EP4698527A1 - Aminopyridine analogues as 5-hydroxytryptamine receptor modulators and uses thereof - Google Patents
Aminopyridine analogues as 5-hydroxytryptamine receptor modulators and uses thereofInfo
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- EP4698527A1 EP4698527A1 EP24792296.6A EP24792296A EP4698527A1 EP 4698527 A1 EP4698527 A1 EP 4698527A1 EP 24792296 A EP24792296 A EP 24792296A EP 4698527 A1 EP4698527 A1 EP 4698527A1
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- pyridin
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- optionally substituted
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/72—Nitrogen atoms
- C07D213/73—Unsubstituted amino or imino radicals
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
The present invention relates to the design and development of aminopyridine analogues, which can be used as therapeutic agents for the treatment of endocrine metabolic and central nervous system disorders, and a process of preparing said novel compounds. Specifically, the present invention relates to 6-alkyl/aryl-substituted-2-aminopyridine and their analogues, processes for preparing the said compounds and to their use in the treatment of obesity, substance abuse and related neurological disorders.
Description
AMINOPYRIDINE ANALOGUES AS 5-HYDROXYTRYPTAMINE RECEPTOR MODULATORS AND USES THEREOF FIELD OF THE INVENTION The present invention relates to the development of novel substituted aminopyridine analogues, which can be used as therapeutic agents for the treatment and prevention of endocrine metabolic and central nervous system disorders, and a process of preparing said novel compounds. Specifically, the present invention relates to 6-alkyl/aryl-substituted-2- aminopyridine and their analogues, processes for preparing the said compounds and to their use in the treatment of obesity and related metabolic disorders. The present invention deals with design and development of novel substituted aminopyridine analogues of the general formula I; hydrogen, thiol, thioalkyl, sulfoxide,
Wherein R3 and R4 is selected from hydrogen, optionally substituted alkyl chain (C1-C6) and cycloalkyl group (C1-C10); Where Y= N, O, N-alkyl, N-aryl, N-Substituted aryl, N-heteroaryl;
= optionally substituted aryl, optionally substituted alkoxy, optionally substituted alkyl; R2 = H, halogen, CN T = defined as optionally substituted normal or branched alkyl chain (C1-C6) or as template IA or Template IB or Template IC
Where in template IA, R5-R8 is selected from hydrogen, optionally substituted alkyl, optionally substituted alkoxy, N-alkyl chain (C1-C6), CN, NO2, CF3 and A is X, CF3, CN, NO2, phenyl, optionally substituted phenyl, optionally substituted heteroaryl. Where in template IB and IC, G is selected from hydrogen, hydroxy, optionally substituted alkoxy, halogen, NO2 and R9 is selected from hydrogen, optionally substituted alkyl, optionally substituted aryl BACKGROUND OF THE INVENTION Serotonin (5-hydroxytryptamine; 5-HT) was discovered in mammalian central nervous system (CNS) around 7 decades agon, but we still do not understand completely the mechanisms of 5-HT modulation of various neurophysiological processes. 5-HT modulates plethora of CNS and peripheral function via acting through at least 12 G Protein Coupled Receptors (GPCRs) and one ion channel. Lately, one of the target receptors of 5-HT, 5-HT2C receptor (5-HT2C) have been in focus for new drug discovery and development to treat obesity, schizophrenia and drug addiction (Zhou & Cunningham, Neuropsychopharmacol. 2019 Jan; 44(1): 230–231). In this context, 5- HT2C selective agonist have consistently been demonstrated to induce anorexia (Garfield & Heisler, J. Physiol.2009, 587, 49–60). Therefore, Lorcaserine, a 5HT2C agonist was approved in 2012 by FDA for the treatment of severe obesity, but in Janurary 2020, withdrawn from United States due to possible risk of cancer associated with lorcaserin. Furthermore, several 5-HT2C antagonist has also been found useful in preclinical studies for anxiety, depression and schizophrenia (Harada et al, Eur J Pharmacol.2006; 553:171-84; Millan et al, J Pharmacol Exp Ther. 2012; 340:750-64). Multiple line of evidence has also suggested role of the 5-HT2C in the rewarding and incentive-salience value of several psychostimulants, including ethanol and opioids (Grottick et al, J. Pharmacol. Exp. Ther, 2000, 295, 1183–1191; Anastasio et al, Neuropsychopharmacol.2014; 39:370-82; Moeller et al, Neuropsychopharmacol, 2018, 43, 220– 221). Therefore, several groups in academia and industries are trying to develop new 5-HT2C modulators for drug addiction. Typically, 5-HT2C signal through 5-HT induced coupling to Gαq/11 to activate phospholipase Cβ (PLCβ) mediated hydrolysis of phosphatidylinositol 4,5-biphosphate (PIP2) to generate the intracellular second messenger inositol-1,4,5-trisphosphate (IP3), accumulation of the downstream IP3 metabolite inositol monophosphate (IP1), and diacylglycerol (DAG). Intracellular calcium
(iCa++) mobilization, frequently measured with calcium-binding fluorescent dyes, and IP1 levels, assessed with [3H]-inositol, are well-characterized to be increased following the activation of the 5-HT2C (Millan et al, Trends Pharmacol. Sci, 2008, 29, 454–464). Actually, the elevated iCa++and/or IP1 is widely used parameter in functional cell-based assays to determine the 5-HT2C activation (Roth et al, Pharmacol. Ther, 1998, 79, 231–257). 5-HT2C has also been shown to modulate ion channels and transporter that further activate other downstream effectors, including Phospholipase A2 (PLA2), Phospholipase D (PLD), cyclic nucleotides, and extracellular signal- regulated kinases (Roth BL (eds) The Serotonin Receptors. The Receptors. Humana Press, 2006, pp 1–38). The 5-HT2C signaling mechanisms in whole organism is further complicated by the fact that this receptor is the only known GPCR that under-goes RNA editing (O’Neil et al, Neurobiol. Dis, 2012, 45, 8–13). Five adenosines in second intracellular loop of the 5-HT2C are deaminated by Adenosine Deaminases that Act on RNA (ADAR), resulting in adenosine to inosine substitution which alters the coupling with G protein and thereby limits its ability to activate secondary messengers (Marion et al, J. Biol. Chem, 2004, 279(4), 2945–2954). Despite of some success in recent past, developing highly selective agonist and antagonist of 5- HT2C remains a challenge due to highly conserved orthosteric ligand binding pocket among all three 5-HT2 receptor subtypes (5-HT2A, 5-HT2B, 5-HT2C). Therefore, one strategy that have gained significant traction for 5-HT2C lately is targeting of allosteric site, which are defined as ligand binding sites that are spatially distinct from an orthosteric site (Christopoulos A, Nat Rev Drug Discov.2002; 1(3):198-210). It is widely believed that the allosteric modulation of GPCRs should induce physiologically relevant enhancement of target function compared to an orthosteric synthetic agonists (Conn et al, Nat. Rev. Drug Discov. 2009, 8, 41– 54). Obesity being a main culprit for cardiometabolic and CNS diseases, and upregulation 5-HT2C function have been proven to be successful to some extent, several 5-HT2C PAMs have been discovered recently (Im et al, Mol. Pharmacol. 64 (2003) 78-84; Garcia-Carceles et al, J. Med. Chem. 60 (2017)9575-9584; Singh et al, Eur J Med Chem.2019; 164:499-516; Wild et al, J Med Chem.2019; 62(1):288-305). Considering the withdrawal of several antiobesity drugs post marketing due to serious adverse effect profile, new class of molecules such as 5-HT2C PAMs would be more scrutinized with respects to long terms safety aspects. Since no allosteric modulators of GPCRs have been approved as drug yet, there is a need in the art for effector chemotypes that can readily synthesized for use in 5-HT2C mediated therapeutic benefits.
OBJECTIVES OF THE INVENTION The object of the present invention is to obtain/prepare therapeutically effective compounds/pharmaceutically acceptable formulations/delivery systems having the compound of general formula I; hydrogen, thiol, thioalkyl, sulfoxide,
Wherein R3 and R4 is selected from hydrogen, optionally substituted alkyl chain (C1-C6) and cycloalkyl group (C1-C10); Where Y= N, O, N-alkyl, N-aryl, N-Substituted aryl, N-heteroaryl;
optionally substituted aryl, optionally substituted alkoxy, optionally substituted alkyl; R2 = H, halogen, CN T = defined as optionally substituted normal or branched alkyl chain (C1-C6) or as template IA or Template IB or Template IC
hydrogen, optionally substituted alkyl, optionally substituted alkoxy, N-alkyl chain (C1-C6), CN, NO2, CF3 and A is X, CF3, CN, NO2, phenyl, optionally substituted phenyl, optionally substituted heteroaryl. Where in template IB and IC, G is selected from hydrogen, hydroxy, optionally substituted alkoxy, halogen, NO2 and R9 is selected from hydrogen, optionally substituted alkyl, optionally substituted aryl
The acceptable pharmaceutical formulations such as tablets, capsules, suppository, beads, aerosols, etc. which are useful for the treatment and prevention of endocrine metabolic and central nervous system disorders. SUMMARY OF THE INVENTION Accordingly, the present invention provides a compound of formula I: hydrogen, thiol, thioalkyl, sulfoxide,
Wherein R3 and R4 is selected from hydrogen, optionally substituted alkyl chain (C1-C6) and cycloalkyl group (C1-C10); Where Y= N, O, N-alkyl, N-aryl, N-Substituted aryl, N-heteroaryl;
optionally substituted aryl, optionally substituted alkoxy, optionally substituted alkyl; R2 = H, halogen, CN T = defined as optionally substituted normal or branched alkyl chain (C1-C6) or as template IA or Template IB or Template IC
hydrogen, optionally substituted alkyl, optionally substituted alkoxy, N-alkyl chain (C1-C6), CN, NO2, CF3 and A is X, CF3, CN, NO2, phenyl, optionally substituted phenyl, optionally substituted heteroaryl.
Where in template IB and IC, G is selected from hydrogen, hydroxy, optionally substituted alkoxy, halogen, NO2 and R9 is selected from hydrogen, optionally substituted alkyl, optionally substituted aryl Among the molecules having the formula (I) incorporating substituted aminopyridines and their analogues and their use in the treatment of obesity and related disorders and related compounds shown in examples 1 to 34 and in the drawing accompanying the specification. The Scheme 1 shown in the drawing accompanying the specification represents a preferred embodiment of this process for the compounds having the formula (I); The starting material 2H-pyran-2-ones are known and has been prepared by the reaction of methyl 2-cyano/methoxycarbonyl-3,3-di(methylsulfanyl)acrylate with substituted alkyl/aryl/biaryl/heteroaryl methyl ketone under alkaline conditions in dry DMSO in high yields according to the procedure reported earlier [(a) Tominaga, Y.; Ushirogouchi, A.; Matsuda, Y.; Kobayashi, G. Chem. Pharm. Bull.1984, 32, 3384. (b) Tominaga, Y.; Ushirogouchi, A.; Matsuda, Y. J. Heterocycl. Chem. 1987, 24, 1557. (c) Farhanullah; Agarwal, N.; Goel, A.; Ram, V. J. J. Org. Chem.2003, 68, 2983. (d) Goel, A.; Singh, F. V.; Verma, D. Synlett, 2005, 13, 2027–2030]. Advantage of Invention: Advantages of the present Process over literature methods Method-1: A process for the synthesis of 4,5,6-trisubstituted-2-aminopyridines (Ram et al. Patent Number: IN178626) In this cited paper, 2H-pyran-2-ones were reacted with ammonium acetate in pyridine at 115°C for 6 h to afford 4,5,6-trisubstituted-2-aminopyridines. In the present invention, aqueous ammonia is used in the absence of pyridine (higly toxic). The cited process reaction is performed at higher temperature of 115 oC, while in the present invention, the reaction temperature was between 25- 80 oC. Method-2: Regioselective Syntheses of Functionalized 2-Aminopyridines and 2-Pyridinones through Nucleophile-Induced Ring Transformation Reactions (Goel et al. SYNLETT 2005, No.4, pp 0623–0626): In the cited paper, 2-aminopyridine analogues were prepared by utilizing urea alone at high temperature (150 oC) or in pyridine at reflux temperature (115 oC) but in the present
invention, aminopyridine analogues were prepared at the reaction temperature 25 to 80 oC without using toxic pyridine solvent. Advantages of the present 5-HT2c modulators over literature modulators 15. In comparison to known 5-HT2C modulators reported (Wild et al., J. Med. Chem.2019, 62, 288−305; Ding et al. ACS Chem Neurosci.2012 Jul 18; 3(7): 538–545), the compound 12 exhibited much more propensity to stimulate the effect of serotonin (fold stimulation) 16. The compound 12 exhibited more brain availability than any other 5-HT2C PAM reported in the literature. 17. The present invention for the first time showed that aminopyridine analogues as 5-HT2C modulators could act as antipsychotic agent. BRIEF DESCRIPTION OF DRAWINGS Figure 1: Activity of example compound 5 at human 5-HT2C receptor. A) PAM activity assay in HEK293T cells transiently transfected with human 5-HT2C receptor and NFAT-Luciferase plasmids. compound 5 (1 µM) significantly increased the activity (Emax) of 5-HT in this assay. B) Agonist activity of compound 5 in HEK293T cells transiently transfected with human 5-HT2C receptor and NFAT-Luciferase plasmids. compound 5 stimulated the 5-HT2C receptor dependent luciferase activity with EC50<3 nM. C) PAM activity of compound 5 in HEK293T cells transiently transfected with human 5-HT2C receptor. compound 5 (1 µM) potentiated 5-HT2C receptor-dependent increase in intracellular calcium flux (iCa++) induced by 5-HT. Figure 2: Positive allosteric modulation (PAM) of 5-HT by example compound 12 at human 5- HT2C receptor. A) PAM activity assay in HEK293T cells transiently transfected with human 5- HT2C receptor and NFAT-Luciferase plasmids. Compound 12 (1 µM) significantly increased the activity (Emax) of 5-HT in this assay. B) PAM activity of compound 12 in HEK293T cells transiently transfected with human 5-HT2C receptor. compound 12 (1000 nM and 100 nM) potentiated 5-HT2C receptor-dependent increase in intracellular calcium flux (iCa++) induced by 5-HT in concentration dependent manner. Figure 3: Illustrates concentration time profile of example compound 12 in mice plasma and brain
Figure 4: Effect of example compound 12 (20 mg/kg, PO) on food intake in diet-induced obese (DIO) mice (A), and Sprague-Dawley rats (B) Figure 5: Anti-obesity effect of example compound 12. (A,B) chronic treatment of DIO mice with compound (30 mg/kg, PO, once daily) for 6 weeks significantly inhibited weight gain. *p<0.05 (control:Veh Vs DIO:veh), #p<0.05 (DIO-veh Vs Compd.12), Unpaired t-Test. (C) effect of Compd.12 on plasma level of glucose in intraperitoneal glucose tolerance tests in DIO mice Figure 6: Antipsychotic effect of example compound 12. (A) compound 12 (30 mg/kg, PO) significantly suppressed the D-amphetamine(10 mg/kg, i.p., Amph) induced hyper locomotor activity as measured by total photo-beam breaks at every 5 min interval. (B) histograph representing the cumulative locomotor activity during 60 minutes after administration of veh or Amph or Amph+ compound 12. N=5/group, *P<0.05, One way ANOVA followed by Newman- Keuls multiple comparison test. Figure 7: Scheme 1. DETAILED DESCRIPTION OF THE INVENTION The present invention provides a compound of formula I having preferred examples below: Example 1. Synthesis of 6-isopropyl-4-(methylthio)pyridin-2-amine (Compound 1): 6-isopropyl-4-(methylthio)-2-oxo-2H-pyran-3-carbonitrile (209 mg, 1 mmol) was dissolved in ACN (10 mL) and solution of ammonium hydroxide (525 µL, 15 mmol) was added and the reaction was stirred at 60 oC for 1 hr. At the end the solvent of reaction mixture was evaporated into vacuum and resultant crude was purified on a flash silica column using 15% ethyl acetate in hexane as eluent to yield 110 mg (60%) of methyl 6-isopropyl-4-(methylthio)pyridin-2-amine. White solid, mp 105-107 °C; MS (ESI) m/z 183 [M + H]+; IR (KBr) ν = 3481, 3341 (-NH2) cm-1, 1H NMR (400 MHz, CDCl3): δ = 1.23 (d, J = 6.96 Hz, 6H, 2CH3), 2.43 (s, 3H, -SCH3), 2.76-2.86 (m, 1H, CH), 4.50 (br s, 2H, -NH2), 6.12 (d, J = 1.32 Hz, 1H, Ar), 6.39 (d, J = 1.36 Hz, 1H, Ar) ppm; Example 2. Synthesis of 4-(6-amino-4-(methylthio)pyridin-2-yl)benzonitrile (Compound 2):
6-(4-cyanophenyl)-4-(methylthio)-2-oxo-2H-pyran-3-carbonitrile (268 mg, 1 mmol) was dissolved in dry DMF (10 mL) and solution of ammonium hydroxide (525 µL, 15 mmol) was added and the reaction was stirred at 60 oC for 1 hr. At the end reaction mixture was poured into ice water with vigorous stirring and the solid thus obtained was filtered and purified on a flash silica column using 20% ethyl acetate in hexane as eluent to yield 170 mg (70%) of 4-(6-amino- 4-(methylthio)pyridin-2-yl)benzonitrile. Cream solid, mp (chloroform/methanol) 186-188 °C; MS (ESI) m/z 242 [M + H]+; IR (KBr) ν = 3428, 3328 (-NH2) cm-1, 1H NMR (400 MHz, CDCl3): δ = 2.50 (s, 3H, -SCH3), 4.52 (br s, 2H, - NH2), 6.30 (d, J = 1.25 Hz, 1H, Ar), 6.95 (d, J = 1.34 Hz, 1H, Ar), 7.70 (d, J = 8.76 Hz, 2H, Ar), 8.00 (d, J = 8.76 Hz, 2H, Ar) ppm; Example 3. Synthesis of 4-(methylthio)-6-(4-(trifluoromethyl)phenyl)pyridin-2-amine (Compound 3): 4-(methylthio)-2-oxo-6-(4-(trifluoromethyl)phenyl)-2H-pyran-3-carbonitrile (311 mg, 1 mmol) was dissolved in dry DMF (10 mL) and solution of ammonium hydroxide (525 µL, 15 mmol) was added and the reaction was stirred at 60 oC for 1 hr. At the end reaction mixture was poured into ice water with vigorous stirring and the solid thus obtained was filtered and purified on a flash silica column using 20% ethyl acetate in hexane as eluent to yield 185 mg (65%) of 4-(methylthio)- 6-(4-(trifluoromethyl)phenyl)pyridin-2-amine. White Solid, mp (chloroform/methanol) 116-118 °C; MS (ESI) m/z 285 [M +H]+; IR (KBr) ν = 3476, 3382 (-NH2) cm-1, 1H NMR (400 MHz, CDCl3): δ = 2.50 (s, 3H, -SCH3), 4.54 (br s, 2H, - NH2), 6.32 (d, J = 1.4 Hz, 1H, Ar), 6.97 (d, J = 1.4 Hz, 1H, Ar), 7.68 (d, J = 8.24 Hz, 2H, Ar), 8.00 (d, J = 8.08 Hz, 2H, Ar) ppm; Example 4. Synthesis of 4-(methylthio)-6-(4-(methylthio)phenyl)pyridin-2-amine (Compound 4): 4-(methylthio)-6-(4-(methylthio)phenyl)-2-oxo-2H-pyran-3-carbonitrile (289 mg, 1 mmol) was dissolved in was dissolved in ACN (10 mL) and solution of ammonium hydroxide (525 µL, 15 mmol) was added and the reaction was stirred at 60 oC for 1 hr. At the end the solvent of reaction mixture was evaporated into vacuum and resultant crude was purified on a flash silica column using 15% ethyl acetate in hexane as eluent to yield 197 mg (75%) of 4-(methylthio)-6-(4- (methylthio)phenyl)pyridin-2-amine.
Yellow solid, mp (chloroform/methanol) 110-112 °C; MS (ESI) m/z 263 [M + H]+; IR (KBr) ν = 3460, 3345 (-NH2) cm-1, 1H NMR (400 MHz, CDCl3): δ = 2.49 (s, 3H, -SCH3), 2.51 (s, 3H, - SCH3), 4.46 (br s, 2H, -NH2,), 6.24 (d, J = 1.40 Hz, 1H, Ar), 6.91 (d, J = 1.38 Hz, 1H, Ar), 7.29 (d, J = 8.52 Hz, 2H, Ar), 7.84 (d, J = 8.56 Hz, 2H, Ar) ppm; Example 5. Synthesis of 6-(4-(dimethylamino)phenyl)-4-(methylthio)pyridin-2-amine (Compound 5): 6-(4-(dimethylamino)phenyl)-4-(methylthio)-2-oxo-2H-pyran-3-carbonitrile (286 mg, 1 mmol) was dissolved in dry DMF (10 mL) and solution of ammonium hydroxide (525 µL, 15 mmol) was added and the reaction was stirred at 60 oC for 2 hr. At the end reaction mixture was poured into ice water with vigorous stirring and the solid thus obtained was filtered and purified on a flash silica column using 20% ethyl acetate in hexane as eluent to yield 155 mg (60%) of 6-(4- (dimethylamino)phenyl)-4-(methylthio)pyridin-2-amine. Yellow Solid, mp (chloroform/methanol) 102-104 °C; MS (ESI) m/z 260 [M +H]+; IR (KBr) ν = 3479, 3371 (-NH2) cm-1, 1H NMR (400 MHz, CDCl3): δ = 2.50 (s, 3H, -SCH3), 3.00 (s, 6H, 2CH3), 4.45 (br s, 2H, -NH2), 6.17 (d, J = 1.30 Hz, 1H, Ar), 6.75 (d, J = 8.92 Hz, 2H, Ar), 6.87 (d, J = 1.30 Hz, 1H, Ar), 7.82 (d, J = 8.92 Hz, 2H, Ar) ppm; Example 6. Synthesis of 6-(4-(diethylamino)phenyl)-4-(methylthio)pyridin-2-amine (Compound 6): 6-(4-(diethylamino)phenyl)-4-(methylthio)-2-oxo-2H-pyran-3-carbonitrile (314 mg, 1 mmol) was dissolved in dry DMF (10 mL) and solution of ammonium hydroxide (525 µL, 15 mmol) was added and the reaction was stirred at 60 oC for 1 hr. At the end reaction mixture was poured into ice water with vigorous stirring and the solid thus obtained was filtered and purified on a flash silica column using 20% ethyl acetate in hexane as eluent to yield 179 mg (62%) of 6-(4- (diethylamino)phenyl)-4-(methylthio)pyridin-2-amine. Brown Solid , mp (chloroform/methanol) 104-105 °C; MS (ESI) m/z 288 [M + H]+; IR (KBr) ν = 3583, 3375 (-NH2) cm-1, 1H NMR (400 MHz, CDCl3): δ = 1.18 (t, J = 7.02 Hz, 6H, 2CH3), 2.47 (s, 3H, -SCH3), 3.39 (q, J = 7.05 Hz, 4H, 2CH2), 4.41 (br s, 2H, -NH2), 6.15 (s, 1H, Ar), 6.70 (d, J = 8.66 Hz, 2H, Ar), 6.86 (s, 1H, Ar), 7.79 (d, J = 8.88 Hz , 2H, Ar); Example 7. Synthesis of 6-(4-(ethylamino)phenyl)-4-(methylthio)pyridin-2-amine (Compound 7)
6-(4-(ethylamino)phenyl)-4-(methylthio)-2-oxo-2H-pyran-3-carbonitrile (286 mg, 1 mmol) was dissolved in dry DMF (10 mL) and solution of ammonium hydroxide (525 µL, 15 mmol) was added and the reaction was stirred at 60 oC for 1 hr. At the end reaction mixture was poured into ice water with vigorous stirring and the solid thus obtained was filtered and purified on a flash silica column using 20% ethyl acetate in hexane as eluent to yield 145 mg (56%) of 6-(4- (ethylamino)phenyl)-4-(methylthio)pyridin-2-amine. Dark Green solid (); Rf = 0.54 (EA/Hexane, 20:80, v/v), mp (chloroform/methanol) 106-108 °C; MS (ESI) m/z 260 [M + H]+; IR (KBr) ν = 3489, 3395 (-NH2) cm-1, 1H NMR (400 MHz, CDCl3): δ = 1.27 (t, J = 7.09 Hz, 3H, CH3), 2.48 (s, 3H, -SCH3), 3.20 (q, J = 7.10 Hz, 2H, -CH2), 3.72 (s, 1H), 4.41 (br s, 2H, -NH2), 6.17 (d, J = 1.36 Hz, 1H, Ar), 6.63 (d, J = 8.68 Hz, 2H, Ar), 6.86 (d, J = 1.40 Hz, 1H, Ar), 7.76 (d, J = 8.68 Hz, 2H, Ar) ppm; Example 8: Synthesis of 4-(methylthio)-6-(4-(piperidin-1-yl)phenyl)pyridin-2-amine (Compound 8): 4-(methylthio)-2-oxo-6-(4-(piperidin-1-yl)phenyl)-2H-pyran-3-carbonitrile (326 mg, 1 mmol) was dissolved in dry DMF (10 mL) and solution of ammonium hydroxide (525 µL, 15 mmol) was added and the reaction was stirred at 60 oC for 1 hr. At the end reaction mixture was poured into ice water with vigorous stirring and the solid thus obtained was filtered and purified on a flash silica column using 20% ethyl acetate in hexane as eluent to yield 185 mg (62%) of 4-(methylthio)- 6-(4-(piperidin-1-yl)phenyl)pyridin-2-amine. Cream solid, mp (chloroform/methanol) 150-152 °C; MS (ESI) m/z 300 [M + H]+; IR (KBr) ν = 3473, 3375 (-NH2) cm-1, 1H NMR (400 MHz, CDCl3): δ = 1.68-1.73 (m, 6H), 2.48 (br s, 3H, - SCH3), 3.21-3.24 (m, 4H), 4.45 (br s, 2H, -NH2), 6.18 (d, J = 1.41 Hz, 1H, Ar), 6.88 (d, J = 1.48 Hz, 1H, Ar), 6.95 (d, J = 8.90 Hz, 2H, Ar), 7.82 (d, J = 8.90 Hz, 2H, Ar) ppm; Example 9: Synthesis of 4-(methylthio)-6-(4-morpholinophenyl)pyridin-2-amine (Compound 9) 4-(methylthio)-6-(4-morpholinophenyl)-2-oxo-2H-pyran-3-carbonitrile (328 mg, 1 mmol) was dissolved in dry DMF (10 mL) and solution of ammonium hydroxide (595 µL, 17 mmol) was added and the reaction was stirred at 60 oC for 1 hr. At the end reaction mixture was poured into ice water with vigorous stirring and the solid thus obtained was filtered and purified on a flash silica column using 20% ethyl acetate in hexane as eluent to yield 180 mg (59%) of 4-(methylthio)- 6-(4-morpholinophenyl)pyridin-2-amine.
Cream solid, mp (chloroform/methanol) 208-210 °C; MS (ESI) m/z 300 [M + H]+; IR (KBr) ν = 3465, 3384 (-NH2) cm-1, 1H NMR (400 MHz, CDCl3): δ = 2.48 (s, 3H), 3.20-3.23 (m, 4H), 3.86- 3.88 (m, 4H), 4.42 (br s, 2H, -NH2), 6.20 (d, J = 1.40 Hz, 1H, Ar), 6.89 (d, J = 1.40 Hz, 1H, Ar), 6.93 (d, J = 8.80 Hz, 2H, Ar), 7.84 (d, J = 8.88 Hz, 2H, Ar) ppm; Example 10: Synthesis of 4-(methylthio)-6-(naphthalen-2-yl)pyridin-2-amine (Compound 10) 4-(methylthio)-6-(naphthalen-2-yl)-2-oxo-2H-pyran-3-carbonitrile (293 mg, 1 mmol) was dissolved in dry DMF (10 mL) and solution of ammonium hydroxide (525 µL, 15 mmol) was added and the reaction was stirred at 60 oC for 2 hr. At the end reaction mixture was poured into ice water with vigorous stirring and the solid thus obtained was filtered and purified on a flash silica column using 20% ethyl acetate in hexane as eluent to yield 195 mg (73%) of 4-(methylthio)- 6-(naphthalen-2-yl)pyridin-2-amine. Cream Solid, mp (chloroform/methanol) 127-128 °C; MS (ESI) m/z 267 [M + 2H]+; IR (KBr) ν = 3469, 3382 (-NH2) cm-1, 1H NMR (400 MHz, CDCl3): δ = 2.52 (s, 3H, -SCH3), 4.51 (br s, 2H, - NH2), 6.29 (d, J = 1.38 Hz, 1H, Ar), 7.09 (d, J = 1.35 Hz, 1H, Ar), 7.47-7.50 (m, 2H, Ar), 7.83- 7.95 (m, 3H, Ar), 8.04 (dd, J = 8.6, 1.8 Hz, 1H, Ar), 8.41 (s, 1H, Ar); Example 11: Synthesis of 6-([1,1'-biphenyl]-4-yl)-4-(methylthio)pyridin-2-amine (Compound 11) 6-([1,1'-biphenyl]-4-yl)-4-(methylthio)-2-oxo-2H-pyran-3-carbonitrile (319 mg, 1 mmol) was dissolved in dry DMF (10 mL) and solution of ammonium hydroxide (525 µL, 15 mmol) was added and the reaction was stirred at 60 oC for 1 hr. At the end reaction mixture was poured into ice water with vigorous stirring and the solid thus obtained was filtered and purified on a flash silica column using 20% ethyl acetate in hexane as eluent to yield 197 mg (67%) of 6-([1,1'- biphenyl]-4-yl)-4-(methylthio)pyridin-2-amine. Cream Solid, mp (chloroform/methanol) 118-119 °C; MS (ESI) m/z 293 [M + H]+; IR (KBr) ν = 3466, 3382 (-NH2) cm-1, 1H NMR (400 MHz, CDCl3): δ = 2.51 (s, 3H, -SCH3), 4.48 (br s, 2H, - NH2), 6.28 (d, J = 1.4 Hz, 1H, Ar), 7.00 (d, J = 1.4 Hz, 1H, Ar), 7.33-7.38 (m, 1H, Ar), 7.44-7.47 (m, 2H, Ar), 7.63-7.68 (m, 4H, Ar), 7.99 (d, J = 8.4 Hz, 2H, Ar) ppm; Example 12: Synthesis of 6-(4'-bromo-[1,1'-biphenyl]-4-yl)-4-(methylthio)pyridin-2-amine (Compound 12)
6-(4'-bromo-[1,1'-biphenyl]-4-yl)-4-(methylthio)-2-oxo-2H-pyran-3-carbonitrile (396 mg, 1 mmol) was dissolved in dry DMF (12 mL) and solution of ammonium hydroxide (630 µL, 18 mmol) was added and the reaction was stirred at 60 oC for 2 hr. At the end reaction mixture was poured into ice water with vigorous stirring and the solid thus obtained was filtered and purified on a flash silica column using 20% ethyl acetate in hexane as eluent to yield 260 mg (70%) of 6- (4'-bromo-[1,1'-biphenyl]-4-yl)-4-(methylthio)pyridin-2-amine. Cream Solid, mp (chloroform/methanol) 169-170 °C; MS (ESI) m/z 373 [M + 2H]+; IR (KBr) ν = 3474, 3372 (-NH2) cm-1, 1H NMR (400 MHz, CDCl3): δ = 2.51 (s, 3H, -SCH3), 4.48 (br s, 2H, - NH2), 6.28 (d, J = 1.4 Hz, 1H, Ar), 6.98 (d, J = 1.5 Hz, 1H, Ar), 7.51 (d, J = 8.5 Hz, 2H, Ar), 7.54- 7.63 (m, 4H, Ar), 7.97 (d, J = 8.4 Hz, 2H, Ar) ppm; Example 13: Synthesis of 6-(1H-indol-3-yl)-4-(methylthio)pyridin-2-amine (Compound 13) 6-(1H-indol-3-yl)-4-(methylthio)-2-oxo-2H-pyran-3-carbonitrile (282 mg, 1 mmol) was dissolved in dry DMF (10 mL) and solution of ammonium hydroxide (525 µL, 15 mmol) was added and the reaction was stirred at 60 oC for 1 hr. At the end reaction mixture was poured into ice water with vigorous stirring and the solid thus obtained was filtered and purified on a flash silica column using 20% ethyl acetate in hexane as eluent to yield 120 mg (47%) of 6-(1H-indol-3-yl)-4- (methylthio)pyridin-2-amine Dark Green solid, mp (chloroform/methanol) 108-110 °C; MS (ESI) m/z 263 [M + H]+; IR (KBr) ν = 3461, 3356 (-NH2) cm-1, 1H NMR (400 MHz, DMSO-d6): δ = 2.47 (s, 3H, -SCH3), 5.82 (br s, 2H, -NH2), 6.10 (d, J = 1.5 Hz, 1H, Ar), 6.84 (d, J = 1.5 Hz, 1H, Ar), 7.04-7.14 (m, 2H, Ar), 7.40 (d, J = 7.7 Hz, 1H, Ar), 7.95 (d, J = 2.65 Hz, 1H, Ar), 8.46 (d, J = 7.88 Hz, 1H, Ar), 11.36 (br s, 1H, -NH) ppm; Example 14: Synthesis of 6-(9-ethyl-9H-carbazol-3-yl)-4-(methylthio)pyridin-2-amine (Compound 14) 6-(9-ethyl-9H-carbazol-3-yl)-4-(methylthio)-2-oxo-2H-pyran-3-carbonitrile (360 mg, 1 mmol) was dissolved in dry DMF (10 mL) and solution of ammonium hydroxide (595 µL, 17 mmol) was added and the reaction was stirred at 60 oC for 1 hr. At the end reaction mixture was poured into ice water with vigorous stirring and the solid thus obtained was filtered and purified on a flash silica column using 20% ethyl acetate in hexane as eluent to yield 210 mg (63%) of 6-(9-ethyl- 9H-carbazol-3-yl)-4-(methylthio)pyridin-2-amine.
Brown solid, mp (chloroform/methanol) 165-167 °C; MS (ESI) m/z 334 [M + H]+; IR (KBr) ν = 3466, 3342 (-NH2) cm-1, 1H NMR (400 MHz, CDCl3): δ = 1.45 (t, J = 7.29 Hz, 3H, CH3), 2.53 (s, 3H, -SCH3), 4.39 (q, J = 7.31 Hz, 2H, -CH2), 4.51 (br s, 2H, -NH2), 6.25 (d, J = 1.40 Hz, 1H, Ar), 7.08 (d, J = 1.40 Hz, 1H, Ar), 7.23-7.27 (m, 2H, Ar), 7.41-7.50 (m, 3H, Ar), 8.05 (dd, J = 8.55, 1.79 Hz, 1H, Ar), 8.19 (d, J = 7.9 Hz, 1H, Ar), 8.68 (d, J = 1.2 Hz, 1H, Ar) ppm; Example 15. Synthesis of 6-(4-(diphenylamino)phenyl)-4-(methylthio)pyridin-2-amine (Compound 15) 6-(4-(diphenylamino)phenyl)-4-(methylthio)-2-oxo-2H-pyran-3-carbonitrile (410 mg, 1 mmol) was dissolved in dry DMF (12 mL) and solution of ammonium hydroxide (630 µL, 18 mmol) was added and the reaction was stirred at 60 oC for 2 hr. At the end reaction mixture was poured into ice water with vigorous stirring and the solid thus obtained was filtered and purified on a flash silica column using 20% ethyl acetate in hexane as eluent to yield 195 mg (51 %) of 6-(4- (diphenylamino)phenyl)-4-(methylthio)pyridin-2-amine. Greenish Yellow Solid mp (chloroform/methanol) 236-238 °C; MS (ESI) m/z 384 [M +H]+; IR (KBr) ν = 3467, 3380 (-NH2) cm-1, 1H NMR (400 MHz, CDCl3): δ = 2.48 (s, 3H, -SCH3), 5.32 (br s, 2H, -NH2), 6.30 (s, 1H, Ar), 6.81 (s, 1H, Ar), 7.03-7.28 (m, 12 H, Ar), 7.75-7.77 (m, 2H, Ar) ppm; Example 16: Synthesis of 6-(3-methoxyphenyl)-4-(methylthio)pyridin-2-amine (Compound 16) 6-(3-methoxyphenyl)-4-(methylthio)-2-oxo-2H-pyran-3-carbonitrile (273 mg, 1 mmol) was dissolved in ACN (10 mL) and solution of ammonium hydroxide (525 µL, 15 mmol) was added and the reaction was stirred at 60 oC for 1 hr. At the end the solvent of reaction mixture was evaporated into vacuum and resultant crude was purified on a flash silica column using 15% ethyl acetate in hexane as eluent to yield 178 mg (72 %) of 6-(3-methoxyphenyl)-4-(methylthio)pyridin- 2-amine. Grey Solid mp (chloroform/methanol) 142-144 °C; MS (ESI) m/z 247 [M +H]+; IR (KBr) ν = 3467, 3380 (-NH2) cm-1, 1H NMR 1H NMR (400 MHz, CDCl3): δ = 2.46 (s, 3H, -SCH3), 3.84 (s, 3H, - OCH3), 4.42 (br s, 2H, -NH2), 6.26 (d, J = 1.5 Hz, 1H, Ar), 7.05 – 6.95 (m, 3H, Ar), 7.37-7.30 (m, 1H, Ar), 7.66 (dd, J = 7.6, 1.8 Hz, 1H, Ar), ppm; Example 17: Synthesis of 5,6-bis(4-methoxyphenyl)-4-(methylthio)pyridin-2-amine (Compound 17)
5,6-bis(4-methoxyphenyl)-4-(methylthio)-2-oxo-2H-pyran-3-carbonitrile (379 mg, 1 mmol) was dissolved in dry DMF (12 mL) and solution of ammonium hydroxide (630 µL, 18 mmol) was added and the reaction was stirred at 60 oC for 2 hr. At the end reaction mixture was poured into ice water with vigorous stirring and the solid thus obtained was filtered and purified on a flash silica column using 20% ethyl acetate in hexane as eluent to yield 145 mg (41%) of 5,6-bis(4- methoxyphenyl)-4-(methylthio)pyridin-2-amine. White Solid, mp (chloroform/methanol) 240-241 °C; MS (ESI) m/z 353 [M + H]+; IR (KBr) ν = 3483, 3369 (-NH2) cm-1, 1H NMR (400 MHz, DMSO-d6): δ = 2.28 (s, 3H, -SCH3), 3.66 (s, 3H, - OCH3), 3.71 (s, 3H, -OCH3), 5.92 (br s, 2H, -NH2), 6.31 (s, 1H, Ar), 6.68 (d, J = 8.9 Hz, 2H, Ar), 6.82 (d, J = 8.5 Hz, 2H, Ar), 6.95 (d, J = 8.7 Hz, 2H, Ar), 7.11 (d, J = 8.7 Hz, 2H, Ar) ppm; Example 18: Synthesis of 6-(4-(dimethylamino)phenyl)-4-(ethylthio)pyridin-2-amine (Compound 18) 6-(4-(dimethylamino)phenyl)-4-(ethylthio)-2-oxo-2H-pyran-3-carbonitrile (300 mg, 1 mmol) was dissolved in dry DMF (10 mL) and solution of ammonium hydroxide (630 µL, 18 mmol) was added and the reaction was stirred at 60 oC for 2 hr. At the end reaction mixture was poured into ice water with vigorous stirring and the solid thus obtained was filtered and purified on a flash silica column using 20% ethyl acetate in hexane as eluent to yield 176 mg (64%) of 6-(4- (dimethylamino)phenyl)-4-(ethylthio)pyridin-2-amine Off white solid mp (chloroform/methanol) 103-105 °C; MS (ESI) m/z 274 [M +H]+; IR (KBr) ν = 3483, 3369 (-NH2) cm-1; 1H NMR (400 MHz, CDCl3) δ = 1.39 (t, J = 7.4 Hz, 3H, CH3) 2.95-3.02 (m, 8H), 4.41 (br s, 2H, -NH2), 6.20 (d, J = 1.5 Hz, 1H, Ar), 6.75 (d, J = 9.0 Hz, 2H, Ar), 6.89 (d, J = 1.4 Hz, 1H, Ar), 7.82 (d, J = 8.9 Hz, 2H, Ar) ppm; Example 19: Synthesis of 4-(4-(2-chlorophenyl)piperazin-1-yl)-6-phenylpyridin-2-amine (Compound 19) 4-(4-(2-chlorophenyl)piperazin-1-yl)-2-oxo-6-phenyl-2H-pyran-3-carbonitrile (391 mg, 1 mmol) was dissolved in dry DMF (12 mL) and solution of ammonium hydroxide (700 µL, 20 mmol) was added and the reaction was stirred at 60 oC for 1 hr. At the end reaction mixture was poured into ice water with vigorous stirring and the solid thus obtained was filtered and purified on a flash silica column using 80% chloroform in hexane as eluent to yield 273 mg (75%) of 4-(4-(2- chlorophenyl)piperazin-1-yl)-6-phenylpyridin-2-amine.
White solid mp (chloroform/methanol) 258-260 °C; MS (ESI) m/z 365 [M + H]+; IR (KBr) ν = 3462,3340 (-NH2) cm-1, 1H NMR (400 MHz, CDCl3 ): δ = 3.11-3.24 (m, 4H), 3.45-3.59 (m, 4H), 4.38 (br s, 2H, -NH2), 5.92 (d, J = 2.1 Hz, 1H, Ar), 6.68 (d, J = 2.1 Hz, 1H, Ar), 6.93-7.12 (m, 2H, Ar), 7.19-7.30 (m, 1H, Ar), 7.32-7.47 (m, 4H, Ar), 7.81-7.92 (m, 2H, Ar) ppm; Example 20: Synthesis of 4-(4-(2-chlorophenyl)piperazin-1-yl)-6-(p-tolyl)pyridin-2-amine hydrochloride (Compound 20) 4-(4-(2-chlorophenyl)piperazin-1-yl)-2-oxo-6-(p-tolyl)-2H-pyran-3-carbonitrile (405 mg, 1 mmol) was dissolved in dry DMF (12 mL) and solution of ammonium hydroxide (700 µL, 20 mmol) was added and the reaction was stirred at 60 oC for 1 hr. At the end reaction mixture was poured into ice water with vigorous stirring and the solid thus obtained was filtered and purified on a flash silica column using 80% chloroform in hexane as eluent to yield 265 mg (70%) of 4-(4- (2-chlorophenyl)piperazin-1-yl)-6-(p-tolyl)pyridin-2-amine. Preparation of salt: 4-(4-(2-chlorophenyl)piperazin-1-yl)-6-(p-tolyl)pyridin-2-amine (265 mg, 1 equiv.) was dissolved in 5% methanol in chloroform and etherial hydrochloric acid was added dropwise until precipitate was formed. After that the solid was filtered out to get 285 mg (98%) 4- (4-(2-chlorophenyl)piperazin-1-yl)-6-(p-tolyl)pyridin-2-amine hydrochloride. White solid, mp (chloroform/methanol) 178-182 °C; MS (ESI) m/z 379 [M + H]+; IR (KBr) ν = 3478, 3389 (-NH2) cm-1, 1H NMR (400 MHz, DMSO-d6) δ = 2.40 (s, 3H, CH3), 3.05-3.15 (m, 4H), 3.65-3.70 (m, 4H), 6.10 (d, J = 1.8 Hz, 1H, Ar), 6.91 (s, 1H, Ar), 7.03-7.12 (m, 1H, Ar), 7.21 (dd, J = 8.1, 1.6 Hz, 1H, Ar), 7.30-7.41 (m, 4H, Ar), 7.46 (dd, J = 7.9, 1.5 Hz, 1H, Ar), 7.86 (d, J = 8.3 Hz, 2H, Ar), 12.73 (s, 1H, -NH) ppm; Example 21: Synthesis of 4-(4-(2-chlorophenyl)piperazin-1-yl)-6-(4-fluorophenyl)pyridin-2- amine hydrochloride (Compound 21) 4-(4-(2-chlorophenyl)piperazin-1-yl)-6-(4-fluorophenyl)-2-oxo-2H-pyran-3-carbonitrile (409 mg, 1 mmol) was dissolved in dry DMF (12 mL) and solution of ammonium hydroxide (700 µL, 20 mmol) was added and the reaction was stirred at 60 oC for 1 hr. At the end reaction mixture was poured into ice water with vigorous stirring and the solid thus obtained was filtered and purified on a flash silica column using 80% chloroform in hexane as eluent to yield 264 mg (69%) of 4-(4- (2-chlorophenyl)piperazin-1-yl)-6-(4-fluorophenyl)pyridin-2-amine hydrochloride.
Preparation of salt: 4-(4-(2-chlorophenyl)piperazin-1-yl)-6-(4-fluorophenyl)pyridin-2-amine (264 mg, 1 equiv.) was dissolved in 5% methanol in chloroform and etherial hydrochloric acid was added dropwise until precipitate was formed. After that the solid was filtered out to get 282 mg (98%) 4-(4-(2-chlorophenyl)piperazin-1-yl)-6-(4-fluorophenyl)pyridin-2-amine hydrochloride. Off white solid, mp (chloroform/methanol) 218-220 °C; MS (ESI) m/z 383 [M + H]+; IR (KBr) ν = 3476, 3387 (-NH2) cm-1, 1H NMR (400 MHz, DMSO-d6) δ = 3.05-3.12 (m, 4H), 3.70-3.80 (m, 4H), 6.12 (s, 1H, Ar), 6.93 (s, 1H, Ar), 7.05-7.13 (m, 1H, Ar), 7.16-7.22 (m, 1H, Ar), 7.36 – 7.30 (m, 1H, Ar), 7.48 – 7.38 (m, 4H, Ar), 8.08 – 7.99 (m, 2H, Ar),12.93 (s, 1H, -NH) ppm; Example 22: Synthesis of 6-(4-chlorophenyl)-4-(4-(2-chlorophenyl)piperazin-1-yl)pyridin-2- amine (Compound 22) 6-(4-chlorophenyl)-4-(4-(2-chlorophenyl)piperazin-1-yl)-2-oxo-2H-pyran-3-carbonitrile (425 mg, 1 mmol) was dissolved in dry DMF (12 mL) and solution of ammonium hydroxide (700 µL, 20 mmol) was added and the reaction was stirred at 60 oC for 2 hr. At the end reaction mixture was poured into ice water with vigorous stirring and the solid thus obtained was filtered and purified on a flash silica column using 80% chloroform in hexane as eluent to yield 272 mg (68%) of 6-(4-chlorophenyl)-4-(4-(2-chlorophenyl)piperazin-1-yl)pyridin-2-amine. White solid, mp (chloroform/methanol) 201-203 °C; MS (ESI) m/z 399 [M + H]+; IR (KBr) ν = 3489, 3362 (-NH2) cm-1, 1H NMR (400 MHz, DMSO-d6): δ = 3.09-3.11 (m, 4H), 3.43-3.45 (4, 4H), 5.67 (br s, 2H, -NH2), 5.92 (s, 1H, Ar), 6.80 (s, 1H, Ar), 7.00-7.07 (m, 1H, Ar), 7.20-7.22 (m, 1H, Ar), 7.30-7.34 (m, 1H, Ar), 7.45 (d, J = 8.66 Hz, 3H, Ar), 8.03 (d, J = 8.35 Hz, 2H, Ar) ppm; Example 23: Synthesis of 6-(4-bromophenyl)-4-(4-(2-chlorophenyl)piperazin-1-yl)pyridin-2- amine (Compound 23) 6-(4-bromophenyl)-4-(4-(2-chlorophenyl)piperazin-1-yl)-2-oxo-2H-pyran-3-carbonitrile (470 mg, 1 mmol) was dissolved in dry DMF (12 mL) and solution of ammonium hydroxide (700 µL, 20 mmol) was added and the reaction was stirred at 60 oC for 2 hr. At the end reaction mixture was poured into ice water with vigorous stirring and the solid thus obtained was filtered and purified on a flash silica column using 80% chloroform in hexane as eluent to yield 319 mg (72%) of 6-(4-bromophenyl)-4-(4-(2-chlorophenyl)piperazin-1-yl)pyridin-2-amine.
White solid, mp (chloroform/methanol) 198-200 °C; MS (ESI) m/z 443 [M + H]+; IR (KBr) ν = 3480, 3390 (-NH2) cm-1, 1H NMR (400 MHz, CDCl3 + CD3OD): δ = 3.22-3.24 (m, 4H), 3.76-3.78 (m, 4H), 6.59 (s, 1H, Ar), 7.06-7.13 (m, 2H, Ar), 7.27-7.31 (m, 1H, Ar), 7.42 (dd, J = 7.95,1.48 Hz, 1H, Ar), 7.48 (s, 1H, Ar), 7.66-7.71 (m, 4H, Ar) ppm; Example 24: Synthesis of 4-(4-(2-chlorophenyl)piperazin-1-yl)-6-(4-methoxyphenyl)pyridin-2- amine (Compound 24) 4-(4-(2-chlorophenyl)piperazin-1-yl)-6-(4-methoxyphenyl)-2-oxo-2H-pyran-3-carbonitrile (421 mg, 1 mmol) was dissolved in dry DMF (12 mL) and solution of ammonium hydroxide (700 µL, 20 mmol) was added and the reaction was stirred at 60 oC for 5 hr. At the end reaction mixture was poured into ice water with vigorous stirring and the solid thus obtained was filtered and purified on a flash silica column using 80% chloroform in hexane as eluent to yield 278 mg (70%) of 4-(4-(2-chlorophenyl)piperazin-1-yl)-6-(4-methoxyphenyl)pyridin-2-amine. White solid, mp (chloroform/methanol) 191-193 °C; MS (ESI) m/z 395 [M + H]+; IR (KBr) ν = 3468, 3386 (-NH2) cm-1, 1H NMR (400 MHz, DMSO-d6): δ = 3.09-3.11 (m, 4H), 3.42-3.44 (m, 4H), 3.79 (s, 3H, -OCH3), 5.57 (br s, 2H, -NH2), 5.87 (d, J = 1.67 Hz, 1H, Ar), 6.70 (d, J = 1.78 Hz, 1H, Ar), 6.93-6.97 (m, 2H, Ar), 7.05-7.10 (m, 1H, Ar), 7.22 (dd, , J = 8.1, 1.6 Hz, 1H, Ar), 7.31-7.35 (m, 1H, Ar), 7.44 (dd, J = 8.00, 1.45 Hz, 1H, Ar), 7.93 (d, J = 8.9 Hz, 2H, Ar) ppm; Example 25: Synthesis of 4-(4-(2-chlorophenyl)piperazin-1-yl)-6-(thiophen-2-yl)pyridin-2- amine (Compound 25): 4-(4-(2-chlorophenyl)piperazin-1-yl)-2-oxo-6-(thiophen-2-yl)-2H-pyran-3-carbonitrile (397 mg, 1 mmol) was dissolved in dry DMF (12 mL) and solution of ammonium hydroxide (700 µL, 20 mmol) was added and the reaction was stirred at 60 oC for 2 hr. At the end reaction mixture was poured into ice water with vigorous stirring and the solid thus obtained was filtered and purified on a flash silica column using 80% chloroform in hexane as eluent to yield 265 mg (71%) of 4-(4- (2-chlorophenyl)piperazin-1-yl)-6-(thiophen-2-yl)pyridin-2-amine. White solid, mp (chloroform/methanol) 270-271 °C; MS (ESI) m/z 371 [M + H]+; IR (KBr) ν = 3468, 3357 (-NH2) cm-1, 1H NMR (400 MHz, CDCl3): δ = 3.14-3.21 (m, 4H), 3.45-3.53 (m, 4H), 4.35 (br s, 2H, -NH2), 5.84 (d, J = 2.0 Hz, 1H, Ar), 6.67 (d, J = 2.0 Hz, 1H, Ar), 6.98-7.09 (m, 3H,
Ar), 7.20-7.28 (m, 1H, Ar), 7.31 (dd, J = 5.0, 1.1 Hz, 1H, Ar), 7.40 (dd, J = 7.9, 1.5 Hz, 1H, Ar), 7.51 (dd, J = 3.7, 1.2 Hz, 1H, Ar), ppm; Example 26: 4-(4-(2-chlorophenyl)piperazin-1-yl)-6-(furan-2-yl)pyridin-2-amine hydrochloride (Compound 26) 4-(4-(2-chlorophenyl)piperazin-1-yl)-6-(furan-2-yl)-2-oxo-2H-pyran-3-carbonitrile (381 mg, 1 mmol) was dissolved in dry DMF (12 mL) and solution of ammonium hydroxide (700 µL, 20 mmol) was added and the reaction was stirred at 60 oC for 2 hr. At the end reaction mixture was poured into ice water with vigorous stirring and the solid thus obtained was filtered and purified on a flash silica column using 80% chloroform in hexane as eluent to yield 245 mg (69%) of 4-(4- (2-chlorophenyl)piperazin-1-yl)-6-(furan-2-yl)pyridin-2-amine. Preparation of salt: 4-(4-(2-chlorophenyl)piperazin-1-yl)-6-(furan-2-yl)pyridin-2-amine (245 mg, 1 equiv.) was dissolved in 5% methanol in chloroform and etherial hydrochloric acid was added dropwise until precipitate was formed. After that the solid was filtered out to get 266 mg (98%) 4-(4-(2-chlorophenyl)piperazin-1-yl)-6-(furan-2-yl)pyridin-2-amine hydrochloride. White solid, mp (chloroform/methanol) 230-232 °C; MS (ESI) m/z 355 [M + H]+; IR (KBr) ν = 3458, 3362 (-NH2) cm-1; 1H NMR (400 MHz, DMSO-d6) δ = 3.08-3.14 (m, 4H), 3.66-3.70 (m, 4H), 6.05 (s, 1H, Ar), 6.84 – 6.73 (m, 1H, Ar), 6.93 (s, 1H, Ar), 7.05-7.13 (m, 1H, Ar), 7.15-7.23 (m, 1H, Ar), 7.30-7.36 (m, 1H, Ar), 7.46 (dd, J = 7.9, 1.5 Hz, 2H, Ar), 7.66 (d, J = 3.5 Hz, 1H, Ar), 8.00 (s, 1H, Ar), 13.00 (s, 1H, -NH) ppm; Example 27: Synthesis of 4-(4-(2-chlorophenyl)piperazin-1-yl)-[2,2'-bipyridin]-6-amine hydrochloride (Compound 27) 4-(4-(2-chlorophenyl)piperazin-1-yl)-2-oxo-6-(pyridin-2-yl)-2H-pyran-3-carbonitrile (392 mg, 1 mmol) was dissolved in dry DMF (12 mL) and solution of ammonium hydroxide (700 µL, 20 mmol) was added and the reaction was stirred at 60 oC for 5 hr. At the end reaction mixture was poured into ice water with vigorous stirring and the solid thus obtained was filtered and purified on a flash silica column using 80% chloroform in hexane as eluent to yield 205 mg (56%) of 4-(4- (2-chlorophenyl)piperazin-1-yl)-[2,2'-bipyridin]-6-amine. Preparation of salt: 4-(4-(2-chlorophenyl)piperazin-1-yl)-[2,2'-bipyridin]-6-amine (205 mg, 1 equiv.) was dissolved in 5% methanol in chloroform and etherial hydrochloric acid was added
dropwise until precipitate was formed. After that the solid was filtered out to get 215 mg (96%) 4- (4-(2-chlorophenyl)piperazin-1-yl)-[2,2'-bipyridin]-6-amine hydrochloride. Off white, mp (chloroform/methanol) 278-280 °C; MS (ESI) m/z 366 [M + H]+; IR (KBr) ν = 3470, 3362 (-NH2) cm-1, 1H NMR (400 MHz, CD3OD): δ = 3.20-3.22 (m, 4H), 3.81-3.84 (m, 4H), 6.16 (d, J = 2.28 Hz, 1H, Ar), 7.01-7.06 (m, 1H, Ar), 7.17-7.20 (m, 1H, Ar), 7.27-7.31 (m, 1H, Ar), 7.34-7.35 (m, 1H, Ar), 7.40 (dd, J = 8.00, 1.46 Hz, 1H, Ar), 7.54-7.57 (m, 1H, Ar), 8.01 (td, J = 7.84, 1.65 Hz, 1H, Ar), 8.28-8.30 (m, 1H, Ar), 8.74-8.75 (m, 1H, Ar), 12.13 (s, 1H, -NH) ppm; Example 28: Synthesis of 4-(4-(2-chlorophenyl)piperazin-1-yl)-6-(4- (dimethylamino)phenyl)pyridin-2-amine hydrochloride (Compound 28) 4-(4-(2-chlorophenyl)piperazin-1-yl)-6-(4-(dimethylamino)phenyl)-2-oxo-2H-pyran-3- carbonitrile (434 mg, 1 mmol) was dissolved in dry DMF (12 mL) and solution of ammonium hydroxide (700 µL, 20 mmol) was added and the reaction was stirred at 60 oC for 2 hr. At the end reaction mixture was poured into ice water with vigorous stirring and the solid thus obtained was filtered and purified on a flash silica column using 80% chloroform in hexane as eluent to yield 195 mg (48%) of 4-(4-(2-chlorophenyl)piperazin-1-yl)-6-(4-(dimethylamino)phenyl)pyridin-2- amine. Preparation of salt: 4-(4-(2-chlorophenyl)piperazin-1-yl)-6-(4-(dimethylamino)phenyl)pyridin- 2-amine (195 mg, 1 equiv.) was dissolved in 5% methanol in chloroform and etherial hydrochloric acid was added dropwise until precipitate was formed. After that the solid was filtered out to get 209 mg (98%) 4-(4-(2-chlorophenyl)piperazin-1-yl)-6-(4-(dimethylamino)phenyl)pyridin-2- amine hydrochloride. Off White solid, mp (chloroform/methanol) 380-382 °C; MS (ESI) m/z 408 [M + H]+; IR (KBr) ν = 3487, 3392 (-NH2) cm-1, 1H NMR (400 MHz, DMSO-d6) δ = 3.02 (s, 6H, 2CH3), 3.05-3.10 (m, 4H), 3.65-3.72 (m, 4H), 6.00 (s, 1H, Ar), 6.81 (s, 1H, Ar), 6.89 (d, J = 8.5 Hz, 2H, Ar), 7.14 – 7.04 (m, 1H, Ar), 7.20 (dd, J = 8.1, 1.4 Hz, 1H, Ar), 7.37 – 7.28 (m, 1H, Ar), 7.45 (dd, J = 8.0, 1.4 Hz, 2H, Ar), 7.90 (d, J = 8.7 Hz, 2H, Ar), 12.64 (s, 1H, -NH) ppm; Example 29: Synthesis of 4-(4-(2-chlorophenyl)piperazin-1-yl)-6-(naphthalen-2-yl)pyridin-2- amine hydrochloride (Compound 29)
4-(4-(2-chlorophenyl)piperazin-1-yl)-6-(naphthalen-2-yl)-2-oxo-2H-pyran-3-carbonitrile (441 mg, 1 mmol) was dissolved in dry DMF (12 mL) and solution of ammonium hydroxide (700 µL, 20 mmol) was added and the reaction was stirred at 60 oC for 2 hr. At the end reaction mixture was poured into ice water with vigorous stirring and the solid thus obtained was filtered and purified on a flash silica column using 80% chloroform in hexane as eluent to yield 284 mg (68%) of 4-(4-(2-chlorophenyl)piperazin-1-yl)-6-(naphthalen-2-yl)pyridin-2-amine. Preparation of salt: 4-(4-(2-chlorophenyl)piperazin-1-yl)-6-(naphthalen-2-yl)pyridin-2-amine (284 mg, 1 equiv.) was dissolved in 5% methanol in chloroform and etherial hydrochloric acid was added dropwise until precipitate was formed. After that the solid was filtered out to get 300 mg (97%) 4-(4-(2-chlorophenyl)piperazin-1-yl)-6-(4-(dimethylamino)phenyl)pyridin-2-amine hydrochloride Off White solid, mp (chloroform/methanol) 288-290 °C; MS (ESI) m/z 415 [M + H]+; IR (KBr) ν = 3485, 3393 (-NH2) cm-1, 1H NMR (400 MHz, CDCl3 + CD3OD): δ = 3.21-3.24 (m, 4H), 3.81- 3.84 (m, 4H), 6.15 (d, J = 2.45 Hz, 1H, Ar), 6.93-6.94 (m, 1H, Ar), 7.05-7.09 (m, 1H, Ar), 7.16- 7.19 (m, 1H, Ar), 7.28-7.32 (m, 1H, Ar), 7.44 (dd, J = 7.96, 1.48 Hz, 1H, Ar), 7.59-7.64 (m, 2H, Ar), 7.81-7.84 (m, 1H, Ar), 7.95-7.97 (m, 1H, Ar), 8.02-8.07 (m, 2H, Ar), 8.31-8.32 (m, 1H, Ar) ppm; Example 30: Synthesis of 6-([1,1'-biphenyl]-4-yl)-4-(4-(2-chlorophenyl)piperazin-1-yl)pyridin- 2-amine (Compound 30) 6-([1,1'-biphenyl]-4-yl)-4-(4-(2-chlorophenyl)piperazin-1-yl)-2-oxo-2H-pyran-3-carbonitrile (467 mg, 1 mmol) was dissolved in dry DMF (12 mL) and solution of ammonium hydroxide (700 µL, 20 mmol) was added and the reaction was stirred at 60 oC for 2 hr. At the end reaction mixture was poured into ice water with vigorous stirring and the solid thus obtained was filtered and purified on a flash silica column using 80% chloroform in hexane as eluent to yield 312 mg (71%) of 6-([1,1'-biphenyl]-4-yl)-4-(4-(2-chlorophenyl)piperazin-1-yl)pyridin-2-amine. White solid, mp (chloroform/methanol) 182-184 °C; MS (ESI) m/z 441 [M + H]+; IR (KBr) ν = 3455, 3376 (-NH2) cm-1; 1H NMR (400 MHz, DMSO-d6) δ =3.10-3.15 (m, 4H), 3.48 – 3.45 (m, 4H), 5.65 (br s, 2H, -NH2), 5.95 (d, J = 2.0 Hz, 1H, Ar), 6.84 (d, J = 2.0 Hz, 1H, Ar), 7.05-7.11 (m, 1H, Ar), 7.22 (dd, J = 8.1, 1.6 Hz, 1H, Ar), 7.41 – 7.30 (m, 2H, Ar), 7.43-7.52 (m, 3H, Ar), 7.75 – 7.68 (m, 4H, Ar), 8.09 (d, J = 8.4 Hz, 2H, Ar) ppm;
Example 31: Synthesis of 4-(4-(2-chlorophenyl)piperazin-1-yl)-6-(4-nitrophenyl)pyridin-2- amine hydrochloride (Compound 31): 4-(4-(2-chlorophenyl)piperazin-1-yl)-6-(4-nitrophenyl)-2-oxo-2H-pyran-3-carbonitrile (436 mg, 1 mmol) was dissolved in dry DMF (12 mL) and solution of ammonium hydroxide (700 µL, 20 mmol) was added and the reaction was stirred at 60 oC for 1 hr. At the end reaction mixture was poured into ice water with vigorous stirring and the solid thus obtained was filtered and purified on a flash silica column using 80% chloroform in hexane as eluent to yield 207 mg (50%) of 4-(4- (2-chlorophenyl)piperazin-1-yl)-6-(4-nitrophenyl)pyridin-2-amine. Preparation of salt: 4-(4-(2-chlorophenyl)piperazin-1-yl)-6-(4-nitrophenyl)pyridin-2-amine (207 mg, 1 equiv.) was dissolved in 5% methanol in chloroform and etherial hydrochloric acid was added dropwise until precipitate was formed. After that the solid was filtered out to get 218 mg (97%) 4-(4-(2-chlorophenyl)piperazin-1-yl)-6-(4-nitrophenyl)pyridin-2-amine hydrochloride. White solid, mp (chloroform/methanol) 196-198 °C; MS (ESI) m/z 410 [M + H]+; IR (KBr) ν = 3460, 3354 (-NH2) cm-1; 1H NMR (400 MHz, DMSO-d6) δ =3.08 – 3.15 (m, 4H), 3.75-3.94 (m, 4H), 6.12 (s, 1H, Ar), 6.93 (s, 1H, Ar), 7.05-7.12 (m, 1H, Ar), 7.17-7.20 (m, 1H, Ar), 7.29-7.30 (m, 1H, Ar), 7.50 – 7.39 (m, 4H, Ar), 8.10 – 7.98 (m, 2H, Ar), 12.93 (s, 1H, -NH) ppm; Example 32: Synthesis of 4-(4-methylpiperazin-1-yl)-6-(naphthalen-2-yl)pyridin-2-amine (Compound 32) 4-(4-methylpiperazin-1-yl)-6-(naphthalen-2-yl)-2-oxo-2H-pyran-3-carbonitrile (345 mg, 1 mmol) was dissolved in dry DMF (12 mL) and solution of ammonium hydroxide (700 µL, 20 mmol) was added and the reaction was stirred at 60 oC for 1 hr. At the end reaction mixture was poured into ice water with vigorous stirring and the solid thus obtained was filtered and purified on a flash silica column using 80% chloroform in hexane as eluent to yield of 198 mg (62%) 4-(4- methylpiperazin-1-yl)-6-(naphthalen-2-yl)pyridin-2-amine. Grey Solid, mp (chloroform/methanol) 116-119 °C; MS (ESI) m/z 319 [M +H]+; IR (KBr) ν = 3470, 3362 (-NH2) cm-1, 1H NMR (400 MHz, DMS-d6): δ = 2.23 (s, 3H, CH3), 2.42-2.47 (m, 4H), 3..26-3.32 (m, 4H), 5.64 (s, 2H, Ar), 5.90 (d, J =1.76 Hz, 1H, Ar), 6.89 (d, J = 1.8 Hz, 1H, Ar), 7.49-7.52 (m, 2H, Ar), 7.90-7.93 (m, 2H, Ar), 7.96-7.98 (m, 1H, Ar), 8.15-8.18 (m, 1H, Ar), 8.53 (s, 1H, Ar) ppm;
Example 33: Synthesis of 6-(4'-amino-[1,1'-biphenyl]-4-yl)-4-(methylthio)pyridin-2-amine (Compound 33) 6-(4-bromophenyl)-4-(methylthio)pyridin-2-amine (100 mg, 1 equiv.) and (4- aminophenyl)boronic acid ( 102 mg, 2.2 equiv.) in DMF (5 mL) was degassed with nitrogen for 20 min followed by addition of aq. Na2CO3 (2.0 mL, 2 M) under continuous flow of nitrogen. PdCl2(PPh3)2 (10 mol %) was added to the reaction mixture under a nitrogen atmosphere. The reaction mixture was stirred at 60 °C for 6 hr. After completion, the reaction mixture was diluted with distilled H2O (20 mL) and then extracted 2-3 times with ethyl acetate (10 mL). The combined organic layer was dried over Na2SO4 and the solvent was removed in vacuo and purified on flash chromatography using 20% ethyl acetate in hexane as eluent to yield 48 mg (46%) of 6-(4'-amino- [1,1'-biphenyl]-4-yl)-4-(methylthio)pyridin-2-amine. Dark green solid, mp (chloroform/methanol) 200-202 °C; MS (ESI) m/z 308 [M + H]+; IR (KBr) ν = 3475, 3370 (-NH2) cm-1, 1H NMR (400 MHz, DMSO-d6): δ = 2.48 (s, 3H, -SCH3), 5.27 (br s, 2H, -NH2), 5.98 (br s, 2H, -NH2), 6.26 (d, J = 1.40 Hz, 1H, Ar), 6.66 (d, J = 8.48 Hz, 2H, Ar), 6.92 (d, J = 1.40 Hz, 1H, Ar), 7.43 (d, J = 8.48 Hz, 2H, Ar), 7.58 (d, J = 8.48 Hz, 2H, Ar), 7.97 (d, J = 8.48 Hz, 2H, Ar) ppm; Example 34: Synthesis of 6-(4'-(dimethylamino)-[1,1'-biphenyl]-4-yl)-4-(methylthio)pyridin-2- amine (Compound 34) 6-(4-bromophenyl)-4-(methylthio)pyridin-2-amine (100 mg, 1 equiv.) and (4- (dimethylamino)phenyl)boronic acid ( 124 mg, 2.2 equiv.) in DMF (5 mL) was degassed with nitrogen for 20 min followed by addition of aq. Na2CO3 (2.0 mL, 2 M) under continuous flow of nitrogen. PdCl2(PPh3)2 (10 mol %) was added to the reaction mixture under a nitrogen atmosphere. The reaction mixture was stirred at 60 °C for 6 hr. After completion, the reaction mixture was diluted with distilled H2O (20 mL) and then extracted 2-3 times with ethyl acetate (10 mL). The combined organic layer was dried over Na2SO4 and the solvent was removed in vacuo and purified on flash chromatography using 20% ethyl acetate in hexane as eluent to yield 48 mg (44%) of 6- (4'-(dimethylamino)-[1,1'-biphenyl]-4-yl)-4-(methylthio)pyridin-2-amine. Dark Green, mp (chloroform/methanol) 168-170 °C; MS (ESI) m/z 336 [M +H]+; IR (KBr) ν = 3484, 3365 (-NH2) cm-1, 1H NMR (400 MHz, CDCl3): δ = 2.50 (s, 3H, -SCH3), 3.00 (s, 6H, 2CH3), 4.49 (br s, 2H, -NH2), 6.25 (d, J = 1.43 Hz, 1H, Ar), 6.81 (d, J = 8.9 Hz, 2H, Ar), 6.97 (d, J = 1.41
Hz, 1H, Ar), 7.56 (d, J = 8.8 Hz, 2H, Ar), 7.62 (d, J = 8.5 Hz, 2H, Ar), 7.95 (d, J = 8.4 Hz, 2H, Ar) ppm; Pharmacological Activity: Positive allosteric modulatory: Allosteric modulators of G-protein-coupled receptors have lately gained significant traction in drug discovery. Although 5-HT2C serotonin receptor agonist was approved for the treatment of obesity, it was withdrawn from the market due to adverse effects . Emerging evidence suggest that positive allosteric modulators (PAM) of this receptor might be more effective in achieving desired weight loss and without severe adverse effect profile such as anxiety associated with selective agonists. Considering these facts, and our own previous observations (Singh K et al, Eur J Med Chem.2018 Dec 29;164:499-516), in this invention we have designed a series of 2-aminopyridines and evaluated for positive allosteric modulatory (PAM) activity at human 5-HT2C receptors using NFAT-luciferase activity in HEK293T cells. We first found that compounds 5 acts as high affinity PAM of 5-HT2C receptor ( Table-1, Figure- 1). The COMPOUND 5 (Example-5) was also found to act as agonist at 5-HT2C receptor without any activity at human 5-HT2A and 5-HT2B receptors. Furthermore, compound 12 was also found to act as PAM with EC50 of 28 nM. This acivity of compound 12 was also confirmed for their effect on intracellular calcium influx (iCa++) in transiently transfected HEK293 cells with 5-HT2C receptor, which is a more proximal and orthologous assay Gq-coupled GPCR activation. In this assay also, we observed significant concentration dependent potentiation of 5-HT induced iCa++ by compound 12 (Figure 2, Table 1). Pharmacokinetic analysis of COMPOUND 12: To determine the therapeutic utility of our model compound compound 12, we performed its pharmacokinetic analysis in C57BL/6 mice at 20 mg/kg (PO). Given that 5-HT2C receptor activation in hypothalamus in brain exert anti-obesity effect, we determined the concentration of this compound in plasm and brain homogenate both. As shown in Table 2 and Figure 3, compound 12 exhibited BBB permeability with brain to plasma ratio greater than 1.5 which suggests good blood brain barrier permeability. Further, area under the plasma concentration–time curve up to last sampling time (AUC 0-t) was found to be 4968.30± 699.64 ng/ml*h in plasma, while 7785.13±1228.45 ng/ml*h in brain. Acute effect of model compound compound 12 on food intake in DIO mice and SD rats:
To determine the anorectic effect of compound 12, first 8–10-week-old normal adult C57BL/6 mice were fed with high fat diet (HFD) for 12 weeks to develop diet induced obese (DIO) mice model. Thereafter these 12 hr fasted DIO mice were administered with compound 12 (30 mg/kg, PO) and presented with preweighed HFD and cumulative food intake was determined at 3, 6 and 24 hours. We found that similar to 5-HT2C agonist lorcaserine, our model compound compound 12 significantly suppressed the cumulative food intake after 3 and 6 hours of dosing. However, no effect of lorcaserine or compound 12 were observed on food intake at 24-hour time. Furthermore, similar effect of lorcaserine and compound 12 was also found in normal adult SD rats. These observations suggest that compound 12 activates 5-HT2C receptor in brain and thereby induce anorectic behaviour in DIO mice and SD rats (Figure 4). Chronic effect of model compound COMPOUND 12 on weight gain in DIO mice: To determine if COMPOUND 12 induces wight loss or attenuates weigh gain which are fed with HFD, we administered DIO mice with COMPOUND 12 (30 mg/kg, PO, once daily) for 6 weeks. A shown in Figure 5, COMPOUND 12 administered mice did not gain weight due to HFD in comparison to vehicle group of mice. This effect of COMPOUND 12 starts after 2 weeks of dosing and by the end of 6 weeks significant difference in total body weight of mice were observed between DIO-VEH and DIO-COMPOUND 12 groups. Furthermore, COMPOUND 12 significantly alleviated glucose tolerance in DIO mice similar. COMPOUND 12 attenuated D-Amphetamine induced psychosis like behaviour in DIO mice on weight gain: It has been shown in literature that the behavioural changes in mice induced by amphetamine are a consequence of changes in dopamine metabolism in both the striatum and mesolimbic systems. The acute administration of amphetamine also leads to an increase in tryptophan and 5-HT in the brain stem, striatum and some regions of the limbic system. These increase in 5-HT and dopamine by acute amphetamine closely mimics psychosis like conditions in human beings. Further, strong evidence in literature showed that 5-HT2C agonists have antipsychotic efficacy. Therefore, to determine if COMPOUND 12 induces antipsychotic like effect in mice, we administered the D-Amphetamine (10 mg/kg, IP) and also D-Amphetamine + COMPOUND 12 (30 mg/kg, PO) and measured to locomotor activity in open-field arena. As shown in Figure-6, we observed significant attenuation of locomotor activity by COMPOUND 12, suggesting antipsychotic properties of COMPOUND 12. Table-1. Summary of PAM activity of Aminopyridine analogues on human 5-HT2C receptor
Compound 5-HT2C PAM Activity Compound 5-HT2C PAM Activity Code Code Emax (% 5- EC50 Emax (% 5- EC50 (nM) HT) (nM) HT) Compound 1 83 >10000 Compound 20 112 >10000 Compound 2 98 >10000 Compound 21 104 >10000 Compound 3 157 >10000 Compound 22 68 >10000 Compound 4 53 >10000 Compound 23 58 >10000 Compound 237 23 116 >10000 5 Compound 24 Compound 6 68 >10000 Compound 25 151 >10000 Compound 66 >10000 101 >10000 10 Compound 26 Compound 121 >10000 105 >10000 11 Compound 27 Compound 201 28 99 >10000 12 Compound 28 Compound 105 >10000 74 >10000 14 Compound 29 Compound 133 >10000 78 >10000 15 Compound 30 Compound 131 >10000 109 >10000 16 Compound 31 Compound 54 >10000 63 >10000 17 Compound 32 Compound 109 >10000 87 >10000 18 Compound 33 Compound 101 >10000 93 >10000 19 Compound 34
Table 2: Pharmacokinetic parameters of COMPOUND 12 following oral administration at 20mg/kg in C57BL/6J mice Parameter Unit Mean (plasma) Mean (brain) t1/2 h 2.050 ±0.26 5.92±0.176 Tmax h 4±0 6±0 Cmax ng/ml 887.33 ± 29.18 904.66±21.21 AUC 0-t ng/ml*h 4968.30± 699.64 7785.13±1228.45 AUC 0- ng/ml*h 5251.19±418.004 10142.90±427.42 inf_obs Vz/F_obs (mg/kg)/(ng/ml) 0.01167±0.002 0.0168±0.0004 Cl/F_obs (mg/kg)/(ng/ml)/h 0.00386±0.0003 0.00197± 8.37084E-05 Each value represents the mean ± SEM. AUC 0-t: Area under the plasma concentration–time curve up to last sampling time; Cl/F: Clearance; Cma : Plasma peak concentration; t1/2 : Terminal half-life; tmax : Time to Cmax; Vz/F: Volume of distribution. Biological Methods NFAT-RE Luciferase Assay for PAM Activity: For NFAT-RE assay, HEK 293T cells were transiently transfected by mixing PEI max (1 mg/ml) transfection reagent with 0.1 mg DNA/ well of 5-HT2C or 5-HT2B or 5HT2A plasmid (a kind gift from Bryan Roth, University of North Carolina) and 0.1 mg DNA/well of NFAT-RE luciferase (luc2P/NFAT-RE/Hygro, Promega Corp.) plasmid and plating (50,000 cells/well) in white 96 well clear bottom assay plate as described previously (S. Dogra et al., 2014). All primary screening of synthetic compounds was performed at final concentration of 10 mM concentration (in triplicate). To measure agonist or PAM activity, compounds were added at desired concentration and incubated for 12 h. Post- treatment, luciferase activity was measured within 5 min of addition of Bright-Glo substrate solution (1 mg/ml, final concentration) using multi-mode plate reader (BMG, Labtech). The Relative luminescence units (RLU) values obtained were analyzed via non-linear regression using GraphPad Prizm (version V). The Emax value of serotonin was set/normalized to 100% for comparisons.
Intracellular calcium flux assay [iCa++] in HEK293T cells: HEK293T cells were plated (50,000 cells/well) in a black 96-well optical bottom plate (Corning). The [iCa++] assay was performed in 5-HT2C transfected HEK293T cells as described previously (S.P. Pydi et al., 2014). Briefly, Calcium-binding dye Fluo-4NW (Invitrogen, F36206, excitation 494 nm, emission 516 nm) loaded into 5-HT2C expressing cells and measurement of test compound induced [iCa++] for 10 min were performed using FlexStation (Molecular devices) as per manufacturer's protocol. Fold change [iCa++] was calculated from baseline fluorescence during the first 5s before the addition of ligands. To determine the PAM activity of test compound COMPOUND 12, cell was incubated with this test compound for 15 min then further stimulated with IC50 concentration of serotonin (100 nM) and measured fluorescence intensity at each second for duration of total 120 seconds. Blood brain barrier permeability (BBB) assay of COMPOUND 12: A pharmacokinetic study was performed to examine the BBB permeability of COMPOUND 12. Drug was administered into mice (n=3) at a dose of 20 mg/kg by oral gavage (suspended in 5% Tween 80 and 0.25% carboxymethyl cellulose). Three mice per time point were sacrificed at 0.08, 0.5, 1, 2, 4, 6, 8, 10 and 24 h post dosing. The blood samples were collected from the retro-orbital plexus of mice into microfuge tubes containing heparin as anti-coagulant, and brain were removed from the euthanized animals. Plasma was harvested by centrifuging the blood at 12,000 rpm for 10 min and brain tissue homogenates were prepared by adding normal saline to brain tissue at ratio of 4:1 (mL:g) and then homogenized and stored frozen at −70±10 °C. Simple liquid-liquid extraction technique was used for extraction of drug from plasma and brain homogenate using n-hexane as an extracting solvent. Samples were analyzed using API 4000 mass spectrometer equipped with an API electrospray ionization (ESI) source. The separation was done using Suplex PKB 100 column (5 cm X 4.6 mm, 5.0µm) with a mobile phase consisting of acetonitrile: 0.1%formic acid in the ratio of 90:10 (v/v) at a flow rate of 0.5 mL/min respectively. Data was subjected to non-compartmental pharmacokinetic analysis using WinNonlin software. Evaluation of cumulative food intake in Diet Induce Obese (DIO) mice & normal SD Rats: All in vivo experiments and procedures were performed in accordance with the guidelines established in the guide for the care and use of laboratory animals and were approved by the Institutional Animal Ethics Committee (IAEC) of CSIR-Central Drug Research Institute, Lucknow, India. The IAEC is certified by Animal Welfare Board of India (AWBI) and Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA), which are
statutory bodies of Government of India. Both adult Sparague Dawly (SD) rats with weight of 150- 170 gm (10-12 weeks age) and adult C57BL/6 mice with 20-25 gm body weight (6–8-week age) were house gm, were housed on a 12 h light/dark cycle (lights on at 8.00 am) at 22 C. To develop diet induced obesity (DIO) in C57BL/6J mice (6−8 weeks old, 22−25 g), male mice were fed with HFD (60% kcal from fat, Research Diet Inc; D12492) for 14 weeks, and an experimental control group fed with normal chow diet (10% kcal from fat, Research Diets Inc; cat no. D12450). Obesity was determined by measurement of body weight and associated hyperglycemia validated by glucose tolerance test. For food intake studies, DIO mice or normal SD Rats were starved for 12 h (9:00 PM to 9:00 AM) while water remained available. During starvation, mice or rats housed in cages with no bedding and treated with test compound COMPOUND 12 (30 mg/kg, PO) suspended in 0.5% CMC in normal saline or reference drug lorcaserin (10 mg/kg, PO) suspended in 0.5% CMC in normal saline solution or vehicle (0.5% CMC in normal saline solution). After 30 min of treatment, a weighed amount of food pellets was placed on food rack. Cumulative food intake determined by the difference between initial food and remaining food at 3 h or 6 h or 24 h. Intraperitoneal Glucose Tolerance Test (GTT): Intraperitoneal GTT in DIO mice was performed after a 16-hour fasting period to determine the development of hyperglycaemia. One bolus dose of glucose (2 g/kg) was injected into the intraperitoneal cavity of the DIO or normal mice, and the blood was sampled from the tail vein at different time points (0 min, 30 min, 60 min, 90 min and 120 min). The sampled blood was used to determine the blood glucose level using the Accu-Chek active glucometer (Roche) (C. Sona et al., 2018). Locomotor activity: Measurement of locomotor activity was performed using Opto-varimax 3 system (Columbus Instruments, OH, USA), which is an advanced system using the advance technology to quantify locomotor activity and trace the animal's path for behavioral analysis. This system senses motion with a grid of infra-red photocells placed around the arena (17.5" x 17.5), and provides total, ambulatory and vertical counts of mice locomotor activity in this open arena. Briefly, mice were put in the centre of a clear Plexiglas (40x40x30 cm) open-field arena for 30 minutes and then either vehicle (0.9% normal saline) or Amphetamine (10 mg/kg, IP) or Amphetamine + COMPOUND 12 (30 mg/kg, PO) were administered and were allowed to explore the entire arena for 60 more minutes. Time dependent or cumulative horizontal locomotor activity were presented as total no of beam breaks.
Claims
Claims: 1. A compound having the general formula I or its stereoisomers and a pharmaceutically acceptable salt thereof: thiol, thioalkyl, sulfoxide,
wherein R3 and R4 is selected from hydrogen, optionally substituted alkyl chain (C1-C6) and cycloalkyl group (C1-C10); wherein Y= N, O, N-alkyl, N-aryl, N-Substituted aryl, N-heteroaryl; R1
substituted aryl, optionally substituted alkoxy, optionally substituted alkyl; R2 = H, halogen, CN T = defined as optionally substituted normal or branched alkyl chain (C1-C6) or as template IA or Template IB or Template IC
wherein template IA, R5-R8 is selected from hydrogen, optionally substituted alkyl, optionally substituted alkoxy, N-alkyl chain (C1-C6), CN, NO2, CF3 and A is X, CF3, CN, NO2, phenyl, optionally substituted phenyl, optionally substituted heteroaryl. Where in template IB and IC, G is selected from hydrogen, hydroxy, optionally substituted alkoxy, halogen, NO2 and R9 is selected from hydrogen, optionally substituted alkyl, optionally substituted aryl
2. The compound as claimed in claim 1, wherein the representative compounds are selected from the group consisting of: 6-isopropyl-4-(methylthio)pyridin-2-amine (Compound 1) 4-(6-amino-4-(methylthio)pyridin-2-yl)benzonitrile (Compound 2) 4-(methylthio)-6-(4-(trifluoromethyl)phenyl)pyridin-2-amine
(Compound 3) 4-(methylthio)-6-(4-(methylthio)phenyl)pyridin-2-amine (Compound 4) 6-(4-(dimethylamino)phenyl)-4-(methylthio)pyridin-2-amine (Compound 5) 6-(4-(diethylamino)phenyl)-4-(methylthio)pyridin-2-amine (Compound 6) 6-(4-(ethylamino)phenyl)-4-(methylthio)pyridin-2-amine (Compound 7) 4-(methylthio)-6-(4-(piperidin-1-yl)phenyl)pyridin-2-amine (Compound 8) 4-(methylthio)-6-(4-morpholinophenyl)pyridin-2-amine (Compound 9) 4-(methylthio)-6-(naphthalen-2-yl)pyridin-2-amine (Compound 10) 6-([1,1'-biphenyl]-4-yl)-4-(methylthio)pyridin-2-amine (Compound 11) 6-(4'-bromo-[1,1'-biphenyl]-4-yl)-4-(methylthio)pyridin-2-amine (Compound 12) 6-(1H-indol-3-yl)-4-(methylthio)pyridin-2-amine (Compound 13) 6-(9-ethyl-9H-carbazol-3-yl)-4-(methylthio)pyridin-2-amine (Compound 14) 6-(4-(diphenylamino)phenyl)-4-(methylthio)pyridin-2-amine (Compound 15) 6-(3-methoxyphenyl)-4-(methylthio)pyridin-2-amine (Compound 16) 5,6-bis(4-methoxyphenyl)-4-(methylthio)pyridin-2-amine (Compound 17) 6-(4-(dimethylamino)phenyl)-4-(ethylthio)pyridin-2-amine (Compound 18) 4-(4-(2-chlorophenyl)piperazin-1-yl)-6-phenylpyridin-2-amine (Compound 19) 4-(4-(2-chlorophenyl)piperazin-1-yl)-6-(p-tolyl)pyridin-2-amine hydrochloride (Compound 20) 4-(4-(2-chlorophenyl)piperazin-1-yl)-6-(4-fluorophenyl)pyridin-2-amine hydrochloride (Compound 21) 6-(4-chlorophenyl)-4-(4-(2-chlorophenyl)piperazin-1-yl)pyridin-2-amine (Compound 22) 6-(4-bromophenyl)-4-(4-(2-chlorophenyl)piperazin-1-yl)pyridin-2-amine (Compound 23) 4-(4-(2-chlorophenyl)piperazin-1-yl)-6-(4-methoxyphenyl)pyridin-2-amine (Compound 24) 4-(4-(2-chlorophenyl)piperazin-1-yl)-6-(thiophen-2-yl)pyridin-2-amine (Compound 25)
4-(4-(2-chlorophenyl)piperazin-1-yl)-6-(furan-2-yl)pyridin-2-amine hydrochloride (Compound 26) 4-(4-(2-chlorophenyl)piperazin-1-yl)-[2,2'-bipyridin]-6-amine hydrochloride (Compound 27) 4-(4-(2-chlorophenyl)piperazin-1-yl)-6-(4-(dimethylamino)phenyl)pyridin-2-amine hydrochloride (Compound 28) 4-(4-(2-chlorophenyl)piperazin-1-yl)-6-(naphthalen-2-yl)pyridin-2-amine hydrochloride (Compound 29) 6-([1,1'-biphenyl]-4-yl)-4-(4-(2-chlorophenyl)piperazin-1-yl)pyridin-2-amine (Compound 30) 4-(4-(2-chlorophenyl)piperazin-1-yl)-6-(4-nitrophenyl)pyridin-2-amine hydrochloride (Compound 31) 4-(4-methylpiperazin-1-yl)-6-(naphthalen-2-yl)pyridin-2-amine (Compound 32) 6-(4'-amino-[1,1'-biphenyl]-4-yl)-4-(methylthio)pyridin-2-amine (Compound 33) 6-(4'-(dimethylamino)-[1,1'-biphenyl]-4-yl)-4-(methylthio)pyridin-2-amine (Compound 34) 3. The compound as claimed in claim 1, wherein the pharmaceutically acceptable salt is selected from the group comprising of hydrochloride, formate, acetate, phenyl acetate, trifluroacetate, acrylate, ascorbate, benzoate, chlorobenzoates, bromobenzoates, iodobenzoates, nitrobenzoates, hydroxybenzoates, alkylbenzoates, alkyloxybenzoates, alkoxycarbonylbenzoates, naphthalene-2 benzoate, butyrates, phenylbutyrates, hydroxybutyrates, caprate, caprylate, cinnamate, mandelate, mesylate, citrate, tartarate, fumarate, heptanoate, hippurate, lactate, malate, maleate, malonate, nicotinate, isonicotinate, oxalate, sodium, potassium, phthalate, terephthalate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, propiolate, propionate, phenylpropionate, salicylate, sebacte, succinate, suberate, sulphate, bisulphate, pyrosulphate, sulphite, bisulphate, sulphonate, benzene sulphonate, bromobenzene sulphonates, chlorobenzene sulphonates, ethane sulphonates, methane sulphonates, naphthalene sulphonates, toluene sulphonates.
4. A process for the preparation of compounds claimed in claim 1 wherein the process step comprising; (a) reacting substituted 2H-pyran-2-ones of general formula with aqueous ammonia preferably dissolved organic
dimethyl formamide, dimethyl sulfoxide and the reaction takes place within a period of 10 min to 4 hours at the reaction temperature between 25-80 oC. purifying the product having general formula I by chromatographic method; wherein: wherein SR’ is selected from hydrogen, thiol, thioalkyl, sulfoxide, sulfones, wherein R3 and R4 is selected from hydrogen, optionally substituted alkyl chain (C1-C6) and cycloalkyl group (C1-C10); where Y= N, O, N-alkyl, N-aryl, N-Substituted aryl, N-heteroaryl;
R1 = H, optionally substituted aryl, optionally substituted alkoxy, optionally substituted alkyl; R2 = H, halogen, CN T = defined as optionally substituted normal or branched alkyl chain (C1-C6) or as template IA or Template IB or Template IC
where in template IA, R5-R8 is selected from hydrogen, optionally substituted alkyl, optionally substituted alkoxy, N-alkyl chain (C1-C6), CN, NO2, CF3 and A is X, CF3, CN, NO2, phenyl, optionally substituted phenyl, optionally substituted heteroaryl. where in template IB and IC, G is selected from hydrogen, hydroxy, optionally substituted alkoxy, halogen, NO2 and R9 is selected from hydrogen, optionally substituted alkyl, optionally substituted aryl 5. Use of a compound as claimed in any of claims 1-3 , or a pharmaceutically acceptable salt or a stereoisomer thereof, in the manufacture of a medicament for use in treating a subject of a condition, disease or disorder responsive to modulation of the 5-HT2C receptor. 6. A compound as claimed in any of claims 1-3, or a pharmaceutically acceptable salt or a stereoisomer thereof, for use in treating a condition, disease or disorder in a subject wherein modulation of 5-HT2C receptor(s) provides a benefit in obesity, addiction, anxiety, depression and obesity related comorbidities. 7. A method of treating a condition, disease or disorder in a subject wherein modulation of 5-HT2C receptor(s) provides a benefit, comprising administering a therapeutically effective amount of a compound as claimed in any of claims 1-3 to the subject in need thereof. 8. The method as claimed in claim 7, wherein the 5-HT2C receptor(s) are activated or inhibited. 9. A method of treating or controlling food intake, obesity, addiction, anxiety, depression and obesity related comorbidities in a subject, comprising administering a therapeutically effective amount of a compound as claimed in any of claims 1-3 to the subject in need thereof.
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| PCT/IN2024/050416 WO2024218798A1 (en) | 2023-04-20 | 2024-04-19 | Aminopyridine analogues as 5-hydroxytryptamine receptor modulators and uses thereof |
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