 8.4 Hz, 2H, Ar-H), 7.45 - 7.65 (m, 4H, Ar-H), 12.90 (brs, 1 H, exchangeable in D2O, COOH); MS: m/z 348.7 [M + H]+.
Example 30:
1-(2-chlorophenyl)-5-(4-chlorophenyl)-N-cyclopropyl-4-methyl-1 H-pyrazole-3- carboxamide
To a stirred solution of compound of example 29 (2.0 g, 5.76 mmol) in dichloromethane (20 mL) was added cyclopropylamine (0.447 mL, 6.34 mmol), TBTU (2.035 g, 6.34 mmol) and diisopropyl ethylamine (1 .107 mL, 6.34 mmol) at room temperature and the reaction mixture was stirred for 5 h. The reaction mixture was quenched with water, extracted with dichloromethane, washed with water and brine, dried (anhydrous Na2SO4) and concentrated. The crude material was purified by column chromatography (silica gel, 50 - 60 % ethyl acetate in petroleum ether) to obtain the title compound.
Yield: 76 %; 1H NMR (300 MHz, CDCI3): δ 0.76 - 0.86 (m, 4H, cyclopropyl-CH2), 2.39 (s, 3H, pyrazole-CH3), 2.84 (m, 1 H, cyclopropyl-CH), 7.07 (brd, J = 8.4 Hz, 2H, Ar-H), 7.27 (d, J = 8.4 Hz, 2H, Ar-H), 7.33 (brs, 1 H, exchangeable in D2O, -NH) 7.35 - 7.42 (m, 4H, Ar-H).
Example 31 :
1-(2-Chlorophenyl)-5-(4-chlorophenyl)-N,N'-dicyclopropyl-4-methyl-1 H-pyrazole-3- carboximidamide To a stirred solution of the compound of example 30 (0.200 g, 0.518 mmol) in chlorobenzene (5 mL) was added PCI5 (0.270 g, 1 .294 mmol) and the reaction mixture was heated at 131 °C for 1 .5 h. The mixture was allowed to cool to room temperature, and solvent was removed to give a yellow sticky solid. This solid was dissolved in dichloromethane (5 mL), cyclopropanamine or its hydrochloride (6.0 equivalents) was added, and the mixture was stirred at room temperature for 14 h. The reaction mixture was quenched with water, extracted with dichloromethane, washed with water and brine, dried (anhydrous Na2SO4) and concentrated. The crude material was purified by column chromatography (silica gel, 2-3 % methanol in dichloromethane) to obtain the title compound.
Yield: 50.0 %; 1H NMR (300 MHz, DMSO-a^): δ 0.73 - 0.94 (m, 8H, cyclopropyl-CH2), 2.72 - 2.95 (m, 2H, cyclopropyl-CH), 2.10 (s, 3H, pyrazole-CH3), 7.21 (d, J = 8.4 Hz, 2H, Ar-H), 7.48 (d, J = 8.4 Hz, 2H, Ar-H), 7.66 (m, 4H, Ar-H), 10.20 (brs, 1 H,exchangeable in D2O, NH); MS: m/z 426.0 [M + H]+.
Example 32:
N-((1 S,3R,5S)-Adamantan-1 -yl)-1 -(2-chlorophenyl)-5-(4-chlorophenyl)-N'- cyclopropyl-4-methyl-1 H-pyrazole-3-carboximidamide
The compound of the example 30 (0.150 g, 0.388 mmol) in chlorobenzene (5 mL) was treated with (3s,5s,7s)-adamantan-1 -amine or its hydrochloride (6.0 equivalents) according to the procedure for the preparation of the compound of example 31 to obtain the title compound.
Yield: 5.9 %; 1 H NMR (300 MHz, DMSO-a : δ 0.40 - 0.50 (m, 4H, cyclopropyl-CH2), 1 .22 (m, 3H, adamantyl), 1 .60 (m, 6H, adamantyl), 1 .99 (s, 3H, pyrazole-CH3), 2.05 (m, 6H, adamantyl), 2.49 (m, 1 H, cyclopropyl-C -/), 5.19 (brs, 1 H, exchangeable in D2O, NH), 7.17 (d, J = 8.4 Hz, 2H, Ar-H), 7.42 (d, J = 8.4 Hz, 2H, Ar-H), 7.46 - 7.53 (m, 4H, Ar-H); MS: m/z 520.8 [M + H]+.
Example 33:
1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyclopropyl-N-(1 ,1 -dioxidothio
morpholino)-4-methyl-1 H-pyrazole-3-carboximidamide
The compound of the example 30 (0.150 g, 0.388 mmol) in chlorobenzene (5 mL) was treated with 4-aminothiomorpholine 1 ,1 -dioxide (6.0 equivalents) according to the procedure for the preparation of the compound of example 31 to obtain the title compound.
Yield: 24.8 %; 1H NMR (300 MHz, DMSO-a^): δ 0.43 - 0.46 (m, 4H, cyclopropyl-CH2),
2.07 (s, 3H, pyrazole-CH3), 2.72 (m, 1 H, cyclopropyl-CH), 3.09 - 3.26 (m, 8H, thiomorpholine-CH2), 6.82 (s, 1 H, exchangeable in D2O, HH), 7.20 (d, J = 8.4 Hz, 2H,
Ar-H), 7.42 (d, J = 8.4 Hz, 2H, Ar-H), 7.43 - 7.54 (m, 4H, Ar-H); MS: m/z 519.3 [M + H]+.
Example 34:
1-(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyclopropyl-4-methyl-N-morpholino-1 H- pyrazole-3-carboximidamide
The compound of the example 30 (0.150 g, 0.388 mmol) in chlorobenzene (5 imL) was treated with morpholin-4-amine or its hydrochloride (6.0 equivalents) according to the procedure for the preparation of the compound of example 31 to obtain the title compound.
Yield: 7.7 %; 1H NMR (300 MHz, DMSO-a : δ 0.39 - 0.46 (m, 4H, cyclopropyl-CH2),
2.08 (s, 3H, pyrazole-CH3), 2.49 (brs, 4H, aminomorpholine-CH2), 2.68 (m, 1 H, cyclopropyl-C -/), 3.70 (brs, 4H, aminomorpholine-C -/2), 6.50 (s, 1 H, exchangeable in D2O, HH), 7.20 (d, J = 7.5 Hz, 2H, Ar-H), 7.40 -7.53 (m, 6H, Ar-H); MS: m/z 471 .2 [M + H]+.
Example 35:
1-(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyclopropyl-4-methyl-N-(oxetan-3-yl)- 1 H-pyrazole-3-carboximidamide
The compound of the example 30 (0.200 g, 0.518 mmol) in chlorobenzene (5 imL) was treated with oxetan-3-amine or its hydrochloride (6.0 equivalents) according to the procedure for the preparation of the compound of example 31 to obtain the title compound.
Yield: 8.1 %; 1H NMR (300 MHz, DMSO-a : δ 0.43 - 0.59 (m, 4H, cyclopropyl-CH2), 2.14 (s, 3H, pyrazole-CH3), 2.71 (m, 1 H, cyclopropyl-CH), 3.51 (m, 1 H, exchangeable in D2O, HH), 3.77 - 4.1 1 (m, 4H, oxetane-CH2), 4.89 (m, 1 H, oxetane-CH), 7.22 (d, J = 8.4 Hz, 2H, Ar-H), 7.45 (d, J = 8.4 Hz, 2H, Ar-H), 7.46 - 7.59 (m, 4H, Ar-H); MS: m/z 442.2 [M + H]+. Example 36:
Ethyl 1 -(2-methoxyphenyl)-5-(4-methoxyphenyl)-1 H-pyrazole-3-carboxylate
The sodium salt sodium (Z)-1 -ethoxy-4-(4-methoxyphenyl)-1 ,4-dioxobut-2-en-2- olate [synthesized as described in European Journal of Medicinal Chemistry 45 (2010) 4720-4725] (4.75 g, 19.45 mmol) was suspended in ethanol and (2- methoxyphenyl)hydrazine hydrochloride (3.74 g, 21 .39 mmol) was added. The slurry was refluxed for 16 h. After evaporation of solvent in vacuum, the crude solid was dissolved in acetic acid and refluxed for 18 h. The mixture was allowed to cool and then poured over ice. The aqueous phase was extracted with ethyl acetate. The organic extracs were washed with water, saturated NaHCO3 and finally with brine. The organic layer was dried (anhydrous Na2SO4), filtered and concentrated to obtain the title compound.
Yield: 33 %; 1H NMR (300 MHz, DMSO-a^): δ 1 .28 (t, J = 6.9 Hz, 3H, ethyl-CH3), 3.51 (s, 3H, OCH3), 3.84 (s, 3H, OCH3), 4.30 (q, J = 6.9 Hz, 2H, ethyl-CH2), 6.84 (d, J = 8.4 Hz, 2H, Ar-H), 7.01 - 7.09 (m, 3H, Ar-H), 7.13 (d, J = 8.4 Hz, 2H, Ar-H), 7.39 - 7.51 (m, 2H, Ar-H); MS: m/z 353.4 [M + H]+.
Example 37:
1 -(2-Methoxyphenyl)-5-(4-methoxyphenyl)-1 H-pyrazole-3-carboxylic acid
A solution of the compound of example 36 (1 .50 g, 4.26 mmol) and LiOH (1 .01 ,
42.6 mmol) was refluxed for 12-16 h in THF:water (3:1 ). After evaporation of THF, cone. HCI was added (pH = 4). The white solid formed was filtered and dried in vacuum. The purification of crude solid using column chromatography (silica gel, 5 % methanol in dichloromethane) obtained the title compound.
Yield: 87 %; 1H NMR (300 MHz, DMSO-a^): δ 3.50 (s, 3H, OCH3), 3.70 (s, 3H, OCH3), 6.84 (d, J = 8.7 Hz, 2H, Ar-H), 6.95 (s, 1 H, Ar-H), 7.03 - 7.09 (m, 2H, Ar-H), 7.13 (d, J = 8.7 Hz, 2H, Ar-H),7.39 - 7.50 (m, 2H, Ar-H), 12.84 (brs, 1 H, -COOH); MS: m/z 325.6 [M + H]+. Example 38:
N-Cyclopropyl-1-(2-methoxyphenyl)-5-(4-methoxyphenyl)-1 H-pyrazole-3- carboxamide
To a solution of the compound of example 37 (1 .00 g, 3.08 mmol), N-(3- dimethylamminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC) (2.36 g, 12.33 mmol), and N,N-dimethylpyridin-4-amine (DMAP) (1 .13 g, 9.25 mmol) were added to 15 mL of CH2CI2. The obtained mixture was stirred at room temperature for 30 min. A solution of cyclopropyl amine (0.854 mL, 12.33 mmol) in dichloromethane (5 mL) was added dropwise to the above mixture. The resulting reaction mixture was stirred for 12-16 h at room temperature and then concentrated in vacuo. Water was added to the residue and extracted with ethyl acetate. The organic phases were combined and washed with water and brine. The organic layer was dried (anhydrous Na2SO4), concentrated and purified by column chromatography (silica gel, 35 % ethyl acetate in petroleum ether) to obtain the title compound.
Yield: 55 %; 1H NMR (300 MHz, DMSO-a : δ 0.58-0.64 (m, 4H, cyclopropyl-CH2), 2.79 (m, 1 H, cyclopropyl-CH), 3.51 (s, 3H, OCH3), 3.70 (s, 3H, OCH3), 6.83 (d, J = 8.7 Hz, 2H, Ar-H), 6.88 (s, 1 H, Ar-H), 7.02 - 7.15 (m, 4H, Ar-H), 7.38 - 7.48 (m, 2H, Ar-H), 8.23 (d, J = 4.5 Hz, 1 H, exchangeable in D2O, cyclopropylamine-NH); MS: m/z 365.6 [M + H]+.
Example 39:
N-Cyclohexyl-N'-cyclopropyl-1-(2-methoxyphenyl)-5-(4-methoxyphenyl)-1 H- pyrazole-3-carboximidamide
Compound of example 38 (0.100 g, 0.275 mmol) was dissolved in chlorobenzene and then heated at 1 10 °C in the presence of phosphorous pentachloride (0.06 g, 0.303 mmol) for 2 h. After evaporation of chlorobenzene in vacuum, the residue was dissolved in dichloromethane (6 mL) and treated with triethylamine (0.384 mL, 2.75 mmol) and cyclohexyl amine (0.12 mL, 1 .101 mmol) at room temperature. After stirring for 12-16 h, water was added and extracted with ethyl acetate. The organic extracts were washed with brine, dried (anhydrous Na2S04), concentrated and purified by preparative HPLC using column Waters X-terra RP-18 (150 X 19 mm ) 5 μ, flow 10 mL/minute, λ = 210 nm and 254 nm (mobile phase, ACN:TFA isocratic, 40:60) to obtain the title compound.
Yield: 19 %; 1H NMR (300 MHz, DMSO-a : δ 0.71 (m, 2H, cyclopropyl-CH2), 0.96 (m, 2H, cyclopropyl-CH2), 1 .30 - 1 .36 (m, 4H, cyclohexyl-CH2), 1 .58 - 1 .91 (m, 6H, cyclohexyl-CH2), 2.88 (m, 1 H, cyclohexyl- CH), 3.13 (m, 1 H, cyclopropyl-CH), 3.50 (s, 3H, OCH3), 3.75 (s, 3H, OCH3), 6.90 (d, 2H, J = 8.7 Hz, Ar-H), 7.10 - 7.23 (m, 5H, Ar- H), 7.42 - 7.54 (m, 2H, Ar-H), 9.53 (brs, 1 H, exchangeable in D2O, cyclohexylamine- NH); MS: m/z 445.2 [M + H]+. Example 40:
ferf-Butyl 4-((5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-4-methyl-1 H-pyrazol-3-yl) (cyclopropylimino)methyl)piperazine-1-carboxylate
The compound of example 22 (0.300 g, 0.713 mmol) in chlorobenzene (10 imL) was treated with tert-butyl piperazine-1 -carboxylate (6.0 equivalents) according to the procedure for the preparation of the compound of example 23 to obtain the title compound.
Yield: 16.6 %; 1H NMR (500 MHz, DMSO-d6): δ 0.69 - 0.71 (m, 4H, cyclopropyl-CH2), 1 .42 (s, 9H, -Boc), 2.13 (s ,3H, pyrazole-CH3), 2.80 (m, 1 H, cyclopropyl-CHj, 3.48 - 3.82,(m, 8H, piperazine), 7.30 (d, J = 8.5 Hz, 2H, Ar-H), 7.53 (d, J = 8.5 Hz, 2H, Ar-H), 7.64 (d, J = 8.5 Hz, 1 H, Ar-H), 7.73 (d, J = 8.5 Hz, 1 H, Ar-H), 7.87 (s, 1 H, Ar-H); MS: m/z 589.0 [M]+.
Example 41 :
N-((5-(4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-4-methyl-1 H-pyrazol-3-yl)(piperazin -1-yl)methylene)cyclopropanamine hydrochloride
Compound of example 41 was prepared by the deprotection of the t-butyloxy carbonyl group of the compound of example 40 with dioxane-HCI.
Yield: 48.6 %; 1H NMR (500 MHz, DMSO-d6): δ 0.69 - 0.73 (m, 4H, cyclopropyl-CH2), 2.17 (s, 3H, pyrazole-CH3), 2.83 (m, 1 H, cyclopropyl-CHj, 3.18 (m, 1 H, piperazine), 3.26 (m, 1 H, piperazine), 3.42 - 3.50 (m, 2H, piperazine), 3.62 - 3.75 (m, 2H, piperazine), 4.15 (m, 1 H, piperazine), 4.22 (m, 1 H, piperazine), 7.30 (d, J = 8.5 Hz, 2H, Ar-H), 7.53 (d, J = 8.0 Hz, 2H, Ar-H), 7.64 (d, J = 7.5 Hz, 1 H, Ar-H), 7.74 (m, 1 H, Ar-H), 7.87 (s, 1 H, Ar-H), 9.70 (d, J = 4.5 Hz, 1 H, exchangeable in D2O, NH), 9.95 (d, J = 4.5 Hz, 1 H, exchangeable in D2O, HH), 10.58 (d, J = 4.5 Hz, 1 H, exchangeable in D2O, NH); MS: m/z 523.8 [M - H]+.
Example 42:
N-((5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1 H-pyrazol-3-yl)
(morpholino)methylene)cyclopropanamine
The compound of example 42 was prepared analogous to the compound of example 13, using the procedure comprised in preparation of the compound of example 13, wherein, 2,4-dichlorophenylhydrazine hydrochloride was replaced with 2- chlorophenylhydrazine hydrochloride. Yield: 4.2 %; 1H NMR (300 MHz, DMSO-a^): δ 0.48 - 0.55 (m, 4H, cyclopropyl-CH2), 2.23 (s, 3H, pyrazole-CH3), 2.61 (m, 1 H, cyclopropyl-CHj, 3.13 (m, 4H, morpholine- CH2), 3.46 - 3.57 (m, 4H, morpholine-CH2), 7.33 (d, J = 8.4 Hz, 2H, Ar-H), 7.44 (d, J = 8.4 Hz, 2H, Ar-H), 7.55 (d, J = 8.7 Hz, 1 H, Ar-H), 7.69 (d, J = 8.7 Hz, 1 H, Ar-H), 7.77 - 7.79 (m, 1 H, Ar-H); MS: m/z 489.5 [M]+.
Example 43:
N,N'-Dicyclopropyl-1-(2-methoxyphenyl)-5-(4-methoxyphenyl)-1 H-pyrazole-3- carboximidamide
The compound of the example 38 (0.100 g, 0.275 mmol) in chlorobenzene (5 imL) was treated with cyclopropanamine or its hydrochloride (6.0 equivalents) according to the procedure for the preparation of the compound of example 39 to obtain the title compound.
Yield: 21 .67 %; 1 H NMR (300 MHz, DMSO-a : δ 0.78 (s, 4H, cyclopropyl-CH2), 0.87 (s, 4H, cyclopropyl-CH?), 3.16 (d, J = 3.0 Hz, 1 H, cyclopropyl-CH), 3.50 (s, 3H, OCH3), 3.73 (s, 3H, OCH3), 4.12 (m, 1 H, cyclopropyl-CH), 6.90 (d, J = 5.1 Hz, 2H, Ar-H), 7.1 1 - 7.17 (m, 4H, Ar-H), 7.26 (s, 1 H, Ar-H), 7.46 (d, J = 4.8 Hz, 1 H, Ar-H), 7.52 (m, 1 H, Ar- H), 9.62 (brs, 1 H, exchangeable in D2O, cyclopropylamine-NH); MS: m/z 403.5 [M + H]+.
Example 44:
N'-Cyclopropyl-N-(1 ,1 -dioxidothiomorpholino)-1 -(2-methoxyphenyl)-5-(4-methoxy phenyl )-1 H-pyrazole-3-carboximidamide
The compound of the example 38 (0.100 g, 0.275 mmol) in chlorobenzene (5 imL) was treated with 4-aminothiomorpholine 1 ,1 -dioxide (6.0 equivalents) according to the procedure for the preparation of the compound of example 39 to obtain the title compound.
Yield: 10.75 %; 1H NMR (300 MHz, DMSO-a^): δ 0.50 (m, 4H, cyclopropyl-CH2), 3.07 (m, 5H, cyclopropyl-CH and 4-aminothiomorpholine 1 ,1 -dioxide-C -2), 3.27 (m, 4H, 4- aminothiomorpholine 1 ,1 -dioxide-CH2), 3.48 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 6.63 (brs, 1 H, exchangeable in D2O, 4-aminothiomorpholine 1 ,1 -dioxide-N -/), 6.76 (s, 1 H, Ar-H), 6.82 (d, J = 8.4 Hz, 2H, Ar-H), 7.02 - 7.08 (m, 2H, Ar-H), 7.13 (d, J = 8.1 Hz, 2H, Ar-H ), 7.35 - 7.44 (m, 2H, Ar-H); MS: m/z 496.7 [M+H]+. Example 45:
(5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-1 H-pyrazol-3-yl)methanol
To a stirred solution of the compound of the example 1 (17.5 g, 44.2 mmol) in THF (350 mL) was added LiBH4 (2.89 g, 133 mmol) at room temperature, followed by methanol (1 1 .90 mL) at 0 °C and the reaction mixture was refluxed for 1 .5 h. The mixture was allowed to cool to room temperature, and solvent was removed to give an off-white solid. To the solid was added a solution of saturated NH4CI and extracted with ethyl acetate. The organic extracts were washed with water and brine, dried (anhydrous Na2SO4) and concentrated. The crude material was purified by column chromatography (silica gel, 0-38 % ethyl acetate in petroleum ether) to obtain the title compound.
Yield: 86 %; 1H NMR (300 MHz, DMSO-a : δ 4.50 (d, J = 5.7 Hz, 2H, -CH^OH), 5.27 (t, J = 5.7 Hz, exchangeable in D2O, 1 H, -CH2OH), 6.70 (s, 1 H, pyrazole-H) 7.20 (d, J = 8.4 Hz, 2H, Ar-H), 7.41 (d, J = 8.7 Hz, 2H, Ar-H), 7.55 - 7.76 (m, 2H, Ar-H), 7.80 (d, J = 2.1 Hz, 1 H, Ar-H); MS: m/z 335.0 [M - OH]+.
Example 46:
5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-1 H-pyrazole-3-carbaldehyde
To a stirred solution of the compound of example 45 (13.0 g, 36.80 mmol) in dichloromethane (345 mL) was added DIPEA (64.2 mL, 368 mmol) and DMSO (52.2 mL, 735 mmol) at 0 °C. After stirring for 15 min, SO3-Pyridine complex (58.5 g, 368 mmol) was added portion-wise at 0 °C and the mixture was stirred for 45 min at 0 °C. The reaction mixture was quenched with saturated NaHCO3 solution at 0° C, extracted with ethyl acetate, washed with water and brine, dried (anhydrous Na2SO4) and concentrated. The crude material was purified by column chromatography (silica gel, 0 - 12 % ethyl acetate in petroleum ether) to obtain the title compound.
Yield: 79 %; 1H NMR (300 MHz, DMSO-a^): δ 7.25 - 7.32 (m, 3H, pyrazole and Ar-H), 7.46 (d, J = 8.5 Hz, 2H, Ar-H), 7.67 (dd, J = 2.1 Hz, 8.5 Hz, 1 H, Ar-H), 7.84 (d, J = 8.7 Hz, 1 H, Ar-H), 7.90 (d, J = 2.4 Hz, 1 H, Ar-H), 9.99 (s, 1 H, -CHO); MS: m/z 353.0 [M + H]+.
Example 47:
5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1 H-pyrazole-3-carbonitrile To a stirred solution of the compound of example 46 (10 g, 28.40 mmol) in DMSO (200 mL) was added hydroxylamine hydrochloride (4.35 g, 62.60 mmol) at room temperature followed by heating at 92 °C for 6 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic extracts were washed with water and brine, dried (anhydrous Na2SO4) and concentrated. The crude material was purified by column chromatography (silica gel, 0 - 10 % ethyl acetate in petroleum ether) to obtain the title compound.
Yield: 42 %; 1H NMR (300 MHz, DMSO-a : δ 7.25 (d, J = 8.4 Hz, 2H, Ar-H), 7.47 (d, J = 8.7 Hz, 2H, Ar-H), 7.53 (s, 1 H, pyrazole-H), 7.66 (dd, J = 2.1 Hz, 8.7 Hz, 1 H, Ar-H), 7.83 (d, J = 8.4 Hz, 1 H, Ar-H), 7.88 (d, J = 2.1 Hz, 1 H, Ar-H); MS: m/z 349.9 [M + H]+.
Example 48:
Methyl 5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3-carbimidate
To a stirred solution of the compound of example 47 (4.0 g, 1 1 .47 mmol) in methanol (75 mL) was added sodium methoxide (1 .0 g, 18.52 mmol) slowly and stirred for 12-16 h at room temperature under nitrogen atmosphere. The reaction mixture was neutralised with acetic acid (2.1 19 mL, 37.0 mmol), concentrated, diluted with diethyl ether, stirred and filtered. The filtrate was concentrated to give crude the title compound (4.60 g), which was used without further purification.
Example 49:
Methyl 5-(4-chlorophenyl)-N-cyano-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carbimidate
To a stirred solution of sodium phosphate monobasic monohydrate (6.52 g, 47.30 mmol)s sodium phosphate dibasic (1 .675 g, 1 1 .82 mmol) and cyanamide (0.994 g, 23.64 mmol) in water (45 mL) was added a solution of the compound of example 48 (4.5 g, 1 1 .82 mmol) in THF (45 mL) and the mixture was heated for 12-16 h at 70 °C. The mixture was allowed to cool to room temperature, and solvent was removed to give an off-white sticky solid. This solid was dissolved in ethyl acetate, washed with water and brine, dried (anhydrous Na2SO4) and concentrated. The crude material was purified by column chromatography (silica gel, 0 - 18 % ethyl acetate in petroleum ether) to obtain the title compound.
Yield: 47 %; 1H NMR (300 MHz, DMSO-a : δ 4.05 (s, 3H, OCH3), 7.28 (d, J = 8.4 Hz, 2H, Ar-H), 7.42 (s, 1 H, pyrazole-H), 7.47 (d, J = 8.4 Hz, 2H, Ar-H), 7.68 (dd, J = 2.1 Hz, 8.7 Hz, 1 H, Ar-H), 7.84 (d, J = 8.4 Hz, 1 H, Ar-H), 7.91 (d, J = 2.1 Hz, 1 H, Ar-H); MS: m/z 406.8 [M + H]+.
Example 50:
5-(4-Chlorophenyl)-N'-cyano-1-(2,4-dichlorophenyl)-N-methyl-1 H-pyrazole-3- carboximidamide
To a stirred solution of the compound of example 49 (60 mg, 0.148 mmol) in anhydrous methanol (2 mL) was added methanamine or its hydrochloride (2.20 equivalents) and triethylamine (0.045 mL, 0.325 mmol), and the mixture was stirred for 12-16 h at room temperature under nitrogen atmosphere. After concentration of the reaction mixture, the residue was dissolved in ethyl acetate, washed with water and brine, dried (anhydrous Na2SO4) and concentrated. The crude material was purified either by column chromatography (silica gel, 0 - 30 % ethyl acetate in petroleum ether) to obtain the title compound.
Yield: 58.5 %; 1 H NMR (500 MHz, DMSO-a : δ 2.89 (s, 3H, CH3), 7.29 (d, J = 8.5 Hz, 2H, Ar-H), 7.47 - 7.52 (m, 3H, pyrazole & Ar-H), 7.68 (dd, J = 2.5 Hz, 8.5 Hz, 1 H, Ar-H), 7.86 (d, J = 8.5 Hz, 1 H, Ar-H), 7.89 - 7.91 (m, 1 H, Ar-H), 9.23 (d, J = 4.5 Hz, 1 H, exchangeable in D2O, NH); MS: m/z 406.1 [M+H]+.
Example 51 :
5-(4-Chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-N-ethyl-1 H-pyrazole-3- carboximidamide
The compound of the example 49 (60 mg, 0.148 mmol) in anhydrous methanol (2 mL) was treated with ethanamine or its hydrochloride (2.20 equivalents) according to the procedure for the preparation of the compound of example 50 to obtain the title compound.
Yield: 64.6 %; 1H NMR (300 MHz, DMSO-a : δ 1 .14 (t, J = 7.2 Hz, ethyl-CH3), 3.35 - 3.50 (m, 2H, ethyl-CH2), 7.27 (d, J = 8.4 Hz, 2H, Ar-H), 7.44 - 7.50 (m, 3H, pyrazole & Ar-H), 7.68 (dd, J = 2.1 Hz, 8.0 Hz, 1 H, Ar-H), 7.82 - 7.90 (m, 2H, Ar-H), 9.22 - 9.25 (m, 1 H, exchangeable in D2O, NH); MS: m/z 418.0 [M]+.
Example 52:
5-(4-Chlorophenyl)-N'-cyano-N-cyclopropyl-1-(2,4-dichlorophenyl)-1 H-pyrazole-3- carboximidamide The compound of the example 49 (60 mg, 0.148 mmol) in anhydrous methanol (2 imL) was treated with cyclopropanamine or its hydrochloride (2.20 equivalents) according to the procedure for the preparation of the compound of example 50 to obtain the title compound.
Yield: 56.5 %;1 H NMR (500 MHz, DMSO-a^): δ 0.7 - 0.8 (m, 4H, cyclopropyl-CH2), 2.95 - 3.05 (m, 1 H, cyclopropyl-CH), 7.28 (d, J = 9.0 Hz, 2H, Ar-H), 7.44 - 7.50 (m, 3H, pyrazole & Ar-H), 7.68 (dd, J = 2.0 Hz, 8.5 Hz, 1 H, Ar-H), 7.84 (d, J = 8.5 Hz, 1 H, Ar-H), 7.88 (d, J = 2.0 Hz, 1 H, Ar-H), 9.28 (d, J = 2.0 Hz, 1 H, exchangeable in D2O, NH); MS: m/z 430.8 [M]+.
Example 53:
5-(4-Chlorophenyl)-N'-cyano-N-cyclohexyl-1-(2,4-dichlorophenyl)-1 H-pyrazole-3- carboximidamide
The compound of the example 49 (60 mg, 0.148 mmol) in anhydrous methanol (2 imL) was treated with cyclohexyl amine or its hydrochloride (2.20 equivalents) according to the procedure for the preparation of the compound of example 50 to obtain the title compound.
Yield: 42.9 %; 1H NMR (500 MHz, DMSO-a^): δ 1 .05 - 1 .15 (m, 1 H, cyclohexyl-CH), 1 .25 - 1 .35 (m, 2H, cyclohexyl-CH2), 1 .35 - 1 .48 (m, 2H, cyclohexyl-CH2), 1 .60 - 1 .65 (m, 1 H, cyclohexyl-CH), 1 .70 - 1 .80 (m, 2H, cyclohexyl-CH2), 1 .82 - 1 .90 (m, 2H, cyclohexyl-CH2), 3.85 - 3.95 (m, 1 H, cyclohexyl-CH), 7.28 (d, J = 8.5 Hz, 2H, Ar-H), 7.45 - 7.51 (m, 3H, pyrazole & Ar-H), 7.68 (dd, J = 2.0 Hz, J = 8.5 Hz, 1 H, Ar-H), 7.85 (d, J = 8.5 Hz, 1 H, Ar-H), 7.88 (d, J = 2.5 Hz, 1 H, Ar-H), 9.04 (d, J = 8.0 Hz, 1 H, exchangeable in D2O, NH); MS: m/z 472.7 [M]+.
Example 54:
5-(4-Chlorophenyl)-N'-cyano-1-(2,4-dichlorophenyl)-N-(oxetan-3-yl)-1 H-pyrazole-3- carboximidamide
The compound of the example 49 (60 mg, 0.148 mmol) in anhydrous methanol (2 imL) was treated with oxetan-3-amine or its hydrochloride (2.20 equivalents) according to the procedure for the preparation of the compound of example 50 to obtain the title compound.
Yield: 53.0 %; 1 H NMR (300 MHz, DMSO-d6): δ 4.64 (t, J = 6.6 Hz, 2H, oxetane-CH2), 4.74 (t, J = 6.9 Hz, 2H, oxetane-CH2), 4.92 - 5.04 (m, 1 H, oxetane-CH), 7.28 (d, J = 8.4 Hz, 2H, Ar-H), 7.45 - 7.55 (m, 3H, pyrazole & Ar-H), 7.68 (dd, J = 2.4 Hz, 8.5 Hz, 1 H, Ar-H), 7.82 - 7.92 (m, 2H, Ar-H), 9.88 (s, 1 H, exchangeable in D2O, NH); MS: m/z 447.3 [M + H]+. Example 55:
N-((5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-1 H-pyrazol-3-yl)(4-(oxetan-3-yl) piperidin-1-yl)methylene)cyanamide
The compound of the example 49 (60 mg, 0.148 mmol) in anhydrous methanol (2 mL) was treated with 4-(oxetan-3-yl)piperidine (2.20 equivalents) according to the procedure for the preparation of the compound of example 50 to obtain the title compound.
Yield: 59.1 %; 1 H NMR (300 MHz, DMSO-a^): δ 0.90 - 1 .21 (m, 2H, piperidine-CH2), 1 .56 - 1 .81 (m, 2H, piperidine-CH2), 1 .90 - 2.1 5 (m, 1 H, piperidine-CH), 2.65 - 2.85 (m, 1 H, piperidine-CH), 2.95 - 3.1 5 (m, 1 H, piperidine-CH), 3.1 5 - 3.35 (m, overlap with H2O in DMSO, 1 H, piperidine-CH), 3.75 - 3.95 (m, 1 H, piperidine-CH), 4.20 - 4.40 (m, 2H, oxetane-CH2), 4.50 - 4.70 (m, 3H, oxetane), 7.16 (s, 1 H, pyrazole-H), 7.26 (d, J = 8.7 Hz, 2H, Ar-H), 7.47 (d, J = 8.4 Hz, 2H, Ar-H), 7.61 - 7.68 (m, 1 H, Ar-H), 7.78 (d, J = 8.4 Hz, 1 H, Ar-H), 7.89 (d, J = 2.1 Hz, 1 H, Ar-H); MS: m/z 51 5.8 [M + H]+. Example 56:
5-(4-Chlorophenyl)-N'-cyano-1-(2,4-dichlorophenyl)-N-(1-(oxetan-3-yl)piperidin-4- yl)-1 H-pyrazole-3-carboximidamide
The compound of the example 49 (60 mg, 0.148 mmol) in anhydrous methanol (2 mL) was treated with 1 -(oxetan-3-yl)piperidin-4-amine or its hydrochloride (2.20 equivalents) according to the procedure for the preparation of the compound of example 50 to obtain the title compound.
Yield: 51 .0 %; 1 H NMR (300 MHz, DMSO-a^): δ 1 .55 - 1 .75 (m, 2H, piperidine), 1 .76 - 1 .90 (m, 4H, piperidine), 2.71 (d, J =1 0.2 Hz, 2H, piperidine), 3.25 - 3.50 (m, overlap with H2O in DMSO, 1 H, piperidine), 3.80 - 3.98 (m, 1 H, oxetane), 4.39 (t, J = 6.0 Hz, 2H, oxetane-CH2), 4.51 (t, J = 6.6 Hz, 2H, oxetane-CH2), 7.27 (d, J = 8.4 Hz, 2H, Ar-H), 7.42 - 7.52 (m, 3H, pyrazole & Ar-H), 7.65 - 7.72 (m, 1 H, Ar-H), 7.82 - 7.90 (m, 2H, Ar- H), 9.1 5 (d, J = 8.1 Hz, 1 H, exchangeable in D2O, NH); MS: m/z 530.9 [M + H]+. Example 57:
N-((4- Acetyl pi perazin-1 -yl)(5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol- 3-yl)methylene)cyanamide
The compound of the example 49 (60 mg, 0.148 mmol) in anhydrous methanol (2 imL) was treated with 1 -(piperazin-1 -yl)ethanone (2.20 equivalents) according to the procedure for the preparation of the compound of example 50 to obtain the title compound.
Yield: 53.9 %; 1H NMR (300 MHz, DMSO-a : δ 2.04 (s, 3H, CH3), 3.50 - 3.70 (m, 6H, piperazine), 3.72 - 3.95 (m, 2H, piperazine), 7.18 - 7.34 (m, 3H, pyrazole & Ar-H), 7.48 (d, J = 8.4 Hz, 2H, Ar-H), 7.62 - 7.70 (m, 1 H, Ar-H), 7.79 (d, J = 8.0, 1 H, Ar-H), 7.90 (d, J = 2.0 Hz, 1 H, Ar-H); MS: m/z 502.7 [M + H]+.
Example 58:
ferf-Butyl 4-((5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3-yl)
(cyanoimino)methyl)piperazine-1 -carboxylate
The compound of the example 49 (60 mg, 0.148 mmol) in anhydrous methanol (2 imL) was treated with tert-butyl piperazine-1 -carboxylate (2.20 equivalents) according to the procedure for the preparation of the compound of example 50 to obtain the title compound.
Yield: 36.2 %; 1H NMR (300 MHz, DMSO-a^): δ 1 .40 (s, 9H, -Boc), 3.40 - 3.55 (m, 4H, piperazine), 3.57 - 3.66 (m, 2H, piperazine), 3.79 - 3.89 (m, 2H, piperazine), 7.19 (s, 1 H, pyrazole-H), 7.26 (d, J = 8.4 Hz, 2H, Ar-H), 7.48 (d, J = 8.4 Hz, 2H, Ar-H), 7.66 (dd, J = 2.1 Hz, 8.7 Hz, 1 H, Ar-H), 7.79 (d, J = 8.4, 1 H, Ar-H), 7.89 (d, J = 2.1 Hz, 1 H, Ar-H); MS: m/z 561 .0 [M + H]+.
Example 59:
N-((1 S,3R,5S)-Adamantan-1 -yl)-5-(4-chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl) -1 H-pyrazole-3-carboximidamide
The compound of the example 49 (60 mg, 0.148 mmol) in anhydrous methanol (2 imL) was treated with (3s,5s,7s)-adamantan-1 -amine or its hydrochloride (2.20 equivalents) according to the procedure for the preparation of the compound of example 50 to obtain the title compound.
Yield: 23.2 %; 1 H NMR (500 MHz, DMSO-a : δ 1 .66 (s, 6H, adamantyl), 2.08 (s, 3H, adamantyl), 2.14 (s, 6H, adamantyl), 7.26 (d, J = 8.5 Hz, 2H, Ar-H), 7.38 (s, 1 H, pyrazole-H), 7.48 (d, J = 8.5 Hz, 2H, Ar-H), 7.68 (d, J = 8.5 Hz, 1 H, Ar-H), 7.78 (d, J = 8.5 Hz, 1 H, Ar-H), 7.88 (brs, 1 H, Ar-H), 8.17 (s, 1 H, exchangeable in D2O, NH); MS: m/z 524.7 [M]+. Example 60:
N-((1 s,3s,5s)-1 ,3,5-Triazaadamantan-7-yl)-5-(4-chlorophenyl)-N'-cyano-1 -(2,4- dichlorophenyl)-1 H-pyrazole-3-carboximidamide
The compound of the example 49 (60 mg, 0.148 mmol) in anhydrous methanol (2 mL) was treated with (1 s,3s,5s)-1 ,3,5-triazaadamantan-7-amine (2.20 equivalents) according to the procedure for the preparation of the compound of example 50 to obtain the title compound.
Yield: 15.4 %; 1 H NMR (300 MHz, DMSO-a : δ 3.68 (s, 6H, triazaadamantanyl), 4.01 (d, J = 12.3 Hz, 3H, triazaadamantanyl), 4.34 (d, J = 12.3 Hz, 3H, triazaadamantanyl), 7.25 (d, J = 8.4 Hz, 2H, Ar-H), 7.46 (s, 1 H, pyrazole-H), 7.47 (d, J = 8.4 Hz, 2H, Ar-H), 7.65 - 7.72 (m, 1 H, Ar-H), 7.79 (d, J = 8.4 Hz, 1 H, Ar-H), 7.85 - 7.90 (m, 1 H, Ar-H), 8.36 (s, 1 H, exchangeable in D2O, NH); MS: m/z 528.9 [M + H]+.
Example 61 :
(S)-2-(5-(4-Chlorophenyl)-N'-cyano-1-(2,4-dichlorophenyl)-1 H-pyrazole-3- carboximidamido)propanamide
The compound of the example 49 (60 mg, 0.148 mmol) in anhydrous methanol (2 mL) was treated with (S)-2-aminopropanamide (2.20 equivalents) according to the procedure for the preparation of the compound of example 50 to obtain the title compound.
Yield: 58.6 %; 1 H NMR (300 MHz, DMSO-a^): δ 1 .38 (d, J = 7.0 Hz, 3H, CH3), 4.40 - 4.55 (m, 1 H, CH), 7.23 (s, 1 H, exchangeable in D2O, amide-NH), 7.27 (d, J = 8.5 Hz, 1 H, Ar-H), 7.45 - 7.55 (m, 3H, pyrazole & Ar-H), 7.59 (s, 1 H, exchangeable in D2O, amide-NH), 7.65 - 7.75 (m, 1 H, Ar-H), 7.80 - 7.95 (m, 2H, Ar-H), 8.90 (d, J = 7.0 Hz, 1 H, exchangeable in D2O, NH); MS: m/z 461 .4 [M]+.
Example 62:
(S)-Methyl 2-(5-(4-chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboximidamido)-3-methylbutanoate The compound of the example 49 (60 mg, 0.148 mmol) in anhydrous methanol (2 imL) was treated with (S)-methyl 2-amino-3-methylbutanoate (2.20 equivalents) according to the procedure for the preparation of the compound of example 50 to obtain the title compound.
Yield: 69.6 %; 1 H NMR (500 MHz, DMSO-a^): δ 0.94 (d, J = 7.0 Hz, 3H, -CH3), 0.99 (d, J = 7.0 Hz, 3H, -CH3), 2.20 - 2.32 (m, 1 H, isopropyl-CH), 3.70 (s, 1 H, -CH3), 4.30 - 4.40 (m, 1 H, -CH), 7.29 (d, J = 8.5 Hz, 2H, Ar-H), 7.42 - 7.51 (m, 3H, pyrazole & Ar-H), 7.70 (m, 1 H, Ar-H), 7.85 (d, J = 8.5 Hz, 1 H, Ar-H), 7.89 (s, 1 H, Ar-H), 9.34 (d, J = 8.5 Hz, exchangeable in D2O, NH); MS: m/z 504.4 [M]+.
Example 63:
N-((5-(4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3-yl)(1 ,1 -dioxidothio morpholino)methylene)cyanamide
The compound of the example 49 (60 mg, 0.148 mmol) in anhydrous methanol (2 imL) was treated with thiomorpholine 1 ,1 -dioxide (2.20 equivalents) according to the procedure for the preparation of the compound of example 50 to obtain the title compound.
Yield: 44.6 %; 1 H NMR (500 MHz, DMSO-d6): δ 3.60 (d, 4H, thiomorpholine), 4.0 (brs, 2H, thiomorpholine), 4.24 (brs, 2H, thiomorpholine), 7.22 - 7.30 (m, 3H, pyrazole-H & Ar-H), 7.50 (d, J = 8.5 Hz, 2H, Ar-H), 7.66 (dd, J = 2.0 Hz, 8.5 Hz, 1 H, Ar-H), 7.91 (d, J = 2.0 Hz, 1 H, Ar-H); MS: m/z 508.9 [M]+.
Example 64:
5-(4-Chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-N-(1 ,1 -dioxidothiomorpholino) -1 H-pyrazole-3-carboximidamide
The compound of the example 49 (60 mg, 0.148 mmol) in anhydrous methanol (2 imL) was treated with 4-aminothiomorpholine 1 ,1 -dioxide (2.20 equivalents) according to the procedure for the preparation of the compound of example 50 to obtain the title compound.
Yield: 34.1 %; 1 H NMR (500 MHz, DMSO-d6): δ 3.20 - 3.30 (m, 2H, thiomorpholine), 3.40 - 3.55 (m, 6H, thiomorpholine-CH2), 7.24 - 7.30 (m, 3H, pyrazole-H & Ar-H), 7.46 (d = 8.0 Hz, 2H, Ar-H), 7.67 (dd, J = 2.0 Hz, 8.5 Hz, 1 H, Ar-H), 7.86 - 7.90 (m, 1 H, Ar- H), 1 1 .05 (s, 1 H, exchangeable in D2O, NH); MS: m/z 524.0 [M + H]+. Example 65:
N-((5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-1 H-pyrazol-3-yl)(morpholino) methylene)cyanamide
The compound of the example 49 (60 mg, 0.148 mmol) in anhydrous methanol (2 mL) was treated with morpholine (2.20 equivalents) according to the procedure for the preparation of the compound of example 50 to obtain the title compound.
Yield: 44.0 %; 1 H NMR (500 MHz, DMSO-a^): δ 3.60 - 3.67 (m, 4H, morpholine-CH2), 3.70 (brs, 2H, morpholine-CH2), 3.85 (brs, 2H, morpholine-CH2), 7.20 (s, 1 H, pyrazole- H), 7.28 (d, J = 8.5 Hz, 2H, Ar-H), 7.49 (d, J = 8.5 Hz, 2H, Ar-H), 7.66 (dd, J = 2.0 Hz, 8.5 Hz, 1 H, Ar-H), 7.79 (d, J = 8.5, 1 H, Ar-H), 7.89 (d, J = 1 .5 Hz, 1 H, Ar-H); MS: m/z 461 .1 [M + H]+.
Example 66:
5-(4-Chlorophenyl)-N'-cyano-1-(2,4-dichlorophenyl)-N-morpholino-1 H-pyrazole-3- carboximidamide
The compound of the example 49 (60 mg, 0.148 mmol) in anhydrous methanol (2 mL) was treated with morpholin-4-amine or its hydrochloride (2.20 equivalents) according to the procedure for the preparation of the compound of example 50 to obtain the title compound.
Yield: 42.6 %; 1H NMR (500 MHz, DMSO-a^): δ 2.80 - 3.0 (m, 4H, morpholine), 3.60 - 3.90 (m, 4H, morpholine), 7.28 (d, J = 8.0 Hz, 2H, Ar-H), 7.46 (d, J = 8.0 Hz, 2H, Ar-H), 7.67 (dd, J = 1 .5 Hz, 8.5 Hz, 1 H, Ar-H), 7.87 - 7.91 (m, 2H, pyrazole & Ar-H), 10.66 (brs, 1 H, exchangeable in D2O, NH); MS: m/z 477.0 [M + H]+. Example 67:
5-(4-Chlorophenyl)-N'-cyano-1-(2,4-dichlorophenyl)-N-(4-methoxybenzyl)-1 H- pyrazole-3-carboximidamide
The compound of the example 49 (60 mg, 0.148 mmol) in anhydrous methanol (2 mL) was treated with (4-methoxyphenyl)methanamine (2.20 equivalents) according to the procedure for the preparation of the compound of example 50 to obtain the title compound.
Yield: 46.3 %; 1 H NMR (500 MHz, DMSO-a^): δ 3.72 (s, 3H, -CH3), 4.49 (d, J = 5 Hz, 2H, benzyl-CH2), 6.92 (d, J = 8.5, 2H, Ar-H), 7.28 (d, J = 8.0 Hz, 4H, Ar-H), 7.45 - 7.55 (m, 3H, pyrazole & Ar-H), 7.68 (d, J = 8.5 Hz, 1 H, Ar-H), 7.84 - 7.92 (m, 2H, Ar-H); MS: m/z 510.1 [M]+.
Example 68:
1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-N-ethyl-1 H-pyrazole-3- carboximidamide
The compound of example 68 was prepared analogous to the compound of example 51 , using the procedure comprised in the preparation of the compound of example 51 , wherein ethyl 5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboxylate was replaced with 5-(4-chlorophenyl)-1 -(2-chlorophenyl)-1 H-pyrazole-3- carboxylate.
Yield: 56.4 %; 1H NMR (300 MHz, DMSO-d6): δ 1 .15 (t, J = 7.2 Hz, ethyl-CH3), 3.35 -
3.48 (m, 2H, ethyl-CH2), 7.26 (d, J = 8.7 Hz, 2H, Ar-H), 7.44 (d, J = 8.4 Hz, 2H, Ar-H),
7.49 (s, 1 H, pyrazole-H), 7.50 - 7.68 (m, 3H, Ar-H), 7.76 - 7.82 (m, 1 H, Ar-H), 9.20 (m, 1 H, exchangeable in D2O, NH); MS: m/z 385.6 [M + H]+.
Example 69:
1-(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-N-cyclopropyl-1 H-pyrazole-3- carboximidamide
The compound of example 69 was prepared analogous to the compound of example 52, using the procedure comprised in the preparation of the compound of example 52, wherein ethyl 5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboxylate was replaced with 5-(4-chlorophenyl)-1 -(2-chlorophenyl)-1 H-pyrazole-3- carboxylate.
Yield: 54.6 %; 1H NMR (300 MHz, DMSO-a : δ 0.74 - 0.88 (m, 4H, cyclopropyl-CH2), 2.90 - 3.10 (m, 1 H, cyclopropyl-CH), 7.25 (d, J = 8.5 Hz, 2H, Ar-H), 7.40 - 7.48 (m, 3H, pyrazole & Ar-H), 7.50 - 7.67 (m, 3H, Ar-H), 7.74 - 7.80 (m, 1 H, Ar-H), 9.22 - 9.25 (m, 1 H, exchangeable in D2O, NH); MS: m/z 397.5 [M + H]+. Example 70:
1-(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-N-cyclohexyl-1 H-pyrazole-3- carboximidamide
The compound of example 70 was prepared analogous to the compound of example 53, using the procedure comprised in the preparation of the compound of example 53, wherein ethyl 5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboxylate was replaced with 5-(4-chlorophenyl)-1 -(2-chlorophenyl)-1 H-pyrazole-3- carboxylate.
Yield: 49.4 %; 1 H NMR (300 MHz, DMSO-a^): δ 1 .24 - 1 .50 (m, 4H, cyclohexyl), 1 .51 - 1 .90 (m, 5H, cyclohexyl), 3.80 - 4.0 (m, 1 H, cyclohexyl), 7.25 (d, J = 8.4 Hz, 2H, Ar-H), 7.42 - 7.49 (m, 3H, pyrazole & Ar-H), 7.52 - 7.68 (m, 3H, Ar-H), 7.75 - 7.82 (m, 1 H, Ar- H), 9.0 (d, J = 8.0 Hz, 1 H, exchangeable in D2O, NH); MS: m/z 439.1 [M + H]+.
Example 71 :
1-(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-N-(oxetan-3-yl)-1 H-pyrazole-3- carboximidamide
The compound of example 71 was prepared analogous to the compound of example 54, using the procedure comprised in the preparation of the compound of example 54, wherein ethyl 5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboxylate was replaced with 5-(4-chlorophenyl)-1 -(2-chlorophenyl)-1 H-pyrazole-3- carboxylate.
Yield: 37.5 %; 1 H NMR (300 MHz, DMSO-d6): δ 4.65 (t, J = 6.6 Hz, 2H, oxetane-CH2), 4.74 (t, J = 6.6 Hz, 2H, oxetane-CH2), 4.40 - 5.05 (m, 1 H, oxetane-CH), 7.27 (d, J = 8.7 Hz, 2H, Ar-H), 7.44 (d, J = 8.4 Hz, 2H, Ar-H), 7.51 (s, 1 H, pyrazole-H), 7.55 - 7.70 (m, 3H, Ar-H), 7.76 - 7.85 (m, 1 H, Ar-H), 9.80 (s, 1 H, exchangeable in D2O, NH); MS: m/z 41 3.5 [M + H]+.
Example 72:
N-((1-(2-Chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl)(4-(oxetan-3-yl) piperidin-1 -yl)methylene)cyanamide
The compound of example 72 was prepared analogous to the compound of example 55, using the procedure comprised in the preparation of the compound of example 55, wherein ethyl 5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboxylate was replaced with 5-(4-chlorophenyl)-1 -(2-chlorophenyl)-1 H-pyrazole-3- carboxylate.
Yield: 45.1 %; 1 H NMR (300 MHz, DMSO-a^): δ 1 .00 - 1 .20 (m, 2H, piperidine-CH2), 1 .55 - 1 .80 (m, 2H, piperidine-CH2), 1 .85 - 2.1 0 (m, 1 H, piperidine-CH), 2.60 - 2.80 (m, 1 H, piperidine-CH), 3.0 - 3.15 (m, 1 H, piperidine-CH), 3.20 - 3.30 (m, overlap with H2O in DMSO, 1 H, piperidine-CH), 4.80 - 4.0 (m, 1 H, piperidine-CH), 4.25 - 4.40 (m, 2H, oxetane-CH2), 4.52 - 4.68 (m, 3H, oxetane), 7.16 (s, 1 H, pyrazole-H), 7.24 (d, J = 8.4 Hz, 2H, Ar-H), 7.44 (d, J = 8.4 Hz, 2H, Ar-H), 7.50 - 7.74 (m, 3H, Ar-H); MS: m/z 481 .2 [M + H]+. Example 73:
1-(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-N-(1-(oxetan-3-yl)piperidin-4-yl)- 1 H-pyrazole-3-carboximidamide
The compound of example 73 was prepared analogous to the compound of example 56, using the procedure comprised in the preparation of the compound of example 56, wherein ethyl 5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboxylate was replaced with 5-(4-chlorophenyl)-1 -(2-chlorophenyl)-1 H-pyrazole-3- carboxylate.
Yield: 50.0 %; 1 H NMR (300 MHz, DMSO-a^): δ 1 .50 - 1 .95 (m, 7H, piperidine), 2.62 - 2.78 (m, 2H, piperidine), 3.82 - 3.98 (m, 1 H, oxetane-CH), 4.35 - 4.45 (m, 2H, oxetane- CH2), 4.46 - 4.60 (m, 2H, oxetane- CH2), 7.25 (d, J = 8.1 Hz, 2H, Ar-H), 7.40 - 7.50 (m, 3H, pyrazole & Ar-H), 7.51 - 7.68 (m, 3H, Ar-H), 7.75 - 7.84 (m, 1 H, Ar-H), 9.13 (d, J = 7.5 Hz, 1 H, exchangeable in D2O, NH); MS: m/z 496.3 [M + H]+.
Example 74:
N-((1 S,3R,5S)-Adamantan-1 -yl)-1 -(2-chlorophenyl)-5-(4-chlorophenyl)-N'-cyano- 1 H-pyrazole-3-carboximidamide
The compound of example 74 was prepared analogous to the compound of example 59, using the procedure comprised in the preparation of the compound of example 59, wherein ethyl 5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboxylate was replaced with 5-(4-chlorophenyl)-1 -(2-chlorophenyl)-1 H-pyrazole-3- carboxylate.
Yield: 18.9 %; 1H NMR (300 MHz, DMSO-a : δ 1 .65 (brs, 6H, adamantyl), 2.05 - 2.20 (m, 9H, adamantyl), 7.23 (d, J = 8.4 Hz, 2H, Ar-H), 7.38 (s, 1 H, pyrazole-H), 7.44 (d, J = 8.0 Hz, 2H, Ar-H), 7.52 - 7.68 (m, 3H, Ar-H), 7.69 - 7.76 (m, 1 H, Ar-H), 8.10 (s, 1 H, exchangeable in D2O, NH); MS: m/z 491 .0 [M + H]+.
Example 75:
N-((1 s,3s,5s)-1 ,3,5-Triazaadamantan-7-yl)-1 -(2-chlorophenyl)-5-(4-chlorophenyl)- N'-cyano-1 H-pyrazole-3-carboximidamide The compound of example 75 was prepared analogous to the compound of example 60, using the procedure comprised in the preparation of the compound of example 60, wherein ethyl 5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboxylate was replaced with 5-(4-chlorophenyl)-1 -(2-chlorophenyl)-1 H-pyrazole-3- carboxylate.
Yield: 18.8 %; 1H NMR (300 MHz, DMSO-a^): δ 3.68 (s, 6H, triazaadamantanyl), 3.51 (d, J = 12.0 Hz, 3H, triazaadamantanyl), 4.33 (d, J = 12.3 Hz, 3H, triazaadamantanyl), 7.23 (d, J = 8.4 Hz, 2H, Ar-H), 7.40 (s, 1 H, pyrazole-H), 7.44 (d, J = 8.4 Hz, 2H, Ar-H), 7.52 - 7.67 (m, 3H, Ar-H), 7.71 - 7.78 (m, 1 H, Ar-H), 8.34 (s, 1 H, exchangeable in D2O, NH); MS: m/z 494.4 [M + H]+.
Example 76:
(S)-2-(1-(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-1 H-pyrazole-3- carboximidamido)propanamide
The compound of example 76 was prepared analogous to the compound of example 61 , using the procedure comprised in the preparation of the compound of example 61 , wherein ethyl 5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboxylate was replaced with 5-(4-chlorophenyl)-1 -(2-chlorophenyl)-1 H-pyrazole-3- carboxylate.
Yield: 57.9 %; 1H NMR (300 MHz, DMSO-a^): δ 1 .39 (d, J = 7.0 Hz, 3H, -CH3), 4.40 - 4.54 (m, 1 H, CH), 7.20 - 7.30 (m, 3H, Ar-H and amide-NH (exchangeable in D2O)), 7.45 (d, J = 8.4 Hz, 2H, Ar-H), 7.52 (s, 1 H, pyrazole-H), 7.55 - 7.68 (m, 4H, Ar-H and amide-NH (exchangeable in D2O)), 7.76 - 7.82 (m, 1 H, Ar-H), 8.86 (d, J = 6.6 Hz, 1 H, exchangeable in D2O, NH); MS: m/z 428.4 [M + H]+.
Example 77:
(S)-Methyl 2-(1 -(2-chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-1 H-pyrazole-3- carboximidamido)-3-methylbutanoate
The compound of example 77 was prepared analogous to the compound of example 62, using the procedure comprised in the preparation of the compound of example 62, wherein ethyl 5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboxylate was replaced with 5-(4-chlorophenyl)-1 -(2-chlorophenyl)-1 H-pyrazole-3- carboxylate. Yield: 59.2 %; 1 H NMR (300 MHz, DMSO-a^): δ 0.93 (d, J = 7.0 Hz, 3H, CH3), 0.98 (d, J = 7.0 Hz, 3H, CH3), 2.22 - 2.27 (m, 1 H, isopropyl-CH), 3.68 (s, 1 H, CH3), 4.33 (t, J = 7.5 Hz, 1 H, -CH), 7.25 (d, J = 8.4 Hz, 2H, Ar-H), 7.40 - 7.47 (m, 3H, pyrazole & Ar-H), 7.50 - 7.67 (m, 3H, Ar-H), 7.72 - 7.80 (m, 1 H, Ar-H), 9.30 (d, J = 7.2 Hz, exchangeable in D2O, NH); MS: m/z 471 .6 [M + H]+.
Example 78:
(S)-2-(1-(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-1 H-pyrazole-3- carboximidamido)-3-methylbutanamide
The compound of example 78 was prepared analogous to the compound of example 76, using the procedure comprised in the preparation of the compound of example 76, wherein (S)-2-aminopropanamide was replaced with (S)-2-amino-3- methylbutanamide.
Yield: 67.9 %; 1 H NMR (300 MHz, DMSO-a^): δ 0.85 - 1 .00 (m, 6H, -CH3), 2.10 - 2.21 (m, 1 H, isopropyl-CH), 4.30 - 4.40 (m, 1 H, CH), 7.22 - 7.34 (m, 3H, Ar-H and amide- NH (exchangeable in D2O)), 7.45 (d, J = 8.4 Hz, 2H, Ar-H), 7.51 (s, 1 H, pyrazole-H), 7.54 - 7.70 (m, 4H, Ar-H and amide-NH (exchangeable in D2O)), 7.78 - 7.82 (m, 1 H, Ar-H), 8.64 (d, J = 8.4 Hz, 1 H, exchangeable in D2O, NH); MS: m/z 456.6 [M + H]+. Example 79:
1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-N-(1 ,1 -dioxidothiomorpholino)- 1 H-pyrazole-3-carboximidamide
The compound of example 79 was prepared analogous to the compound of example 64, using the procedure comprised in the preparation of the compound of example 64, wherein ethyl 5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboxylate was replaced with 5-(4-chlorophenyl)-1 -(2-chlorophenyl)-1 H-pyrazole-3- carboxylate.
Yield: 37.9 %; 1 H NMR (300 MHz, DMSO-a^): δ 3.10 - 3.50 (m, overlap with H2O in DMSO, 8H, thiomorpholine), 7.20 - 7.30 (m, 3H, pyrazole & Ar-H), 7.42 (d, = 8.4 Hz, 2H, Ar-H), 7.51 - 7.68 (m, 3H, Ar-H), 7.78 - 7.84 (m, 1 H, Ar-H), 1 1 .02 (s, 1 H, exchangeable in D2O, NH); MS: m/z 490.5 [M + H]+. Example 80:
N-((5-(4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3-yl)(piperidin-1 -yl) methylene)cyanamide
The compound of the example 49 (60 mg, 0.148 mmol) in anhydrous methanol (2 mL) was treated with piperidine (2.20 equivalents) according to the procedure for the preparation of the compound of example 50 to obtain the title compound.
Yield: 21 .4 %; 1H NMR (300 MHz, DMSO-a^): δ 1 .50 - 1 .75 (m, 6H, piperidine), 3.52 (s, 2H, piperidine), 3.80 (s, 2H, piperidine), 7.16 (s, 1 H, pyrazole-H), 7.26 (d, J = 8.1 Hz, 2H, Ar-H), 7.47 (d, J = 8.1 Hz, 2H, Ar-H), 7.62 - 7.68 (m, 1 H, Ar-H), 7.78 (d, J = 8.7 Hz, 1 H, Ar-H), 7.89 (s, 1 H, Ar-H); MS: m/z 458.3 [M]+.
Example 81 :
ferf-Butyl (1 -((5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3-yl)
(cyanoimino)methyl)piperidin-4-yl)carbamate
The compound of the example 49 (60 mg, 0.148 mmol) in anhydrous methanol (2 mL) was treated with tert-butyl piperidin-4-ylcarbamate (2.20 equivalents) according to the procedure for the preparation of the compound of example 50 to obtain the title compound.
Yield: 47.1 %; 1 H NMR (500 MHz, DMSO-a^): δ 1 .30 - 1 .50 (m, 1 1 H, piperidine-H and - Boc), 1 .75 - 1 .95 (m, 2H, piperidine), 3.20 - 3.32 (m, 2H overlap with H2O in DMSO, piperidine), 3.60 - 3.70 (m, 1 H, piperidine), 3.75 - 3.90 (m, 1 H, piperidine), 4.45 (d, J = 12.5 Hz, 1 H, piperidine), 6.69 (d, J = 7.5 Hz, 1 H, exchangeable in D2O, NH), 7.18 (s, 1 H, pyrazole-H), 7.42 (d, J = 8.5 Hz, 2H, Ar-H), 7.48 (d, J = 8.5, 2H, Ar-H), 7.66 (dd, J = 2.0 Hz, 8.5 Hz, 1 H, Ar-H), 7.79 (d, J = 9.0, 1 H, Ar-H), 7.91 (d, J = 1 .5 Hz, 1 H, Ar-H); MS: m/z 475.2 [M + H]+.
Example 82:
N-((4-Aminopiperidin-1 -yl)(5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3- yl)methylene)cyanamide hydrochloride
The compound of example 82 was prepared by the deprotection of the t-butyl oxy carbonyl group of the compound of example 81 using dioxane-HCI.
Yield: 37.5 %; 1 H NMR (500 MHz, DMSO-a^): δ 1 .52 - 1 .67 (m, 2H, piperidine), 1 .95 - 2.05 (m, 1 H, piperidine), 2.05 - 2.15 (m, 1 H, piperidine), 3.10 - 3.25 (m, 1 H, piperidine), 3.25 - 3.40 (m, 2H overlap with H2O in DMSO, piperidine), 3.95 (d, J = 12.5 Hz, 1 H, piperidine), 4.62 (d, J = 13.0 Hz, 1 H, piperidine), 7.20 (s, 1 H, pyrazole-H), 7.28 (d, J = 8.5 Hz, 2H, Ar-H), 7.50 (d, J = 8.5, 2H, Ar-H), 7.65 - 7.69 (m, 1 H, Ar-H), 7.80 (d, J = 8.5 Hz, 1 H, Ar-H), 7.91 - 7.40 (m, 1 H, Ar-H), 8.82 (brs, 3H, exchangeable in D2O, NH); MS: m/z 473.1 [M - HCI]+.
Example 83:
N-((5-(4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3-yl)(piperazin-1 -yl) methylene)cyanamide hydrochloride
The compound of example 83 was prepared by the deprotection of the t-butyl oxy carbonyl group of the compound of example 58 using dioxane-HCI.
Yield: 58.2 %; 1 H NMR (500 MHz, DMSO-a^): δ 3.20 - 3.45 (m, 4H, piperazine), 3.86 (brs, 2H, piperazine), 4.06 (brs, 2H, piperazine), 7.22 - 7.32 (m, 3H, pyrazole & Ar-H), 7.50 (d, J = 8.5 Hz, 2H, Ar-H), 7.68 (dd, J = 2.0 Hz, 8.5 Hz, 1 H, Ar-H), 7.79 (d, J = 8.5, 1 H, Ar-H), 7.92 (d, J = 2.0 Hz, 1 H, Ar-H), 9.32 (brs, 2H, exchangeable in D2O, NH); MS: m/z 459.1 [M - HCI]+.
Example 84:
2-(5-(4-Chlorophenyl)-N'-cyano-1-(2,4-dichlorophenyl)-1 H-pyrazole-3- carboximidamido)-2-methylpropanamide
The compound of the example 49 (60 mg, 0.148 mmol) in anhydrous methanol (2 mL) was treated with 2-amino-2-methylpropanamide (2.20 equivalents) according to the procedure for the preparation of the compound of example 50 to obtain the title compound.
Yield: 39.8 %; 1 H NMR (500 MHz, DMSO-a^): δ 1 .59 (s, 6H, -CH3), 7.28 (d, J = 8.5 Hz, 1 H, Ar-H), 7.34 (s,1 H, exchangeable in D2O, amide-NH), 7.49 (d, J = 8.5 Hz, 1 H, Ar-H), 7.54 (s, 1 H, exchangeable in D2O, amide-NH), 7.55 (s, 1 H, pyrazole-H), 7.69 (dd, J = 2.5 Hz, 8.5 Hz, 1 H, Ar-H), 7.85 (d, J = 8.5 Hz, 1 H, Ar-H), 7.90 (d, J = 2.0 Hz, 1 H, Ar-H), 8.87 (s, 1 H, exchangeable in D2O, NH); MS: m/z 475.2 [M]+. Example 85:
1 -(5-(4-Chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboximidamido)cyclopropanecarboxamide
The compound of the example 49 (60 mg, 0.148 mmol) in anhydrous methanol (2 mL) was treated with 1 -aminocyclopropanecarboxamide (2.20 equivalents) according to the procedure for the preparation of the compound of example 50 to obtain the title compound.
Yield: 35.7 %; 1H NMR (300 MHz, DMSO-a : δ 1 .08 (s, 2H, cyclopropyl-CH2), 1 .36 (s, 2H, cyclopropyl-CH2), 7.1 1 (brs, 1 H, exchangeable in D2O, amide-NH), 7.24 (d, J = 8.4 Hz, 1 H, Ar-H), 7.38 (brs, 1 H, exchangeable in D2O, amide-NH), 7.45 - 7.52 (m, 3H, pyrazole & Ar-H), 7.68 (dd, J = 2.1 Hz, 8.4 Hz, 1 H, Ar-H), 7.79 (d, J = 8.7 Hz, 1 H, Ar-H), 7.87 (d, J = 2.1 Hz, 1 H, Ar-H), 9.54 (s, 1 H, exchangeable in D2O, NH). MS: m/z 473.4 [M]+.
Example 86:
1 -(5-(4-Chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboximidamido)cyclopentanecarboxamide
The compound of the example 49 (60 mg, 0.148 mmol) in anhydrous methanol (2 imL) was treated with 1 -aminocyclopentanecarboxamide (2.20 equivalents) according to the procedure for the preparation of the compound of example 50 to obtain the title compound.
Yield: 39.9 %; 1H NMR (500 MHz, DMSO-c/5): δ 1 .60 - 1 .80 (m, 4H, cyclopentyl-CH2), 2.05 - 2.14 (m, 2H, cyclopentyl-CH2), 2.15 - 2.25 (m, 2H, cyclopentyl-CH2), 6.99 (s, 1 H, exchangeable in D2O, amide-NH), 7.20 (s,1 H, exchangeable in D2O, amide-NH), 7.27 (d, J = 8.0 Hz, 1 H, Ar-H), 7.46 - 7.54 (m, 3H, pyrazole & Ar-H), 7.69 (dd, J = 2.0 Hz, 8.5 Hz, 1 H, Ar-H), 7.81 (d, J = 8.5 Hz, 1 H, Ar-H), 7.89 (d, J = 2.0 Hz, 1 H, Ar-H), 8.85 (s, 1 H, exchangeable in D2O, NH); MS: m/z 501 .1 [M + H]+.
Example 87:
(S)-2-(5-(4-Chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboximidamido)-3-methylbutanoic acid
The compound of the example 49 (60 mg, 0.148 mmol) in anhydrous methanol (2 imL) was treated with (S)-2-amino-3-methylbutanoic acid (2.20 equivalents) according to the procedure for the preparation of the compound of example 50 to obtain the title compound.
Yield: 49.4 %; 1 H NMR (500 MHz, DMSO-a^): δ 0.90 - 1 .10 (m, 6H, CH3), 2.21 - 2.28 (m, 1 H, isopropyl-CH), 4.28 (d, J = 6.5 Hz, 1 H, CH), 7.28 (d, J = 8.5 Hz, 2H, Ar-H), 7.45 - 7.50 (m, 3H, pyrazole & Ar-H), 7.69 (d, J = 8.5 Hz, 1 H, Ar-H), 7.85 (d, J = 8.5 Hz, 1 H, Ar-H), 7.89 (s, 1 H, Ar-H), 9.08 (d, J = 7.5 Hz, NH), 1 3.01 (brs, 1 H, exchangeable in D2O, COOH); MS: m/z 490.9 [M]+.
Example 88:
(S)-2-(5-(4-Chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboximidamido)-3-methylbutanamide
The compound of the example 49 (60 mg, 0.148 mmol) in anhydrous methanol (2 mL) was treated with (S)-2-amino-3-methylbutanamide (2.20 equivalents) according to the procedure for the preparation of the compound of example 50 to obtain the title compound.
Yield: 24.8 %; 1 H NMR (500 MHz, DMSO-a^): δ 0.90 - 1 .00 (m, 6H, -CH3), 2.1 2 - 2.31 (m, 1 H, isopropyl-CH), 4.31 - 4.40 (m, 1 H, CH), 7.28 (d, J = 8.0 Hz, 2H, Ar-H), 7.31 (s, 1 H, exchangeable in D2O, amide-NH), 7.46 - 7.54 (m, 3H, pyrazole & Ar-H), 7.66 (s, 1 H, exchangeable in D2O, amide-NH), 7.69 (d, J = 9.0 Hz, 1 H, Ar-H), 7.89 (s, 1 H, Ar-H), 8.66 (brs, 1 H, exchangeable in D2O, NH); MS: m/z 51 1 .7 [M + Na]+.
Example 89:
ferf-Butyl 9-((5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3-yl)
(cyanoimino)methyl)-2,9-diazaspiro[5.5]undecane-2-carboxylate
The compound of the example 49 (60 mg, 0.148 mmol) in anhydrous methanol
(2 mL) was treated with tert-butyl 2,9-diazaspiro[5.5]undecane-2-carboxylate (2.20 equivalents) according to the procedure for the preparation of the compound of example 50 to obtain the title compound.
Yield: 60.3 %; 1 H NMR (500 MHz, DMSO-a^): δ 1 .30 - 1 .60 (m, 1 6H, diazaspiro-H and - Boc), 3.20 - 3.42 (m, 4H overlap with H2O in DMSO, diazaspiro), 3.45 - 3.55 (m, 1 H, diazaspiro), 3.56 - 3.72 (m, 2H, diazaspiro), 3.90 - 4.1 0 (m, 2H, diazaspiro), 7.1 9 (s, 1 H, pyrazole-H), 7.28 (d, J = 8.5 Hz, 2H, Ar-H), 7.49 (d, J = 8.5, 2H, Ar-H), 7.64 - 7.69 (m, 1 H, Ar-H), 7.80 (d, J = 8.0 Hz, 1 H, Ar-H), 7.90 - 7.94 (m, 1 H, Ar-H). MS: m/z 629.5 [M + H]+.
Example 90:
N-((5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-1 H-pyrazol-3-yl)(2,9-diazaspiro[5.5] undecan-9-yl)methylene)cyanamide hydrochloride The compound of example 90 was prepared by the deprotection of the t-butyl oxy carbonyl group of the compound of example 89 using dioxane-HCI.
Yield: 57.9 %; 1H NMR (500 MHz, DMSO-a : δ 1 .50 - 1 .80 (m, 7H, diazaspiro), 2.90 - 3.10 (m, 4H, diazaspiro), 3.40 - 3.70 (m, 3H overlap with H2O in DMSO, diazaspiro), 3.75 - 3.95 (m, 2H, diazaspiro), 7.19 (s, 1 H, pyrazole-H), 7.28 (d, J = 8.5 Hz, 2H, Ar-H), 7.49 (d, J = 8.0, 2H, Ar-H), 7.65 - 7.0 (m, 1 H, Ar-H), 7.81 (d, J = 8.5 Hz, 1 H, Ar-H), 7.91 (s, 1 H, Ar-H), 8.76 (brs, 2H, exchangeable in D2O, NH); MS: m/z 529.2 [M - HCI]+.
Example 91 :
N-((1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl)(piperidin-1 -yl) methylene)cyanamide
The compound of example 91 was prepared analogous to the compound of example 80, using the procedure comprised in the preparation of the compound of example 80, wherein ethyl 5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboxylate was replaced with 5-(4-chlorophenyl)-1 -(2-chlorophenyl)-1 H-pyrazole-3- carboxylate.
Yield: 29.2 %; 1 H NMR (300 MHz, DMSO-c/5): δ 1 .50 - 1 .75 (m, 6H, piperidine), 3.53 (s, 2H, piperidine), 3.80 (s, 2H, piperidine), 7.16 (s, 1 H, pyrazole-H), 7.25 (d, J = 8.4 Hz, 2H, Ar-H), 7.45 (d, J = 7.8 Hz, 2H, Ar-H), 7.50 - 7.63 (m, 2H, Ar-H), 7.63 - 7.74 (m, 2H, Ar-H); MS: m/z 425.5 [M + H]+.
Example 92:
N-((4- Acetyl pi perazin-1 -yl)(1 -(2-chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl) methylene)cyanamide
The compound of example 92 was prepared analogous to the compound of example 57, using the procedure comprised in the preparation of the compound of example 57, wherein ethyl 5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboxylate was replaced with 5-(4-chlorophenyl)-1 -(2-chlorophenyl)-1 H-pyrazole-3- carboxylate.
Yield: 40.2 %; 1H NMR (300 MHz, DMSO-a : δ 2.04 (s, 3H, -CH3), 3.50 - 3.75 (m, 6H, piperazine), 3.75 - 4.00 (m, 2H, piperazine), 7.18 - 7.29 (m, 3H, pyrazole & Ar-H), 7.45 (d, J = 8.4 Hz, 2H, Ar-H), 7.50 - 7.64 (m, 2H, Ar-H), 7.64 - 7.70 (m, 1 H, Ar-H), 7.70 - 7.78 (m, 1 H, Ar-H); MS: m/z 468.4 [M + H]+. Example 93:
1 -(1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-1 H-pyrazole-3- carboximidamido)cyclopentanecarboxamide
The compound of example 93 was prepared analogous to the compound of example 86, using the procedure comprised in the preparation of the compound of example 86, wherein ethyl 5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboxylate was replaced with 5-(4-chlorophenyl)-1 -(2-chlorophenyl)-1 H-pyrazole-3- carboxylate.
Yield: 37.1 %; 1 H NMR (500 MHz, DMSO-a^): δ 1 .58 - 1 .78 (m, 4H, cyclopentyl-CH2), 2.05 - 2.15 (m, 2H, cyclopentyl-CH2), 2.15 - 2.24 (m, 2H, cyclopentyl-CH2), 6.99 (s, 1 H, exchangeable in D2O, amide-NH), 7.20 (s, 1 H, exchangeable in D2O, amide-NH), 7.25 (d, J = 8.5 Hz, 1 H, Ar-H), 7.45 - 7.51 (m, 3H, pyrazole & Ar-H), 7.57 - 7.68 (m, 3H, Ar- H), 7.75 (dd, J = 2.0 Hz, 7.5 Hz, 1 H, Ar-H), 8.82 (s, 1 H, exchangeable in D2O, NH); MS: m/z 467.2 [M]+.
Example 94:
ferf-Butyl 9-((1 -(2-chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl)(cyanoimino) methyl )-2,9-diazaspiro[5.5]undecane-2-carboxylate
The compound of example 94 was prepared analogous to the compound of example 89, using the procedure comprised in the preparation of the compound of example 89, wherein ethyl 5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboxylate was replaced with 5-(4-chlorophenyl)-1 -(2-chlorophenyl)-1 H-pyrazole-3- carboxylate.
Yield: 42.5 %; 1 H NMR (300 MHz, DMSO-a^): δ 1 .20 - 1 .60 (m, 17H, diazaspiro-H and - Boc), 3.15 - 3.35 (m, 4H, overlap with H2O in DMSO, diazaspiro), 3.45 - 3.80 (m, 3H, diazaspiro), 3.85 - 4.05 (m, 1 H, diazaspiro), 7.17 (s, 1 H, pyrazole-H), 7.23 (d, J = 8.4 Hz, 2H, Ar-H), 7.44 (d, J = 8.4, 2H, Ar-H), 7.49 - 7.62 (m, 2H, Ar-H), 7.62 - 7.69 (m, 1 H, Ar-H), 7.69 - 7.75 (m, 1 H, Ar-H); MS: m/z 593.3 [M]+. Example 95:
5-(4-Chlorophenyl)-N'-cyano-N-cyclohexyl-1-(2,4-dichlorophenyl)-4-methyl-1 H- pyrazole-3-carboximidamide
The compound of example 95 was prepared analogous to the compound of example 53, using the procedure comprised in the preparation of the compound of example 53, wherein ethyl 5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboxylate was replaced with 5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-4-methyl-1 H- pyrazole-3-carboxylic acid.
Yield: 25.9 %; 1H NMR (300 MHz, DMSO-a^): δ 1 .14 - 1 .22 (m, 2H, cyclohexyl), 1 .32 - 1 .35 (m, 3H, cyclohexyl), 1 .57 - 1 .62 (m, 1 H, cyclohexyl), 1 .73 - 1 .90 (m, 4H, cyclohexyl), 2.13 (s, 3H, pyrazole-CH3), 3.88 (m, 1 H, cyclohexyl), 7.21 (d, J = 8.4 Hz, 2H, Ar-H), 7.48 (d, J = 8.1 Hz, 2H, Ar-H), 7.61 (m, 2H, Ar-H), 7.80 (m, 1 H, Ar-H), 9.1 1 (d, J = 7.8 Hz, 1 H, exchangeable in D2O, NH); MS: m/z 487.4 [M + H]+. Example 96:
(fl)-2-(5-(4-Chlorophenyl)-N'-cyano-1-(2,4-dichlorophenyl)-4-methyl-1 H-pyrazole-3- carboximidamido)propanamide
The compound of example 96 was prepared analogous to the compound of example 61 , using the procedure comprised in the preparation of the compound of example 61 , wherein ethyl 5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboxylate was replaced with 5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-4-methyl-1 H- pyrazole-3-carboxylic acid.
Yield: 35.3 %; 1H NMR (300 MHz, DMSO-d6): δ 1 .38 (d, J = 7.2 Hz, 3H, alanine-CH3), 2.16 (s, 3H, pyrazole-CH3), 4.50 (m, 1 H, alanine-CH), 7.20 - 7.23 (m, 3H), 7.49 (d, J = 8.4 Hz, 2H, Ar-H), 7.58 - 7.66 (m, 3H), 7.80 (m, 1 H), 9.16 (d, J = 6.9 Hz, 1 H, exchangeable in D2O, HH); MS: m/z 477.4 [M + H]+.
Example 97:
2-(5-(4-Chlorophenyl)-N'-cyano-1-(2,4-dichlorophenyl)-4-methyl-1 H-pyrazole-3- carboximidamido)-2-methylpropanamide
The compound of example 97 was prepared analogous to the compound of example 84, using the procedure comprised in the preparation of the compound of example 84, wherein ethyl 5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboxylate was replaced with 5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-4-methyl-1 H- pyrazole-3-carboxylic acid.
Yield: 17.1 %; 1H NMR (500 MHz, DMSO-a^): δ 1 .55 (s, 6H, dimethyl), 2.18 (s ,3H, pyrazole-CH3), 7.20 (brs, 1 H, exchangeable in D2O, CONH), 7.23 (d, J = 8.5 Hz, 2H, Ar-H), 7.33 (brs, 1 H, exchangeable in D2O, CONHj, 7.50 (d, J = 8.5 Hz, 2H, Ar-H), 7.63 - 7.64 (m, 2H, Ar-H), 7.81 - 7.82 (m, 1 H, Ar-H), 8.88 (s, 1 H, exchangeable in D2O, NH); MS: m/z 489.4 [M]+.
Example 98:
1 -(5-(4-Chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-4-methyl-1 H-pyrazole-3- carboximidamido)cyclopropanecarboxamide
The compound of example 98 was prepared analogous to the compound of example 85, using the procedure comprised in the preparation of the compound of example 85, wherein ethyl 5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboxylate was replaced with 5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-4-methyl-1 H- pyrazole-3-carboxylic acid.
Yield: 25.1 %; 1H NMR (300 MHz, DMSO-d6): δ 1 .13 - 1 .42 (m, 4H, cyclopropyl), 2.18 (s ,3H, pyrazole-CH3), 7.15 (brs, 1 H, exchangeable in D2O, CONH), 7.20 (d, J = 8.4 Hz, 2H, Ar-H), 7.26 (brs, 1 H exchangeable in D2O, CONHj, 7.48 (d, J = 8.4 Hz, 2H, Ar-H), 7.60 - 7.68 (m, 2H, Ar-H), 7.79 (m, 1 H, Ar-H), 9.49 (s, 1 H, exchangeable in D2O, NH); MS: m/z 487.1 [M]+.
Example 99:
1 -(5-(4-Chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-4-methyl-1 H-pyrazole-3- carboximidamido)cyclopentanecarboxamide
The compound of example 99 was prepared analogous to the compound of example 86, using the procedure comprised in the preparation of the compound of example 86, wherein ethyl 5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboxylate was replaced with 5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-4-methyl-1 H- pyrazole-3-carboxylic acid.
Yield: 19.5 %; 1H NMR (500 MHz, DMSO-a^): δ 1 .24 (m, 1 H, cyclopentyl), 1 .69 (m, 4H, cyclopentyl), 2.13 - 2.14 (m, 3H, cyclopentyl), 2.16 (s, 3H, pyrazole-CH3), 7.05
- 7.09 (m, 2H, exchangeable in D2O, CONH2), 7.21 (d, J = 8.5 Hz, 2H, Ar-H), 7.50 (d, J = 8.5 Hz, 2H, Ar-H), 7.62 - 7.63 (m, 2H, Ar-H), 7.81 - 7.82 (m, 1 H, Ar-H), 9.12 (s, 1 H, exchangeable in D2O, NH); MS: m/z 514.9 [M - H]+.
Example 100:
2-(5-(4-Chlorophenyl)-N'-cyano-1-(2,4-dichlorophenyl)-4-methyl-1 H-pyrazole-3- carboximidamido)-3-methylbutanamide The compound of example 100 was prepared analogous to the compound of example 88, using the procedure comprised in the preparation of the compound of example 88, wherein ethyl 5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboxylate was replaced with 5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-4-methyl-1 H- pyrazole-3-carboxylic acid.
Yield: 23.3 %; 1H NMR (500 MHz, DMSO-d6): δ 0.97 (d, J = 6.0 Hz, 6H, valine-CH3), 1 .16 - 1 .19 (m, 1 H, valine-CH), 2.16 (s, 3H, pyrazole- CH3), 4.36 (t, J = 7.5 Hz, 1 H), 7.22 (d, J = 8.5 Hz, 2H, Ar-H), 7.25 (s, 1 H, exchangeable in D2O, CONH), 7.50 (d, J = 8.5 Hz, 2H, Ar-H), 7.64 - 7.65 (m, 3H, Ar-H and CONH(exchangeable in D2O)), 7.82 (s, 1 H, Ar-H), 9.13 (d, J = 8.0 Hz, 1 H, exchangeable in D2O, NH); MS m/z 503.4 [M + H]+.
Example 101 :
1-(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-N-cyclopropyl-4-methyl-1 H- pyrazole-3-carboximidamide
The compound of example 101 was prepared analogous to the compound of example 69, using the procedure comprised in the preparation of the compound of example 69, wherein ethyl 5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboxylate was replaced with 5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-4-methyl-1 H- pyrazole-3-carboxylic acid.
Yield: 28.2 %; 1H NMR (500 MHz, DMSO-a^): δ 0.73 - 0.85 (m, 4H, cyclopropyl), 2.15 (s, 3H, pyrazole- CH3), 3.02 - 3.05 (m, 1 H, cyclopropyl), 7.21 (d, J = 8.5 Hz, 2H, Ar-H), 7.46 (d, J = 8.5 Hz, 2H, Ar-H), 7.49 - 7.61 (m, 4H, Ar-H), 9.26 (d, J = 4.5 Hz, 1 H, exchangeable in D2O, NH); MS: m/z 410.1 [M]+. Example 102:
1-(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-N-cyclohexyl-4-methyl-1 H- pyrazole-3-carboximidamide
The compound of example 102 was prepared analogous to the compound of example 70, using the procedure comprised in the preparation of the compound of example 70, wherein ethyl 5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboxylate was replaced with 5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-4-methyl-1 H- pyrazole-3-carboxylic acid.
Yield: 34.1 %; 1H NMR (300 MHz, DMSO-a^): δ 1 .13 - 1 .15 (m, 1 H, cyclohexyl), 1 .32 - 1 .35 (m, 4H, cyclohexyl), 1 .60 - 1 .62 (m, 1 H, cyclohexyl), 1 .75 (m, 2H, cyclohexyl), 1 .90 (m, 2H, cyclohexyl), 2.15 (s, 3H, pyrazole-CH3), 3.90 (m, 1 H, cyclohexyl), 7.21 (d, J = 8.5 Hz, 2H, Ar-H), 7.47 (d, J = 8.5 Hz, 2H, Ar-H), 7.49 - 7.54 (m, 2H, Ar-H), 7.57 - 7.59 (m, 2H, Ar-H), 9.10 (d, J = 7.5 Hz, 1 H, exchangeable in D2O, NH); MS: m/z 452.2 [M]+. Example 103:
(S)-2-(1-(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-4-methyl-1 H-pyrazole-3- carboximidamido)propanamide
The compound of example 103 was prepared analogous to the compound of example 76, using the procedure comprised in the preparation of the compound of example 76, wherein ethyl 5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboxylate was replaced with 5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-4-methyl-1 H- pyrazole-3-carboxylic acid.
Yield: 31 .4 %; 1H NMR (500 MHz, DMSO-d6): δ 1 .40 (d, J = 4.2 Hz, 3H, alanine-CH3), 2.18 (s, 3H, pyrazole-CH3), 4.50 - 4.53 (m, 1 H, alanine-CH), 7.18 (brs, 1 H, exchangeable in D2O, CONH), 7.22 (d, J = 8.5 Hz, 2H, Ar-H), 7.47 (d, J = 8.5 Hz, 2H, Ar-H), 7.51 - 7.54 (m, 2H, Ar-H), 7.57 - 7.62 (m, 3H, Ar-H), 9.15 (d, J = 7.0 Hz, 1 H, exchangeable in D2O, HH); MS: m/z 441 .4 [M + H]+.
Example 104:
1 -(1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-4-methyl-1 H-pyrazole-3- carboximidamido)cyclopropanecarboxamide
The compound of example 104 was prepared analogous to the compound of example 103, using the procedure comprised in the preparation of the compound of example 103, wherein (S)-2-aminopropanamide was replaced with 1 - aminocyclopropanecarboxamide.
Yield: 17.0 %; 1H NMR (500 MHz, DMSO-a^): δ 1 .14 (m, 2H, cyclopropyl), 1 .44 (m, 2H, cyclopropyl), 2.20 (s, 3H, pyrazole-C -/3), 7.15 (brs, 1 H, exchangeable in D2O, CONH), 7.20 (d, J = 8.0 Hz, 2H, Ar-H), 7.27 (brs, 1 H, exchangeable in D2O, CONH), 7.48 (d, J = 8.5 Hz, 2H, Ar-H), 7.50 - 7.57 (m, 2H, Ar-H), 7.62 - 7.64 (m, 2H, Ar-H), 9.47 (s, 1 H, exchangeable in D2O, HH); MS: m/z 455.4 [M + H]+.
Example 105:
1 -(1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-4-methyl-1 H-pyrazole-3- carboximidamido)cyclopentanecarboxamide The compound of example 105 was prepared analogous to the compound of example 93, using the procedure comprised in the preparation of the compound of example 93, wherein ethyl 5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboxylate was replaced with 5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-4-methyl-1 H- pyrazole-3-carboxylic acid.
Yield: 16.0 %; 1H NMR (500 MHz, DMSO-a^): δ 1 .24 (m, 1 H, cyclopentyl), 1 .69 (m, 4H, cyclopentyl), 2.13 - 2.14 (m, 3H, cyclopentyl), 2.17 (s, 3H, pyrazole-CH3), 7.05 - 7.09 (m, 2H, exchangeable in D2O, CONH2), 7.20 (d, J = 8.5 Hz, 2H, Ar-H), 7.47 (d, J = 8.5 Hz, 2H, Ar-H), 7.52 - 7.54 (m, 2H, Ar-H), 7.56 - 7.59 (m, 2H, Ar-H), 9.10 (s, 1 H, exchangeable in D2O, HH); MS: m/z 481 .4 [M + H]+.
Example 106:
(S)-2-(5-(4-chlorophenyl)-N'-cyano-1-(2,4-dichlorophenyl)-4-methyl-1 H-pyrazole-3- carboximidamido)-3-methylbutanamide
The compound of example 106 was prepared analogous to the compound of example 78, using the procedure comprised in the preparation of the compound of example 78, wherein ethyl 5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboxylate was replaced with 5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-4-methyl-1 H- pyrazole-3-carboxylic acid.
Yield: 24.6 %; 1H NMR (500 MHz, DMSO-a^): δ 0.97 (d, J = 6.5 Hz, 6H, valine-CH3), 1 .18 - 1 .24 (m, 1 H, valine-CH), 2.16 (s, 3H, pyrazole-CH3), 4.36 (t, J = 7.5 Hz, 1 H), 7.21 (d, J = 8.5 Hz, 2H, Ar-H), 7.26 (s, 1 H, exchangeable in D2O, CONH), 7.47 (d, J = 8.5 Hz, 2H, Ar-H), 7.64 - 7.65 (m, 4H, Ar-H and CONH(exchangeable in D2O)), 7.82 (s, 1 H, Ar-H), 9.1 1 (d, J = 7.5 Hz, 1 H, exchangeable in D2O, NH); MS: m/z 471 .1 [M + H]+.
Example 107:
ferf-Butyl 9-((1 -(2-chlorophenyl)-5-(4-chlorophenyl)-4-methyl-1 H-pyrazol-3-yl) (cyanoimino)methyl)-2,9-diazaspiro[5.5]undecane-2-carboxylate
The compound of example 107 was prepared analogous to the compound of example 94, using the procedure comprised in the preparation of the compound of example 94, wherein ethyl 5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboxylate was replaced with 5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-4-methyl-1 H- pyrazole-3-carboxylic acid. Yield: 57.1 %; 1H NMR (500 MHz, DMSO-a6): δ 1 .38 - 1 .45 (m, 1 8H, diazaspiro CH2 & -Boc), 2.1 1 (s, 3H, pyrazole-CH3), 3.01 - 3.20 (m, 1 H, diazaspiro), 3.40 - 3.65 (m, 3H, diazaspiro), 3.87 (m, 2H, diazaspiro), 4.14 (m, 1 H, diazaspiro), 7.25 (d, J = 8.5 Hz, 2H, Ar-H), 7.47 (d, J = 8.5 Hz, 2H, Ar-H), 7.48 (m, 1 H, Ar-H), 7.51 - 7.54 (m, 1 H, Ar-H) 7.59 - 7.63 (m, 2H, Ar-H); MS: m/z 607 [M]+.
Example 108:
ferf-Butyl 4-((1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-4-methyl-1 H-pyrazol-3-yl) (cyanoimino)methyl)-1-oxa-4,8-diazaspiro[5.5]undecane-8-carboxylate
The compound of example 1 08 was prepared analogous to the compound of example 1 07, using the procedure comprised in the preparation of the compound of example 1 07, wherein tert-butyl 2,9-diazaspiro[5.5]undecane-2-carboxylate was replaced with tert-butyl 1 -oxa-4,8-diazaspiro[5.5]undecane-8-carboxylate.
Yield: 60.7 %; 1H NMR (500 MHz, DMSO-a6): δ 1 .1 8 - 1 .24 (m, 3H, oxa-diazaspiro), 1 .36 (m, 9H, Boc), 1 .50 - 1 .66 (m, 3H, oxa-diazaspiro), 2.1 3 (s ,3H, pyrazole-CH3), 2.80 - 3.1 0 (m, 1 H, oxa-diazaspiro), 3.40 - 3.55 (m, 2H, oxa-diazaspiro), 3.62 - 3.91 (m, 5H, oxa-diazaspiro) , 7.25 (d, J = 8.0 Hz, 2H, Ar-H), 7.48 (d, J = 8.5 Hz, 2H, Ar-H), 7.51 - 7.54 (m, 3H, Ar-H), 7.60 - 7.61 (m, 1 H, Ar-H); MS: m/z 609.3 [M]+. Example 109:
1-(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-4-methyl-N-(quinuclidin-3-yl)-1 H- pyrazole-3-carboximidamide
The compound of example 1 09 was prepared analogous to the compound of example 1 08, using the procedure comprised in the preparation of the compound of example 1 08, wherein tert-butyl 2,9-diazaspiro[5.5]undecane-2-carboxylate was replaced with (1 R,3S,4R)-quinuclidin-3-amine.
Yield: 20.9 %; 1H NMR (300 MHz, DMSO-a6): δ 1 .21 - 1 .36 (m, 1 H, quinuclidine), 1 .59 (m, 2H, quinuclidine), 1 .70 - 1 .85 (m, 1 H, quinuclidine), 2.03 (m, 1 H, quinuclidine) 2.1 3 (s, 3H, pyrazole-CH3), 2.60 - 2.91 (m, 4H, quinuclidine), 3.12 - 3.25 (m, 2H, quinuclidine), 3.95 - 4.1 5 (m, 1 H, quinuclidine), 7.1 8 (d, J = 8.1 Hz, 2H, Ar-H), 7.45 (d, J = 8.1 Hz, 2H, Ar-H), 7.50 - 7.55 (m, 4H, Ar-H), 9.25 (m, 1 H, exchangeable in D2O, NH); MS: m/z 479.2 [M]+. Example 110:
N-((1 S,2R,4S)-Bicyclo[2.2.1]hept-5-en-2-ylmethyl)-1-(2-chlorophenyl)-5-(4- chlorophenyl)-N'-cyano-4-methyl-1 H-pyrazole-3-carboximidamide
The compound of example 1 10 was prepared analogous to the compound of example 109, using the procedure comprised in the preparation of the compound of example 109, wherein (1 R,3S,4R)-quinuclidin-3-amine was replaced with (1 R,2S,4R)- bicyclo[2.2.1 ]hept-5-en-2-ylmethanamine.
Yield: 32.3 %; 1H NMR (300 MHz, DMSO-a^): δ 0.53 - 0.57 (m, 1 H, norbornene), 1 .22 - 1 .24 (m, 2H, norbornene), 1 .31 (m, 1 H, norbornene), 1 .83 (m, 1 H, norbornene), 2.14 (s, 3H, pyrazole- CH3), 2.77 - 2.83 (m, 2H, norbornene), 3.03 - 3.1 1 (m, 2H, norbornene), 6.02 (m, 1 H, norbornene-CH=C -/), 6.19 (m, 1 H, norbornene-C - =CH), 7.18 (d, J = 8.1 Hz, 2H, Ar-H), 7.45 (d, J = 7.8 Hz, 2H, Ar-H), 7.50 - 7.55 (m, 4H, Ar-H), 9.24 (m, 1 H, exchangeable in D2O, NH); MS: m/z 476.2 [M]+. Example 111 :
1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazole-3-carboxylic acid
The compound of example 1 1 1 was prepared analogous to the compound of example 2, using the procedure comprised in the preparation of the compound of example 2, wherein 2,4-dichlorophenylhydrazine hydrochloride was replaced with 2- chlorophenylhydrazine hydrochloride.
Yield: 91 .74 %; 1H NMR (300 MHz, DMSO-a^): δ 7.18 (s, 1 H, Ar-H), 7.23 (d, 2H, J = 8.4 Hz, Ar-H), 7.41 (d, 2H, J = 8.4 Hz, Ar-H), 7.51 -7.73 (m, 4H., Ar-H), 12.94 (brs, 1 H, pyrazole acid-OH); MS: m/z 334.9 [M+H]+. Example 112:
1 -(2-chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-amine
To a solution of the compound of example 1 1 1 (1 .00 g, 3.00 mmol) in t-BuOH was added diphenylphosphorylazide (1 .30 mL, 6.00 mmol) and triethylamine (0.83mL, 6.00 mmol) at room temperature. The reaction mixture was heated at 140 °C in a microwave reactor. After 20 min, the reaction mixture was concentrated. Water was added to the reaction mixture and extracted with ethyl acetate. The organic extracts were dried (anhydrous Na2SO4) and evaporated under vacuum. The crude material was purified by column chromatography (silica gel, 25 % ethyl acetate in petroleum ether) to obtain the title compound. Yield: 32 %; 1H NMR (300 MHz, DMSO-a^): δ 5.28 (s, 2H, exchangeable in D2O, pyrazole-NH2), 5.82 (s, 1 H, Ar-H), 7.40 (d, J = 8.4 Hz, 2H, Ar-H), 7.49-7.55 (m, 3H, Ar- H), 7.64 - 7.66 (m, 1 H, Ar-H), 7.67 (d, J = 9 Hz, 2H, Ar-H); MS: m/z 304.0 [M]+. Example 113:
1 -(1 -(2-Ch!orophesiyl)-5-(4-chforophenyl)-1 H-pyrazol-3-yl)-3-cycfopropylurea
To a solution of the compound of example 1 12 (0.070 g, 0.230 mrnol) in THF (3 mL) was added sodium hydride (0.055g, 2.301 mrnol) at room temperature under nitrogen atmosphere and the mixture was stirred for 1 h. Triphosgene (0.137 g, 0.460 mrnol) was added at 0 °C and the reaction mixture was stirred at room temperature. After 1 h, cyclopropyl amine (0.048 mL, 0.690 mrnol) was added and the mixture was stirred for 12-16 h. The evaporation of THF under vacuum, followed by addition of water, led to the formation of a crude solid, which was purified by column chromatography (silica gel, 5 % methanol in dichloromethane) to obtain the title compound.
Yield: 56 %; 1H NMR (300 MHz, DMSO-a^): δ 0.39 (s, 2H, cyclopropyl-CH2), 0.63 (d, J = 5.1 Hz, 2H, cyclopropyl-CH?), 6.70 (brs, 2H, Ar-H and cyclopropyl-NH), 7.16 (d, J = 8.4 Hz, 2H, Ar-H), 7.37 (s, J = 8.4 Hz, 2H, Ar-H), 7.49 - 7.58 (m, 4H, Ar-H), 8.48 (brs, 1 H, pyrazole-NH); MS: m/z 388.26 [M + H]+.
Example 114:
1 -(1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl)-2-cyclopropyl-3- ethylguanidine
A solution of the compound of example 1 13 (0.042 g, 0.108 mrnol), in phosphoryl chloride (3 mL), was refluxed at 120 °C for 2 h. Excess phosphoryl chloride was distilled off, and the residue was dissolved in dichloromethane (4 mL), followed by addition of triethylamine (0.151 mL, 1 .085 mrnol) and ethanamine (3.0 equivalents) at room temperature. After stirring for 12-16 h, water was added and extracted with dichloromethane. Organic extracts were dried (anhydrous Na2SO4), concentrated and purified by column chromatography (silica gel, 10 % methanol in dichloromethane) to obtain the title compound.
Yield: 14.06 %; 1H NMR (300 MHz, DMSO-a^): δ 0.67 (brs, 2H, cyclopropyl-CH2 ), 0.87 (brs, 2H, cyclopropyl-CH?), 1 .17 (m, 3H, ethyl-CH3), 2.72 (m, 1 H, cyclopropyl-CH), 2.88 (q, 2H, overlap with solvent peak, ethylamine-CH?), 6.66 (s, 1 H, Ar-H), 7.36 (d, J= 7.8 H, 2H, Ar-H), 7.42 (d, J = 7.80 Hz, 2H, Ar-H), 7.53-7.62 (m, 4H, Ar-H), 8.55 (brs, 1 H, exchangeable in D2O, ethylamine-NH), 10.33 (brs, 1 H, exchangeable in D2O, pyrazole- NH); MS: m/z 41 6.2 [M + H]+. Example 115:
1 -(1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl)-2,3-dicyclopropyl guanidine
The compound of the example 1 1 3 (0.042 g, 0.1 08 mmol), in phosphoryl chloride (3 mL) was treated with cyclopropyl amine (3.0 equivalents) according to the procedure for the preparation of the compound of example 1 14 to obtain the title compound.
Yield: 56.0 %; 1 H NMR (300 MHz, DMSO-d6): δ 0.52 (brs, 4H, cyclopropyl-CH2), 0.72 - 0.74 (d, 4H, J = 5.5 Hz, cyclopropyl-CH2), 2.62 (m. 2H, cyclopropyl-CH), 6.36 (s, 1 H, Ar- H), 7.1 6 (d, J = 8.4 Hz, 2H, Ar-H),7.37 (d, J = 8.1 Hz, 2H, Ar-H), 7.44 - 7.48 (m, 2H, Ar- H), 7.59-7.61 (m, 2H, Ar-H); MS: m/z 427.3 [M + H]+.
Example 116:
1 -Benzyl-3-(1 -(2-chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl)-2-cyclopropyl guanidine
The compound of the example 1 1 3 (0.042 g, 0.1 08 mmol), in phosphoryl chloride (3 mL) was treated with phenylmethanamine (3.0 equivalents) according to the procedure for the preparation of the compound of example 1 14 to obtain the title compound.
Yield: 1 5.1 5 %; 1 H NMR (300 MHz, DMSO-d6): δ 0.52 (brs, 2H, cyclopropyl-CH2), 0.79 (brs, 2H, cyclopropyl-CH2), 2.62 (m, 1 H, cyclopropyl-CH), 4.55 (d, J = 5.1 Hz, 2H, benzyl-CH2), 6.33 (brs, 1 H, Ar-H), 7.1 5 (d, 2H, J = 8.1 Hz, Ar-H), 7.24-7.33 (m, 5H, Ar- H), 7.47 (d, J = 8.4 Hz, 2H, Ar-H), 7.46-7.60 (m, 5H, Ar-H), 8.22 (brs, 1 H, exchangable with D2O, pyrazole-NH); MS: m/z 477.3 [M + H]+.
Example 117:
N-(1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl)-N'-cyclopropylthio morpholine-4-carboximidamide 1 ,1 -dioxide
The compound of the example 1 1 3 (0.042 g, 0.1 08 mmol), in phosphoryl chloride (3 mL) was treated with thiomorpholine 1 ,1 -dioxide (3.0 equivalents) according to the procedure for the preparation of the compound of example 1 14 to obtain the title compound.
Yield: 18.28 %; 1H NMR (300 MHz, DMSO-a : δ 0.65 (s, 2H, cyclopropyl-CH2), 0.84 (s, 2H, cyclopropyl-CH?), 2.49 (m, 1 H, cyclopropyl-CH), 3.22 (brs, 4H, thiomorpholine 1 ,1 - dioxide-CH?), 3.77 (brs, 4H, thiomorpholine 1 ,1 -dioxide-CH?), 6.50 (s, 1 H, Ar-H), 7.19 (d, J = 7.8 Hz, 2H, Ar-H), 7.36 (d, J = 7.8 Hz , 2H, Ar-H),7.47 - 7.59 (m, 4H, Ar-H); MS: m/z 505.0 [M+H]+.
Example 118:
N-(1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl)-N'-cyclopropyl morpholine-4-carboximidamide
The compound of the example 1 13 (0.042 g, 0.108 mmol), in phosphoryl chloride (3 ml_) was treated with morpholine (3.0 equivalents) according to the procedure for the preparation of the compound of example 1 14 to obtain the title compound.
Yield: 16.32 %; 1 H NMR (300 MHz, DMSO-a : δ 0.69 (brs, 2H, cyclopentyl-CH2), 2.65 (m, 1 H, cyclopentyl-CH?), 3,32 (brs, 4H, morpholine-CH2), 3.64 (brs, 4H, morpholine- CH2), 7.18 (d, J = 8.4 Hz, 2H, Ar-H), 7.38 (d, J = 8.4 Hz, 2H, Ar-H), 7.49 - 7.58 (m, 5H, Ar-H); MS: m/z 457.2 [M + H]+. Example 119:
1 -(1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl)-2-cyclopropyl-3- morpholinoguanidine
The compound of the example 1 13 (0.042 g, 0.108 mmol), in phosphoryl chloride (3 ml_) was treated with 4-aminothiomorpholine 1 ,1 -dioxide (3.0 equivalents) according to the procedure for the preparation of the compound of example 1 14 to obtain the title compound.
Yield: 9.4 %; 1H NMR (300 MHz, DMSO-a^): δ 0.67 (s, 2H, cyclopropyl-CH2), 0.89 (s, 2H, cyclopropyl-CH? ), 2.49 (m, 1 H, cyclopropyl-CH), 2.94 (brs, 4H, morpholine-CH?), 3.74 (brs, 4H, morpholine-CH?), 6.72 (s, 1 H, Ar-H ), 7.19 (d, J = 7.8 Hz, 2H, Ar-H), 7.43 (d, J = 7.8 Hz, 2H, Ar-H), 7.54 - 7.65 (m, 4H, Ar-H), 8.70 (brs, 1 H, exchangeable in D2O, morpholin-4-amine-NH), 10.22 (brs, 1 H, exchangeable in D2O, pyrazole-NH); MS: m/z 472.2 [M]+. Example 120:
1 -((1 r,3r,5r,7r)-Adamantan-2-yl)-3-(1 -(2-chlorophenyl)-5-(4-chlorophenyl)-1 H- pyrazol-3-yl)-2-cyclopropylguanidine
The compound of the example 1 13 (0.042 g, 0.108 mmol), in phosphoryl chloride (3 mL) was treated with (3s,5s,7s)-adamantan-1 -amine (3.0 equivalents) according to the procedure for the preparation of the compound of example 1 14 to obtain the title compound.
Yield: 16.4 %; 1 H NMR (300 MHz, DMSO-a : δ 0.67 (s, 2H, cyclopropyl-CH2), 0.89 (s, 2H, cyclopropyl-CH?), 1 .21 - 1 .62 (m, 4H, adamantyl), 1 .62 - 1 .81 (m, 1 1 H, adamantyl), 2.72 (m, 1 H, cyclopropyl-CH), 3.88 (m, 1 H, adamantyl), 6.60 (s, 1 H, Ar-H), 7.24 (d, J = 8.7 Hz, 2H, Ar-H), 7.44 (d, J = 7.8 Hz, 2H, Ar-H), 7.50 - 7.53 (m, 3H, Ar-H), 7.63 (m, 1 H, Ar-H), 8.14 (brs, 1 H, exchangeable in D2O, adamantyl-NH), 10.46 (brs, 1 H, exchangeable in D2O, pyrazole-NH); MS: m/z 521 .1 [M + H]+. Example 121 :
1 -(1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl)-2-cyano-3-cyclopropyl guanidine
To a solution of the compound of example 1 12 (0.030 g, 0,099 mmol) in DMF (1 mL) was added sodium hydride (0.024 ml, 0.986 mmol) at 0 °C and the reaction mixture was stirred at room temperature. After 30 min, diphenyl cyanocarbonimidodithioate (0.028 g, 0.1 18 mmol) was added and the reaction mixture was stirred for a further 30 min. Cyclopropylamine (0.034 mL, 0.493 mmol) was then added and the reaction mixture was stirred at room temperature for 3 h. DMF was removed under vacuum and water was added. The mixture was extracted with ethyl acetate, dried (anhydrous Na2SO4) concentrated to afford a crude gummy solid, which was purified by preparative thin layer chromatography (5% methanol in dichloromethane) to obtain the title compound.
Yield: 25 %; 1H NMR (300 MHz, DMSO-a^): δ 0.39 (brs, 2H, cyclopropyl-CH2), 0.62- 0.64 (d, J = 6Hz, 2H, cyclopentyl- CH2), 2.30 (m, 1 H, cyclopropyl-CH), 6.70 (s, 1 H, Ar- H),7.16 (d, J = 8.7 Hz, 2H, Ar-H), 7.37 (d, J = 8. 4Hz, 2H, Ar-H), 7.45 - 7.58 (m, 5H, Ar- H), 8.84 (brs, 1 H, exchangeable in D2O, pyrazole-NH); MS: m/z 412.4 [M + H]+. Example 122:
N-(1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl) cyclopropane
carboxamide
To a solution of compound of example 1 12 (1 .00 g, 3.29 mmol) in pyridine (20 imL) was added cyclopropanecarbonyl chloride (0.478 imL, 5.26 mmol) at room temperature. After stirring for 2 h, pyridine was evaporated and water was added to obtain a crude solid, which was purified by column chromatography (silica gel, 20% ethyl acetate in petroleum ether) to obtain the title compound.
Yield: 49 %; 1H NMR (300 MHz, DMSO-a^): δ 0.80 (brs, 4H, cyclopropyl-CH2), 1 .85 (m, 1 H, cyclopropyl-CH), 6.94 (s, 1 H, Ar-H), 7.17 (d, J = 9Hz, 2H, Ar-H), 7.37 (d, J = 8.4 Hz, 2H, Ar-H), 7.48 - 7.50 (m, 2H, Ar-H), 7.59 (m, 2H, Ar-H), 10.95 (s, 1 H, exchangeable in D2O, pyrazole-NH); MS: m/z 373.4 [M + H]+.
Example 123:
4-(((1 -(2-chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl)imino)(cyclopropyl) methyl) thiomorpholine 1 ,1 -dioxide
A solution of the compound of example 122 (0.075, 0.201 mmol) in chlorobenzene was heated at 1 10 °C in presence of phosphorous pentachloride (0.050 g, 0.242 mmol) for 2 h. After evaporation of chlorobenzene in vacuo, the residue was dissolved in dichioromethane (6 mL) and treated with triethylamine (0.280 mL, 2.015 mmol) and thiomorpholine 1 ,1 -dioxide (0.191 g, 1 .410 mmol). After stirring for 12-16 h, water was added and extracted with ethyl acetate. The organic extracts were washed with brine, dried (anhydrous Na2S04), and concentrated. The crude solid obtained was purified by preparative HPLC using column Waters X-terra RP-18 (150 X 19 mm) 5 μ, flow 10 mL/minute, λ = 210 nm and 254 nm, Mobile phase ACN FA isocratic 40:60 to obtain the title compound.
Yield: 18 %; 1 H NMR (300 MHz, DMSO-a^): δ 0.54 (d, J = 4.8 Hz, 2H, cyclopropyl-CH2 ), 0.83 (d, J = 7.5 Hz, 2H, cyclopropyl-CH2), 1 .76 (m, 1 H, cyclopropyl-CH), 3.20 (brs, 4H, thiomorpholine 1 ,1 -dioxide-C -2), 4.07 (brs, 4H, thiomorpholine 1 ,1 -dioxide-C -2), 6.28 (s, 1 H, Ar-H), 7.16 (d, J = 8.1 Hz, 2H, Ar-H), 7.44 (d, J = 8.1 Hz, 2H, Ar-H), 7.48 - 7.54 (m, 4H, Ar-H); MS: m/z 490.4 [M + H]+. Example 124:
1 -(1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl)-3-cyclohexyl-2- cyclopropylguanidine
The compound of the example 122 (0.075, 0.201 mmol) in chlorobenzene was treated with cyclohexyl amine (4 equivalents) according to the procedure for the preparation of the compound of example 123 to obtain the title compound.
Yield: 15.27 %; 1 H NMR (300 MHz, DMSO-a^): δ 0.62 (s, 2H, cyclopropyl-CH2), 0.82 (s, 2H, cyclopropyl-CH?), 1 .22 - 1 .32 (m, 10H, cyclohexyl-CH?), 2.71 (m, 1 H, cyclohexyl- CH), 3.68 (m, 1 H, cyclopropyl-CH), 6.53 (s, 1 H, Ar-H), 7.19 (d, J = 8.1 Hz, 2H, Ar-H), 7.41 (d, J = 8.1 2H, Hz, Ar-H), 7.50 - 7.52 (m, 4H, Ar-H), 8.25 ( brs, 1 H, exchangeable in D2O, cyclohexyl-NH), 10.26 (brs, 1 H, exchangeable in D2O, pyrazole-NH); MS: m/z 469.0 [M+H]+.
Example 125:
N'-(1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl)-N-(1 ,1 -dioxidothio morpholino)cyclopropanecarboximidamide
The compound of the example 122 (0.075, 0.201 mmol) in chlorobenzene was treated with 4-aminothiomorpholine 1 ,1 -dioxide (2 equivalents) according to the procedure for the preparation of the compound of example 123 to obtain the title compound.
Yield: 14.81 %; 1H NMR (300 MHz, DMSO-a^ ): δ 1 .10 (m, 4H, cyclopropyl-CH?), 2.17 (m, 1 H, cyclopropyl-CH), 3.32 (brs, 4H, 4-aminothiomorpholine 1 ,1 -dioxide-CH?), 3.41 (brs, 4H, 4-aminothiomorpholine 1 ,1 -dioxide-CH?), 6.93 (s, 1 H, Ar-H), 7.24 (d, J = 8.4 Hz, 2H, Ar-H), 7.44 (d, J = 8.4 Hz, 2H, Ar-H), 7.54 - 7.69 (m, 4H, Ar-H), 10.85 (brs, 1 H, exchangeable in D2O, 4-aminothiomorpholine 1 ,1 -dioxide-A/H); MS: m/z 505.5 [M + H]+.
Example 126:
N-Benzyl-N'-(1 -(2-chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl) cyclopropane carboximidamide
The compound of the example 122 (0.080, 0.215 mmol) in chlorobenzene was treated with phenylmethanamine (2 equivalents) according to the procedure for the preparation of the compound of example 123 to obtain the title compound. Yield: 37.5 %; 1 H NMR (300 MHz, DMSO-a^): δ 1 .27 (m, 4H, cyclopropy-CH?), 2.27 (m, 1 H, cyclopropyl-CH), 4.97 (d, J = 6.0 Hz, 2H, benzyl-CH2), 6.70 (s, 1 H, Ar-H), 7.23 (d, J = 8.4 Hz, 2H, Ar-H), 7.36 - 7.46 (m, 7H, Ar-H), 7.50 - 7.60 (m, 4H, Ar-H), 10.64 (s, 1 H, exchangeable in D2,O benzylamine-NH); MS: m/z 462.26 [M + H]+.
Example 127:
5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-N-(methylsulfonyl)-1 H-pyrazole-3- carboxamide
To a solution of the compound of example 2 (4.00 g, 10.88 mmol), 4- dimethylaminopyridine (1 .72 g, 14.1 mmol) and 1 -(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (2.71 g, 14.15 mmol), in dichloromethane (40 mL) was added methane sulfonamide (1 .34 g, 14. 14 mmol). After stirring at room temperature for 16 h, the reaction mixture was quenched by addition of 1 N HCI (10 mL). The aqueous layer was extracted with dichloromethane. The combined organic extracts were washed with water, dried (anhydrous Na2SO4) and evaporated under vacuum. The residue was purified by column chromatography (silica gel, 2 % methanol in dichloromethane) to obtain the title compound.
Yield: 45 %; 1H NMR (500 MHz, DMSO-a^): δ 3.35 (s, 3H, methylsulphonamide-CH3), 7.27 (d, J = 8.5 Hz, 2H, Ar-H), 7.38 (s, 1 H, Ar-H), 7.47 (d, J = 8.5 Hz, 2H, Ar-H), 7.67 (dd, J = 2.0 Hz, 8.5 Hz, 1 H,Ar-H), 7.84 (d, J = 8.5 Hz, 2H, Ar-H), 7.88 (d, J = 2Hz, 1 H, Ar-H), 12.15 (brs, 1 H, exchangeable with D2O, methyl sulphonamide-NH); MS: m/z 443.8 [M - H]+.
Example 128:
5-(4-Chlorophenyl)-N-cyclohexyl-1 -(2,4-dichlorophenyl)-N'-(methylsulfonyl)-1 H- pyrazole-3-carboximidamide
A solution of the compound of example 127 (0.080 g, 0.180 mmol) and phosphorous pentachloride (0.045 g, 0.216 mmol) in chlorobenzene (5 mL) was refluxed at 120 °C for 3 h. The solvent was evaporated to afford a yellow gummy solid. The gummy solid was dissolved in dichloromethane (10 mL) and cooled to room temperature. To this solution, cyclohexyl amine (4 equivalent) and triethylamine (2.50 mL, 1 .799 mmol) were added and stirred for 12-16 h at room temperature. The reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was separated, dried (anhydrous Na2S04), concentrated and purified using preparative thin layer chromatography to obtain the titled compound.
Yield: 14.88 %; 1 H NMR (500 MHz, DMSO-a^): δ 1 .10 - 1 .40 (m, 4H, cyclohexyl-CH?), 1 .60 - 1 .73 (m, 3H, cyclohexyl- CH2), 2.96 (s, 3H, methylsulphonamide-CH3), 3.56 (m, 1 H, cyclohexyl-CH), 7.23 (d, J = 8.5 Hz, 2H, Ar-H), 7.25 (s, 1 H, Ar-H), 7.47 (d, J = 8.5 Hz, 2H, Ar-H), 7.65 - 7.70 (m, 1 H, Ar-H), 7.88 (s, 1 H, Ar-H), 8.69 (d, J = 7.5 Hz, 1 H, exchangeable with D2O, cyclohexylamine-NH); MS: m/z 524.9 [M - H]+.
Example 129:
N-Benzyl-5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-N'-(methylsulfonyl)-1 H- pyrazole-3-carboximidamide
The compound of example 127 (0.080 g, 0.180 mmo!) in chlorobenzene was treated with phenylmethanamine (2 equivalents) according to the procedure for the preparation of the compound of example 128 to obtain the title compound.
Yield: 23.95 %; 1 H NMR (300 MHz, DMSO-a^): δ 2.96 (s, 3H, methylsulphonamide- CH3), 4.51 (d, J = 6.0 Hz, 2H, benzyl-CH2), 7.24 (d, J = 8.5 Hz, 2H, Ar-H), 7.28 (m, 1 H, Ar-H), 7.36 - 7.39 (m, 5H, Ar-H), 7.47 (d, J = 9.0 Hz, 2H, Ar-H), 7.67 (m, 1 H, Ar-H), 7.77 (d, J = 8.5 Hz, 1 H, Ar-H), 7.88 (d, J = 2.0 Hz, 1 H, Ar-H), 9.14 (s, 1 H, benzylamine-NH); MS: m/z 535.1 [M + H]+.
Example 130:
N-((5-(4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3-yl)(4-ethylpiperazin-1 - yl)methylene)methanesulfonamide
The compound of example 127 (0.060 g, 0.135 mmol) in chlorobenzene was treated with 1 -ethylpiperazine (3 equivalents) according to the procedure for the preparation of the compound of example 128 to obtain the title compound.
Yield: 28.8 %; 1H NMR (300 MHz, DMSO-a^): δ 0.98 (t, J = 6.9 Hz, 3H, ethyl-CH3), 2.32 - 2.34 (q, 2H, overlapped with solvent peak, ethyl-CH?), 2.35 (brs, 4H, piperazine-CH?), 2.83 (s, 3H, methylsulfonamide-CH3), 3.36 (brs, 2H, piperazine-CH?), 3.81 (brs, 2H, piperazine-CH2), 6.99 (s, 1 H, Ar-H), 7.21 (d, J = 8.4 Hz, 2H, Ar-H), 7.44 (d, J = 8.4 Hz, 2H, Ar-H), 7.64 - 7.67 (m, 2H, Ar-H), 7.87 (s, 1 H, Ar-H); MS: m/z 542.2 [M+H]+.
Example 131 :
N-((4-Benzylpiperazin-1 -yl)(5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol- 3-yl)methylene)methanesulfonamide
The compound of example 127 (0.075 g, 0.169 mmol) in chlorobenzene was treated with 1 -benzylpiperazine (2 equivalents) according to the procedure for the preparation of the compound of example 128 to obtain the title compound.
Yield: 21 .64 %; 1 H NMR (300 MHz, DMSO-a : δ 2.38 (brs, 4H, piperazine-CH2), 2.83(s, 3H, methylsulphonamide-CH3), 3.32 (s, 2H, benzyl-CH2), 3.50 (brs, 2H, piperazine- CH2), 3.82 (brs, 2H, piperazine-CH2), 6.98 (brs, 1 H, Ar-H), 7.20 (d, J = 8.7 Hz, 2H, Ar- H), 7.26-7.29 (m, 5H, Ar-H), 7.43 - 7.45 (m, 2H, Ar-H), 7.63 (d, J = 8.7 Hz, 2H, Ar-H), 7.86 (brs, 1 H, Ar-H); MS: m/z 604.2 [M+H]+.
Example 132:
N-((5-(4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3-yl)(1 ,1 -dioxido thiomorpholino)methylene)methanesulfonamide
The compound of example 127 (0.080 g, 0.180 mmol) in chlorobenzene was treated with thiomorpholine 1 ,1 -dioxide (3 equivalents) according to the procedure for the preparation of the compound of example 128 to obtain the title compound.
Yield: 26.7 %; 1H NMR (500 MHz, DMSO-c/5): δ 2.93 (s, 3H, methylsulphonamide-CH3), 3.81 (brs, 4H, thiomorpholine 1 ,1 -dioxide-CH?), 4.22 (brs, 4H, thiomorpholine 1 ,1 - dioxide-CH?), 7.1 1 (s, 1 H, Ar-H), 7.23 (d, J = 8.5 Hz, 2H, Ar-H), 7.49 (d, J = 8.5 Hz, 2H, Ar-H), 7.68 (m, 2H, Ar-H), 7.91 (d, J = 2Hz, 1 H, Ar-H); MS: m/z 563.1 [M+H]+.
Example 133:
N-((5-(4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3-yl) (morpholino) methylene) methanesulfonamide
The compound of example 127 (0.080 g, 0.180 mmol) in chlorobenzene was treated with morpholine (3 equivalents) according to the procedure for the preparation of the compound of example 128 to obtain the title compound.
Yield: 30.3 %; 1H NMR (500 MHz, DMSO-a^): δ 2.88 (s, 3H, methylsulphonamide-CH3), 3.42 (brs, 2H, morpholine-CH2), 3.63 (m, 4H, morpholine-CH2), 3.85 (brs, 2H, morpholine-CH2), 7.03 (s, 1 H, Ar-H), 7.23 (d, J = 8.5 Hz, 2H, Ar-H), 7.47 (d, J = 8.5 Hz, 2H, Ar-H), 7.64 - 7.69 (m, 2H, Ar-H), 7.89 (d, 1 H J = 2Hz, Ar-H); MS: m/z 515.1 [M+H]+.
Example 134:
N-((5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-1 H-pyrazol-3-yl)(4-(oxetan-3-yl) piperidin-1-yl)methylene)methanesulfonamide
The compound of example 127 (0.080 g, 0.180 mmol) in chlorobenzene was treated with 4-(oxetan-3-yl)piperidine (3 equivalents) according to the procedure for the preparation of the compound of example 128 to obtain the title compound.
Yield: 14.36 %; 1H NMR (500 MHz, DMSO-a^): δ 0.94 - 1 .1 1 (m, 2H, 4-
(piperidine-CH2), 1 .62 - 1 .77 (m, 2H, piperidine-CH^;, 1 .98 - 2.00 (m, 1 H, piperidine- CH), 2.75 (m, 1 H, oxetane-CH), 2.84 (s, 3H, methylsulphonamide-CH3), 3.0 - 3.10 (m, 1 H, piperidine-CH), 3.14 - 3.17 (m, 1 H, piperidine-CH), 3.14 (brd, 1 H, piperidine-CH), 4.33 - 4.35 (m, 2H, oxetane-CH2), 4.59 - 4.61 (m, 2H, oxetane-CH2), 4.66 (brd, 1 H, piperidine-CH), 7.01 (s, 1 H, Ar-H), 7.23 (d, J = 8.5 Hz, 2H, Ar-H), 7.46 (d, J = 8.5 Hz, 2H, Ar-H), 7.63 - 7.68 (m, 2H, Ar-H), 7.89 (d, J = 2Hz, 1 H, Ar-H); MS: m/z 569.2
[M+H] +.
Biological Assay
The biological activity of the compounds as CB1 receptor antagonist can be confirmed by a number of biological assays known in the art. The exemplified biological assay, given below, has been carried out with certain representative compounds of the formula 1 (referred to as the test compounds) synthesized in the above examples.
The following abbreviations are used in the biological assay described below:
BSA : Bovine serum albumin
CHO : Chinese hamster ovary
DMSO : Dimethyl sulfoxide
[3H]CP55,940 : Radiolabelled[3H](-)-cis-3-[2-hydroxy-4-(1 ,1 - dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol
MgC : Magnesium chloride
TRIS : Tris(hydroxymethyl)aminomethane.
Example 135:
Radioligand Binding Assay:
The CB1 receptor antagonist activity of the certain representative compounds of the present invention was determined by performing an in vitro radioligand binding assay. Representative compounds of formula 1 of the present invention (referred to as test compounds) were tested for their CB1 receptor binding activity using the assays and the methods described below: Materials:
Radioligand CP55,940: [3H](-)-cis-3-[2-hydroxy-4-(1 ,1 -dimethylheptyl)phenyl]- trans-4-(3-hydroxypropyl)cyclohexanol (final concentration 0.1 nM); Human cannabinoid 1 (CB1 ) receptors source: membrane preparations of Chinese hamster ovary (CHO) cells stably expressing the CB1 receptor subtype (50 μg of protein/vial); assay buffer (composition: 50 imM TRIS, 3 imM MgCI2, 0.1 % BSA, pH 7.4); washing buffer (composition: 50 imM TRIS, 0.1 % BSA, pH 7.4); Microscint 0 (Perkin Elmer); Topcount NXT (Packard).
Stock solutions of the test compound were prepared in DMSO. The final DMSO concentration in the assay was 2.5 %.
Method:
60 μΙ_ of membrane preparations of CB1 receptor expressing CHO cells were mixed with 465 μΙ_ of assay buffer containing 60 μΙ_ of [3H]CP55,940 and 15 μΙ_ of each test compound in DMSO. Unlabeled CP55,940 (10 μΜ ) was used to determine nonspecific binding. Total binding was determined by adding DMSO without the test compound. The mixture was incubated for 2 h at room temperature in multiscreen micro-plates, to allow the test compound or [3H]CP55,940 to bind to the receptor. The binding reaction was terminated by rapid filtration through GF/B glass fiber filters pre- soaked for 0.5 h with 0.3 % aqueous polyethyleneimine solution, using a Brandel 48- channel cell harvester (Brandel, Gaithersburg, MD). The filters were washed four times with ice-cold washing buffer (50 imM TRIS, 0.1 % BSA, pH 7.4) to remove free [3H]CP55,940 and dried for 1 .5 h at 50 °C. 50 μΙ_ Microscint 0 (Perkin Elmer) was added per well, and the amount of bound radioactivity was determined with a Topcount NXT (Packard). IC50 values (the concentration of the test compound required to inhibit 50 % of the binding of [3H]CP55,940 to the receptor) were calculated. The IC50 values for test compounds are given in table 2.
Table 1 : Symbols used to indicate IC50 range class
Sr.No. Symbol IC50 range class
1 + 0.0001 μΜ to 1 μΜ
2 ++ 1 .1 μΜ to 10 μΜ Table 2: IC50 values for the representative compounds of the formula 1 for their CB1 receptor binding activity
Example no. IC50 range class (μΜ) Example no. IC50 range class (μΜ)
4 + 52 +
5 + 53 +
6 + 54 +
7 + 55 +
8 + 56 +
9 + 57 ++
10 + 58 +
1 1 + 59 +
12 + 60 +
13 + 61 +
14 ++ 62 +
15 + 63 ++
16 + 64 ++
17 + 65 ++
18 ++ 66 +
19 + 67 +
23 + 68 +
24 + 69 +
25 + 70 +
26 + 71 +
27 + 72 +
31 + 73 +
32 + 74 +
33 + 75 +
34 + 76 +
35 + 77 +
39 + 78 +
50 ++ 79 +
51 + 1 14 + Example no. IC50 range class (μΜ) Example no. IC50 range class (μΜ)
115 + 119 +
116 + 120 +
117 + 121 ++
118 + 123 +

Claims

We Claim:
1 . A compound of formula 1 ,
Figure imgf000122_0001
Formula 1
wherein,
Ri and R2 are independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, (CrC8)-alkyl, (CrC8)-alkoxy, halo(CrC8)-alkyl, (C3-Ci2)-cycloalkyl, C(O)Ra, CO2Ra and NRaRb;
X is hydrogen, halogen, hydroxy, (Ci-C8)-alkyl, halo(CrC8)-alkyl, or (Ci-C8)-alkoxy; Q is:
Figure imgf000122_0002
wherein (*) indicates the point of attachment;
R3 IS hydrogen, cyano, (Ci -C8)-alkyl, halo(Ci -C8)-alkyl, (C3-Ci 2)-cycloalkyl, heterocyclyl, heteroaryl, C(O) Ra, CO2Ra, CON RaRb, S(O)qRc or S(O)qN RaRb;
R4 is cyano, (d-C8)-alkyl, halo(CrC8)-alkyl, (C3-Ci2)-cycloalkyl, (C5-C8)-cycloalkenyl, (C6-Ci 4)-aryl, (C6-Ci4)ar-(Ci -C8)-alkyl, heterocyclyl, heteroaryl, CORa, CO2Ra, CON RaRb, S(O)qRc or S(O)qN RaRb;
R5 is hydrogen, cyano, (d-C8)-alkyl, halo(CrC8)-alkyl, (C3-d2)-cycloalkyl, (C5-C8)- cycloalkenyl, (C6-C )-aryl, (C6-Ci 4)ar-(d-C8)-alkyl, heterocyclyl, heteroaryl, CORa, CO2Ra, CON RaRb, S(O)qRc or S(O)qN RaRb; or
R3 and R5 can join together to form a 3-12 membered saturated or unsaturated monocyclic or bicyclic ring system, optionally containing one to three heteroatoms independently selected from the group consisting of O, N and S; or R4 and R5 can join together to form a 3-12 membered saturated or unsaturated, monocyclic or bicyclic ring system including spiro ring systems, optionally containing one to three heteroatoms independently selected from the group consisting of O, N and S;
wherein each of the said 3-12 membered rings can be unsubstituted or substituted with one or more groups selected from the group consisting of halogen, hydroxy, oxo, cyano, (C C8)-alkyl, halo(C C8)-alkyl, (C C8)-alkoxy, halo(C C8)-alkoxy, (C3-Ci2)- cycloalkyl-(Rd)o-2, O-(C3-Ci2)-cycloalkyl-(Rd)0-2, (C6-Ci4)-aryl-(Rd)0-2, O-(C6-Ci4)-aryl- (Rd)o-2, heterocyclyl-(Rd)o-2, O-heterocyclyl-(Rd)0-2, heteroaryl-(Rd)0-2, C(O)Ra, CO2Ra, C(O)NRaRb, NRaRb, N RaC(O)Rb, S(O)qRc and S(O)qNRaRb;
Ra and Rb are independently selected from the group consisting of hydrogen, hydroxy, (CrCs)-alkyl, (C C8)-alkoxy, (C3-Ci2)-cycloalkyl, (C5-C8)-cycloalkenyl, (C6-Ci4)-aryl, heterocyclyl and heteroaryl; or
Ra and Rb together with the nitrogen atom can form a 3-12 membered ring system, optionally containing one to three heteroatoms independently selected from the group consisting of O, N and S;
Rc is (CrCs)-alkyl, (C3-Ci2)-cycloalkyl, (C6-Ci4)-aryl, (C6-Ci4)ar-(Ci-C8)-alkyl, heterocyclyl or heteroaryl;
m and n are integers selected from 0, 1 or 2;
q is an integer 1 or 2; wherein each of the (CrC8)-alkyl and (CrC8)-alkoxy group can be unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, oxo, cyano, (CrC8)-alkoxy, halo(CrC8)-alkoxy, (C3-C-i2)-cycloalkyl- (Rd)o-2, O-(C3-Ci2)-cycloalkyl-(Rd)o-2, (C6-Ci4)-aryl-(Rd)0-2, O-(C6-Ci4)-aryl-(Rd)0-2, heterocyclyl-(Rd)o-2, O-heterocyclyl-(Rd)0-2, heteroaryl-(Rd)0-2, C(O)Ra, OC(O)Ra, CO2Ra, C(O)NRaRb, NRaRb, N RaC(O)Rb, NRaC(O)NRaRb, S(O)qRc and S(O)qNRaRb;
each of the (C3-Ci2)-cycloalkyl, (C5-C8)-cycloalkenyl and (C6-Ci4)-aryl can be unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, oxo, cyano, (CrC8)-alkyl, halo(CrC8)-alkyl, (d- C8)-alkoxy, halo(CrC8)-alkoxy, (C3-Ci2)-cycloalkyl-(Rd)0-2, O-(C3-Ci2)-cycloalkyl-(Rd)0-2, (C6-Ci4)-aryl-(Rd)o-2. O-(C6-Ci4)-aryl-(Rd)0-2, heterocyclyl-(Rd)0-2, O-heterocyclyl-(Rd)0-2, heteroaryl-(Rd)0-2, C(O)Ra, OC(O)Ra, CO2Ra, C(O)NRaRb, NRaRb, NRaC(O)Rb, NRaC(O)N RaRb, S(O)qRc and S(O)qNRaRb; the heterocyclyl is a 3-12 membered saturated or partially unsaturated, monocyclic or bicyclic ring system, including spiro ring systems, containing one to four heteroatoms independently selected from the group consisting of O, N and S; wherein the heterocyclyl can be unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, oxo, cyano, (CrC8)-alkyl, halo(C C8)-alkyl, (C C8)-alkoxy, halo(C C8)-alkoxy, (C3-C12)-cycloalkyl-(Rd)o-2, O-(C3- Ci2)-cycloalkyl-(Rd)o-2, (C6-Ci4)-aryl-(Rd)o-2, O-(C6-Ci4)-aryl-(Rd)o-2, heterocyclyl-(Rd)o-2, O-heterocyclyl-(Rd)o-2, heteroaryl-(Rd)0-2, C(O)Ra, OC(O)Ra, CO2Ra, C(O)NRaRb, NRaRb, NRaC(O)Rb, NRaC(O)NRaRb, S(O)qRc and S(O)qNRaRb;
the heteroaryl is a 5-10 membered monocyclic or bicyclic aromatic ring system containing one to four heteroatoms independently selected from O, N or S, wherein the heteroaryl can be unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, oxo, cyano, (CrC8)-alkyl, halo(C C8)-alkyl, (C C8)-alkoxy, halo(C C8)-alkoxy, (C3-C12)-cycloalkyl-(Rd)o-2, O-(C3- Ci2)-cycloalkyl-(Rd)o-2, (C6-Ci4)-aryl-(Rd)0-2, O-(C6-Ci4)-aryl-(Rd)0-2, heterocyclyl-(Rd)0-2, O-heterocyclyl-(Rd)o-2, heteroaryl-(Rd)0-2, C(O)Ra, OC(O)Ra, CO2Ra, C(O)NRaRb, NRaRb, NRaC(O)Rb, NRaC(O)NRaRb, S(O)qRc and S(O)qNRaRb; and
Rd at each occurrence is independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, (CrC8)-alkyl, halo(CrC8)alkyl, (C3-Ci2)-cycloalkyl, (C6-C-|4)- aryl, (C6-C14)-ar-(C C8)-alkyl, heteroaryl, heterocyclyl, CORa, CO2Ra, CONRaRb, CONRaNRaRb, S(O)qRc, S(O)qNRaRb, NRaRb, NRaC(O)Rb, NRaC(O)NRaRb, NRaC(O)ORb and NRaS(O)qNRaRb;
or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.
2. The compound according to claim 1 ,
wherein,
Ri and R2 are halogen;
Q is:
Figure imgf000124_0001
wherein * indicates the point of attachment;
or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.
3. The compound according to claim 1 ,
wherein,
Ri and R2 are halogen;
Q is:
Figure imgf000125_0001
wherein * indicates the point of attachment;
or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.
4. The compound according to claim 1 ,
wherein,
Ri and R2 are halogen;
Q is:
Figure imgf000125_0002
wherein * indicates the point of attachment;
or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.
5. The compound according to claim 1 ,
wherein,
Ri and R2 are independently selected from the group consisting of hydrogen, halogen, (C C8)-alkyl, halo-(C C8)-alkyl and (C C8)-alkoxy; n is 1 ;
m is 1 or 2;
X is hydrogen, halogen or (C-i-C8)-alkyl;
Q is:
Figure imgf000126_0001
wherein * indicates the point of attachment;
R3 is hydrogen, cyano, (CrC8)-alkyl, halo(CrC8)-alkyl, (C3-Ci2)-cycloalkyl, C(O)Ra, C(O)2Ra or S(O)qRc; wherein q, Ra, and Rc are as defined in claim 1 ;
or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.
6. The compound according to any one of the claims 1 , 2 and 5,
wherein,
Ri and R2 are halogen;
n is 1 ;
m is 1 or 2;
X is hydrogen, halogen or (CrC8)-alkyl;
Q is:
Figure imgf000126_0002
wherein * indicates the point of attachment;
R3 is hydrogen, cyano, (CrC8)-alkyl, (C3-Ci2)-cycloalkyl or S(O)qRc; wherein q and Rc are as defined in claim 1 ;
or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.
7. The compound according to claim 1 or claim 2,
wherein,
Ri and R2 are halogen;
n is 1 ; m is 1 or 2;
X is hydrogen, halogen or (CrC8)-alkyl;
Q is:
Figure imgf000127_0001
wherein * indicates the point of attachment;
R3 and R5 can join together to form a 3-12 membered saturated or unsaturated monocyclic or bicyclic ring system, optionally containing one to three heteroatoms independently selected from the group consisting of O, N and S;
wherein the said 3-12 membered ring can be unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, oxo, cyano, (CrC8)-alkyl, halo(CrC8)-alkyl, (CrC8)-alkoxy, halo(CrC8)-alkoxy, (C3- C12)-cycloalkyl-(Rd)o-2, O-(C3-C12)-cycloalkyl-(Rd)0-2, (C6-C14)-aryl-(Rd)0-2, O-(C6-C14)- aryl-(Rd)o-2, heterocyclyl-(Rd)o-2, O-heterocyclyl-(Rd)o-2, heteroaryl-(Rd)0-2, C(O)Ra, CO2Ra, C(O)NRaRb, NRaRb, NRaC(O)Rb, S(O)qRc and S(O)qNRaRb; wherein q, Ra, Rb, Rc and Rd are as defined in claim 1 ;
or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.
8. The compound according to any one of the claims 1 , 2, 5 and 6,
wherein,
Ri and R2 are halogen;
n is 1 ;
m is 1 or 2;
X is hydrogen, halogen or (CrC8)-alkyl;
Q is:
Figure imgf000127_0002
wherein * indicates the point of attachment;
R3 is hydrogen, cyano, (CrC8)-alkyl, (C3-Ci2)-cycloalkyl or S(O)qRc; wherein q and Rc are as defined in claim 1 ; and R4 and R5 can join together to form a 3-12 membered saturated or unsaturated, monocyclic or bicyclic ring system including spiro ring systems, optionally containing one to three heteroatoms independently selected from the group consisting of O, N and S;
wherein the said 3-12 membered ring can be unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, oxo, cyano, (Ci-C8)-alkyl, halo(CrC8)-alkyl, (Ci-C8)-alkoxy, halo(CrC8)-alkoxy, (C3- Ci2)-cycloalkyl-(Rd)o-2, O-(C3-d2)-cycloalkyl-(Rd)0-2, (C6-Ci4)-aryl-(Rd)0-2, O-(C6-d4)- aryl-(Rd)o-2, heterocyclyl-(Rd)0-2, O-heterocyclyl-(Rd)0-2, heteroaryl-(Rd)0-2, C(0)Ra, CO2Ra, C(O)NRaRb, NRaRb, NRaC(O)Rb, S(O)qRc and S(O)qNRaRb; wherein q, Ra, Rb, Rc and Rd are as defined in claim 1 ;
or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.
9. The compound according to claim 1 ,
wherein,
Ri and R2 are independently selected from the group consisting of hydrogen, halogen, (CrC8)-alkyl, halo (C C8)-alkyl and (C C8)-alkoxy;
n is 1 ;
m is 1 or 2;
X is hydrogen, halogen or (Ci-C8)-alkyl;
Q is:
Figure imgf000128_0001
wherein * indicates the point of attachment;
R3 is hydrogen, cyano, (d-C8)-alkyl, halo(d-C8)-alkyl, (C3-d2)-cycloalkyl, C(O)Ra, C(O)2Raor S(O)qRc; wherein q, Ra and Rc are as defined in claim 1 ;
or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.
10. The compound according to any one of the claims 1 , 3 and 9, wherein,
Ri and R2 are halogen;
n is 1 ;
m is 1 or 2;
X is hydrogen, halogen or (CrC8)-alkyl;
Q is:
Figure imgf000129_0001
wherein * indicates the point of attachment;
R3 is hydrogen, cyano, (d-CsJ-alkyl, (C3-Ci 2)-cycloalkyl or S(O)qRc; wherein q and Rc are as defined in claim 1 ;
or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.
1 1 . The compound according to claim 1 or claim 3,
wherein,
Ri and R2 are halogen;
n is 1 ;
m is 1 or 2;
X is hydrogen, halogen or (d-CsJ-alkyl;
Q is:
Figure imgf000129_0002
wherein * indicates the point of attachment;
R3 and R5 can join together to form a 3-12 membered saturated or unsaturated monocyclic or bicyclic ring system, optionally containing one to three heteroatoms independently selected from the group consisting of O, N and S; wherein the said 3-12 membered ring can be unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, oxo, cyano, (Ci-C8)-alkyl, halo(CrC8)-alkyl, (Ci-C8)-alkoxy, halo(CrC8)-alkoxy, (C3- Ci2)-cycloalkyl-(Rd)o-2, O-(C3-Ci2)-cycloalkyl-(Rd)0-2, (C6-d4)-aryl-(Rd)0-2, O-(C6-d4)- aryl-(Rd)o-2, heterocyclyl-(Rd)0-2, O-heterocyclyl-(Rd)0-2, heteroaryl-(Rd)0-2, C(0)Ra, CO2Ra, C(O)NRaRb, NRaRb, NRaC(O)Rb, S(O)qRc and S(O)qNRaRb; wherein q, Ra, Rb, Rc and Rd are as defined in claim 1 ;
or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.
12. The compound according to any one of the claims 1 , 3, 9 and 10,
wherein,
Ri and R2 are halogen;
n is 1 ;
m is 1 or 2;
X is hydrogen, halogen or (Ci-C8)-alkyl;
Q is:
Figure imgf000130_0001
wherein * indicates the point of attachment;
R3 is hydrogen, cyano, (d-C8)-alkyl, (C3-d2)-cycloalkyl or S(O)qRc; wherein q and Rc are as defined in claim 1 ; and
R4 and R5 can join together to form a 3-12 membered saturated or unsaturated, monocyclic or bicyclic ring system including spiro ring systems, optionally containing one to three heteroatoms independently selected from the group consisting of O, N and S;
wherein the said 3-12 membered ring can be unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, oxo, cyano, (d-C8)-alkyl, halo(d-C8)-alkyl, (d-C8)-alkoxy, halo(d-C8)-alkoxy, (C3- C12)-cycloalkyl-(Rd)0-2, O-(C3-C12)-cycloalkyl-(Rd)0-2, (C6-C14)-aryl-(Rd)0-2, O-(C6-C14)- aryl-(Rd)o-2, heterocyclyl-(Rd)0-2, O-heterocyclyl-(Rd)0-2, heteroaryl-(Rd)0-2, C(O)Ra, CO2Ra, C(O)NRaRb, NRaRb, NRaC(O)Rb, S(O)qRc and S(O)qNRaRb; wherein q, Ra, Rb, Rc and Rd are as defined in claim 1 ;
or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.
13. The compound according to claim 1 ,
wherein,
Ri and R2 are independently selected from the group consisting of hydrogen, halogen,
(C C8)-alkyl, halo (C C8)-alkyl and (C C8)-alkoxy;
n is 1 ;
m is 1 or 2;
X is hydrogen, halogen or (C-i-C8)-alkyl;
Q is:
Figure imgf000131_0001
wherein Indicates the point of attachment;
R3 is hydrogen, cyano, (CrC8)-alkyl, halo(CrC8)-alkyl, (C3-Ci2)-cycloalkyl, C(O)Ra, C(O)2Ra or S(O)qRc; wherein q, Ra and Rc are as defined in claim 1 ;
or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.
14. The compound according to any one of the claims 1 , 4 and 13,
wherein,
Ri and R2 are halogen;
n is 1 ;
m is 1 or 2;
X is hydrogen, halogen or (CrC8)-alkyl;
Q is:
Figure imgf000132_0001
wherein * indicates the point of attachment;
R3 is hydrogen, cyano, (CrC8)-alkyl, (C3-Ci2)-cycloalkyl or S(O)qRc; wherein q and Rc are as defined in claim 1 ;
or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.
15. The compound according to claim 1 or claim 4,
wherein,
Ri and R2 are halogen;
n is 1 ;
m is 1 or 2;
X is hydrogen, halogen or (CrC8)-alkyl;
Q is:
Figure imgf000132_0002
wherein * indicates the point of attachment;
R3 and R5 can join together to form a 3-12 membered saturated or unsaturated monocyclic or bicyclic ring system, optionally containing one to three heteroatoms independently selected from the group consisting of O, N and S;
wherein the said 3-12 membered ring can be unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, oxo, cyano, (d-CsJ-alkyl, halo(CrC8)-alkyl, (Ci-Cs)-alkoxy, halo(CrC8)-alkoxy, (C3- C12)-cycloalkyl-(Rd)o-2, O-(C3-C12)-cycloalkyl-(Rd)0-2, (C6-C14)-aryl-(Rd)0-2, O-(C6-C14)- aryl-(Rd)o-2, heterocyclyl-(Rd)0-2, O-heterocyclyl-(Rd)0-2, heteroaryl-(Rd)0-2, C(0)Ra, CO2Ra, C(O)NRaRb, NRaRb, NRaC(O)Rb, S(O)qRc and S(O)qNRaRb; wherein q, Ra, Rb, Rc and Rd are as defined in claim 1 ; or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.
16. The compound according to any one of the claims 1 , 4, 13 and 14,
wherein,
Ri and R2 are halogen;
n is 1 ;
m is 1 or 2;
X is hydrogen, halogen or (CrC8)-alkyl;
Q is:
Figure imgf000133_0001
wherein * indicates the point of attachment;
R3 is hydrogen, cyano, (CrC8)-alkyl, (C3-Ci2)-cycloalkyl or S(O)qRc; wherein q and Rc are as defined in claim 1 ; and
R4 and R5 can join together to form a 3-12 membered saturated or unsaturated, monocyclic or bicyclic ring system including spiro ring systems, optionally containing one to three heteroatoms independently selected from the group consisting of O, N and S;
wherein the said 3-12 membered ring can be unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, oxo, cyano, (CrC8)-alkyl, halo(CrC8)-alkyl, (CrC8)-alkoxy, halo(CrC8)-alkoxy, (C3- Ci2)-cycloalkyl-(Rd)o-2, O-(C3-Ci2)-cycloalkyl-(Rd)0-2, (C6-Ci4)-aryl-(Rd)0-2, 0-(C6-Ci4)- aryl-(Rd)o-2, heterocyclyl-(Rd)o-2, O-heterocyclyl-(Rd)o-2, heteroaryl-(Rd)0-2, C(0)Ra, CO2Ra, C(O)NRaRb, NRaRb, NRaC(O)Rb, S(O)qRc and S(O)qNRaRb; wherein q, Ra, Rb, Rc and Rd are as defined in claim 1 ;
or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.
17. The compound according to claim 1 ,
wherein, Ri and R2 are halogen;
n is 1 ;
m is 1 or 2;
X is hydrogen, halogen or (d-CsJ-alkyl;
Q is:
Figure imgf000134_0001
wherein * indicates the point of attachment;
R3 is hydrogen, cyano, (d-CsJ-alkyl, (C3-Ci2)-cycloalkyl or S(O)qRc; wherein q and Rc are as defined in claim 1 ;
R4 is (d-C8)-alkyl, (C3-Ci2)-cycloalkyl, (C6-C )-aryl, heterocyclyl or heteroaryl;
R5 is hydrogen, (d-CsJ-alkyl, (C3-Ci2)-cycloalkyl, (C6-C )-aryl, heterocyclyl or heteroaryl; or
R3 and R5 can join together to form a 3-12 membered saturated or unsaturated monocyclic or bicyclic ring system, optionally containing one to three heteroatoms independently selected from the group consisting of O, N and S; or
R4 and R5 can join together to form a 3-12 membered saturated or unsaturated, monocyclic or bicyclic ring system including spiro ring systems, optionally containing one to three heteroatoms independently selected from the group consisting of O, N and S;
wherein the said 3-12 membered ring can be unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, oxo, cyano, (d-CsJ-alkyl, halo(Ci-C8)-alkyl, (d-CsJ-alkoxy, halo(Ci-C8)-alkoxy, (C3- C12)-cycloalkyl-(Rd)o-2, O-(C3-C12)-cycloalkyl-(Rd)0-2, (C6-C14)-aryl-(Rd)o-2, O-(C6-C14)- aryl-(Rd)o-2, heterocyclyl-(Rd)0-2, O-heterocyclyl-(Rd)0-2, heteroaryl-(Rd)0-2, C(0)Ra, CO2Ra, C(O)NRaRb, NRaRb, NRaC(O)Rb, S(O)qRc and S(O)qNRaRb; wherein q, Ra, Rb, Rc and Rd are as defined in claim 1 ;
or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, N-oxide or S-oxide thereof.
18. The compound according to any of the claims 1 to 17, wherein said compound is selected from:
4-Chloro-5-(4-chlorophenyl)-N,N'-dicyclopropyl-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboximidamide;
N-((1 S,3R,5S)-Adamantan-1 -yl)-4-chloro-5-(4-chlorophenyl)-N'-cyclopropyl-1 -(2,4- dichlorophenyl)-1 H-pyrazole-3-carboximidamide;
4-Chloro-5-(4-chlorophenyl)-N'-cyclopropyl-1 -(2,4-dichlorophenyl)-N-(1 ,1 - dioxidothiomorpholino)-1 H-pyrazole-3-carboximidamide;
4- Chloro-1 -(2-chlorophenyl)-5-(4-chlorophenyl)-N'-cyclopropyl-N-(1 ,1 -dioxidothio morpholino)-1 H-pyrazole-3-carboximidamide;
5- (4-Chlorophenyl)-N,N'-dicyclopropyl-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboximidamide;
N-((1 S,3R,5S)-Adamantan-1 -yl)-5-(4-chlorophenyl)-N'-cyclopropyl-1 -(2,4- dichlorophenyl)-1 H-pyrazole-3-carboximidamide;
N-((2R)-Adamantan-2-yl)-5-(4-chlorophenyl)-N'-cyclopropyl-1 -(2,4-dichlorophenyl)-1 H- pyrazole-3-carboximidamide;
5-(4-Chlorophenyl)-N'-cyclopropyl-1 -(2,4-dichlorophenyl)-N-(1 ,1 -dioxidothiomorpholino)- 1 H-pyrazole-3-carboximidamide;
4- ((5-(4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol3-yl)(cyclopropylimino) methyl)thiomorpholine 1 ,1 -dioxide;
5- (4-Chlorophenyl)-N'-cyclopropyl-1 -(2,4-dichlorophenyl)-N-morpholino-1 H-pyrazole-3- carboximidamide;
2-(5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3-yl)-1 -cyclopropyl-4-isopropyl- 1 H-imidazol-5(4H)-one;
1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyclopropyl-N-(1 ,1 -dioxidothiomorpholino)-1 H- pyrazole-3-carboximidamide;
1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N-cyclohexyl-N'-cyclopropyl-1 H-pyrazole-3- carboximidamide;
4- ((5-(4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3-yl)(methylimino)methyl) thiomorpholine 1 ,1 -dioxide;
5- (4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-N'-ethyl-N-morpholino-1 H-pyrazole-3- carboximidamide;
4-((5-(4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3-yl)(ethylimino)methyl) thiomorpholine 1 ,1 -dioxide; 5-(4-Chlorophenyl)-N,N'-dicyclopropyl-1 -(2,4-dichlorophenyl)-4-methyl-1 H-pyrazole-3- carboximidamide;
5-(4-Chlorophenyl)-N'-cyclopropyl-1 -(2,4-dichlorophenyl)-N-(1 ,1 -dioxidothiomorpholino) 4-methyl-1 H-pyrazole-3-carboximidamide;
4- ((5-(4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-4-methyl-1 H-pyrazol-3-yl)
(cyclopropylimino)methyl)thiomorpholine 1 ,1 -dioxide;
5- (4-Chlorophenyl)-N'-cyclopropyl-1 -(2,4-dichlorophenyl)-4-methyl-N-morpholino-1 H- pyrazole-3-carboximidamide;
N-((5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-4-methyl-1 H-pyrazol-3-yl)(morpholino) methylene)cyclopropanamine;
1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N,N'-dicyclopropyl-4-methyl-1 H-pyrazole-3- carboximidamide;
N-((1 S,3R,5S)-Adamantan-1 -yl)-1 -(2-chlorophenyl)-5-(4-chlorophenyl)-N'-cyclopropyl-4 methyl-1 H-pyrazole-3-carboximidamide;
1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyclopropyl-N-(1 ,1 -dioxidothiomorpholino)-4- methyl-1 H-pyrazole-3-carboximidamide;
1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyclopropyl-4-methyl-N-morpholino-1 H- pyrazole-3-carboximidamide;
1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyclopropyl-4-methyl-N-(oxetan-3-yl)-1 H- pyrazole-3-carboximidamide;
N-Cyclohexyl-N'-cyclopropyl-1 -(2-methoxyphenyl)-5-(4-methoxyphenyl)-1 H-pyrazole-3- carboximidamide;
te/t-Butyl 4-((5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-4-methyl-1 H-pyrazol-3-yl) (cyclopropylimino)methyl)piperazine-1 -carboxylate;
N-((5-(4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-4-methyl-1 H-pyrazol-3-yl)(piperazin-1 - yl)methylene)cyclopropanamine hydrochloride;
N-((5-(4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-4-methyl-1 H-pyrazol-3-yl)(morpholino) methylene)cyclopropanamine;
N,N'-Dicyclopropyl-1 -(2-methoxyphenyl)-5-(4-methoxyphenyl)-1 H-pyrazole-3- carboximidamide;
N'-Cyclopropyl-N-(1 ,1 -dioxidothiomorpholino)-1 -(2-methoxyphenyl)-5-(4- methoxyphenyl)-1 H-pyrazole-3-carboximidamide;
5-(4-Chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-N-methyl-1 H-pyrazole-3- carboximidamide; 5-(4-Chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-N-ethyl-1 H-pyrazole-3- carboximidamide;
5-(4-Chlorophenyl)-N'-cyano-N-cyclopropyl-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboximidamide;
5-(4-Chlorophenyl)-N'-cyano-N-cyclohexyl-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboximidamide;
5-(4-Chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-N-(oxetan-3-yl)-1 H-pyrazole-3- carboximidamide;
N-((5-(4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3-yl)(4-(oxetan-3-yl) piperidin 1 -yl)methylene)cyanamide;
5-(4-Chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-N-(1 -(oxetan-3-yl)piperidin-4-yl)-1 H pyrazole-3-carboximidamide;
N-((4-Acetylpiperazin-1 -yl)(5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3- yl)methylene)cyanamide;
te/t-Butyl 4-((5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3-yl)(cyanoimino) methyl)piperazine-1 -carboxylate;
N-((1 S,3R,5S)-Adamantan-1 -yl)-5-(4-chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-1 H pyrazole-3-carboximidamide;
N-((1 s,3s,5s)-1 ,3,5-Triazaadamantan-7-yl)-5-(4-chlorophenyl)-N'-cyano-1 -(2,4- dichlorophenyl)-1 H-pyrazole-3-carboximidamide;
(S)-2-(5-(4-Chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboximidamido)propanamide;
(S)-Methyl 2-(5-(4-chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboximidamido)-3-methylbutanoate;
N-((5-(4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3-yl)(1 ,1 -dioxidothio morpholino)methylene)cyanamide;
5-(4-Chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-N-(1 ,1 -dioxidothiomorpholino)-1 H- pyrazole-3-carboximidamide;
N-((5-(4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3-yl) (morpholino)
methylene)cyanamide;
5-(4-Chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-N-morpholino-1 H-pyrazole-3- carboximidamide;
5-(4-Chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-N-(4-methoxybenzyl)-1 H-pyrazole- 3-carboximidamide; 1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-N-ethyl-1 H-pyrazole-3- carboximidamide;
1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-N-cyclopropyl-1 H-pyrazole-3- carboximidamide;
1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-N-cyclohexyl-1 H-pyrazole-3- carboximidamide;
1 - (2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-N-(oxetan-3-yl)-1 H-pyrazole-3- carboximidamide;
N-((1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl)(4-(oxetan-3-yl)piperidin-1 - yl)methylene)cyanamide;
1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-N-(1 -(oxetan-3-yl)piperidin-4-yl)-1 H- pyrazole-3-carboximidamide;
N-((1 S,3R,5S)-Adamantan-1 -yl)-1 -(2-chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-1 H- pyrazole-3-carboximidamide;
N-((1 s,3s,5s)-1 ,3,5-Triazaadamantan-7-yl)-1 -(2-chlorophenyl)-5-(4-chlorophenyl)-N'- cyano-1 H-pyrazole-3-carboximidamide;
(S)-2-(1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-1 H-pyrazole-3- carboximidamido)propanamide;
(S)-Methyl 2-(1 -(2-chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-1 H-pyrazole-3- carboximidamido)-3-methylbutanoate;
(S)-2-(1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-1 H-pyrazole-3- carboximidamido)-3-methylbutanamide;
1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-N-(1 ,1 -dioxidothiomorpholino)-1 H- pyrazole-3-carboximidamide;
N-((5-(4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3-yl)(piperidin-1 -yl) methylene)cyanamide;
tert- ut \ (1 -((5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3-yl)
(cyanoimino)methyl)piperidin-4-yl)carbamate;
N-((4-Aminopiperidin-1 -yl)(5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3-yl) methylene)cyanamide hydrochloride;
N-((5-(4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3-yl)(piperazin-1 -yl) methylene)cyanamide hydrochloride;
2- (5-(4-Chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboximidamido)-2-methylpropanamide; 1 -(5-(4-Chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboximidamido)cyclopropanecarboxamide;
1 -(5-(4-Chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboximidamido)cyclopentanecarboxamide;
(S)-2-(5-(4-Chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboximidamido)-3-methylbutanoic acid;
(S)-2-(5-(4-Chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboximidamido)-3-methylbutanamide;
te/t-Butyl 9-((5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3-yl)(cyanoimino) methyl)-2,9-diazaspiro[5.5]undecane-2-carboxylate;
N-((5-(4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3-yl)(2,9-diazaspiro[5.5] undecan-9-yl)methylene)cyanamide hydrochloride;
N-((1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl)(piperidin-1 -yl) methylene) cyanamide;
N-((4-Acetylpiperazin-1 -yl) ( 1 -(2-chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl) methylene)cyanamide;
1 -(1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-1 H-pyrazole-3-carboximidamido) cyclopentanecarboxamide;
te/t-Butyl 9-((1 -(2-chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl)(cyanoimino) methyl)-2,9-diazaspiro[5.5]undecane-2-carboxylate;
5-(4-Chlorophenyl)-N'-cyano-N-cyclohexyl-1 -(2,4-dichlorophenyl)-4-methyl-1 H-pyrazole- 3-carboximidamide;
(H)-2-(5-(4-Chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-4-methyl-1 H-pyrazole-3- carboximidamido)propanamide;
2-(5-(4-Chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-4-methyl-1 H-pyrazole-3- carboximidamido)-2-methylpropanamide;
1 -(5-(4-Chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-4-methyl-1 H-pyrazole-3- carboximidamido)cyclopropanecarboxamide;
1 -(5-(4-Chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-4-methyl-1 H-pyrazole-3- carboximidamido)cyclopentanecarboxamide;
2-(5-(4-Chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-4-methyl-1 H-pyrazole-3- carboximidamido)-3-methylbutanamide;
1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-N-cyclopropyl-4-methyl-1 H-pyrazole-3- carboximidamide; 1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-N-cyclohexyl-4-methyl-1 H-pyrazole-3- carboximidamide;
(S)-2-(1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-4-methyl-1 H-pyrazole-3- carboximidamido)propanamide;
1 -(1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-4-methyl-1 H-pyrazole-3- carboximidamido)cyclopropanecarboxamide;
1 -(1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-4-methyl-1 H-pyrazole-3- carboximidamido)cyclopentanecarboxamide;
(S)-2-(5-(4-chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-4-methyl-1 H-pyrazole-3- carboximidamido)-3-methylbutanamide;
te/t-Butyl 9-((1 -(2-chlorophenyl)-5-(4-chlorophenyl)-4-methyl-1 H-pyrazol-3-yl)
(cyanoimino)methyl)-2,9-diazaspiro[5.5]undecane-2-carboxylate;
tert-Butyl 4-((1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-4-methyl-1 H-pyrazol-3-yl)
(cyanoimino)methyl)-1 -oxa-4,8-diazaspiro[5.5]undecane-8-carboxylate;
1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-4-methyl-N-(quinuclidin-3-yl)-1 H- pyrazole-3-carboximidamide;
N-((1 S,2R,4S)-Bicyclo[2.2.1 ]hept-5-en-2-ylmethyl)-1 -(2-chlorophenyl)-5-(4- chlorophenyl)-N'-cyano-4-methyl-1 H-pyrazole-3-carboximidamide;
1 -(1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl)-2-cyclopropyl-3- ethylguanidine;
1 -(1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl)-2,3-dicyclopropylguanidine; 1 -Benzyl-3-(1 -(2-chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl)-2-cyclopropyl guanidine;
N-(1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl)-N'-cyclopropyl
thiomorpholine-4-carboximidamide 1 ,1 -dioxide;
N-(1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl)-N'-cyclopropylmorpholine-4- carboximidamide;
1 -(1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl)-2-cyclopropyl-3- morpholinoguanidine;
1 -((1 r,3r,5r,7r)-Adamantan-2-yl)-3-(1 -(2-chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3- yl)-2-cyclopropylguanidine;
1 -(1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl)-2-cyano-3-cyclopropyl guanidine; 4- (((1 -(2-chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl)imino)(cyclopropyl) methyl)thiomorpholine 1 ,1 -dioxide;
1 -(1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl)-3-cyclohexyl-2- cyclopropylguanidine;
N'-(1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl)-N-(1 ,1 -dioxidothio
morpholino)cyclopropanecarboximidamide;
N-Benzyl-N'-(1 -(2-chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl)cyclopropane carboximidamide;
5- (4-Chlorophenyl)-N-cyclohexyl-1 -(2,4-dichlorophenyl)-N'-(methylsulfonyl)-1 H- pyrazole-3-carboximidamide;
N-Benzyl-5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-N'-(methylsulfonyl)-1 H-pyrazole-3- carboximidamide;
N-((5-(4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3-yl)(4-ethylpiperazin-1 -yl) methylene)methanesulfonamide;
N-((4-Benzylpiperazin-1 -yl)(5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3- yl)methylene)methanesulfonamide;
N-((5-(4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3-yl)(1 ,1 -dioxido
thiomorpholino)methylene)methanesulfonamide;
N-((5-(4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3-yl)(morpholino)
methylene)methanesulfonamide; or
N-((5-(4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3-yl)(4-(oxetan-3-yl) piperidin- 1 -yl)methylene)methanesulfonamide;
or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.
19. The compound according to any of the claims 1 to 18, wherein said compound is selected from:
4-Chloro-5-(4-chlorophenyl)-N,N'-dicyclopropyl-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboximidamide;
N-((1 S,3R,5S)-Adamantan-1 -yl)-4-chloro-5-(4-chlorophenyl)-N'-cyclopropyl-1 -(2,4- dichlorophenyl)-1 H-pyrazole-3-carboximidamide;
4-Chloro-5-(4-chlorophenyl)-N'-cyclopropyl-1 -(2,4-dichlorophenyl)-N-(1 ,1 - dioxidothiomorpholino)-1 H-pyrazole-3-carboximidamide;
4-Chloro-1 -(2-chlorophenyl)-5-(4-chlorophenyl)-N'-cyclopropyl-N-(1 ,1 -dioxidothio morpholino)-1 H-pyrazole-3-carboximidamide; 5-(4-Chlorophenyl)-N,N'-dicyclopropyl-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboximidamide;
N-((1 S,3R,5S)-Adamantan-1 -yl)-5-(4-chlorophenyl)-N'-cyclopropyl-1 -(2,4- dichlorophenyl)-1 H-pyrazole-3-carboximidamide;
N-((2R)-Adamantan-2-yl)-5-(4-chlorophenyl)-N'-cyclopropyl-1 -(2,4-dichlorophenyl)-1 H- pyrazole-3-carboximidamide;
5-(4-Chlorophenyl)-N'-cyclopropyl-1 -(2,4-dichlorophenyl)-N-(1 ,1 -dioxidothiomorpholino) 1 H-pyrazole-3-carboximidamide;
4- ((5-(4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol3-yl)(cyclopropylimino) methyl)thiomorpholine 1 ,1 -dioxide;
5- (4-Chlorophenyl)-N'-cyclopropyl-1 -(2,4-dichlorophenyl)-N-morpholino-1 H-pyrazole-3- carboximidamide;
2-(5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3-yl)-1 -cyclopropyl-4-isopropyl- 1 H-imidazol-5(4H)-one;
1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyclopropyl-N-(1 ,1 -dioxidothiomorpholino)-1 H pyrazole-3-carboximidamide;
1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N-cyclohexyl-N'-cyclopropyl-1 H-pyrazole-3- carboximidamide;
4- ((5-(4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3-yl)(methylimino)methyl) thiomorpholine 1 ,1 -dioxide;
5- (4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-N'-ethyl-N-morpholino-1 H-pyrazole-3- carboximidamide;
4- ((5-(4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3-yl)(ethylimino)methyl) thiomorpholine 1 ,1 -dioxide;
5- (4-Chlorophenyl)-N,N'-dicyclopropyl-1 -(2,4-dichlorophenyl)-4-methyl-1 H-pyrazole-3- carboximidamide;
5-(4-Chlorophenyl)-N'-cyclopropyl-1 -(2,4-dichlorophenyl)-N-(1 ,1 -dioxidothiomorpholino) 4-methyl-1 H-pyrazole-3-carboximidamide;
4- ((5-(4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-4-methyl-1 H-pyrazol-3-yl)
(cyclopropylimino)methyl)thiomorpholine 1 ,1 -dioxide;
5- (4-Chlorophenyl)-N'-cyclopropyl-1 -(2,4-dichlorophenyl)-4-methyl-N-morpholino-1 H- pyrazole-3-carboximidamide;
N-((5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-4-methyl-1 H-pyrazol-3-yl)(morpholino) methylene)cyclopropanamine; 1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N,N'-dicyclopropyl-4-methyl-1 H-pyrazole-3- carboximidamide;
N-((1 S,3R,5S)-Adamantan-1 -yl)-1 -(2-chlorophenyl)-5-(4-chlorophenyl)-N'-cyclopropyl-4 methyl-1 H-pyrazole-3-carboximidamide;
1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyclopropyl-N-(1 ,1 -dioxidothiomorpholino)-4- methyl-1 H-pyrazole-3-carboximidamide;
1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyclopropyl-4-methyl-N-morpholino-1 H- pyrazole-3-carboximidamide;
1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyclopropyl-4-methyl-N-(oxetan-3-yl)-1 H- pyrazole-3-carboximidamide;
N-Cyclohexyl-N'-cyclopropyl-1 -(2-methoxyphenyl)-5-(4-methoxyphenyl)-1 H-pyrazole-3- carboximidamide;
5-(4-Chlorophenyl)-N' -cyano-1 -(2,4-dichlorophenyl)-N-methyl-1 H-pyrazole-3- carboximidamide;
5-(4-Chlorophenyl)-N' -cyano-1 -(2,4-dichlorophenyl)-N-ethyl-1 H-pyrazole-3- carboximidamide;
5-(4-Chlorophenyl)-N' -cyano-N-cyclopropyl-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboximidamide;
5-(4-Chlorophenyl)-N' -cyano-N-cyclohexyl-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboximidamide;
5-(4-Chlorophenyl)-N' -cyano-1 -(2,4-dichlorophenyl)-N-(oxetan-3-yl)-1 H-pyrazole-3- carboximidamide;
N-((5-(4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3-yl)(4-(oxetan-3-yl) piperidin 1 -yl)methylene)cyanamide;
5-(4-Chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-N-(1 -(oxetan-3-yl)piperidin-4-yl)-1 H pyrazole-3-carboximidamide;
N-((4-Acetylpiperazin-1 -yl)(5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3- yl)methylene)cyanamide;
te/t-Butyl 4-((5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3-yl)(cyanoimino) methyl)piperazine-1 -carboxylate;
N-((1 S,3R,5S)-Adamantan-1 -yl)-5-(4-chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-1 H pyrazole-3-carboximidamide;
N-((1 s,3s,5s)-1 ,3,5-Triazaadamantan-7-yl)-5-(4-chlorophenyl)-N'-cyano-1 -(2,4- dichlorophenyl)-1 H-pyrazole-3-carboximidamide; (S)-2-(5-(4-Chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboximidamido)propanamide;
(S)-Methyl 2-(5-(4-chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3- carboximidamido)-3-methylbutanoate;
N-((5-(4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3-yl)(1 ,1 -dioxidothio morpholino)methylene)cyanamide;
5-(4-Chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-N-(1 ,1 -dioxidothiomorpholino)-1 H- pyrazole-3-carboximidamide;
N-((5-(4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3-yl) (morpholino)
methylene)cyanamide;
5-(4-Chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-N-morpholino-1 H-pyrazole-3- carboximidamide;
5-(4-Chlorophenyl)-N'-cyano-1 -(2,4-dichlorophenyl)-N-(4-methoxybenzyl)-1 H-pyrazole- 3-carboximidamide;
1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-N-ethyl-1 H-pyrazole-3- carboximidamide;
1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-N-cyclopropyl-1 H-pyrazole-3- carboximidamide;
1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-N-cyclohexyl-1 H-pyrazole-3- carboximidamide;
1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-N-(oxetan-3-yl)-1 H-pyrazole-3- carboximidamide;
N-((1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl)(4-(oxetan-3-yl)piperidin-1 - yl)methylene)cyanamide;
1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-N-(1 -(oxetan-3-yl)piperidin-4-yl)-1 H- pyrazole-3-carboximidamide;
N-((1 S,3R,5S)-Adamantan-1 -yl)-1 -(2-chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-1 H- pyrazole-3-carboximidamide;
N-((1 s,3s,5s)-1 ,3,5-Triazaadamantan-7-yl)-1 -(2-chlorophenyl)-5-(4-chlorophenyl)-N'- cyano-1 H-pyrazole-3-carboximidamide;
(S)-2-(1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-1 H-pyrazole-3- carboximidamido)propanamide;
(S)-Methyl 2-(1 -(2-chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-1 H-pyrazole-3- carboximidamido)-3-methylbutanoate; (S)-2-(1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-1 H-pyrazole-3- carboximidamido)-3-methylbutanamide;
1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-N'-cyano-N-(1 ,1 -dioxidothiomorpholino)-1 H- pyrazole-3-carboximidamide;
N-((5-(4-Chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazol-3-yl)(piperidin-1 -yl) methylene)cyanamide;
1 -(1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl)-2-cyclopropyl-3- ethylguanidine;
1 -(1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl)-2,3-dicyclopropylguanidine; 1 -Benzyl-3-(1 -(2-chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl)-2-cyclopropyl guanidine;
N-(1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl)-N'-cyclopropyl
thiomorpholine-4-carboximidamide 1 ,1 -dioxide;
N-(1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl)-N'-cyclopropylmorpholine-4- carboximidamide;
1 -(1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl)-2-cyclopropyl-3- morpholinoguanidine;
1 -((1 r,3r,5r,7r)-Adamantan-2-yl)-3-(1 -(2-chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3- yl)-2-cyclopropylguanidine;
1 -(1 -(2-Chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl)-2-cyano-3-cyclopropyl guanidine; or
4-(((1 -(2-chlorophenyl)-5-(4-chlorophenyl)-1 H-pyrazol-3-yl)imino)(cyclopropyl) methyl)thiomorpholine 1 ,1 -dioxide;
or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.
20. A pharmaceutical composition comprising a therapeutically effective amount of a compound as defined in any one of the claims 1 -19, or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof; and at least one pharmaceutically acceptable carrier or excipient.
21 . A method for the treatment of a disease or disorder mediated by cannabinoid 1 (CB1 ) receptor, comprising administering to a subject in need thereof; a therapeutically effective amount of a compound as defined in any one of the claims 1 -19, or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof.
22. The method according to claim 21 , wherein the disease or disorder is gastrointestinal disorder; inflammatory disease or disorder; cardiovascular disease; cancer; metabolic disorder; osteoporosis; nephropathy; glaucoma; psychiatric disorder; neurological disorder; autoimmune hepatitis and encephalitis; pain; reproductive disorder; skin inflammatory disease or fibrotic disease.
23. The method according to claim 22, wherein the disease or disorder is a metabolic disorder.
24. The method according to claim 23, wherein the metabolic disorder is obesity, dyslipidemia, hyperlipidemia, low HDL (high density lipoprotein) cholesterol level, high LDL (low density lipoprotein) cholesterol level, hypertriglyceridemia, low adiponectin level, dyslipoproteinemia, impaired glucose tolerance, insulin resistance, increase in HbA1 c (glycosylated haemoglobin) level, type 2 diabetes, reduced metabolic activity, hypertension or non-alcoholic fatty liver disease.
25. The method according to claim 23 or claim 24, wherein the metabolic disorder is obesity.
26. The method according to claim 23 or claim 24, wherein the metabolic disorder is type 2 diabetes, insulin resistance, impaired glucose or reduced metabolic activity.
27. The method according to any one of the claims 23, 24 and 26, wherein the metabolic disorder is type 2 diabetes.
28. The method according to claim 22, wherein the disease or disorder is an inflammatory disease or disorder selected from arthritis, hepatitis, inflammatory bowel disease, ulcerative colitis, Crohn's disease or congestive obstructive pulmonary disorder.
29. The method according to claim 22, wherein the disease or disorder is a cardiovascular disease selected from aneurysm, angina, arrhythmia, atherosclerosis, cardiomyopathy, cerebrovascular accident (stroke), cerebrovascular disease, congenital heart disease, congestive heart failure, myocarditis, valve disease, coronary artery disease, dilated cardiomyopathy, diastolic dysfunction, endocarditis, high blood pressure (hypertension), hypertrophic cardiomyopathy and its associated arrhythmias and dizziness, mitral valve prolapse, myocardial infarction (heart attack), venous thromboembolism, varicose veins or pulmonary embolism.
30. The method according to claim 22, wherein the disease or disorder is cancer selected from thyroid carcinoma, cardiac sarcoma, lung carcinoma, gastrointestinal carcinoma, genitourinary tract carcinoma, liver carcinoma, mantle cell lymphoma, bone sarcoma, sarcoma of the nervous system, gynaecological carcinoma, haematological cancer, adrenal gland neuroblastoma, skin cancer, astrocytic cancer, breast cancer, colorectal cancer, endometrial cancer, head and neck cancer or oral cancer.
31 . A compound as defined in any one of the claims 1 -19, or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof; for use as cannabinoid 1 (CB1 ) receptor antagonists.
32. A compound as defined in any one of the claims 1 -19, or a stereoisomer, a tautomer or a pharmaceutically acceptable salt or a solvate thereof; for use in the treatment of a disease or a disorder mediated by cannabinoid 1 (CB1 ) receptors.
33. A compound for the use according to claim 32, wherein the disease or disorder is gastrointestinal disorder; inflammatory disease or disorder; cardiovascular disease; cancer; metabolic disorder; osteoporosis; nephropathy; glaucoma; psychiatric disorder; neurological disorder; autoimmune hepatitis and encephalitis; pain; reproductive disorder; skin inflammatory disease or fibrotic disease.
34. A compound for the use according to claim 33, wherein the disease or disorder is a metabolic disorder.
35. A compound for the use according to claim 34, wherein the metabolic disorder is obesity, dyslipidemia, hyperlipidemia, low HDL (high density lipoprotein) cholesterol level, high LDL (low density lipoprotein) cholesterol level, hypertriglyceridemia, low adiponectin level, dyslipoproteinemia, impaired glucose tolerance, insulin resistance, increase in HbA1 c (glycosylated haemoglobin) level, type 2 diabetes, reduced metabolic activity, hypertension or non-alcoholic fatty liver disease.
36. A compound for the use according to claim 34 or claim 35, wherein the metabolic disorder is obesity.
37. A compound for the use according to claim 34 or claim 35, wherein the metabolic disorder is type 2 diabetes, insulin resistance, impaired glucose or reduced metabolic activity.
38. A compound for the use according to any one of the claims 34, 35 and 37, wherein the metabolic disorder is type 2 diabetes.
39. A compound for the use according to claim 33, wherein the disease or disorder is an inflammatory disease or disorder selected from arthritis, hepatitis, inflammatory bowel disease, ulcerative colitis, Crohn's disease or congestive obstructive pulmonary disorder.
40. A compound for the use according to claim 33, wherein the disease or disorder is a cardiovascular disease selected from aneurysm, angina, arrhythmia, atherosclerosis, cardiomyopathy, cerebrovascular accident (stroke), cerebrovascular disease, congenital heart disease, congestive heart failure, myocarditis, valve disease, coronary artery disease, dilated cardiomyopathy, diastolic dysfunction, endocarditis, high blood pressure (hypertension), hypertrophic cardiomyopathy and its associated arrhythmias and dizziness, mitral valve prolapse, myocardial infarction (heart attack), venous thromboembolism, varicose veins or pulmonary embolism.
41 . A compound for the use according to claim 33, wherein the disease or disorder is cancer selected from thyroid carcinoma, cardiac sarcoma, lung carcinoma, gastrointestinal carcinoma, genitourinary tract carcinoma, liver carcinoma, mantle cell lymphoma, bone sarcoma, sarcoma of the nervous system, gynaecological carcinoma, haematological cancer, adrenal gland neuroblastoma, skin cancer, astrocytic cancer, breast cancer, colorectal cancer, endometrial cancer, head and neck cancer or oral cancer.
42. Use of a compound as defined in any one of the claims 1 -19 or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof; in combination with one further therapeutically active agent; for the treatment of a disease or a disorder mediated by cannabinoid 1 (CB1 ) receptors.
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