WO2007113634A1 - Novel dipeptidyl peptidase iv inhibitors and processes for their preparation and pharmaceutical compositions containing them - Google Patents

Novel dipeptidyl peptidase iv inhibitors and processes for their preparation and pharmaceutical compositions containing them Download PDF

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Publication number
WO2007113634A1
WO2007113634A1 PCT/IB2007/000830 IB2007000830W WO2007113634A1 WO 2007113634 A1 WO2007113634 A1 WO 2007113634A1 IB 2007000830 W IB2007000830 W IB 2007000830W WO 2007113634 A1 WO2007113634 A1 WO 2007113634A1
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Prior art keywords
carbonitrile
salts
mmol
alkyl
pyrrolidine
Prior art date
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PCT/IB2007/000830
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English (en)
French (fr)
Inventor
Balasubramanian Gopalan
Dhamjewar Ravi
Mohammed Rasheed
Swamy Keshavapura Hosamane Sreedhara
Ahmad Ishtiyaque
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Mylan Laboratories Ltd
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Matrix Laboratories Ltd
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Priority to DK07734152.7T priority Critical patent/DK2004601T3/da
Priority to CA2682846A priority patent/CA2682846C/en
Priority to US12/295,930 priority patent/US7985759B2/en
Priority to AT07734152T priority patent/ATE500219T1/de
Priority to MX2008012756A priority patent/MX2008012756A/es
Priority to EP07734152A priority patent/EP2004601B1/en
Priority to BRPI0709894-4A priority patent/BRPI0709894A2/pt
Priority to CN2007800183871A priority patent/CN101448785B/zh
Priority to DE602007012845T priority patent/DE602007012845D1/de
Priority to NZ571319A priority patent/NZ571319A/en
Application filed by Matrix Laboratories Ltd filed Critical Matrix Laboratories Ltd
Priority to AU2007232311A priority patent/AU2007232311B2/en
Priority to JP2009503673A priority patent/JP2009532454A/ja
Publication of WO2007113634A1 publication Critical patent/WO2007113634A1/en
Priority to IL194163A priority patent/IL194163A/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
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    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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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    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
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    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
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    • C07D207/323—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to the ring nitrogen atoms
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    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D233/30—Oxygen or sulfur atoms
    • C07D233/32—One oxygen atom
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    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole 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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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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Definitions

  • the present invention relates to novel compounds represented by formula I, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their bioisosters, their diastereomers, their polymorphs, their pharmaceutically acceptable salts, solvates and pharmaceutically acceptable compositions containing them, which are useful in treating type II diabetes and diabetic complications as well as for the treatment of dislipidemia, hypercholesterolemia, obesity, and hyperglycemia.
  • WLmr invention relates to pharmaceutically acceptable compositions containing the aforementioned compounds.
  • R 1 and R 5 are selected from hydrogen, Ci-C 4 alkyl, and hydroxy,
  • R 2 is selected from hydrogen, C 1 -C 4 alkyl, substituted alkyl, Ci -4 alkoxy C 1-4 alkyl, C 1-4 hydroxyalkyl, R 5 NHC 1-4 alkyl, and R 5 NHC(NH)NHC M alkyl,
  • R 3 is selected from hydrogen and Ci-C 4 alkyl
  • R R 11 , R 12 , or R 13 , in which Rn comprises at least one of the groups selected from below a), b), or c), whereupon the optionally substituted cycloalkyl, heterocyclyl, and heteroaryl groups are linked to the nor- adamantyl moiety either directly or via a methylene or ethylene adjacent, either by C-C linkage or by C-N linkage.
  • Examples of possible cycloalkyl groups are cyclopentane, cyclohexane, cyclopentane dione, cylohexane dione and the possible substitutions include C 1 -C 4 alkyl, dialkyl, and oxo.
  • An optionally substituted heteroaryl group preferably a 5 to 10 membered ring system, in which the heteroaryl ring is a monocyclic aromatic ring system or a bicyclic aromatic ring system comprising one, two, or more heteroatoms selected from nitrogen, sulfur, and oxygen.
  • Possible heteroaryl groups include but not limited to tetrazole, triazole, pyrazole, imidazole, oxadiazole, pyridine, pyrimidine, indole, furan, benzofuran, benzimidazole, indazole, thiophene, and benzothiophene and the substitutions on the heteroaryl ring may be the same or different and are selected from R 6 and R 7 , wherein R 6 is hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, hydroxy, hydroxy alkyl, alkylamino, haloalkyl, amino, acyl, COOR 9 , or COR 9 , and R 7 is selected from a group consisting of hydrogen, hydroxy, halogen, amino, nitro, C 1 -C 8 alkyl, C 2 -C 4 alkenyl, COOR 9 , CONR 8 R 9 , COR 9 , NHCOOR 8 , NHS(O
  • R 6 and R 7 When R 6 and R 7 are present on adjacent carbon atoms of the ring system, they may together form a six membered aromatic ring such as phenyl or a heterocyclic ring such as pyridine with further substitutions such as amino, hydroxy, alkyl, alkyl sulfonyl, alkyl thio, alkyl sulf ⁇ nyl, carboxy, or oxo.
  • heterocyclyl group optionally substituted by C 1 -C 3 alkyl, dialkyl and oxo groups
  • the heterocyclic ring system is a 4- to 10-membered mono- or bicyclic ring system with one or more heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, wherein the heteroatoms can also be present as functional groups, such as N- oxides, sulfur oxides, and sulfur dioxides, wherein the heterocyclic ring system may contain one or two double bonds
  • the monocyclic heterocyclic ring may be optionally fused to a heteroaryl, aryl, or a cycloalkyl ring optionally substituted with C 1 -C 5 alkyl, halogens, hydroxy, amino, nitro, haloalkyl, alkylamino, carboxy, NH(CO)R 8 , NHS(O) 2 R 8 , NHC(O)NHR 9 , NHSOR 8 , NHS(O) 2 NHR 8
  • heterocyclic ring radicals include but are not limited to imidazolidinone, isothiazolidine- 1,1 -dioxide, pyrrolidine, pyrrolidinedione, oxopyrrolidine, isoxazolidinedione, isoindoledione, morpholine, thiomorpholine, thiomorpholine- 1,1 -dioxide, thiophene-1,1- dioxide, thiazolidinedione, piperidine, piperazine, tetrahydro pyrimidinone, [1,2]- thiazinane- 1,1 -dioxide, tetrahydro thiophene- 1,1 -dioxide, piperidinone, and tetra- hydrothiopyran-1 , 1 -dioxide.
  • R 12 is selected from hydrogen, halogen, haloalkyl, hydroxy, carboxy, nitro, amino, cyano, alkyl sulfinyl, alkylsulfonyl, alkylthio, amidinyl, alkoxy, alkoxy carbonylamino, ureido, thiureido, alkanoyl, alkanoyloxy, alkanoyl amino, carbamoyl, guanidyi, optionally substituted C 1 -C 8 alkyl, and C 2 -C 6 alkenyl.
  • R 13 is optionally substituted aryl, wherein the substituents may be the same or different and comprises at least one of the groups selected from a) hydrogen; b) C 1 -C 8 alkyl, C 2 -C 6 alkenyl, halo, alkylhalo, alkoxy, alkylsulfonyl, alkylsulfinyl, alkoxy, alkanoyl, alkanoyloxy, acylamino, carbonylamino, guanidyi, nitro, amino, COOR 9 ,
  • R 8 NHC(O)R 9 , COR 9 , CONR 8 R 9 , NHC(O)OR 8 , NHC(O)R 8 , NHC(O)NR 8 R 9 , NHC(O)NR 8 R 9 , NHS(O) 2 R 8 , NHS(O)R 8 , NHS(O) 2 NHR 8 , NHS(O) 2 NHC(O)R 8 , NRsCOOR 9 , NR 8 COR 9 , NR 8 S(O) 2 R 9 , NR 8 CONR 8 R 9 , NR 8 C(S)NR 8 R 9 , NHC(O)NHS(O) 2 R 8 , S(O) 2 R 8 , SOR 8 , SR 8 , S(O) 2 NR 8 R 9 , OCF 3 , OS(O) 2 R 8 , or OC(O)NR 8 R 9 .
  • heterocyclic ring system optionally substituted by one or more groups selected from C1-C3 alkyl, C 2 -C 6 alkenyl, dialkyl, and oxo, wherein the heterocyclic ring system is a 4- to 10-membered ring with one or more heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, wherein the heteroatoms can also he present as functional groups, such as N- oxides, sulfur oxides, and sulfur dioxides.
  • heterocyclic ring radicals include, but are not limited to pyridine, pyrimidine, imidazolidinone, imidazolidinethione, indazole, indole, isoindole, quinazoline, quinoline, isoquinoline, cinnalone, isothiazolidine- 1,1 -dioxide, pyrrolidinone, 2-piperidinone, tetrahydropyrimidinone, azitidinone, and thiazane- 1 , 1 -dioxide.
  • R 8 , R 9 , and R t o-groups which are optionally substituted by halogen, hydroxy, alkoxy, cyano, nitro, alkyl, acyl, acyloxy, hydroxyalkyl, amino, alkylthio, or thioalkyl groups, may be the same or different and are individually selected from hydrogen, optionally substituted
  • R 8 and R 9 are present together on a nitrogen atom they may form a 5- or 6-membered saturated, partially unsaturated, or unsaturated cyclic system containing carbon atoms, at least one nitrogen atom and optionally one or more other heteroatoms selected from oxygen, sulfur, and nitrogen.
  • the present invention also relates to a process for the preparation of compounds of formula I, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their bioisosters, their diastereomers, their polymorphs, their pharmaceutically acceptable salts, and their solvates.
  • the present invention also relates to novel intermediates, processes for their preparation, their use in the preparation of compounds of formula I, and their derivatives, their analogs, their tautomeric forms, their stereoisomers, their bioisosters, their diastereomers, their polymorphs, their pharmaceutically acceptable salts, and their solvates.
  • Diabetes is characterized by elevated levels of plasma glucose or hyperglycemia in the fasting state or after administration of glucose during an oral glucose tolerance test.
  • Type 1 diabetes is usually diagnosed in children and young adults, and was previously known as juvenile diabetes. In type 1 diabetes, the body does not produce insulin.
  • Type 2 diabetes is the most common form of diabetes. In type 2 diabetes, either the body does not produce enough insulin or the cells ignore the insulin.
  • Patients with type 2 diabetes are at increased risk of macro vascular and micro vascular complications, including coronary artery disease, stroke, hypertension, nephropathy, peripheral vascular disease, neuropathy, and retinopathy.
  • DPP-IV serine peptidase dipeptidyl peptidase IV
  • CD26 or DPP-IV is a membrane-associated peptidase of 766 amino acids that is widely distributed in numerous tissues.
  • DPP-4 also exists as a soluble circulating form in plasma and significant DPP-4- like activity is detectable in plasma from humans and rodents.
  • DPP-IV The principal biological activity of CD26 (DPP-IV) is its enzymatic function. DPP-IV prefers substrates with an amino-terminal proline or alanine at position 2, but may also cleave substrates with non- preferred amino acids at position 2.
  • the structure of GIP, GLP-I and GLP-2 reveals a highly conserved alanine at position 2, rendering these peptides ideal putative substrates for the aminopeptidase dipeptidyl peptidase 4 (DPP- 4). EurJBiochem. 1993, 214(3), 829- 35.
  • alpha glucosidase inhibitors such as acarbose and miglitol, which function by interfering with the action of the alpha-glucosidases present in the small intestinal brush border.
  • the consequence of this inhibition is a reduction in digestion and the consequent absorption of glucose into the systemic circulation.
  • the reduction in glucose uptake allows the pancreatic beta-cells to regulate the insulin secretion more effectively.
  • the advantage of the use of the alpha-glucosidase inhibitors is that they function locally in the intestine and have no major systemic action.
  • hypoglycemia does not usually occur with the use of alpha-glucosidase inhibitors but they are effective in reducing fasting plasma glucose (FPG) levels and levels of glycosylated hemoglobin (HbA 10 ).
  • FPG fasting plasma glucose
  • HbA 10 glycosylated hemoglobin
  • the sulfonylureas and meglitinide classes of oral hypoglycemic drugs are referred to as endogenous insulin secretagogues because they induce the pancreatic release of endogenous insulin. Because these drugs can induce pronounced hypoglycemia, treatment is initiated with the lowest possible dose and carefully monitored until the dose results in a FPG of 110-140mg/dL.
  • Sulfonylureas function by binding to and inhibiting the pancreatic ATP-dependent potassium channel that is normally involved in glucose-mediated insulin secretion. Sulfonylureas have no significant effects on circulating triglycerides, lipoproteins, or cholesterol.
  • the non-sulfonylurea insulin secretagogues are both fast acting and of short duration.
  • meglitinides do exert effects on potassium conductance. Like the sulfonylureas, the meglitinides have no direct effects on the circulating levels of plasma lipids.
  • the biguanides lower serum glucose levels by enhancing insulin-mediated suppression of hepatic glucose production and enhancing insulin-stimulated glucose uptake by skeletal muscle.
  • Metformin is a member of this class and is currently the most widely prescribed insulin-sensitizing drug in clinical use. Metformin administration does not lead to increased insulin release from the pancreas and as such the risk of hypoglycemia is minimal. Because the major site of action for metformin is the liver its use can be contraindicated in patients with liver dysfunction. In adolescent females with type 2 diabetes, the use of metformin is highly recommended to reduce the incidence as well as the potential for polycystic ovarian syndrome. However the two biguanides, phenformin and metformin can induce lactic acidosis and nausea/diarrhea.
  • PPAR peroxisome proliferator-activated nuclear receptor
  • This class is able to reduce triglyceride levels and is also able to improve insulin sensitivity and as a result dual PPAR alpha/PPAR gamma agonists have been developed with proposed beneficial effects over existing PPAR gamma- and alpha-preferential drugs in treatment of type 2 diabetes. But safety issues slowed down the entry of these drugs
  • GLP-I agonists One of the exciting classes of agents in development are GLP-I agonists.
  • the primary metabolic responses to GLP-I release from the enteroendocrine L-cells of the gut are inhibition of glucagon secretion and enhancement of glucose-dependent insulin release from the pancreas, both effects lead to decreased glycemic excursion.
  • the hormonal action of GLP-I is rapidly terminated as a consequence of enzymatic cleavage by DPP IV.
  • Recent clinical evidence has shown that either infusion of GLP-I or inhibition of DPP IV can result in dramatic reductions in plasma glucose concentrations, reductions in HbA 10 , and improvement in pancreatic beta-cell function.
  • Dipeptidyl peptidase IV is a multifunctional protein involved in cleaving incretin hormones, hence serving to regulate glucose homeostasis and consequently viewed as a target for the management of Type 2 diabetes.
  • Dipeptidyl peptidase IV in the treatment of Type 2 diabetes is based on the fact that Dipeptidyl peptidase IV in vivo readily inactivates GLP-I and GIP. These are the incretins that are produced when food is consumed. These incretins stimulate production of insulin. Inhibition of Dipeptidyl peptidase IV leads to decreased inactivation of incretins, in turn increased efficacy of incretins in stimulating insulin production by pancreas. Therefore Dipeptidyl peptidase IV inhibition results in an increased level of serum insulin. An interesting observation is that incretins are produced only when food is consumed.
  • Dipeptidyl peptidase IV inhibition is not expected to increase the level of insulin between meals which can lead to hypoglycemia. Inhibition of Dipeptidyl peptidase IV is therefore expected to increase insulin without increasing the risk of hypoglycemia.
  • Investigational Dipeptidyl peptidase IV inhibitors offer an advantage over other novel therapies since they can be administered orally. Compliance in patients is much higher with orally delivered drugs than with those that require injection. Thus Dipeptidyl peptidase IV inhibitors are a promising new approach to treat type 2 diabetes, which function, at least in part, as indirect stimulators of insulin secretion. Mechanism and use of DPPIV inhibitors in various diseases is well explained in prior art patents like WO 2005/033106 and is herein incorporated by reference in its entirety.
  • R is substituted adamantyl
  • A is an optionally substituted adamantyl group.
  • n 0, 1,2, or 3.
  • R2 is substituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclicgroup, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl,
  • -NR 3 R 4 -NH-S(O)Hi-R 3 , -NH-CR 3 R 4 , C(O)-R 5 , -C(O)O-R 3 , -C(O)NR 3 R 4 , -S(0)m-, NR 3 R 4 , nitro, cyano, formyl, acetyl, halogen, -SR a , or a protecting group.
  • one of the possible B substituents is adamantyl amine.
  • the objective of the present invention is to provide novel compounds of formula I, having serine protease inhibiting activity, particularly dipeptidyl peptidase IV inhibiting activity for lowering blood glucose levels, lipid levels, cholesterol levels and reducing body weight, against type II diabetes and diabetic complications.
  • the main objective of the present invention is therefore, to provide novel nor-adamantyl cyano pyrrolidine compounds represented by formula I, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their bioisosteres, their diastereomers, their polymorphs, their pharmaceutically acceptable salts, solvates and pharmaceutically acceptable compositions containing them.
  • Another aspect of the present invention is to provide a process for the preparation of noradamantyl cyano pyrrolidine compounds represented by formula I, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their bioisosters, their diastereomers, their polymorphs, their pharmaceutically acceptable salts, and their pharmaceutically acceptable solvates.
  • Another aspect of the present invention is to provide novel intermediates, processes for their preparation and use of these intermediates in processes for the preparation of saind noradamantyl cyano pyrrolidine compounds represented by formula I and their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their bioisosters, their diastereomers, their pharmaceutically acceptable salts, and solvates.
  • Another aspect of the present invention is to provide pharmaceutical compositions containing the compounds of the present invention represented by formula I, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their bioisosters, their diastereomers, their polymorphs, their salts, solvates, or their mixtures in combination with suitable carriers, solvents, diluents and other media normally employed in preparing such compositions.
  • the present invention is to provide compounds represented by formula I
  • X CH 2 , CHF, CF 2 , CHCl, CHOH, CHOCH 3 , NH, NCOCH 3 , CHPh, O, or S,
  • R 1 and R 5 are selected from hydrogen, Ci-C 4 alkyl, and hydroxy,
  • R 2 is selected from hydrogen, C 1 -C 4 alkyl, substituted alkyl, C 1-4 alkoxy C 1-4 alkyl, C 1-4 hydroxyalkyl, R 5 NHC 1-4 alkyl , and R 5 NHC(NH)NHC 1-4 alkyl ,
  • R 3 is selected from hydrogen and C 1 -C 4 alkyl
  • R R 11 , R 12 , or Ri 3 , in which
  • Rn comprises at least one of the groups selected from a), b), or c), whereupon the optionally substituted cycloalkyl, heterocyclyl, and heteroaryl groups are linked to the noradamantyl moiety either directly or via a methylene or ethylene adjacent, either by C-C linkage or by C-N linkage
  • a cycloalkyl group which is optionally substituted by C 1 -C 4 alkyl, dialkyl, or oxo, pre- ferably a C 4 -C 7 ring system, more preferably a C 5 -C 6 ring system, which may be further functionalized or substituted with multiple degrees of substitution.
  • Examples of possible cycloalkyl groups are cyclopentane, cyclohexane, cyclopentane dione, cylohexane dione and the possible substitutions include C 1 -C 4 alkyl, dialkyl, and oxo.
  • heteroaryl group preferably a 5 to 10 membered ring system, in which the heteroaryl ring is a monocyclic aromatic ring system or a bicyclic aromatic ring system comprising one, two, or more heteroatoms selected from nitrogen, sulfur, and oxygen.
  • Possible heteroaryl groups include but are not limited to tetrazole, triazole, pyrazole, imidazole, oxadiazole, pyridine, pyrimidine, indole, furan, benzofuran, benzimidazole, indazole, thiophene, and benzothiophene and the substitutions on the heteroaryl ring may be the same or different and are selected from R 6 and R 7 , wherein R 6 is hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, hydroxy, hydroxy alkyl, alkylamino, haloalkyl, amino, acyl, COOR 9 , or COR 9, and R 7 is selected from a group consisting of hydrogen, hydroxy, halogen, amino, nitro, C 1 -C 8 alkyl, C 2 -C 4 alkenyl, COOR 9 , CONR 8 R 9 , COR 9 , NHCOOR 8 , NHS(O)
  • R 6 and R 7 When R 6 and R 7 are present on adjacent carbon atoms of the ring system, they may together form a six membered aromatic ring such as phenyl or a heterocyclic ring such as pyridine with further substitutions such as amino, hydroxy, alkyl, alkyl sulfonyl, alkyl thio, alkyl sulf ⁇ nyl, carboxy, or oxo.
  • heterocyclyl group optionally substituted by C 1 -C 3 alkyl, dialkyl and oxo groups
  • the heterocyclic ring system is a 4- to 10-membered mono- or bicyclic ring system with one or more heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, wherein the heteroatoms can also be present as functional groups, such as N- oxides, sulfur oxides, and sulfur dioxides, wherein the heterocyclic ring system may contain one or two double bonds
  • the monocyclic heterocyclic ring may be optionally fused to a heteroaryl, aryl, or a cycloalkyl ring optionally substituted with C 1 -C 5 alkyl, halogens, hydroxy, amino, nitro, haloalkyl, alkylamino, carboxy, NH(CO)R 8 , NHS(O) 2 R 8 , NHC(O)NHR 9 , NHSOR 8 , NHS(O) 2 NHR 8
  • heterocyclic ring radicals include but are not limited to imidazolidinone, isothiazolidine- 1,1 -dioxide, pyrrolidine, pyrrolidinedione, oxopyrrolidine, isoxazolidinedione, isoindoledione, morpholine, thiomorpholine, thiomorpholine-1,1- dioxide, thiophene- 1,1 -dioxide, thiazolidinedione, piperidine, piperazine, tetrahydro pyrimidinone, [1, 2] -thiazinane- 1,1 -dioxide, tetrahydro thiophene-1,1 -dioxide, piperidinone, and tetrahydrothiopyran- 1,1 -dioxide.
  • R 7 is as described above and Z is CH 2 , O, S, SO 2 , NH, NR 6 , or CH(OH). These examples do not limit the present invention.
  • R 12 is selected from hydrogen, halogen, haloalkyl, hydroxy, carboxy, nitro, amino, cyano, alkyl sulfinyl, alkylsulfonyl, alkylthio, amidinyl, alkoxy, alkoxy carbonylamino, ureido, thiureido, alkanoyl, alkanoyloxy, alkanoyl amino, carbamoyl, guanidyl, optionally substituted C 1 -C 8 alkyl, and C 2 -C 6 alkenyl.
  • R 13 is optionally substituted aryl, wherein the substituents may be the same or different and comprises at least one of the groups selected from a) hydrogen; b) C 1 -C 8 alkyl, C 2 -C 6 alkenyl, halo, alkylhalo, alkoxy, alkylsulfonyl, alkylsulfmyl, alkoxy, alkanoyl, alkanoyloxy, acylamino, carbonylamino, guanidyl, nitro, amino, COOR 9 , R 8 NHC(O)R 9 , COR 9 , CONR 8 R 9 , NHC(O)OR 8 , NHC(O)R 8 , NHC(O)NR 8 R 9 , NHC(O)NR 8 R 9 , NHS(O) 2 R 8 , NHS(O)R 8 , NHS(O) 2 NHR 8 , NHS(O) 2 NHC(O)R 8 , NR 8 COOR 9 ,
  • heterocyclic ring system optionally substituted by one or more groups selected from C 1 -C 3 alkyl, C 2 -C 6 alkenyl, dialkyl, and oxo, wherein the heterocyclic ring system is a 4- to 10-membered ring with one or more heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, wherein the heteroatoms can also be present as functional groups, such as N- oxides, sulfur oxides, and sulfur dioxides.
  • heterocyclic ring radicals include, but are not limited to pyridine, pyrimidine, imidazolidinone, imidazolidinethione, indazole, indole, isoindole, quinazoline, quinoline, isoquinoline, cinnalone, isothiazolidine- 1,1 -dioxide, pyrrolidinone, 2-piperidinone, tetrahydropyrimidinone, azitidinone, and thiazane- 1 , 1 -dioxide.
  • R 8 , R 9 , and R ⁇ -groups which are optionally substituted by halogen, hydroxy, alkoxy, cyano, nitro, alkyl, acyl, acyloxy, hydroxyalkyl, amino, alkylthio, or thioalkyl groups, may be the same or different and are individually selected from hydrogen, optionally substituted Ci-Cg alkyl, aryl, arylalkyl, alkoxy carbonyl, and arylalkoxy carbonyl.
  • R 8 and R 9 When R 8 and R 9 are present together on a nitrogen atom they may form a 5- or 6-membered saturated, partially unsaturated, or unsaturated cyclic system containing carbon atoms, at least one nitrogen atom and optionally one or more other heteroatoms selected from oxygen, sulfur, and nitrogen.
  • Certain compounds of the present invention of formula I may contain one or more chiral centers and the present invention incorporates the isolated stereoisomers, their mixtures, as well as the corresponding racemates.
  • alkyl refers to a saturated straight or branched aliphatic hydrocarbon chain that optionally may be substituted with multiple degrees of substitution.
  • Examples of “alkyl” include but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, and isobutyl.
  • the substitutions may be selected from halogens, hydroxy, alkoxy, acyl, amino, and nitro.
  • alkyl group refers to a Ci-C 8 -group.
  • alkenyl used herein, either alone or in combination with other radicals, denotes a straight or branched C 2 -C 6 aliphatic hydrocarbon chain containing one or more carbon- to-carbon double bonds that may be optionally substituted with multiple degrees of substitution.
  • alkenyl includes dienes and trienes of straight and branched chains and include groups such as vinyl, allyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4- pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-heptenyl, 3-he ⁇ tenyl, 4-heptenyl, 5-heptenyl, and 6- heptenyl
  • acyl refers to a -C(O)R a -group, wherein R a is C 1 -C 4 straight or branched alkyl or aryl.
  • acylamino used herein is represented by a -NHC(O)R a -group, wherein R a is defined as above and examples are CH 3 CONH, C 2 H 5 CONH, C 3 H 7 CONH, C 6 H 5 CONH.
  • alkanoyloxy refers to a -OC(O)R a -group, wherein R 3 is C 1 -C 4 straight or branched alkyl as defined above; examples are acetyloxy and propanyloxy.
  • alkanoyl refers to a -C(O) R a -group, wherein R 3 is Ci-C 4 straight or branched alkyl as defined above; examples are acetyl and propanoyl.
  • alkanoylamino refers to a -NH-C(O)R a -group, wherein R a is C 1 -C 4 straight or branched alkyl as defined above; examples are CH 3 CONH- and C 2 H 5 CONH-.
  • alkoxy refers to a -OR a -group, wherein R a is alkyl as defined herein. Represen- tative examples include but are not limited to methoxy and ethoxy.
  • alkoxycarbonyl refers to a -C(0)OR a -group, wherein R 3 is alkyl as defined herein.
  • Alkoxycarbonylamino refers to a -NHC(O)OR a -group where R a is alkyl as defined herein.
  • alkylamino refers to a -N(R a ) 2 -group, wherein one R a is alkyl and the other R a is independently H or alkyl as defined herein.
  • alkyl sulfinyl refers to a -S(O)R a -group, wherein R a is alkyl as defined herein.
  • alkyl sulfonyl refers to a -S(O) 2 R a -group, wherein R 3 is alkyl as defined herein
  • alkylthio refer to a -SR a -group, wherein R a is alkyl as defined herein. Representative examples include but are not limited to -S-CH 3 , -S-CH 2 CH 3 .
  • alkylhalo refers to a R a X-group, wherein R a is alkyl as defined above and X represents a halogen atom selected from fluorine, chlorine, bromine, and iodine.
  • Halogen refers to fluorine, chlorine, bromine, or iodine.
  • hydroxyalkyl refers to a R a OH-group, wherein R a is alkyl as defined herein and representative examples include but are not limited to hydroxy methyl, hydroxy ethyl, and hydroxy propyl.
  • aryl refers to an aromatic ring system with five to ten carbon atoms, which may be monocyclic or bicyclic and unsaturated or partially saturated, and one or more carbons may optionally be replaced by one or more heteroatoms selected from N, O, and S.
  • aryl includes ring(s) optionally substituted with multiple degrees of substitution and the substitutions may include alkyl, alkylene, Dialkyl, and oxo.
  • aralkyl refers to a Ar-R a -group, wherein Ar and R a are as defined above.
  • arylalkoxycarbonyl refers to a -C(O)OR a Ar-group, wherein Ar and R 3 are as defined above.
  • heteroaryl refers to a monocyclic aromatic ring system or a fused bicyclic aromatic ring system comprising two or more aromatic rings, preferably two rings. These heteroaryl rings contain one or more heteroatom, such as nitrogen, sulfur, and oxygen, wherein functional groups, such as N-oxides, sulfur oxides, and dioxides are permissible as heteroatom substitutions .
  • heteroaryl includes optionally substituted ring systems.
  • heteroaryl groups include furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole, pyridine, pyridazine, pyrazine, pyrimidine, quinoline, isoquinoline, benzofuran, benzothiophene, indole, indazole, and substituted versions thereof.
  • heterocyclyl refers to a 3 to 15 membered ring that is either saturated or has one or more double bonds. These heterocyclic rings contain one or more heteroatoms such as nitrogen, sulfur, and/or oxygen atoms, wherein functional groups such as N-oxides, sulfur oxides, and dioxides are permissible heteroatom substitutions. Such ring may be optionally fused to one or more other heterocyclic ring(s), aryl ring(s) or cycloalkyl ring(s).
  • stereoisomers refers to certain compounds described herein that contain one or more chiral centres or may otherwise be capable of existing as multiple stereoisomers. Scope of the present invention includes pure stereoisomers, mixtures of stereoisomers such as purified enantiomers/diastereomers or enantiomerically/diastereomerically enriched mixtures, and racemates.
  • bioisosteres refers to compounds or groups that possess near molecular shapes and volumes, approximately the same distribution of electrons and which exhibit similar physical properties such as hydrophobicity.Bioisostereic compounds affect the same biochemically associated systems as agonist or antagonists and thereby produce biological properties that are related to each other.
  • salts includes salts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, Al, and Mn, salts of organic bases such as N 5 N'- diacetylethylenediamine, 2-dimethylaminoethanol, isopropylamine, morpholine, piperazine, piperidine, procaine, diethylamine, triethylamine, trimethylamine, tripropylamine, tromethamine, adamantyl amine, diethanolamine, ethylenediamine, N 5 N- benzyl phenylethylamine, choline hydroxide, dicyclohexylamine, metformin, benzylamine, phenylethylamine, dialkylamine, trialkylamine, thiamine, aminopyrimidine, aminopyridine, purine, pyrimidine, and spermidine, chiral bases like alkylphenylamine, gly
  • Salts may include acid addition salts such as sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides selected from HCl, HBr, HI, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulfonates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, and ketoglutarates.
  • acid addition salts such as sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides selected from HCl, HBr, HI, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulfonates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycero
  • solvates refers adducts and co-crystallates, such as hydrates or solvates comprising other solvents, e.g. alcohols.
  • compounds of the invention or “present invention” refers to the compounds of the present invention represented by formula I as defined herein, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their bioisosters, their diastereomers, their polymorphs, as well as their pharmaceutically acceptable salts and solvates.
  • suitable pharmaceutically acceptable carriers include solid fillers or diluents and sterile aqueous or organic solutions.
  • the active ingredient will be present in such pharmaceutical compositions in amounts sufficient to provide the desired effect as described above.
  • the compounds can be combined with a suitable solid, liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions etc.
  • the pharmaceutical compositions may contain additional components such as flavourants, sweeteners, and excipients.
  • Preferred compounds of the present invention are represented by formula Ia and the generic structure given below. Additionally, preferred embodiments are represented by their derivatives, their analogs, their tautomeric forms, their stereoisomers, their bioisosters, their diastereomers, their polymorphs, their pharmaceutically acceptable salts and their pharmaceutically acceptable solvates.
  • R 3 is independently selected from hydrogen and Ci-C 4 alkyl
  • R 4 is hydrogen, C 1 -C 4 alkyl, substituted alkyl, C 1 -C 4 Alkoxy, C 1 -C 4 alkanoyloxy, hydroxy, amino, nitro, C 2 -C 6 alkenyl, acyl, or halogen
  • R is R 1 1, R 12 or R 13 and Rn, R 12 , Ri 3 are as defined above.
  • Preferred compounds of the present invention comprise the following compounds:
  • Another aspect of the present invention provides processes for the preparation of the compounds of general formula I as described above.
  • P is H or a protecting group
  • L is a leaving group selected from the group consisting of halogens, tosylates, mesylates, and triflates
  • R, R 1 , R 2 , R 3, R 4 , n, m, X, and Y are as described above
  • a Coupling one equivalent of a compound of formula III with about 1 to 5 equivalents of an amine compound of formula II in its free form or as a salt or as a compound, wherein the amine is protected, in the presence of one or more bases, such as but are not limited to alkali metal hydrides like NaH and KH; organolithiums such as CH 3 Li and BuLi; alkoxides like NaOMe 5 NaOEt, and KOtBu; tertiary amines like triethylamine and DBU; carbonates like potassium carbonate, potassium bicarbonate, sodium carbonate, and cesium carbonate.
  • bases such as but are not limited to alkali metal hydrides like NaH and KH; organolithiums such as CH 3 Li and BuLi; alkoxides like NaOMe 5 NaOEt, and KOtBu; tertiary amines like triethylamine and DBU; carbonates like potassium carbonate, potassium bicarbonate, sodium carbonate, and ces
  • Said coupling is carried at a temperature ranging from about -5 0 C to about 120°C in an inert solvent such as dichloromethane, dimethyl formamide, tetrahydrofuran, acetonitrile, DMSO etc. c. Said coupling is carried for 0.5 to 72 hours, preferably for 0.5 to 60 hours. d. Isolating the resulting compound of formula I.
  • the compounds of formula III can be prepared by methods found in the state of the art
  • Grignard reagent is selected from the group comprising methyl metal halides like
  • oxidizing agent in solvents like water, THF, benzene, or a combination of the said solvents followed by treatment with a base in a protic solvent such as water, alcohols to form Ib.
  • Preferred alcohols are C 1 -C 4 alcohols and the base is selected from alkalis like NaOH and KOH.
  • the oxidising agent may be selected from chlorine monoxide, hypochlorites like NaOCl or lead tetraacetate in the presence of iodine. II.
  • the phenyl group of compound Ib is converted to a carboxylic acid group in the presence of an oxidizing agent like NaIO 4 ZRuCl 3 at ambient temperature to form Ic.
  • the carboxylic group of compound Ic is converted to its alkyl ester, the keto group is protected with an 1,2-diol such as 1,2-ethane diol or an 1,3-diol such as 1,3 -propane diol in the presence of organic solvents like benzene or toluene at their reflux temperature using an acid catalyst such as p-TSA, CSA, and BF 3 etherate.
  • an acid catalyst such as p-TSA, CSA, and BF 3 etherate.
  • the ester is reduced to the alcohol by a reducing agent such as LiAlH 4 , NaBH 4j and DIBAL-H in an inert solvent like THF, ether, or mixtures thereof at a temperature of about 0°C to form Id.
  • a reducing agent such as LiAlH 4 , NaBH 4j and DIBAL-H in an inert solvent like THF, ether, or mixtures thereof at a temperature of about 0°C to form
  • Scheme III is described in the following steps: Ia.
  • the hydroxy group of Ia, at 5 th position is alkylated by an alkylating agent like alkyl halides (such as CH 3 I, CH 3 Br or isopropyl bromide) using strong bases such as NaH, KH, or NaOCH 3 to form 5-hydroxy adamantanone; followed by ring contraction.
  • an alkylating agent like alkyl halides (such as CH 3 I, CH 3 Br or isopropyl bromide) using strong bases such as NaH, KH, or NaOCH 3 to form 5-hydroxy adamantanone; followed by ring contraction.
  • 5-alkoxy adamantanone is converted to 5-alkoxy noradamantyl ethanone by converting it to 2-methyl ⁇ 5-alkoxy adamantan-2-ol by Grignard-reaction followed by ring contraction of adamantanone to noradamantane in the presence of an oxidizing agent in a solvent like water, THF, benzene, or a combination of such solvents followed by the treatment with a base in a protic solvent such as water, alcohols, or mixtures thereof to form 5-alkoxy noradamantyl ethanone.
  • a solvent like water, THF, benzene, or a combination of such solvents followed by the treatment with a base in a protic solvent such as water, alcohols, or mixtures thereof to form 5-alkoxy noradamantyl ethanone.
  • the ethanone group in the compound obtained by step 1 is converted to a carboxylic acid by treatment with an oxidizing agent like hypobromites, hypochlorites (such as NaOBr, NaOCl), etc. at about 0°C followed by an amination step.
  • an oxidizing agent like hypobromites, hypochlorites (such as NaOBr, NaOCl), etc. at about 0°C followed by an amination step.
  • the hydroxyl group of compound Ia is benzylated by reaction with benzylhalides like benzylbromide in a solvent (e.g., THF, DMF, NMP) at about O 0 C for about 10-18 hrs to form benzyloxy adamantanone followed by ring contraction to form benzyloxy noradamantyl ethanone.
  • a solvent e.g., THF, DMF, NMP
  • step III The benzyloxy noradamantyl ethanone obtained in step III is converted to the corresponding acid by an oxidizing agent followed by an amination step (b).
  • the amine thus formed is protected by conventional amine protecting groups like Boc, Cbz or Fmoc followed by debenzylation(d).
  • the debenzylation is carried out in in a H 2 atmosphere under Pd/C-catalysis in protic solvents like methanol, ethanol or IPA at room temperature for 1-3 hrs to form hydroxy noradamantyl amine, wherein the amine group is protected.
  • X 1 halo
  • Y 1 SO 2 ,CO
  • P Boc, CBz, Fmoc
  • k 1, 2, 3
  • step Ib The nitrophenyl noradamantyl ethanone obtained in step Ia is oxidized to convert the ethanone to the corresponding acid by an oxidizing agent followed by an animation step.
  • Ic The conversion of the acid to the amine is carried out by treatment with an azide like NaN 3 or W-Bu 4 NN 3 under acidic conditions in the presence of solvents like CHCl 3 , CH 2 Cl 2 , or acetonitrile at a temperarure of about 35 to 50°C. Ha.
  • the amine group in the compound obtained from step I is protected by a conventional amine protecting group like Boc, Cbz, or Fmoc.
  • the nitro group is reduced to an amine by reducing agents such as Pd/C, Pd(OAc) 2 , Zn/ammonium formate, or Fe/NH 4 C1 etc. in the presence of solvents like esters (e.g., ethyl acetate), alcohols (e.g., methanol, ethanol), THF, water or a combination thereof to form the phenyl amino compound (4).
  • reducing agents such as Pd/C, Pd(OAc) 2 , Zn/ammonium formate, or Fe/NH 4 C1 etc.
  • solvents like esters (e.g., ethyl acetate), alcohols (e.g., methanol, ethanol), THF, water or a combination thereof to form the phenyl amino compound (4).
  • phenyl amino compound (4) obtained by step II is reacted with X ⁇ CHa) n Y 1 X 1 , wherein X 1 is a halo group selected from F, Cl, Br, I, Y 1 is SO 2 or CO, in the presence of an organic base like triethylamine or DBU and an inert solvent like THF, CH 2 Cl 2 , acetonitrile, or DMF followed by cyclization in the presence of alkali metal hydroxides such as LiOH, NaOH, or KOH in water with phase transfer catalyst such as tetraalkylammonium halides (e.g., tetrabutyl ammoniumiodide) and deprotection of the amine protecting group to get the corresponding heterocycle substituted phenyl noradamantyl amine compound (5).
  • X 1 is a halo group selected from F, Cl, Br, I
  • Y 1 is SO 2 or CO
  • an organic base like triethyl
  • step II compound (2) obtained from step II is reacted with X 1 (CH 2 )NCO in the presence of organic bases like triethylamine or DBU, a solvent like THF, CH 2 Cl 2 , acetonitrile, DMF, or mixtures thereof; followed by cyclization to obtain the corresponding heterocycle substituted compound, which, by further amine deprotection, form the corresponding heterocycle substituted phenyl noradamantyl amine compounds (6).
  • organic bases like triethylamine or DBU
  • a solvent like THF, CH 2 Cl 2 , acetonitrile, DMF, or mixtures thereof
  • the phenyl amino compound (2) obtained from step II is reacted with 2,5-dimethoxy tetrahydrofuran in glacial acetic acid at reflux temperature to form pyrrole substituted compounds, which, on further amine deprotection, form the corresponding pyrrole substituted phenyl noradamantyl amine compounds (7).
  • VIa The ethanone group of the phenylnoradamantylethanone (Ib) (as obtained in schemell) is converted to an acid-group by an oxidizing agent followed by an amination step.
  • step II The oxidation of the compound obtained by step II is carried out by oxidizing agents to obtain a carboxylic acid derivative.
  • This carboxylic acid group of the compound obtained from step IIIc is converted to an amine by azide-treatement with e.g. NaN 3 in an acidic medium or with diphenylphosphorylazide in the presence of organic bases like triethylamine, in a solvent like benzene or toluene at reflux temperature followed by hydrolysis with a metal hydroxide such as KOH, NaOH, LiOH in water at room temperature to form the corresponding amine substituted noradamantylamine (9).
  • a metal hydroxide such as KOH, NaOH, LiOH in water at room temperature
  • step I The amino compound (If) obtained from step I is reacted with X ⁇ CH 2 ) I1 Y 1 X 1 , wherein X 1 is halogen and Y 1 Is -SO 2 - or -CO- in the presence of organic bases like triethylamine and a solvent like THF or CH 2 Cl 2 followed by cyclization using alkalimetal hydroxides in water with a phase transfer catalyst such as tetrabutylammonium iodide to get the corresponding heterocycle substituted compounds with an ethanone group, which, after oxidation and amination steps as described in IIIc and IHd, is converted to the corresponding heterocycle substituted noradamantylamines (10).
  • a phase transfer catalyst such as tetrabutylammonium iodide
  • the hydroxyl group of compound Id is transformed into a leaving group L by e.g. messylation, tosylation, or halogenation in the presence of an organic base like triethylamine, N,N-diisopropyl-ethylamine, pyridine, NMP, or N-methyl- morpholine at a temperature of about 0°C.
  • an organic base like triethylamine, N,N-diisopropyl-ethylamine, pyridine, NMP, or N-methyl- morpholine at a temperature of about 0°C.
  • the leaving group L of Ie is replaced by R 11 ⁇ oUp in the presence of a base and a solvent at a temperature of about 80-120°C to form Ii.
  • the bases are selected from alkali carbonates or bicarbonates like Na 2 CO 3 , NaHCO 3 ; K 2 CO 3 , or KHCO 3 .
  • the solvents are selected from dimethylformamide, DMSO, NMP, or similar.
  • IHa The protected keto group of compound Ii obtained from step II is deprotected by, e.g., reaction with p-TSA in acetone at reflux temperature to form an ethanone compound. HIb.
  • the ethanone compound is oxidized to the corresponding carboxylic acid in the presence of an oxidizing agent, which may be selected from chlorine monoxide, hypochlorites like NaOCl or lead tetraacetate in the presence of iodine.
  • an oxidizing agent which may be selected from chlorine monoxide, hypochlorites like NaOCl or lead tetraacetate in the presence of iodine.
  • the carboxylic acid is converted to an amine by reaction with an azide like NaN 3 under acidic conditions in the presence of solvents like CHCl 3 , CH 2 Cl 2 , or acetonitrile at about 35 to 45°C to form the R 11 substituted noradamantylamine (11).
  • the hydroxyl group of Id as obtained from scheme II is benzylated by reaction with benzylhalides like benzylbromide in solvents like THF, DMF, or NMP at about 0 0 C for about 10-18 hrs to form the keto protected benzyloxy noradamantane (Ig). Va.
  • the protected keto group of compound Ig is deprotected to obtain the ethanone as described in step Ilia.
  • step Vc The carboxylic group of the compound obtained from step Vb is converted to an amine by reaction with diphenylphosphorylazide in the presence of organic bases like triethylamine, solvents like benzene, or toluene at reflux temperature followed by hydrolysis with metal hydroxides such as KOH, NaOH, or LiOH in water at room temperature to form benzyloxy noradamantylamine (Ih).
  • organic bases like triethylamine, solvents like benzene, or toluene at reflux temperature
  • metal hydroxides such as KOH, NaOH, or LiOH
  • step Vc The amine group of the compound Ih obtained from step Vc is protected by conventional amine protecting groups as described earlier followed by a debenzylation step.
  • step VIb The debenzylation is carried out in the presence of H 2 atmosphere over Pd/C in protic solvents like methanol, ethanol, or IPA at room temperature for 1-3 hrs to form compound
  • hydroxyl group of compound Ij is mesylated, tosylated, or halogenated to form a leaving group in the presence of organic bases like triethylamine, N,N-diisopropyl ethylamine, pyridine, N-methyl-piperidine, or N-methyl-morpholine at ambient temperature.
  • the compound obtained from Vila is reacted with a R 11 group in the presence of a base and a solvent at a temperature range of about 80-120°C.
  • the bases are selected from alkali carbonates or bicarbonates like Na 2 CO 3 , NaHCO 3, K 2 CO 3, and BCHCO 3 .
  • Solvents are selected from DMF, DMSO, NMP etc.
  • the protected amine group of the R 11 substituted compound obtained from step VIIb is deprotected by conventional methods, e.g. by treatment with dry HCl in solvents like EtOAc, ether, or 1,4-dioxane at a temperature between 0°C and room temperature to form a R '-substituted noradamantylamine as hydrochloride salt (12).
  • the hydroxyl group of Ij is reacted with the R 11 group in the presence of triphenylphosphine, diisopropylazodicarboxylate, and an organic solvent like benzene, toluene, or THF at a temperature from about 20°C to about 110°C for about 2-6 hours to form the R 1 [ -substituted compound.
  • step Villa The protected amine group of the R n -substituted compound obtained from step Villa is deprotected by treatment with trifluoroacetic acid in a solvent like CH 2 Cl 2 or CHCl 3 at about 0°C to form the R ⁇ -substituted noradamantanarnine as a TFA salt (13).
  • the obtained intermediate compounds 11,12, 13 are reacted with chloroacetylcyano pyrrolidines to form the corresponding final compounds according to Scheme I.
  • the hydroxy group of compound Ij is mesylated, tosylated, or halogenated in the presence of organic bases like triethylamine, N 5 N- diisopropyl ethylamine, pyridine, N- methyl-piperidine, or N-methyl-morpholine at an ambient temperature.
  • organic bases like triethylamine, N 5 N- diisopropyl ethylamine, pyridine, N- methyl-piperidine, or N-methyl-morpholine at an ambient temperature.
  • the compound obtained from Ia is reacted with a cyanating agent like NaCN in the presence of an aprotic solvent like DMF at 100-110°C for about 12-15 hrs to obtain a compound (Ik).
  • any reactive group in the substrate molecule may be protected according to any conventional procedure known in the prior art.
  • Suitable protecting groups comprise tertiarybutyldimethylsilyl, methoxymethyl, triphenyl methyl, benzyloxycarbonyl, THP etc. for the protection of hydroxyl or phenolic hydroxy groups; N-Boc, N-Cbz, N-Fmoc, and benzophenoneimine for the protection of amino or anilino groups; acetal protection for aldehydes, ketal protection for ketones.
  • the methods for the formation and removal of such protecting groups depend on the molecule to be protected which are known in the art.
  • a leaving group it may be selected from the group comprising halogens (like chlorine, bromine), o- toluene sulphonyl, o-methyl sulphonyl.
  • stereoisomers of the compounds according to this invention may be prepared by using reactants in their single enantiomeric form in the process wherever possible or by conducting the reaction in the presence of reagents or catalysts in their single enantiomer form or by resolving the mixture of stereoisomers by conventional methods.
  • Some of the preferred methods include use of microbial resolution, resolving the diastereomeric salts formed with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, or lactic acid wherever applicable or chiral bases such as brucine, cinchona alkaloids, or their derivatives.
  • the pharmaceutically acceptable salts can be prepared by reacting the compound of formula I with about 1 to 5 equivalents of bases such as alkalimetal hydroxides, alkalimetal alkoxides, calcium hydroxide, or magnesium hydroxide in protic or aprotic solvents like methanol, ethanol, propanol, IPA, ether, THF, dioxane etc.
  • bases such as alkalimetal hydroxides, alkalimetal alkoxides, calcium hydroxide, or magnesium hydroxide in protic or aprotic solvents like methanol, ethanol, propanol, IPA, ether, THF, dioxane etc.
  • acid addition salts are prepared by treatment with acids such as hydrohalic acids like HCl, HBr; nitric acid, sulfuric acid, phosphoric acid, p-toluene sulphonic acid, methane sulphonic acid, acetic acid, or citric acid in solvents comprising at least one selected from ethyl acetate, ethers, alcohols, acetone, THF 5 dioxane, or mixtures thereof
  • acids such as hydrohalic acids like HCl, HBr; nitric acid, sulfuric acid, phosphoric acid, p-toluene sulphonic acid, methane sulphonic acid, acetic acid, or citric acid in solvents comprising at least one selected from ethyl acetate, ethers, alcohols, acetone, THF 5 dioxane, or mixtures thereof
  • solvents comprising at least one selected from ethyl acetate, ethers, alcohols, acetone,
  • the compounds may be purified by using techniques such as crystallization from solvents such as pentane, diethylether, isopropyl ether, chloroform, dichloromethane, ethylacetate, acetone, methanol, ethanol, isopropanol, water, or their combinations, or compound I may be purified by column chromatography using alumina or silica gel and eluting the column with solvents such as hexane, petroleum ether, dichloromethane, chloroform, ethylacetate, acetone, methanol, or combinations thereof.
  • solvents such as pentane, diethylether, isopropyl ether, chloroform, dichloromethane, ethylacetate, acetone, methanol, or combinations thereof.
  • the present invention also provides pharmaceutical compositions containing the compounds as defined above, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their bioisosters, their polymorphs, their enantiomers, their diastereomers, their pharmaceutically acceptable salts, or their pharmaceutically acceptable solvates in combination with suitable pharmaceutically acceptable carriers or diluents.
  • the pharmaceutical compositions according to the present invention are useful as antidiabetics, hypolipidemics and antihypercholesterolemics.
  • Suitable pharmaceutically acceptable carriers include solid fillers, diluents, and sterile aqueous or organic solutions.
  • the active ingredient will be present in such pharmaceutical compositions in amounts sufficient to provide the desired effect as described above.
  • the compounds can be combined with a suitable solid or liquid carrier or a diluent to form e.g. capsules, tablets, powders, syrups, solutions, or suspensions.
  • the pharmaceutical compositions may, if desired, contain additional components such as flavourants, sweeteners, or excipients.
  • the route of administration may be oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, or parenteral e.g. rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, as an ophthalmic solution or an ointment, which effectively transports the active compound of the present invention which inhibits the DPPIV enzymatic activity to the appropriate or desired site of action.
  • a solid carrier the preparation may be in form of tablet, or may be placed in a hard gelatin capsule in powder or pellet form, or it can be in form of a troche or a lozenge.
  • the preparation may be in the form of a syrup, emulsion, soft gelatin capsule, or a sterile injectable liquid such as an aqueous or non aqueous liquid suspension or solution.
  • a liquid carrier in particular an aqueous carrier, is used as an aerosol application.
  • suitable compositions are injectable solutions or suspensions, preferably aqueous solutions.
  • a further aspect of the present invention is the use of compounds of the invention as a pharmaceutical composition in a therapeutically effective amount for the treatment of metabolic disorders, blood glucose lowering, for the treatment of type II diabetes, for the treatment of impaired glucose tolerance, for the treatment of impaired fasting glucose, for the treatment of obesity, for the prevention of hyperglycemia, for the treatment of dislipidemia, hypercholesteromia, and hypolipidemia.
  • dosages may be about 0.05 to lOOOmg, and preferably about 0.1 to 500 mg per day.
  • the exact dosage depends on the mode of administration, on the therapy required, the form in which the active ingredient is administered and the patient to be treated; the body weight of the subject to be treated and the preference and experience of the physician in charge.
  • the subject is considered as a human being.
  • the invention also encompasses prodrugs of compounds of the invention, which on administration undergo chemical conversion by metabolic processes before becoming active pharmacological substances.
  • prodrugs will be functional derivatives of compounds of the invention, which are readily convertible in vivo into compounds of the invention.
  • the invention also encompasses the active metabolites of the compounds of the present invention.
  • DPP-IV The inhibition of proteolytic activity of DPP-IV was assayed by following the hydrolysis of Ala-Pro-7-amino-4-trifluoromethylcoumarin (Ala-Pro-AFC) and fluorometric quantitation of the liberated AFC.
  • Human recombinant DPP-IV (expressed in insect Sf9 cells) was used for the assay.
  • Test compounds were dissolved in dimethyl sulfoxide (DMSO). Generally, the enzyme (about 20 ng/ml in 100 mM Tris-HCl buffer, pH 8.0) was preincubated in the absence (1% DMSO) and presence of various concentrations of the test compounds for 15 min at 37 0 C.
  • the reaction was initiated by the addition of 20 ⁇ M Ala- Pro-AFC and further incubated for 30 min at 37 0 C.
  • the AFC liberated was measured in a spectrofluorometer with excitation and emission wavelengths set at 400 nm and 510 nm, respectively. Results are expressed as percent inhibition of enzyme activity.
  • a reference standard (a known inhibitor of DPP-IV) was always included in the assay.
  • the compounds of the present invention were found to inhibit DPPIV induced fluorescence with inhibitory constants in a range of about 0.5nM to 50OnM .In a preferred range, the compounds of the present invention inhibited DPPIV induced fluorescence with inhibitory constants of about O.lnM to 30OnM and in a more preferred range the compounds of the present invention inhibited DPPIV induced fluorescence with inhibitory constants of about InM to 12OnM.
  • Step I Adamantanone (12 g, 80 mmol) was added under stirring to nitric acid (98%, 100 mL) at ice bath temperature over a period of 15 minutes. The reaction mixture was stirred at room temperature for 72 h and then heated to 60 °C, for 2 h until most of the nitrogen dioxide evaporated. Excess nitric acid was distilled off under reduced pressure. The light yellow oil solidified upon cooling (NO 3 adduct of the hydroxyketone). Water (40 mL) and cone. H 2 SO 4 (98%, 15 mL) were added. The resulting clear yellow solution was heated on the steam bath in a hood (nitrous fumes) for 1 h.
  • Step II To a stirred solution of compound 5-hydroxyadamantan-2-one (10.0 g, 60.2 mmol) in benzene (180 mL) was added trifluoromethanesulfonic acid (5.3 mL, 60.2 mmol) over a period of 30 minutes at r.t. After stirring the reaction mixture for 5 minutes at r.t, it was refluxed for 4 h. The reaction mixture was cooled to 0°C and sat. aq. NaHCO 3 (76 mL) was added over a period of 30 minutes.
  • Step III Freshly prepared methylmagnesium iodide in ether (1 M, 85 mL), was added through a canola to 5-phenyladamantan-2-one (9.6 g, 42.5 mmol) obtained in step II, in THF (85 mL) at O 0 C. After stirring at 0 0 C for 0.5 h, the reaction mixture was quenched by adding sat. aq. NH 4 Cl solution. The organic layer was separated and the aqueous layer was extracted with diisopropylether.
  • Step IV 2-Methyl-5-phenyl-adamantan-2-ol (20 g, 82.6 mmol) obtained in step III, (86 g, 355.4 mmol), dissolved in a mixture of AcOH (76.3 mL) and THF (360 mL) was added dropwise via an addition funnel to the ice bath cooled NaOCI (4%, 3.5 L) solution over a period of 15 minutes. Solid W-Bu 4 NI (13.1 g, 35.6 mmol) was added and the reaction mixture was stirred for 1.5 h. The two layers were separated, the aqueous layer was extracted with diisopropylether and the combined organic layer was washed with water and brine, dried over Na 2 SO 4 , and the solvent was removed under reduced pressure.
  • Step I To a stirred mixture of l-(l-Phenyltricyclo[3.3.1.0 J>/ ]non-3-yl)ethanone (8.0 g, 33.3 mmol) as obtained in preparation 1, carbontetrachloride (66 mL), acetonitrile (66 mL) and water (100 mL), cooled to 0 0 C, was added sodiumperiodate (31.9 g, 149 mmol) and ruthenium (III) chloride hydrate (0.44 g, 1.7 mmol). The reaction mixture was gradually warmed to ambient temperature and stirred for 2 h.
  • reaction mixture was diluted with diisopropylether (100 mL) and stirred for 15 minutes to precipitate black RuO 2 .
  • the reaction mixture was then filtered through a pad of celite and the organic layer was extracted with IN NaOH solution (3x25 mL). The organic layer was dried over Na 2 SO 4 and the solvent was evaporated under vacuum to obtain unreacted starting material (3.04 g 12.67 mmol).
  • the aqueous layer was acidified with cone. HCl and extracted with EtOAc.
  • Step II To 3-acetyltricyclo[3.3.1.0 3)7 ]nonane-l-carboxylic acid (2.4 g, 11.4 mmol) obtained in stepl, in MeOH (48 mL) cooled to ice bath temperature, was added acetyl chloride (1.64 mL, 22.8 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 2 h. The volatiles were removed under reduced pressure and the crude product was purified by column chromatography to obtain methyl 3- acetyltricyclo[3.3.1.0 3 ' 7 ]nonane-l-carboxylate (2.4 g) in 93% yield as viscous liquid, m/z (M+l) 223.
  • Step III A mixture of methyl 3-acetyltricyclo[3.3.1.0 3 ' 7 ]nonane-l-carboxylate (2.0 g, 8.9 mmol) obtained in step II, 1,2-ethanediol (8.9 mL), p- ⁇ SA (47 mg, 5 mol%) and benzene (36 mL) was refluxed using a Dean-Stark apparatus for 1 h. The reaction mixture was cooled to room temperature, 10% aq. NaHCO 3 (36 mL) was added, and the two layers were separated. The aqueous layer was extracted with EtOAc.
  • Step IV Methyl 3-(2-methyl- 1 ,3-dioxolan-2-yl)tricyclo[3.3.1.0 3>7 ]nonane- 1 -carboxylate (2.3 g, 8.64 mmol) obtained in step III, in THF (15 mL) was added slowly under N 2 atmosphere through a dropping funnel to a suspension of LiAlH 4 (0.32 g, 8.64 mmol) in ether (15 mL) at ice bath temperature. The reaction mixture was stirred for 30 minutes before being quenched by addition of sat. aq.
  • Step V To a solution of [3-(2-Methyl-l,3-dioxolan-2-yl)tricyclo[3.3.1.0 3 ' 7 ]non-l- yljmethanol (2.0 g, 8.47 mmol) obtained in step IV, in THF (35 mL) at ice bath temperature, was sequentially added triethylamine (3.5 mL, 25.4 mmol), DMAP (52 mg, 0.42 mmol), and methanesulfonyl chloride (0.97 mL, 12.7 mmol). After stirring the reaction mixture at the same temperature for 0.5 h, it was diluted with water and extracted with EtOAc.
  • Step I To a suspension of NaH (60% dispersed in nujol, 3.36 g, 21 tnmol) in THF (84 niL) cooled to ice bath temperature was added a solution of [3-(2-Methyl-l,3-dioxolan-2- yl)tricycle [3.3.1.0 3>7 ]non-l-yl]methanol (10.0 g, 42.0 mmol) (as obtained in preparation 2 step IV) in THF (84 mL) via a syringe over a period of 30 minutes.
  • Step II A mixture of 2-[l-(benzyloxymethyl)tricyclo[3.3.1.0 3 ' 7 ]n°n-3-yl]-2-methyl-l,3- dioxolane (2.6 g, 7.9 mmol), p-toluenes ⁇ lfonic acid (0.3 g, 1.6 mmol), and acetone (31.6 mL) was refluxed for 4 h. The volatiles were removed under vacuum and the residue was diluted with EtOAc, washed with 10% aq.
  • Step III To a mixture of NaOH (30.6 g, 765 mmol), H 2 O (255 niL) and 1,4 dioxane (51 mL) at ice bath temperature was added Br 2 (15.2 mL, 285.6 mmol) and stirred for 15 minutes. This hypobromite solution was added dropwise to a stirred solution of 1- ⁇ 1- [(benzyloxy) methyl] tricyclo[3.3.1.0 3 ' 7 ]non-3-yl ⁇ ethanone (14.5 g, 51.0 mmol) in 1,4- dioxane (51 mL) at ice bath temperature. The reaction mixture was gradually warmed to r.t. and stirred for 1 h.
  • Step IV To a stirred mixture of l-[(benzyloxy)methyl]tricyclo[3.3.1.0 3 ' 7 ]nonane-3- carboxylic acid (1.8 g, 6.3 mmol) obtained in step III, triethylamine (2.6 mL, 18.9 mmol) and toluene (25 mL) at ice bath temperature was added diphenylphosphoryl azide (1.5 mL, 6.93 mmol). The reaction mixture was warmed to r.t, stirred for one hour, and then refluxed for 4 h. Upon completion of the reaction, the reaction mixture was transferred to a separatory funnel and washed with water. The organic layer was stirred with aq.
  • Step V To a stirred solution of l-[(benzyloxy)methyl]tricyclo[3.3.1.0 3 ' 7 ]nonan-3-amine (0.82 g, 3.2 mmol) obtained in step IV in dichloromethane (13 mL) at ice bath temperature was added Et 3 N (0.67 mL, 4.8 mmol) and ditertiary butyldicarbonate (0.77 g, 3.5 mmol).
  • Step VI To a stirred mixture of tert-bvkyl [l-(benzyloxymethyl) tricyclo[3.3.1.0 ' ]non-3- yl] carbamate (1.0 g, 2.8 mmol) obtained in stepV in MeOH (11 mL), Pd/C (10%, 0.2 g) was added. The H 2 pressure was then applied with the balloon for 2 h.
  • Step VII To a stirred solution of tert-butyl [l-(hydroxymethyl)tricyclo[3.3.1.0 3 ' 7 ]non-3- yljcarbamate (0.65 g, 2.45 mmol) obtained in step VI in THF (10 mL) at ice bath temperature, was sequentially added Et 3 N (1.0 mL, 7.35 mmol), DMAP (20 mg, 0.16 mmol), and methanesulfonyl chloride (0.29 mL, 3.7 mmol). After stirring the reaction at the same temperature for 0.5 h, it was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na 2 SO 4 , and the solvent was removed under reduced pressure.
  • Step I Nitration mixture (1 mL) [the nitration mixture was prepared by mixing of 10.5 g of nitric acid (d 1.375 at 22 0 C), 180.0 g of cone, sulphuric acid (d 1.84 at 22 0 C), and 16 g of H 2 O) was added drop wise to a stirred solution of l-(l-phenyltricyclo[3.3.1.0 3>7 ]non-3- yl)ethanone (240 mg, 1.0 mmol) obtained in preparation 1, in nitromethane (4 mL) at 0 0 C.
  • Step II To a stirred solution of NaOH (6.3 g, 158.0 mmol), H 2 O (54.0 mL) and 1,4 dioxane (7 mL) at ice bath temperature was added Br 2 (3.2 mL, 59.0 mmol) and stirred for 5 minutes. The formed hypobromite solution was added dropwise to a stirred solution of 1- [l-(4-nitrophenyl) tricyclo[3.3.1.0 3 ' 7 ]non-3-yl]ethanone (3.0 g, 10.53 mmol) obtained in step I, in 1,4-dioxane (14 mL) at ice bath temperature. The reaction mixture was gradually warmed to r.t.
  • Step III To the stirred solution of l-(4-nitrophenyl)tricyclo[3.3.1.0 3>7 ]nonane-3-carboxylic acid (3.0 g, 10.45 mmol) obtained in step II, in CHCl 3 (21 mL) was added cone. H 2 SO 4 (4.2 mL, 78.9 mmol) then solid NaN 3 was added in portions, so that the temperature of the reaction did not rise above 40°C. The reaction mixture was warmed to 45°C and after stirring for 2 h it was cooled again to ice bath temperature, diluted with water and extracted with EtOAc. The aqueous layer was basifled with 50% NaOH solution and extracted with CHCl 3 .
  • Step IV To a stirred mixture of l-(4-nitrophenyl)tricyclo[3.3.1.0 ' ]nonan-3-amine (2.0 g, 8.0 mmol) obtained in step III, K 2 CO 3 (3.5 g, 24 mmol) in THF (80 niL), cooled to ice- bath temperature was added benzylchloroformate (50% w/v in Toluene, 2.2 mL, 12 mmol). After stirring the reaction mixture at r.t for 2 h, it was diluted with water and extracted with EtOAc.
  • Step V To a stirred solution of benzyl[2-(4-nitro ⁇ henyl)hexahydro-2,5-methanopentalen- 3a(lH)-yl]carbamate (1.0 g, 2.55 mmol) as obtained in step IV in a 1:2:4 mixture of water, THF, and ethanol respectively (10 mL) was added solid NH 4 Cl (0.5 g, 9.3 mmol) and Fe powder (0.5 g, 9.0 mmol). The reaction mixture was heated to reflux for 2h. The reaction mixture was cooled to room temperature and filtered through a small pad of celite. The filtrate was evaporated under reduced pressure and the residue was diluted with water and extracted with EtOAc.
  • Step I To a stirred solution of (2S, 4i?)-4-hydroxypyrrolidine-2-carboxylic acid (13.1 g, 0.1 mol) in methanol (400 mL) cooled to 0°C was added acetyl chloride (14.3 mL, 0.2 mol) over a period of 30 min. The reaction mixture was warmed to room temperature and stirred for 2 h.
  • Step II To a stirred suspension of the hydrochloride salt obtained in step I (14.5 g, 0.1 mol) in CH 2 Cl 2 (400 mL) cooled to 0°C was added Et 3 N (28 mL, 0.2 mol), DMAP (0.61 g,
  • Step III To a stirred solution of compound obtained in step II (24.5 g, 0.1 mol) in 1,2- dichloroethane (300 rnL) cooled to -10 0 C was added diethylaminosulfur trifaoride (19.7 mL, 0.15 mol) over a period of 30 minutes. The reaction mixture was stirred at this temperature for 1 h then at room temperature for 16 h. The reaction mixture was quenched by adding mixture of crushed ice (300 g) and solid NaHCO 3 (25.2 g, 0.3 mol). The two layers were separated and the aqueous layer was extracted with dichloromethane.
  • Step IV To the stirred solution of l-tert-butyl-2-methyl (2 i S r ,4,S)-4-fluoro ⁇ yrrolidme-l,2- dicarboxylate (24.7 g, 0.1 mol) obtained in step III in THF (200 mL) cooled to 0°C was added a solution of LiOH (3.6 g, 0.15 mol) in water (200 mL) over a period of 30 min. The reaction mixture was warmed to room temperature and stirred for 12 h until the TLC reveals completion of the reaction. The reaction mixture was diluted with water, ether, and two layers were separated. The aqueous layer was acidified with cone. HCl and extracted with EtOAc.
  • Step V To a stirred solution of acid obtained in step IV (17.3 g, 0.074 mol) in acetonitrile (220 mL) at room temperature was added pyridine (6.6 mL, 0.082 mol), Boc anhydride (2O mL, 0.089 mol).
  • Step VI To a stirred solution of the amide obtained in the previous step (17.9 g, 0.077 mol) in EtOAc (35 mL) at 0°C was added dry HCl in EtOAc (4 N, 225 mL) over a period of 30 min. After stirring at 0°C for 1 h the volatiles were removed under reduced pressure and the residue was triturated with ether several times to obtain (25,4 ⁇ -4-SuOrO pyrrolidine-2-carboxamide, hydrochloride salt as an off-white powder (12 g) in 92% yield.
  • Step VII To a stirred suspension of hydrochloride salt as obtained in step VI (12 g, 0.071 mol) in dichloromethane (140 mL) cooled to 0°C was added Et 3 N (30 mL, 0.213 mol), chloroacetyl chloride (8.1 mL, 0.107 mol). The reaction mixture was gradually warmed to r.t. and stirred for 1 h.
  • reaction mass was filtered through a sintered funnel, washed the salt bed with ether and the filtrate was evaporated under vacuum to obtain a crude product (2S, 45)-l-(chloroacetyl)-4-fluoropyrrolidine-2-carboxamide (14.8 g) as a viscous liquid in 3:1 mixture of rotomers.
  • Step VIII To a stirred solution of the compound obtained in step VII (14.7 g, 0.07 mol) in dry THF (140 mL) under N 2 atmosphere at 0°C was added trifluoroacetic anhydride (15 mL, 0.107 mol). The reaction mixture was gradually warmed to r.t. and stirred for 1 h. Water was added and the two layers were separated. The aqueous layer was extracted with EtOAc and the combined organic layer was washed with brine, dried over anhydrous Na 2 SO 4 .
  • the compound (25 r ,4i?)-l-(2-chloroacetyl)-4-fluoropyrrolidine-2-carbonitrile is synthesized from (26 r ,45)-4-hydroxypyrrolidine-2-carboxylic acid using the same sequence of steps and procedures as outlined above for (2$,4S)- l-(2-chloroacetyl)-4-fluoropyrrolidine-2- carbonitrile starting from (2S,4i?)-4-hydroxypyrrolidine-2-carboxylic acid.
  • (2S,4R)-l-(2- chloroacetyl)-4-fluoropyrrolidine-2-carbonitrile Solid, 4: 1 mixture of two rotomers; m/z
  • Step I To a stirred solution of 40% aq. formaldehyde (40 mL) at 0°C was added in portions solid L-cystein (12.1 g, 0.1 mol) over a period of 30 minutes. The reaction mixture was stirred for 4 h, after which the reaction mixture was filtered through a sintered funnel. The solids were washed with absolute ethanol then with diethyl ether. The solids were dried under high vacuum to obtain (4/?)-l,3-thiazolidine-4-carboxylic acid (12.5 g) in 94% yield.
  • Step II To a stirred mixture of the compound obtained in step I (13.3 g, O.lmol) in acetonitrile (400 mL) cooled to 0°C, was added pyridine (20.1 mL, 0.22 mol) and Boc- anhydride (58 mL, 0.24 mol). After stirring the reaction mixture for 1 h at room temperature, solid NH 4 HCO 3 (11.8 g, 0.15 mol) was added and the reaction mixture was stirred for another 2h. The reaction mixture was partitioned between ethylacetate and 1 : 1 mixture of 2N HCl and brine solution.
  • Step III To a stirred solution of tert-butyl (4i?)-4-(aminocarbonyl)-l,3-thiazolidine-3- carboxylate (23 g, 0.1 mol) in ethylacetate (50 mL) at 0°C was added dry HCl in ethylacetate (3.5 N, 250 mL). The resulting mixture was stirred at room temperature for 2 h, the volatiles were removed under reduced pressure and the residue was triturated with ethylacetate several times to obtain (4i?)-l,3-thiazolidine-4-carboxamide hydrochloride salt as an off-white powder (16.5 g) quantitatively.
  • Step IV To a stirred suspension of the hydrochloride salt obtained in step III (16.5 g, 0.1 mol) in dichloromethane (200 mL) cooled to 0°C were added Et 3 N (41 mL, 0.3 mol) and chloroacetyl chloride (8.8 mL, 0.11 mol). The reaction mixture was slowly warmed to room temperature and stirred for 1 h.
  • Step V To a stirred solution of the compound obtained in step IV (20.7 g, 0.1 mol) in dry THF (200 mL) under N 2 atmosphere at 0°C was added trifluoroacetic anhydride (21 mL,
  • Step I To a solution of the carboxylic acid obtained in preparation 2 step I (2.7 g, 12.9 mmol) in toluene (52 mL) at ice bath temperature Et 3 N (5.8 mL, 38.7 mmol) and diphenylphosphoryl azide (3.3 mL, 15.5 mmol) were added. The reaction mixture was gradually warmed to room temperature, stirred for one hour, and refluxed for 4 h. Upon cooling to room temperature, the reaction mixture was transferred to a separatory funnel and washed once with water. The organic layer was transferred to an RB flask cooled to ice bath temperature and aq.
  • Step II To a stirred solution of the amino compound obtained in step I (1.3 g, 7.26 mmol) in dichloromethane (29 mL) at ice bath temperature Et 3 N (2 mL, 14.5 mmol), Boc anhydride (2.1 mL, 8.7 mmol), and DMAP (44 mg, 0.36 mmol) were added.
  • Step IH To a mixture of NaOH (1.32 g, 33.0 mmol), H 2 O (8.8 mL), and 1,4 dioxane (2 mL) at ice bath temperature was added Br 2 (0.6 mL, 12.3 mmol) and stirred for 5 minutes. The resulting hypobromite solution was added dropwise to a stirred solution of the compound obtained in step II (0.6 g, 2.2 mmol) in 1,4-dioxane (2.4 mL) at around 10°C. The reaction mixture was gradually warmed to r.t, stirred for 1 h, then cooled to 0 °C and quenched by adding acetic acid (2 mL, 36.3 mmol).
  • Step IV To a solution of the acid (0.55 g, 1.95 mmol) obtained in step III in toluene (8 mL) at ice bath temperature Et 3 N (1.2 mL, 8.8 mmol) and diphenylphosphoryl azide (0.5 mL, 2.3 mmol) were added. The reaction mixture was gradually warmed to r.t., stirred for one hour, and then refluxed for 4 h. Upon cooling to room temperature, the reaction mixture was transferred to a separatory funnel and washed once with water. The organic layer was transferred to a RB flask cooled to ice bath temperature and an aq.
  • Step I To a stirred solution of the compound obtained by preparation 8 step I (0.9 g, 5.0 mmol) in THF (20 rnL) at 0°C, Et 3 N (2.1 mL, 15 mmol) and 4-chloro butyroyl chloride (1.02 g, 7.5 mmol) were added. After stirring the reaction mixture at room temperature for 1 h, an aqueous solution of NaOH (50%, 10 mL) was added drop-wise followed by addition of Tz-Bu 4 NI (182 mg, 10 mol %). After stirring the reaction mixture for 16 h, it was diluted with water and extracted in EtOAc. The combined organic layers were washed with brine, dried over Na 2 SO 4 , and the solvent was removed under reduced pressure.
  • Step II To a stirred mixture of NaOH (2.4 g, 60.6 mmol), H 2 O (16 mL) and 1,4 dioxane (4 mL) at ice bath temperature was added Br 2 (1.13 mL, 22.6 mmol) and stirred for 5 minutes. The resulting hypobromite solution was added dropwise to a stirred solution of the compound obtained in step I (1.0 g, 4.04 mmol) in 1,4-dioxane (18 mL) at 10°C. The temperature of the reaction was brought to room temperature and the reaction mixture was stirred for 1 h. Then it was cooled to ice bath temperature and quenched by adding acetic acid (3.9 mL, 65.7 mmol).
  • Step IH To a stirred solution of the acid obtained in step II (0.5 g, 2.0 mmol) in CHCl 3 (21 mL) at room temperature was added cone. H 2 SO 4 (1.0 mL, 20 mmol) followed by NaN 3 (0.39 g, 6.0 mmol) in portions over a period of 30 min., so that the temperature of the reaction did not rise above 4O 0 C. The reaction was warmed to 45 0 C and stirred for 2 h, then cooled to ice bath temperature, diluted with water and extracted with EtOAc. The aqueous layer was basified by adding 50% NaOH solution and extracted with CHCl 3 .
  • Step I To a stirred solution of the compound obtained from the preparation 8 step I (1.0 g, 5.6 mmol) in THF (23 mL) at 0°C was added Et 3 N (1.2 niL, 8.4 mmol), followed by the addition of 4-chlorobutyrylchloride (1.02 g, 7.5 mmol). After stirring the reaction mixture at r.t for 1 h, an aqueous NaOH solution (50%w/v, 11 mL) was added; followed by the addition of W-Bu 4 NI (182 mg, 0.56 mmol). The reaction mixture was stirred for 16 h, diluted with water, and extracted with EtOAc.
  • Step II To a stirred mixture of NaOH (2.1 g, 53.0 mmol), H 2 O (14 mL), and 1,4 dioxane (4 mL) at ice bath temperature was added Br 2 (1.0 mL, 19.8 mmol) and the mixture was stirred for 5 minutes. Thus formed hypobromite solution was added drop-wise to a stirred solution of the compound obtained in step I (1.0 g, 3.53 mmol) in 1,4-dioxane (7 mL) at 10 0 C. The temperature of the reaction was gradually brought to room temperature and the reaction was stirred for 1 h, then it was cooled to ice bath temperature and quenched by adding AcOH (3.9 mL, 65.7 mmol).
  • Step III To a stirred solution of the acid obtained in step II (0.29 g, 1.0 mmol) in CHCl 3 (5 rtiL) at room temperature was added cone. H 2 SO 4 (0.53 niL, 10 mmol) followed by the addition NaN 3 (0.2 g, 3.0 mmol) in portions over a period of 30 min; while maintaining the temperature below 40°C. The reaction mixture was warmed to 45°C and stirred for 2 h. The reaction mixture was cooled to ice bath temperature, diluted with water and extracted with EtOAc. The aqueous layer was basified by adding a 50% NaOH solution and extracted with CHCl 3 .
  • Step I To a suspension of NaH (60% dispersed in nujol, 1.92 g, 80 mmol) in THF (80 mL) cooled to ice bath temperature was added 4-hydroxyadamantanone (6.64 g, 40 mmol) dis- solved in THF (80 mL) via a syringe over a period of 15 minutes. After stirring the reaction mixture for 30 min., RBu 4 NI (1.4 g, 4 mmol) was added followed by the addition of benzylbromide (5.26 mL). The reaction mixture was warmed to room temperature and stirred for 16 h until TLC revealed disappearance of hydroxyadamantanone. Excess NaH was quenched by adding sat.
  • Step II Freshly prepared methylmagnesium iodide in ether (0.5M, 114 mL), was added through a canula to the compound obtained in step I (7.3 g, 28.5 mmol) in THF (57 mL) at O 0 C. After stirring it for 0.5 h, the reaction mixture was quenched by adding sat. aq. NH 4 Cl solution. The organic layer was separated and the aqueous layer was extracted with isopropyl ether.
  • Step HI The compound obtained in step II (7.5 g, 27.5 mmol) was dissolved in a mixture of AcOH ((5.5 mL) and THF (28 mL) and added drop-wise through an additional funnel to the ice cold solution of NaOCl (4%, 275 mL) over a period of 15 minutes.
  • W-Bu 4 NI 210 mg, 2 mol%) was added and the reaction mixture was stirred for 1.5 h.
  • the reaction mixture was poured into a separation funnel and two layers were separated. The aqueous layer was extracted in diisopropylether and the combined organic layer was washed with water and brine, dried over Na 2 SO 4 , and the solvent was removed under reduced pressure.
  • Step IV To a mixture of NaOH (10.8 g, 270 mmol), H 2 O (72 mL) and 1,4-dioxane (20 mL) at ice bath temperature was added Br 2 (5.2 mL, 100.8 mmol) and stirred for 5 minutes. This hypobromite solution was added drop-wise to a solution of the compound obtained from step III (4.84 g, 18 mmol) in 1,4-dioxane (18 mL) kept at ice bath temperature. The reaction mixture was gradually warmed to room temperature and stirred for 1 h, after which it was cooled to ice bath temperature and quenched by adding AcOH (3.9 mL, 65.7 mmol), diluted with water, and extracted in EtOAc.
  • Step V To a solution of the acid obtained from step IV (1.36 g, 5 mmol) in toluene (20 mL) at ice bath temperature was added Et 3 N (2.1 mL, 15 mmol) and diphenylphosphoryl azide (DPPA, 1.3 mL, 6 mmol). The reaction mixture was slowly warmed to room temperature and stirred for one hour, after which the temperature was risen to reflux for 4 h. Upon cooling to room temperature, it was transferred to a separatory funnel and washed once with water. The organic layer was transferred back to the RB flask cooled to ice bath temperature and aq.
  • Et 3 N 2.1 mL, 15 mmol
  • DPPA diphenylphosphoryl azide
  • Step VI To a solution of the amino compound obtained from step V (590 mg, 2.4 mmol) in dichloromethane (10 mL) at ice bath temperature was added Et 3 N (0.5 mL, 3.6 mmol) followed by addition of Boc anhydride (654 mg, 3.0 mmol). The reaction mixture was stirred at room temperature for 1 h.
  • Step VII A mixture of the compound obtained from step VI (730 g, 2.1 mmol) and Pd(OH) 2 /C (20% wet, 150 mg) in MeOH (9 mL) was stirred under H 2 atmosphere at room temperature for 2 h. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure to obtain fert-butyl (1 -hydroxy tricyclo
  • Stepl A stirred mixture of [3-(2-Methyl-l,3-dioxolan-2-yl)tricyclo[3.3.1.0 3 ' 7 ]non-l-yl] methyl methanesulfonate (2.4 g, 1.5 mmol) [as obtained from preparation 2], K 2 CO 3 (4.5 g, 34.2 mmol), and 1,2,4-triazole (1.5 g, 22.5 mmol) in DMF (30 mL) was heated to HO 0 C for 5 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethylacetate. The combined organic layer was washed with brine, dried over Na 2 SO 4 , and the solvent was removed under reduced pressure.
  • StepII A stirred solution of l- ⁇ [3-(2-Methyl-l,3-dioxolan-2-yl)tricyclo[3.3.1.0 3l7 ]non-l-yl] methyl ⁇ -IH- 1,2,4-triazole (2.6 g, 9.09 mmol) obtained from Step I and p-toluenesulfonic acid (0.16 g) in acetone (36 mL) was refluxed for 4 h. The volatiles were removed under reduced pressure and the residue was diluted with ethylacetate, washed with 10% aq.
  • hypobromite solution was added drop- wise to a stirred solution of l-[l-(liJ-l,2,4-triazol-l-ylmethyl) tricyclo [3.3.1.O 3 ' 7 ] non-3- yl] ethanone (0.7 g, 2.92 mmol) in 1,4-dioxane (4 mL) at ice bath temperature.
  • the reaction mixture was gradually warmed to room temperature and stirred for 1 h. Then it was cooled to ice bath temperature and quenched by adding AcOH (3.9 mL, 65.7 mmol).
  • the crude reaction mixture was diluted with water and extracted with EtOAc.
  • StepIV To a stirred suspension of l-(l#-l,2,4-triazol-l-ylmethyl) tricyclo [3.3.1.O 3 ' 7 ] nonane-3-carboxylic acid (0.13 g, 0.52 mmol) obtained in step III, in CHCl 3 (2.6 mL) was added cone. H 2 SO 4 (0.25 mL, 5.2 mmol). To this homogenous solution NaN 3 (0.1 g, 1.56 mmol) was added in portions over a period of 30 minutes, while keeping the temperature of the reaction below 40°C. After stirring the reaction mixture for 2 h at r.t, the reaction mixture was cooled to ice bath temperature, diluted with water and extracted with EtOAc.
  • l-(lH-l,2,4-triazol-l-ylmethyl) tricyclo [3.3.1.0 3 ' 7 ]nonan-3-amine (0.08 g) as a viscous liquid in 70% yield, m/z (M+l) 219; 1 H NMR (CDCl 3 ) 300 MHz ⁇ 7.98 (s, IH), 7.93 (s, IH), 4.07 (s, 2H), 2.38-2.30 (m, IH), 2.06-1.98 (m, IH), 1.96-1.80 (m, 2H), 1.72-1.57 (m, 4H), 1.55-1.36 (m, 4H).
  • Step V To a stirred mixture of l-(lH-l,2,4-triazol-l-ylmethyl) tricyclo [3.3.1.O 3 ' 7 ] nonan- 3-amine (0.06g, 0.38 mmol) and K 2 CO 3 (0.13 g, 0.96 mmol) in DMSO (1 mL) at an ice bath temperature was added compound (2iS)-l-(chloroacetyl)pyrrolidine-2-carbonitrile (0.07 g, 0.32 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 3 h.
  • the crude product was purified by column chromatography to obtain (25,4SM-IlUOrO- 1 - ⁇ N-[2-(lH- 1 ,2,4-triazol- 1 -ylmethyl)hexahydro-2,5-methanopentalen- 3a(lH)-yl]glycyl ⁇ pyrrolidine-2-carbonitrile as an off-white powder (0.4 g) in 36% yield.
  • step IV example 1 To a stirred mixture of the triazole amine as obtained in step IV example 1 (0.27 g, 1.05 mmol) and K 2 CO 3 (0.58 g, 4.2 mmol) in DMSO (4 mL) at ice bath temperature was added (4i?)-3-(chloroacetyl)-l,3-thiazolidine-4-carbonitrile (0.2 g, 1.05 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 3 h. Upon completion of the reaction (by TLC), the reaction mixture was diluted with EtOAc and washed with water and brine, dried over Na 2 SO 4 , and the solvent was removed under reduced pressure.
  • Step I A mixture of ⁇ 3-[(fert-butoxy carbonyl) amino] tricyclo [3.3.1.0 3 ' 7 ]non-l-yl ⁇ methyl methanesulfonates as obtained in preparation 3 (0.8 g, 2.3 mmol), K 2 CO 3 (0.95 g, 6.9 mmol), tetrazole (0.24 g, 3.45 mmol), and DMF (10.0 mL) was heated to 110 0 C for 12 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc. The combined organic layer was washed with brine, dried over Na 2 SO 4 , and the solvent was removed under reduced pressure.
  • Step II To a stirred solution of the compound obtained in step I above (0.2 g, 0.62 mmol) in EtOAc (2.0 mL) cooled to ice bath temperature was added a solution of dry HCl in EtOAc (3N, 3mL).
  • Step III To a stirred solution of the hydrochloride salt obtained in step II (0.162g, 0.62 mmol) in DMSO (2.5 mL) at room temperature under nitrogen atmosphere was added (25)-l-(chloroacetyl)pyrrolidine-2-carbonitrile (0.11 g, 0.62 mmol) and K 2 CO 3 (0.34 g, 2.48 mmol). After stirring the reaction mixture for 3 h, it was diluted with EtOAc, and washed with water and brine, dried over Na 2 SO 4 , and the solvent was removed under reduced pressure.
  • Example 5A Hydrochloride salt: To a stirred solution of the compound obtained in example 5 (36 mg, 0.1 mmol) in methanol (2 mL) cooled to 0°C was added TMS-Cl (25 ⁇ L, 0.2 mmol). After 30 minutes, the volatiles were removed under reduced pressure and the residue was triturated several times with ether to obtain off-white hydrochloride salt of (26)-l- ⁇ iV-[2-(l/f-tetrazol-l-ylmethyl) hexahydro-2,5-methanopentalen-3a(lH)-yl] glycyl ⁇ pyrrolidine -2-carbonitrile (38 mg).
  • Step I A mixture of ⁇ 3-[(tert-butoxy carbonyl) amino] tricyclo [3.3.1.0 3 ' 7 ]non-l-yl ⁇ methyl methanesulfonates as obtained in preparation 3 (0.85 g, 2.4 mmol), K 2 CO 3 (1.0 g, 7.2 mmol), N-methylpiperazine (0.37 mL, 3.6 mmol) and DMF (10.0 mL) was heated to HO 0 C for 12 h. The reaction mixture was cooled to room temperature, diluted with water and extracted in EtOAc. The combined organic layer was washed with brine, dried over Na 2 SO 4 and the solvent was removed under reduced pressure.
  • Step II To a stirred solution of the compound obtained according to step I (0.38 g, 1.09 mmol), in EtOAc (4.0 mL) cooled to ice bath temperature was added a solution of dry HCl in EtOAc (3 N, 6 mL). The reaction mixture was stirred at the same temperature for 2 h and the volatiles were removed under reduced pressure to obtain a crude products, which was triturated with diethyl ether several times to obtain l-[(4-methylpiperazin-l-yl) methyl] tricyclo [3.3.1.O 3 ' 7 ] nonan-3 -amine hydrochloride salt (330 mg) in 85% yield.
  • Step III To a stirred solution of the hydrochloride (0.33 g, 0.92 mmol) obtained in step II, in DMSO (3.7 mL) at room temperature under nitrogen atmosphere (2iS)-l-(chloroace- tyl)pyrrolidine-2-carbonitrile (0.16 g, 0.92 mmol) and K 2 CO 3 (0.76 g, 5.53 mmol) were added. After stirring the reaction mixture for 3 h, it was diluted with EtOAc and washed with water and brine, dried over Na 2 SO 4 , and the solvent was removed under reduced pressure.
  • Example 6A Hydrochloride salt: To a stirred solution of the compound obtained in example 7 (39 mg, 0.1 mmol) in methanol (2 mL) cooled to O 0 C was added TMS-Cl (25 ⁇ L, 0.2 mmol). After 30 minutes, the volatiles were removed under reduced pressure and the residue was triturated several times with diethyl ether to obtain (2S)-l- ⁇ N-[2-[(4- methylpiperazin-l-yl)methyl]hexahydro-2,5-methanopentalen-3a(lH)-yl]glycyl ⁇ pyrrolidine -2-carbonitrile hydrochloride salt as an off-white solid (41 mg).
  • Step I A mixture of ⁇ 3-[(tert-butoxy carbonyl) amino] tricyclo [3.3.1.O 3 ' 7 ] non-l-yl ⁇ methyl methanesulfonates as obtained in preparation 3 (0.85 g, 2.4 mmol), K 2 CO 3 (1.0 g, 7.2 mmol), thiomorpholine (0.4 mL, 3.6 mmol) and DMF (10.0 mL) was heated to HO 0 C for 12 h. The reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The combined organic layer was washed with brine, dried over Na 2 SO 4 , and the solvent was removed under reduced pressure.
  • Step II To a stirred solution of the compound (0.22 g, 0.63 mmol) obtained in step I, in
  • Step III To a stirred solution of the hydrochloride salt (0.17 g, 0.51 mmol) obtained in step II above in DMSO (2.0 mL) at room temperature under nitrogen atmosphere was added (26)-l-(chloroacetyl)pyrrolidine-2-carbonitrile (0.09 g, 0.52 mmol) and K 2 CO 3 (0.35 g, 2.55 mmol. After stirring the reaction mixture for 3 h, it was diluted with EtOAc and washed with water and brine, dried over Na 2 SO 4 and the solvent was removed under reduced pressure.
  • Example 7A Hydrochloride salt: To a stirred solution of the compound obtained in example 7 (39 mg, 0.1 mmol), in methanol (2 mL) cooled to 0°C was added TMS-Cl (25 ⁇ L, 0.2 mmol). After 30 minutes, the volatiles were removed under reduced pressure and the residue was triturated several times with diethyl ether to obtain the hydrochloride salt of (25)-l- ⁇ N-[2-(thiomorpholin-4-ylmethyl) hexahydro-2,5-methanopentalen-3a(lH)-yl] glycyl ⁇ pyrrolidine-2-carbonitrile as off-white solid (41 mg).
  • Step I A stirred mixture of [3-(2-Methyl-l,3-dioxolan-2-yl)tricyclo[3.3.1.0 3 ' 7 ]non-l-yl] methyl methanesulfonate as obtained in preparation 2 (1.0 g, 2.9 mmol), K 2 CO 3 (1.16 g, 8.7 mmol) and isothiazolidine- 1,1 -dioxide (0.53 g, 4.35 mmol) in DMF (12.0 mL) was heated to 110°C for 16 h. The reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The combined organic layer was washed with brine, dried over Na 2 SO 4 and the solvent was removed under reduced pressure.
  • Step II A stirred solution of the compound obtained by Step I (0.68 g, 2.0 mmol) and p- toluenesulfonic acid (38 mg, 0.2 mmol) in acetone (8 mL) was refluxed for 4 h. The reaction mixture was diluted with EtOAc and washed with 10% aq. NaHCO 3 and brine, dried over Na 2 SO 4 , and the solvent was evaporated under reduced pressure to obtain 1- ⁇ 1- [(1,1-dioxido isothiazolidin-2-yl)methyl]tricyclo[3.3.1.0 3 ' 7 ]non-3-yl ⁇ ethanone (0.55g) in 92% yield as a viscous liquid.
  • Step III To a stirred mixture of NaOH (1.2 g, 27.8 mmol), H 2 O (8 mL), and 1,4 dioxane
  • Step IV To a stirred solution of the acid obtained in step III (0.39 g, 1.31 mmol) in CHCl 3 (7 mL) was added cone. H 2 SO 4 (1.4 mL, 26 mmol). Solid NaN 3 (0.26 g, 3.93 mmol) was added slowly in portions by keeping the reaction temperature below 40°C. The reaction mixture was stirred at r.t for 2, h then it was cooled to ice bath temperature, diluted with water, and extracted with EtOAc. The aqueous layer was basified by adding 50% NaOH solution and extracted with CHCl 3 .
  • Step V To a stirred mixture of the amine obtained in step IV (0.26 g, 0.96 mmol) and K 2 CO 3 (0.42 g, 2.9 mmol) in DMSO (4.0 mL) at ice bath temperature was added under nitrogen atomsphere (S)-l-(2-chloro-acetyl) pyrrolidine-2-carbonitrile (0.17 g, 1.0 mmol). After stirring the reaction mixture for 3 h at r.t, it was diluted with EtOAc, washed with water and brine, dried over Na 2 SO 4 , and the solvent was evaporated under reduced pressure.
  • S nitrogen atomsphere
  • Step I A mixture of the compound obtained in preparation 3 (0.9 g, 2.6 mmol), K 2 CO 3 (1.1 g, 7.8 mmol) and thiazolidine-2,4-dione (0.47 g, 4.0 mmol) in DMF (10.5 mL) was heated to HO 0 C for 12 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc. The combined organic layer was washed with brine, dried over Na 2 SO 4 , and the solvent was removed under reduced pressure.
  • Step II To a stirred solution of the compound obtained in step I (0.2 g, 0.54 mmol) in EtOAc (2.0 mL) cooled to ice bath temperature was added a solution of dry HCl in EtOAc (3N, 3mL).
  • Step III To a stirred solution of the hydrochloride salt obtained in step II (0.165g, 0.54 mmol) in DMSO (2.2 mL) at room temperature under nitrogen atmosphere (S)-I -(2- chloro-acetyl)pyrrolidine-2-carbonitrile (0.1 g, 0.54 mmol) and K 2 CO 3 (0.23 g, 1.62 mmol) was added sequentially. After stirring the reaction mixture for 3 h, it was diluted with EtOAc and washed with water and brine, dried over Na 2 SO 4 , and the solvent was removed under reduced pressure.
  • Step I To a stirred solution of tert-butyl [l-(hydroxymethyl)tricyclo[3.3.1.0 3 ' 7 ]non-3- yl] carbamate (as obtained in step VI preparation 3) (0.67 g, 2.5 mmol) in toluene (10 niL) was added phthalimide (0.52 g, 3.5 mmol), triphenylphosphine (1.05 g, 4.0 mmol), and diisopropylazodicarboxylate (0.8 mL, 4.0 mmol). The reaction mixture was heated to 90°C for 4 h.
  • Step II To a stirred solution of the compound obtained from step I (0.45 g, 1.12 mmol) in dichloromethane (1.1 mL) at 0°C was added trifluoroacetic acid (1.1 mL). The reaction mixture was gradually warmed to room temperature and stirred for 1 h.
  • Step III To a stirred mixture of the compound obtained from step II (0.4 g, 0.98 mmol) and K 2 CO 3 (0.54 g, 3.92 mmol) in DMSO (4.0 mL) at ice bath temperature under nitrogen atomsphere was added (S)-I -(2-chloro-acetyl) pyrrolidine-2-carbonitrile (0.17 g, 1.0 mmol). After stirring the reaction mixture at r.t for 3 h, it was diluted with EtOAc and washed with water and brine, dried over Na 2 SO 4 , and the solvent was removed under reduced pressure.
  • Step I To a stirred solution of benzyl [2-(4-aminophenyl)hexahydro-2,5-methano pentalene-3a(lH)-yl]carbamate (1.1 g, 3.03 mmol) obtained from preparation 4, in THF (30 rnL) at 0°C was added Et 3 N (0.66 mL, 4.6 mmol) and 3-chloropropanesulfonylchloride (0.42 mL, 3.3 mmol). The reaction mixture was warmed to room temperature and stirred for 1 h. An aqueous solution of NaOH (50% w/v, 6 mL) was added followed by addition of W-Bu 4 NI (56 mg, 0.15 mmol).
  • StepII A mixture of benzyl [2-[4-(l,l-dioxidoisothiazolidin-2-yl)phenyl) hexahydro-2,5- methanopentalene-3a(lH)-yl]carbamate (0.8 g, 1.7 mmol) obtained in step I, Pd/C (10%, 0.4 g) in MeOH (17 niL) was stirred at room temperature under H 2 atmosphere for 2 h.
  • reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure to obtain l-[4-(l,l-dioxidoisothiazolidin-2-yl)phenyl] tricyclo [3.3.1.0 3 ' 7 ] nonan-3-amine as an off-white solid (0.49g) in 85% yield, m/z (M+l) 333; IR cm "1 3418, 1652, 1137, 772.
  • Step III To a stirred mixture of l-[4-(l,l-dioxidoisothiazolidin-2-yl) phenyl] tricyclo [3.3.1.O 3 ' 7 ] nonan-3-amine (0.4 g, 1.2 mmol) and K 2 CO 3 (0.48 g, 3.6 mmol) in DMSO (4.8 mL) at ice bath temperature was added (25)-l-(chloroacetyl) pyrrolidine-2-carbonitrile (0.25 g, 1.44 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 3 h.
  • Step I To a stirred solution of benzyl [2-(4-aminophenyl) hexahydro-2,5-methano pentalene-3a(lH)-yl] carbamate (1.1 g, 3.03 mmol) obtained in preparation 4, in THF (30 mL) at O 0 C was added sequentially Et 3 N (0.66 mL, 4.6 mmol) and 4-chlorobutyrylchloride (0.37 mL, 3.3 mmol). The reaction mixture was warmed to room temperature and stirred for 1 h.
  • Step II A mixture of benzyl [2-[4-(2-Oxopyrrolidin-l-yl)phenyl) hexahydro-2,5- methanopentalene-3a(lH)-yl]carbamate (0.73 g, 1.7 mmol) obtained in step I and Pd/C (10%, 0.4 g) in MeOH (17 mL) was stirred at room temperature under H 2 atmosphere for 2 h.
  • Step III To a stirred solution of l-[4-(3-amino1ricyclo[3.3.1.0 3 ' 7 ]non-l-yl)phenyl] pyrrolidin-2-one obtained in step II (0.36 g, 1.2 mmol) in DMSO (4.8 niL) at an ice bath temperature under nitrogen atmosphere was added K 2 CO 3 (0.48 g, 3.6 mmol) followed by addition of (25)-l-(chloroacetyl) pyrrolidine-2-carbonitrile (0.21 g, 1.2 mmol).
  • step II To a stirred mixture of the lactam amine obtained in example 12, step II (0.15 g, 0.5 mmol) and K 2 CO 3 (0.21 g, 1.5 mmol) in DMSO (2 mL) at ice bath temperature was added (4R)-3-
  • Step I To a stirred solution of benzyl [2-(4-aminophenyl) hexahydro-2,5- methanopentalene-3a(lH)-yl] carbamate obtained from preparation 4 (1.09 g, 3.0 mmol) in glacial acetic acid (12 mL) was added 2,5-dimethoxytetrahydrofuran (0.44 g, 3.3 mmol). The reaction mixture was heated under reflux for 1 h. The mixture was diluted with ethylacetate, washed with water, 10% aq. NaHCO 3 and brine. The combined organic layer was dried over anhydrous Na 2 SO 4 and the solvent was evaporated under reduced pressure.
  • Step II To a stirred solution of the compound obtained from step I (0.8 g, 1.94 mmol) in MeOH (20 mL) Pd/C (10%, 0.1 g) was added. The reaction mixture was stirred at r.t. for 2 h under H 2 pressure with a balloon.
  • Step III To a stirred mixture of the compound obtained from step II (0.41 g, 1.5 mmol) and K 2 CO 3 (0.62 g, 4.5 mmol) in DMSO (6 mL) at ice bath temperature under N 2 atmosphere was added (S)-l-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (0.26 g, 1.5 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 3 h. Upon completion of the reaction (checked by TLC), the reaction mixture was diluted with EtOAc and washed with water and brine, dried over Na 2 SO 4 , and the solvent was removed under reduced pressure.
  • Step I To a stirred solution of benzyl [2-(4-aminophenyl) hexahydro-2,5-methano pentalene-3a(lH)-yl]carbamate obtained by preparation 4 (1.09 g, 3.0 mmol) in THF (12 mL) at O 0 C was added Et 3 N (0.65 mL, 4.5 mmol), followed by addition of 2-chloro ethylisocyanate (0.3 mL, 3.3 mmol). The reaction mixture was warmed to room temperature and stirred for 1 h.
  • Step II To a stirred solution of the compound obtained from step I (0.65 g, 1.5 mmol) in MeOH (15 mL) Pd/C (10%, 0.1 g) was added. The reaction mixture was stirred at room temperature for 2 h under H 2 pressure with a balloon. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure to obtain l-[4-(3-amino tricyclo [3.3.1.0 3>7 ]non-l-yl)phenyl]imidazolidin-2-one (0.4 g) as an off- white solid in 90% yield.
  • Step III To a stirred mixture of the compound obtained from step II (0.4 g, 1.35 mmol) and K 2 CO 3 (0.56 g, 4.05 mmol) in DMSO (6 mL) at ice bath temperature under N 2 atmosphere was added (S)-l-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (0.23g, 1.35 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 3 h. Upon completion of the reaction (checked by TLC), the reaction mixture was diluted with EtOAc and washed with water and brine, dried over Na 2 SO 4 , and the solvent was evaporated under reduced pressure.
  • Step I To a stirred mixture of tricyclo [3.3.1.0 3 ' 7 ] nonan-3-amine (0.28 g, 2.0 mmol) and K 2 CO 3 (0.83 g, 6.0 mmol) in DMSO (8 mL) at ice bath temperature under N 2 atmosphere was added (S)-l-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (0.34 g, 2.0 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 3 h. Upon completion of the reaction (checked by TLC), the reaction mixture was diluted with EtOAc and washed with water and brine, dried over Na 2 SO 4 , and the solvent was removed under reduced pressure.
  • Example 19 A Hydrochloride salt: To a stirred solution of the compound obtained in example 18 (27 mg, 0.1 mmol) in methanol (2 mL) cooled to 0 0 C was added TMS-Cl (25 ⁇ L, 0.2 mmol). After 30 minutes, the volatiles were removed under reduced pressure and the residue was triturated several times with diethyl ether to obtain hydrochloride salt of (2 * S)-l-[(tricyclo [3.3.1.0 ' ]non-3-ylamino)acetyl]pyrrolidine-2-carbonitrile as an off-white solid (31 mg).
  • Step I To a stirred solution of tert-butyl (1-hydroxytricyclo [3.3.1.0 ' ]non-3-yl)carbamate as obtained in preparation 11 (500 mg, 1.97 mmol) in EtOAc (5 mL) cooled to ice bath temperature was added a solution of dry HCl in EtOAc (4N, 5 mL). After the reaction mixture was stirred for 2 h, the volatiles were removed under reduced pressure.
  • Step II To a stirred mixture of the compound obtained in step I (280 mg, 1.5 mmol) and K 2 CO 3 (820 mg, 6 mmol) in DMSO (6 mL) at ice bath temperature under N 2 atmosphere was added (S)-l-(2-chloro-acetyl) pyrrolidine-2-carbonitrile (205 mg, 1.2 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 3 h. Upon completion of the reaction (checked by TLC), the reaction mixture was diluted with EtOAc and washed with water and brine, dried over Na 2 SO 4 , and the solvent was removed under reduced pressure.
  • Stepl To a suspension of NaH (60% dispersed in nujol, 0.96 g, 24 mmol) in THF (40 mL) cooled to ice bath temperature was added hydroxyadamantanone (3.32 g, 20 mmol) dissolved in THF (40 mL) via a syringe over a period of 15 minutes. After stirring the reaction mixture for 30 min., iodomethane (1.38 mL, 22 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 16 h until TLC revealed completion of the reaction. Excess NaH was quenched by adding saturated aq. NH 4 Cl solution to the ice cooled reaction mixture.
  • StepII Freshly prepared methyl magnesium iodide in ether (IM, 32 mL), was added through a canula to 5-methoxyadamantan-2-one (3.0 g, 16 mmol) in THF (32 mL) at 0°C. After stirring the mixture at O 0 C for 0.5 h, the reaction mixture was quenched by adding saturated aq.NH 4 Cl solution. The organic layer was separated and the aqueous layer was extracted with diethyl ether.
  • StepIII 5-methoxy-2-methyladamantan-2-ol (3.0 g, 15 mmol), dissolved in a mixture of AcOH (3.0 mL) and THF (15 mL) was added dropwise by a dropping funnel to an ice bath cooled solution of NaOCl (4%, 150 mL) over a period of 15 minutes.
  • W-Bu 4 NI (0.55 g, 1.5 mmol) was added and the reaction mixture was stirred for 1.5 h. The reaction mixture was separated into two layers.
  • hypochlorite was diluted with methanol (30 mL) and solid KOH (1.68 g, 30 mmol) was added.
  • the reaction mixture was refluxed for Ih. The volatiles were removed and the crude product was diluted with ether, washed with water, brine, dried over anhydrous Na 2 SO 4 , and the solvent was evaporated under vacuum.
  • StepIV To a mixture of NaOH (5.8 g, 147 mmol), H 2 O (40.0 mL) and 1,4 dioxane (10 mL) at ice bath temperature was added Br 2 (2.8 mL, 55.0 mmol) and stirred for 5 minutes. The resulting hypobromite solution was added drop-wise to a stirred solution of 1-(1- methoxytricyclo [3.3.1.0 3>7 ]non-3-yl)ethanone obtained from step III (1.9 g, 9.8 mmol), in 1,4-dioxane (10 mL) at ice bath temperature. The reaction mixture was gradually warmed to room temperature and stirred for 1 h.
  • StepV To the suspension of 1-methoxytricyclo [3.3.1.0 3 ' 7 ]nonane-3-carboxylic acid obtained from step IV (0.39 g, 2.0 mmol) in CHCl 3 (10 mL) was added cone. H 2 SO 4 (1.0 mL, 20 mmol). Solid NaN 3 (0.39 g, 6.0 mmol) was added in portions by keeping the reaction temperature below 40 °C. After stirring at room temperature for 2 hrs, the reaction mixture was cooled to ice bath temperature, diluted with water and extracted with EtOAc. The aqueous layer was basified by adding 50% NaOH solution and extracted with CHCl 3 .
  • Step VI To a stirred solution of the amino compound obtained by step V (0.16g, 0.95 mmol) in DMSO (4.0 mL) was added (S)-I -(2-chloro-acetyl)pyrrolidine-2-carbonitrile (0.17 g, 0.96 mmol) and K 2 CO 3 (0.4 g, 2.9 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 3 h. The reaction mixture was diluted with EtOAc and washed with water ad brine, dried over Na 2 SO 4 , and the solvent was removed under reduced pressure.
  • Example 16A Hydrochloride salt : To a stirred solution of the compound prepared in example 16 (30 mg, 0.1 mmol) in methanol (2 mL) cooled to 0°C was added TMS-Cl (25 ⁇ L, 0.2 mmol). After 30 minutes, the volatiles were removed under reduced pressure and the residue was triturated several times with diethyl ether to obtain (25)-l- ⁇ [(l- methoxytricyclo [3.3.1.0 ' ]non-3-yl)amino]acetyl ⁇ pyrrolidine-2-carbonitrile hydrochloride salt as off-white solid (30 mg).
  • Step I To a suspension of NaH (60% dispersed in nujol, 0.96 g, 24 mmol) in THF (40 mL) cooled to ice bath temperature was added hydroxyadamantanone (3.32 g, 20 mmol) dissolved in THF (40 mL) via a syringe over a period of 15 minutes. The reaction mixture was stirred for 30 min then W-Bu 4 NI (0.74 g, 2 mmol) and ethyl bromide (1.6 mL, 22 mmol) were added. The reaction mixture was warmed to room temperature and stirred for
  • Example 17A Hydrochloride salt: To a stirred solution of the compound obtained from example 17 (32 mg, 0.1 mmol) in methanol (2 mL) cooled to 0°C was added TMS-Cl (25 ⁇ L, 0.2 mmol). After 30 minutes, the volatiles were removed under reduced pressure and the residue was triturated several times with diethyl ether to obtain the hydrochloride salt of (2S)-I- ⁇ [(1-ethoxy tricyclo[3.3.1.0 3 ' 7 ]non-3-yl)amino]acetyl ⁇ pyrrolidine-2-carbonitrile as an off-white solid (30 mg).
  • Step I To a stirred mixture of the compound obtained in preparation 8 (0.3 g, 1.2 mmol) and K 2 CO 3 (0.5 g, 3.6 mmol) in DMSO (5 mL) at ice bath temperature under N 2 atmosphere was added (S)-l-(2-chloro-acetyl) pyrrolidine-2-carbonitrile (0.14 g, 0.83 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 3 h. Upon completion of the reaction (checked by TLC), the reaction mixture was diluted with EtOAc and washed with water and brine, dried over Na 2 SO 4 , and the solvent was removed under reduced pressure.
  • Step II To a stirred solution of the compound obtained in step I (0.04 g, 0.1 mmol) in EtOAc (2 rnL) cooled to ice bath temperature was added a solution of dry HCl in EtOAc (3N, 2 mL).
  • Step I To a stirred solution of fer/-butyl (1-hydroxytricyclo [3.3.1.0 3 ' 7 ]non-3-yl)carbamate obtained from preparation 11 (1.1 g, 4.34 mmol) in dichloromethane cooled to — 15°C, under N 2 atmosphere was added diethylaminosulfur trifluoride (0.85 mL, 6.51 mmol). The reaction mixture was stirred at this temperature for 1 h and subsequently stirred at room temperature for 16 h. The reaction mixture was cooled to ice bath temperature and quenched by adding a mixture of crushed ice and solid NaHCO 3 (1.1 g, 13 mmol). Two layers were separated and the aqueous layer was extracted with chloroform.
  • Step II To a stirred solution of the compound obtained from step I (0.25 g, 0.98 mmol) in EtOAc (1 mL) cooled to ice bath temperature was added a solution of dry HCl in EtOAc (3N, 3 mL). After stirring the reaction mixture for 2 h, the volatiles were removed under reduced pressure.
  • Step III To a stirred mixture of the hydrochloride salt obtained from step II (0.19 g, 0.98 mmol) and K 2 CO 3 (0.53 g, 4.0 mmol) in DMSO (4.0 mL) at ice bath temperature under nitrogen atmosphere (S)-l-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (0.17 g, 1.0 mmol) was added. After stirring the reaction mixture at r.t. for 3 h, the reaction mixture was diluted with EtOAc and washed with water and brine, dried over Na 2 SO 4 , and the solvent was removed under reduced pressure.
  • Example 23A Hydrochloride salt: To a stirred solution of the compound obtained from example 23 (29 mg, 0.1 mmol) in methanol (2 mL) cooled to 0 0 C was added TMS-Cl (25 ⁇ L, 0.2 mmol). After 30 minutes, the volatiles were removed under reduced pressure and the residue was triturated several times with ether to obtain hydrochloride salt of (25)- 1 - [iV-(2-fluorohexahydro-2,5-methanopentalen-3a(li ⁇ )-yl)glycyl]pyrrolidine-2-carbonitrile as an off-white solid (30 mg).
  • TMS-Cl 25 ⁇ L, 0.2 mmol
  • Step I To a stirred mixture of l-(3-aminotricyclo [3.3.1.0 ' 7 ]non-l-yl)pyrrolidin-2-one prepared as in preparation 9 (0.25 g, 1.1 mmol) and K 2 CO 3 (0.46 g, 3.3 mmol) in DMSO (5 mL) at an ice bath temperature was added (S)-l-(2-chloro-acetyl)pyrrolidine-2- carbonitrile (0.2 g, 1.1 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 3 h.
  • Example 2OA Hydrochloride salt: To a stirred solution of the compound obtained from example 19 (36 mg, 0.1 mmol) in methanol (2 mL) cooled to 0°C was added TMS-Cl (25 ⁇ L, 0.2 mmol). After 30 minutes, the volatiles were removed under reduced pressure and the residue was triturated several times with ether to obtain the hydrochloride salt of (25)- l- ⁇ N-[2-(2-oxopyrrolidin-l-yl)hexahydro-2,5-methanopentalen-3a(lH)-yl] glycyl ⁇ pyrrolidine-2-carbonitrile as off-white solid (38 mg).
  • TMS-Cl 25 ⁇ L, 0.2 mmol
  • Step I To a stirred mixture of l-(l,l-dioxidoisothiazolidin-2-yl)tricyclo[3.3.1.0 ' Jnonan- 3-amine prepared as in preparation 10 (0.17 g, 0.66 mmol), and K 2 CO 3 (0.28 g, 2.0 mmol) in DMSO (2.6 mL) at ice bath temperature was added (S)-I -(2-chloro-acetyl)pyrrolidine-2- carbonitrile (0.13 g, 0.66 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 3 h.
  • Example 2 IA Hydrochloride salt: To a stirred solution of the compound obtained in example 20 (39 mg, 0.1 mmol) in methanol (2 mL) cooled to O 0 C was added TMS-Cl (25 ⁇ L, 0.2 mmol). After 30 minutes, the volatiles were removed under reduced pressure and the residue was triturated several times with diethyl ether to obtain the hydrochloride salt of (25)-l- ⁇ iV-[2-(l,l-dioxidoisothiazolidin-2-yl)hexahydro-2,5-methanopentalen-3a (IH)- yljglycyl ⁇ pyrrolidine-2-carbonitrile as an off-white solid (41 mg).
  • Step I To a stirred mixture of NaOH (2.4 g, 60.0 mmol), H 2 O (16 mL), and 1,4 dioxane (2 mL) at ice bath temperature was added Br 2 (0.56 mL, 10.4 mmol) and stirred for 15 minutes. The resulting hypobromite solution was added dropwise to a stirred solution of 1 - (1-phenyltricyclo [3.3.1.0 3 ' 7 ]non-3-yl)ethanone obtained from preparation I (1.0 g, 4.0 mmol) in 1,4-dioxane (6 mL) at ice bath temperature. After stirring the reaction mixture at r.t.
  • Step II To a stirred solution of 1-phenyltricyclo [3.3.1.0 3>7 ]nonane-3-carboxylic acid (0.6 g, 2.48 mmol) obtained from step I and triethylamine (1.0 mL, 7.44 mmol) in toluene (10 mL) under N 2 atmosphere at ice bath temperature was added diphenylphosphoryl azide (0.64 mL, 3.0 mmol). The reaction mixture was warmed to room temperature and stirred for 1 h, then it was refluxed for 4 h. The reaction mixture was cooled to r.t., washed with water and stirred with aq.
  • Step III To a stirred mixture of the compound obtained from step II (0.2 g, 0.94 mmol) and K 2 CO 3 (0.39 g, 2.8 mmol) in DMSO (4.0 mL) at ice bath temperature under nitrogen atomsphere (S)-l-(2-chloro-acetyl) pyrrolidine-2-carbonitrile (0.16 g, 0.94 mmol) was added. After stirring the reaction mixture for 3 h at r.t, it was diluted with EtOAc and washed with water and brine, dried over Na 2 SO 4 , and the solvent was removed under reduced pressure.
  • Example 26A Hydrochloride salt: To a stirred solution of the compound obtained from example 26 (35 mg, 0.1 mmol) in methanol (2 mL) cooled to 0°C was added TMS-Cl (25 ⁇ L, 0.2 mmol). After 30 minutes, the volatiles were removed under reduced pressure and the residue was triturated several times with diethyl ether to obtain the hydrochloride salt of (25)-l-[N-(2-phenylhexahydro-2,5-methanopentalen-3a(lH)-yl)glycyl]pyrrolidine-2- carbonitrile as an off-white solid (38 mg).
  • TMS-Cl 25 ⁇ L, 0.2 mmol
  • Step I A stirred mixture of the compound obtained in preparation 3 (1.1 g, 3.18 mmol), sodium cyanide (0.164 g, 3.5 mmol) in DMF (7.0 mL) was heated to HO 0 C for 12 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na 2 SO 4 , and the solvent was removed under reduced pressure.
  • Step II To a stirred solution of the compound obtained from step I (0.25 g, 0.9 mmol) in a
  • Step HI To a stirred solution of the compound obtained from step II (0.15 g, 0.47 mmol) in CH 2 Cl 2 (2 mL) cooled to 0°C was added trifluoroacetic acid (0.5 mL). The reaction mixture was gradually warmed to room temperature and stirred for Ih.
  • Step rV TO a stirred solution of the compound obtained from step III (0.12 g, 0.36 mmol) in DMSO (1.5 mL) at room temperature under nitrogen atmosphere was added, (S)-l-(2- chloro-acetyl)pyrrolidine-2-carbonitrile (0.06 g, 0.0.36 mmol) and K 2 CO 3 (0.2 g, 1.44 mmol). After stirring the reaction mixture for 3 h, it was diluted with EtOAc and washed with water and brine, dried over Na 2 SO 4 , and the solvent was removed under reduced pressure.
  • Example 3 IA Hydrochloride salt: To a stirred solution of the compound obtained from example 31 (20 mg, 0.056 mmol) in methanol (1 mL) cooled to 0°C was added TMS-Cl (15 ⁇ L, 0.12 mmol). After 30 minutes, the volatiles were removed under reduced pressure and the residue was triturated several times with ether to obtain the hydrochloride salt of the compound as an off-white solid (21 mg).
  • Step I To a stirred suspension of NaH (50% dispersed in nujol, 50 mg, 1.05 mmol) in THF (3 mL) cooled to 0°C, under N 2 atmosphere was added drop-wise with a syringe a solution of the compound obtained in Example 19, step I (0.3 g, 0.7 mmol) in THF (4 mL). After stirring the reaction mixture at room temperature for 30 minutes, it was cooled again to ice- bath temperature and MeI (0.1 mL, 1.5 mmol) was added. The reaction mixture was slowly warmed to room temperature and stirred for 2 h. Excess NaH was quenched by adding aq. NH 4 Cl solution after cooling the reaction mixture to ice-bath temperature.
  • Step II To a stirred solution of the compound obtained from step I (0.25 g, 0.56 mmol) in a l:l-mixrure Of CH 2 Cl 2 and MeOH (10 mL) was added Pd/C (10% w/w, 0.1 g) and stirred at room temperature under H 2 atmosphere for 2 h. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure to obtain 1 -[4-(3a-aminohexahydro-2,5-methanopentalen-2(lH)-yl)phenyl]-3-methylimidazolidin-2- one (0.15 g) as an off-white solid in 86% yield. M.R.
  • Step III To a stirred mixture of the compound obtained from step II (0.15 g, 0.48 mmol) and K 2 CO 3 (0.21 g, 1.5 mmol) in DMSO (2 mL) at ice bath temperature was added compound (S)-l-(2-chloro-acetyl) pyrrolidine-2-carbonitrile (0.09 g, 0.5 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 3 h. Upon completion of the reaction (checked by TLC), the reaction mixture was diluted with EtOAc and washed with water and brine, dried over Na 2 SO 4 , and the solvent was removed under reduced pressure.

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RU2485952C2 (ru) * 2011-08-18 2013-06-27 Открытое акционерное общество "Химико-фармацевтический комбинат "АКРИХИН" (ОАО "АКРИХИН") Ингибирующее дипептидилпептидазу iv средство и фармацевтическая композиция на его основе
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US8748457B2 (en) 2009-06-18 2014-06-10 Lupin Limited 2-amino-2- [8-(dimethyl carbamoyl)- 8-aza- bicyclo [3.2.1] oct-3-yl]-exo- ethanoyl derivatives as potent DPP-IV inhibitors
WO2016151018A1 (en) 2015-03-24 2016-09-29 INSERM (Institut National de la Santé et de la Recherche Médicale) Method and pharmaceutical composition for use in the treatment of diabetes
RU2712097C1 (ru) * 2018-09-28 2020-01-24 Общество с ограниченной ответственностью "Необиотек" Ингибитор дипептидилпептидазы-4 для лечения сахарного диабета 2-го типа, соединения (варианты)
US11548893B2 (en) 2017-07-15 2023-01-10 Arisan Therapeutics Inc. Enantiomerically pure adamantane carboxamides for the treatment of filovirus infection
WO2023135528A1 (en) 2022-01-11 2023-07-20 Suven Life Sciences Limited Heteroalicyclic derivatives and their use in the treatment of cns disorders
US12240857B2 (en) 2016-01-18 2025-03-04 Arisan Therapeutics Inc. Adamantane derivatives for the treatment of filovirus infection
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