OA17288A - 2-phenyl-5-heterocyclyl-tetrahydro-2H-pyran3-amine compounds for use in the treatment of diabetes and its associated disorders. - Google Patents

2-phenyl-5-heterocyclyl-tetrahydro-2H-pyran3-amine compounds for use in the treatment of diabetes and its associated disorders. Download PDF

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OA17288A
OA17288A OA1201500132 OA17288A OA 17288 A OA17288 A OA 17288A OA 1201500132 OA1201500132 OA 1201500132 OA 17288 A OA17288 A OA 17288A
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tetrahydro
pyran
alkyl
methyl
phenyl
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OA1201500132
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Ranjit C. Desai
Rajesh Bahekar
Pradip Jadav
Amitgiri Goswami
Pankaj Patel
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Cadila Healthcare Limited
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Abstract

The present invention relates to novel compounds of the general formula (I)

Description

Cadila Heâlthtare Limited
2-PIIENYL-5-1IETEROCYCLYL-TETRAHYDRO-2II-PYRAN-3-AMINE COMPOUNDS FOR USE IN THE TREATMENT OF DIABETES AND ITS ASSOCIATED DISORDERS
HELD OF INVENTION
The présent invention relates to novel compounds of the general formula (I) their tautomeric forms, their enantiomers, their diastereoisomers, their pharmaceutically accepted salts, or pro-drugs thereof, which are useful for the treatment or prévention of diabètes and its associated disorders, obesity and other metabolic disorders. The invention also relates to process for the manufacture of said compounds, and pharmaceutical compositions containing them and their use.
BACKGROUND OFTHE INVENTION
The metabolic syndrome (or syndrome X) is a collection of associated disorders, affected by lifestyle, genetic disposition and environment (Lancet, 365, 1415, 2005; Diabètes, 41, 715, 1992). Obesity and diabètes are emerging as the global épidémie of the 21a century and becoming major health problems worldwide (Diabetic Medicine, 14, S7-S85, 1997; Nature Med., 12,62-66,2006; Diabètes Care, 27, 1047-1053,2004). Diabètes mellitus (DM) refers to a disease derived from multiple causative factors and characterized by elevated levels of plasma glucose (hyperglycemia), in fasting state or after administration of glucose during an oral glucose tolérance test (Diabètes Care, 26, 3160-3167,2003; Diabètes Care, 33, S62-S69,2010).
There are two generally reorganized forms of diabètes. In type 1 or Insuündependent diabètes mellitus (IDDM), patients produce little or no insulin (insulin defîciency), due to autoimmunological destruction of the insulin-producing pancreatic β-cells. Type 1 diabètes most commonly occurs in children. In type 2 diabètes mellitus (T2DM) or non-insulin dépendent diabètes mellitus (NIDDM), patients often hâve plasma insulin levels that are the same or elevated compared to non-diabetic subjects (Diabètes Care, 20, 1183-1197, 1997; Diabet Med., 15, 539-553, 1998). Majority of diabetic people are diagnosed with T2DM and of these, 90% are obese or overweight (Diabetologia, 42,499-518, 1999; Nature, 414,782-787,2001).
T2DM is a common chronic and progressive disease arising from a complex pathophysiology involving the dual endocrine effects of insulin résistance and impaired insulin sécrétion. Abnormal glucose homeostasis is associated both directly and indirectly with alterations of the lipid, lipoprotein and apolipoprotein metabolism and other metabolic and hémodynamie disease. Therefore patients with T2DM are at increased risk of macrovascular and microvascular complications, including coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy, and retinopathy (Diabètes Metab., 23(5), 454-455 1997; Diabet Med., 15(7), 539-53, 1998). Thus, therapeutical control of glucose homeostasis, lipid metabolism and hypertension are critically important in the clinical management and treatment of T2DM (Med. J. Aust, 179(7), 379-383,2003).
The treatment of T2DM typically begins with diet and exercise, followed by oral antidiabetic monotherapy (N. Engl. J. Med., 344, 1343-1350, 2001; Diabètes Care, 20, 537-544, 1997). The current antidiabetic therapeutics include compounds that increase the amount of insulin secreted by the pancréas, compounds that decrease the rate at which glucose is absoibed from the gastrointestinal tract and compounds that increase the sensitivity of target organs to insulin (Ann. Intem. Med., 147, 386-399, 2007; Clin.Ther., 29, 1236-1253, 2007). Conventional monotherapy may initially control blood glucose in some patients; however it is associated with a high secondary failure rate.
The limitations of single-agent therapy for maintaining glycémie control may be overcome, by combining multiple antidiabetic drugs (Cardiovasc. Diabetol., 10, 12-62, 2013). Current treatments for diabetic patients include various oral antihyperglycemic agents; however, over a period of time nearly half of T2DM patients lose their response to these agents and thereby require insulin therapy. Also, adverse events (such as weight gain and hypoglycemia with insulin; lactic acidosis, nausea & diarrhea with biguanides; liver toxîcity and CVS risk with glitazones) associated with the existing antihyperglycemic agents raise safety concems (Drugs, 68(15), 2131-2162, 2008; Drugs, 65(3), 385-411,2005; Diabètes Obes Metab., 9,799-812,2007).
Thus, along with healthy Iifestyle, majority of T2DM patients need pharmacological intervention, which mainly consists of combination of oral antidiabetic drugs with subcutaneous insulin injections (Clin Ther., 29, 1236-1253, 2007). Despite large efforts to discover new antidiabetic drugs, only three classes of 2 oral hypoglycémie agents (sulfonylureas, biguanides, and insulin sensîtizers) are available for the treatment of T2DM. Except incretin thérapies, most of the available anti-hyperglycemic agents including insulin promote weight gain, which further aggravâtes obesity-associated cardiovascular risk and insulin résistance (Diabètes Care,
27, 1535-1540, 2004; Ann. Intem. Med., 147, 386-399, 2007). Thus, there is an urgent need to develop novel agents for glycémie control that can complément with existing thérapies and prevent the progression of secondary complications associated with diabètes.
Despite such épidémie proportion of the disease, only 4 out of 10 patients treated 10 for diabètes meet the treatment targets, forcing clinicians to move from initial treatment with one agent to more aggressive intervention with multiple oral thérapies, as well as insulin. Hence, new therapeutic agents which would treat diabètes along with its comorbidities are constantly needed in current regimen.
Dipeptidyl peptidase-IV (DPP-IV) is a serine protease, which selectively cleaves 15 the N-terminal dipeptide from the penultimate position of Glucose-dependent Insulinotropic Polypeptide (GIP) and Glucagon-Like Peptide (GLP-I) thus makes them inactive (Diabètes Obes Metab., 10, 376-387, 2008; Diabètes Care, 30, 1979-1987, 2007). GLP-1 is an incretin hormone secreted by intestinal L-Cells in response to food intake. The active GLP-1 stimulâtes insulin sécrétion, inhibits glucagon reiease and 20 slows gastric emptying, which together contributes for effective glucose homeostasis in patients with T2DM. Inhibition of DPPIV activity extends the duration of action of endogenous GLP-1, thereby exhibiting ail the favorable attributes of GLP-1 (Lancet, 368,1696-1705,2006; Horm Metab Res., 36(11-12), 867-76,2004).
DPP-IV inhibitors offer a number of potential advantages over existing diabètes 25 thérapies, including a lowered risk of hypoglycemia, weight gain and the potential for régénération and différentiation of pancreatic β-cells (Handbook Exp Pharmacol., 203, 53-74, 2011; Curr Med Res Opin., 23(4), 919-31, 2007). Because of these multiple benefîts of GLP-1 mediated glucose homeostasis, orally bioavailable DPP-IV inhibitors has been developed as promising therapeutic agents for the treatment of T2DM (Am. J. 30 Ther., 15(5), 484-91,2008).
The therapeutic potential of DPP-IV inhibitors for the treatment of T2DM hâve been discussed and reviewed extensively (Exp. Opin. Invest. Drugs, 12, 87-100, 2003; Exp. Opin. Ther. Patents, 13, 499-510, 2003; Exp. Opin. Investig. Drugs, 13, 10913
1102, 2004; Curr. Opin. Drug Discovery Development, 11, 512-532, 2008 and Trends in Molecular Medicine, 14, 161-168, 2008).Various DPPIV inhibitors such as Vildagliptin (Galvus), Saxagliptin (Onglyza), Alogliptin (Nesina), Linagliptin (Tradjenta) and Sitagliptin (Januvia) are in clinic for the treatment of T2DM.
Patent applications WO 97/40832; WO 98/19998; WO 01/68603; WO 02/38541; WO 02/076450; WO 03/000180; WO 03/000181; WO 03/024942; WO 03/033524; WO 03/035057; WO 03/035067; WO 03/037327; WO 03/074500; WO 03/082817; WO 04/007468; WO 04/018467; WO 04/026822; WO 04/032836; WO 04/037181; WO 04/041795; WO 04/043940; WO 04/046106; WO 04/050022; WO 04/058266; WO 04/064778; WO 04/069162; WO 04/071454; WO 06/039325; WO 07/024993; WO 08/060488; WO 09/139362; WO 10/056708; WO 11/028455; WO 11/037793; WO 11/146358; WO 12/118945; WO 13/003249; WO 13/003250; U.S. Patent Nos. 5,939,560; 6,011,155; 6,107,317; 6,110,949; 6,166,063; 6,124,305; 6,303,661; 6,432,969; 6,617,340; 0,232,676; 0220766; 8415297; 0157940, 6,699,871; Bioorg. Med. Chem. 17, 1783-1802, 2009 etc. represents different structural classes of DPP-IV inhibitors.
Structurally, DPP-IV enzyme resembles with several other proteases, so while designîng new class of DPP-IV inhibitors, it is essential to consider selectivity of DPP-IV inhibitors over other serine protease, especially DPP-2, DPP-8 and DPP-9 (Diabètes, 54, 2988-2994, 2005; Bioorganic Med. Chem. Lett., 17, 3716-3721, 2007). Though several DPP-TV inhibitors are in the market, attempts are still underway to develop potent and sélective DPP-IV inhibitors, which are better or are of comparable efficacy with the présent DPP-IV inhibitors, hâve lesser side effects, require a lower dosage régime or frequency of administration and hâve advantage of treating other metabolic disorders.
PRIOR ART
Earlier, a sériés of invention relating to substituted aminocyclohexanes (WO 06/127530; WO 07/87231), substituted aminopiperidines (WO 06/039325; US 05/034775), substituted aminotetrahydrothiopyrans (WO 11/103256; US 11/025182), substituted aminopiperidines (WO 11/037793; US 10/048871) and substituted aminotetrahydropyrans (WO 11/028455; US 10/046270; WO 10/056708; US 09/063976; WO 13/003250; US 12/043924; WO 13/003249; US 12/043922; US
13/8415297; US 13/0157940; WO 07/097931; WO 08/060488; US 07/0232676; WO
07/136603; WO 07/126745; WO 06/009886; US 05/021556; EPI761532), with a general formula of (A), wherein ‘V’ represent seiected bicyclic hetero-aromatic ring
Systems, hâve been reported as DPP-IV inhibitors for the effective treatment of T2DM, by Merck Sharp & Dohme (MSD) Corporation Limited.
Wherein: X=-CH2; -NR; O; S
We herein disclose novel compounds of general formula (I) which are DPP-IV inhibitors and are useful for the prévention and treatment of diseases states mediated by DPP-IV enzyme.
SUMMARY OF THE INVENTION
The présent invention discloses novel compounds of the general formula (I) that are DPP-IV inhibitors and are useful for the prévention and treatment of disease states mediated by DPP-IV enzyme. The compounds of the présent invention are useful in the treatment of human or animal body, by inhibition of DPP-IV. The compounds of this invention are therefore suitable for the prévention and treatment of disease states mediated by DPP-IV enzyme. Surprisingly it was found that some of these compounds were found to hâve longer half-life and an extended pharmacokinetic profile. Such properties may allow for an extended dosing interval of more than one day.
EMBODIMENT(S) OFTHE INVENTION
An embodiment of the présent invention provides novel compounds of the general formula (I), their tautomeric forms, their enantiomers, their diastereoisomers, their stereoisomers, their pharmaceutically acceptable salts, and pharmaceutical compositions containing them or their suitable mixtures.
In a further embodiment of the présent invention is provided pharmaceutical compositions containing compounds of the general formula (I), their tautomeric forms, their enantiomers, their diastereoisomers, their stereoisomers, their pharmaceutically acceptable salts, or their mixtures in combination with suitable carriers, solvents, diluents and other media normally employed in preparing such compositions.
In a still further embodiment is provided the use of novel compounds of the présent invention as DPP-IV inhibitors, by administering a therapeutically effective and non-toxic amount of compounds of general formula (I) or their pharmaceutically acceptable compositions to the mammals for the treatment of diabètes and associated disorders.
In yet another embodiment is provided a composition comprising the compounds of formula (I) along with atleast a second suitable médicament for the treatment of diabètes and associated disorders.
In another embodiment is provided processes for preparing the compounds of the présent invention.
DESCRIPTION OFTHE INVENTION
Accordingiy, the présent invention relates to compounds of the general formula (I) represented below & includes their solvatés, hydrates as well as their pharmaceutically acceptable salts and includes their suitable pharmaceutically acceptable formulations
Wherein:
R1 at each occurrence is independently selected from hydrogen, halo, cyano, nitro, hydroxyl, optionally substituted groups selected from amino, alkyl, C2-6 alkenyl, C2-6 alkynyl, Cj-6 alkoxy, C2-6 alkenoxy, C2-6 alkynyloxy, cycloalkoxy, aryl, cycloalkyl, carbocycle, heterocyclyl, heteroaryl, heterocycloalkyl, cyc!oalkyl(C|. é)alkyl, heterocycloalkyl(Ci^)alkyl, aralkyl, heteroarylalkyl, arytoxy, heteroaryloxy, heterocyclyloxy, wherein each of these groups, whenever applicable, is further substituted with one to three substituent(s) independently selected from hydroxy, (Ci4)alkoxy, halo, cyano, amino, (Ct^)alkylamino, nitro, COO(CM)alkyl, S(O)„, S(O)nNH2, S(O)nNH(C,^)aIkyl, C(O); C(O)NH(C|^) alkyl groups;
R is selected from the following bicyclic non aromatic ring Systems
Wherein R 3 at each occurrence is independently selected from hydrogen, halo, haloalkyl, cyano, optionally substituted groups selected from amino, Ci^ alkyl, C2-6 5 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, carbocycle, heterocycloalkyl, cycloalkyl(Ci. 6)alkyl, heterocycloalkyl(Ci^)alkyl, S(O)n, S(O)n(C|^)alkyl, S(O)n(C|^)aryl, S(O)nNH2, S(O)nNH(C|^)alkyl, S(O)„NHcycloalkyl, S(O)nNHaryl, S(O)nNHheteroaryl, (C]. 6)alkylamino, nitro, COO(CM)alkyl, S((O)=NH)-alkyl, S((O)=NH)-aryl, S((O)=NH)cycloalkyl, S((O)=NH)-hetroaryl, S((O)=N-alkyl)-alkyl, S((O)=N-alkyl)-aryl, 10 S((O)=N-aIkyl)-cycloalkyl, S((0)=N-alkyl)-hetroaryl, S((O)=N-aryl)-alkyl, S((O)=Naryl)-aryl, S((O)=N-aryl)-cycloalky], S((O)=N-aryl)-hetroaryl, S((O)=N-(SO2-alkyl))alkyl, S((O)=N-(SO2-alkyl))-aryl, S((0)=N-(S02-alkyl))-cyc!oalkyl, S((O)=N-(SO2alkyl))-hetroaryl, S((O)=N-(SO2-aryl))-alkyl, S((O)=N-(SO2-aryl))-aryl, S((O)=N7 (SOraryl))-cycloalkyl, S((O)-N^SO2-aryl)>hetroaiyl, C(O), C(O)NH(C|js)alkyl groups.
When R3 is substituted, the preferred substituents on Rj wherever applicable are selected from hydrogen, halo, haloalkyl, amino, cyano, methyl, ethyl, propyl, butyl, 5 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, -CH2.COOH, -C(=O)-Omethyl, -C(=O)-O-trifluromethyl, -C(=O)-O-ethyl, -C(=O)-O-phenyl, -C(=O)-NHmethyl, -C(=O)-NH-ethyl, -C(=O)-NH-propyl, -C(=O)-NH-cyclopropyl, -C(=O)-NHphenyl,-C(=O)-NH-trifluromethyl, -C(=O)-methyl, -C(=O)-ethyl, -C(=O)CH2-methyl, C(=O)CH2-phenyl, S(O)2-phenyl, S(O>2-methyl, S(O)2-ethyl, S(0>2-propyl, S(O)2I0 butyl, S(0)2-cyclopropyl, S(O>2-cyclobutyl, S(O>2-cyc]opentyl, S(O)2-cyclohexyl, S(O>2-phenyl, S(O>2-flurophenyl, S(0)2-cynophenyl, S(O>2NH2, SfO^NH-methyl, S(OhNH-ethyl, S(O>2NH-propyl, SfO^NH-butyl, S(OhNH-pentyl, S(OhNHcyclopropyl, SfO^NH-cyclobutyl, SfO^NH-cyclopentyl, S(OhNH-cyclohexyl, StOhNH-phenyl, S((O)=NH)-methyl, S((O)=NH)-ethyl, S((O)=NH>phenyl, 15 S((O)=NH)-cyclopentyI, S((O)=NH)-pyridine, S((O)=N-methyl)-methyl, S((O)=Nmethyl)-phenyl, S((0)=N-ethyl)-cyclopropyl, S((O)=N-methyl)-pyridine, S((O)=Nphenyl)-methyl, S((O)=N-phenyl)-phenyI, S((O)=N-phenyl)-cyclopentyl, S((O)=Nphenyl)-pyridine, S((0)=N-(SO2-rnethyl))-methyI, S((0)=N-(SO2-methyl))-phenyl, S((O)=N-(SO2-ethyl))-cyclohexyl, S((O)=N-(SO2-methyl))-pyridine, S((O)=N-(SO220 phenyl))-methyl, S((O)=N-(SO2-phenyl))-phenyl, S((O)=N-(SO2-phenyl))-cyclopentyl, S((O)=N-(SO2-phenyl))-pyridine.
Wherein n = 0-7;
p = 1-5;
X = -CH2.-NR4,0, S;
R4 is independently selected from hydrogen, halo, amino, cyano, nitro, (Cj. 4)alkyl, (Ci^)alkylcarbonyl, (C2^)alkenyl, (C2^)alkynyl, -(CH2)nCOO(CM)alkyl, (CH2)nCOOH, -C(=O)CH2alkyl, -C(=O)CH2aryl, -C(=O)CH2heteroaryl, (CH2)naryl, (CH2)nheteroaryl, (CFhK-N-heteroaryl, (CH2)n-N-heterocyclyl, S(O)n, S(O)„aryl, 30 S(O)nalkyl, S(O)n(C^)a!kyl, S(O)n(Cw)aryl, S(O)nNH2, S(O)nNH(C,^)alkyl groups.
In an altemate embodiment, when any of the groups defined above is further substituted, the substituents, if présent, may be selected from those defined above.
In a preferred embodiment ofthe présent invention, —
R* at each occurrence is independently selected from hydrogen, halo, cyano, optionaily substituted groups selected from amino, Cm alkyl, Ü2^ alkenyl, C2-6 alkynyl, aryl, cycloalkyl, carbocycle, heterocycloalkyl, cycloalkyI(C|^)alkyl, heterocycloalkyl(C|^)alkyl groups wherein any amino, alkyl, alkenyl, alkynyl, cycloalkyl heterocycloalkyl group is further substituted on available carbon atom with one to three subsistent(s) independently selected from hydroxy, (Cm)alkoxy, halo, cyano, amino, (Ci^)alkylamino, nitro, COO(C|_4)alkyl, S(O)n, S(O)nNH2, S(O)nNH(C|. 6)alkyl, C(O); C(O)NH (CMalkyl groups;
R4 is selected from hydrogen, halo, amino, cyano, nitro, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-COOH, -C(=O)CH2methyl, -C(=O)CH2-phenyl, S(O)2-phenyl, S(Oh-methyl, SfO^NHj, S(OhNH-methyl groups.
Wherein ‘n* and ‘p* are defined as earlier and the substituents on any of the substitutions defined above, if présent, may be selected from those defined above.
In a preferred embodiment, the groups, radicals described above may be selected from:
“Alkyl”, as well as other groups having the prefix “alk”, such as alkoxy and alkanoyl, means carbon chain which may be substituted with an oxygen atom as is well understood by a skilled artisan, which may further be either linear or branched, and combinations thereof, unless the carbon chain is defined otherwise. Examples of alkyl group include but not are limited to methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, rerf.-butyl, pentyl, hexyl etc. Where the specified number of carbon atoms permits e.g. from Cj-to, the term alkyl also includes cycloalkyl groups, and combinations of linear or branched alkyl chains combined with cycloalkyl structures. When no number of carbon atoms is specified, Cm is intended.
“Alkenyl” means carbon chains which contain at least one carbon-carbon double bond, and which may be linear or branched or combinations thereof, unless the carbon chain is defined otherwise. Examples of alkenyl include but not limited to vinyl, allyl, isopropenyl, hexenyl, pentenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl etc. Where the specified number of carbon atoms permits, e. g., from C5.10, the term alkenyl also includes cycloalkenyl groups and combinations of linear, branched and cyclic structures. When no number of carbon atoms is specified, Q2-6) is intended.
“Alkynyl” means carbon chains which contain at least one carbon-carbon triple bond, and which may be linear or branched or combinations thereof. Examples of alkynyl include ethynyl, propargyl, 3-methyl-1-pentynyl etc. When no number of carbon atoms is specifîed, Q2-6) is intended.
As used herein, carbocycle or caibocyclic residue is intended to mean any stable monocyclic or bicyclic or tricyclic ring, any of which may be saturated, partially unsaturated, or aromatic. Exemptes of such caibocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), 10 [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralîn). In a broader perspective, the term carbocycle is intended to include, wherever applicable, the groups representing cycloalkyl, phenyl and other saturated, partially saturated or aromatic residues;
“Cycloalkyl” is the subset of alkyl and means saturated caibocyclic ring having a specifîed number of carbon atoms, preferably 3-6 carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc. A cycloalkyl group generally is monocyclic unless otherwise stated. Cycloalkyl groups are saturated unless and otherwise stated.
The “alkoxy” refers to the straight or branched chain alkoxides of the number of 20 carbon atoms specifîed.
The term “alkylamino” refers to straight or branched alkylamines of the number of carbon atoms specifîed.
“Aryl” means a mono- or polycyclic aromatic ring system containing carbon ring atoms. The preferred aryls are monocyclic or bicyclic 6-10 membered aromatic ring 25 Systems. Phenyl and naphthyl are preferred aryls.
“Heterocycle” and “heterocyclyl” refer to saturated or unsaturated non-aromatic rings or ring Systems containing at least one heteroatom selected from O, S, N further optionally including the oxidized forms of sulfor, namely SO & SO2. Examples of heterocycles include tetrahydrofuran (THF), dihydroforan, 1,4-dioxane, morpholine, 30 1,4-dithiane, piperazine, piperidine, 1,3-dioxolane, imidazoline, imidazolidine, pyrrolidine, pyrroline, tetrahydropyran, dihydropyran, oxathiolane, dithiolane, 1,3dioxane, 1,3-dithiane, oxathiane, thiomorpholine etc. CL'' “Heteroaryl’* means an aromatic or partially aromatic heterocycle that contains at least one ring heteroatom selected from O, S and N. Heteroaryls thus include heteroaryls fused to the other kinds of rings, such as aryls, cycloalkyls, and heterocycles that are not aromatic. Examples of heteroaryl groups include; pyrrolyl, 5 isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, triazinyl, thienyl, pyrimidyl, benzisoxazolyl, benzoxazolyl, benzthiazolyl, benzothiadiazolyl, dihydrobenzofuranyl, indolinyl, pyridazinyl, indazolyl, isoindolyl, dihydrobenzothienyl, indolinyl, pyridazinyl, indazolyl, isoindolyl, dihydrobenzothienyl, indolizinyl, cinnolinyl, 10 phthalazinyl, quinazolinyl, napthyridinyl, caibazolyl, benzodioxolyl, quinoxalinyl, purinyl, furazanyl, isobenzylfuranyl, benzimidazolyl, benzofuranyl, benzothienyl, quinolyl, indolyl, isoquinolyl, dîbenzofuranyl etc. For heterocyclyl and heteroaryl groups, rings and ring Systems containing from 3-15 carbon atoms are included, forming 1-3 rings.
“Halo/ Halogen” refers to fluorine, chlorine, bromine, iodine. Chlorine and fluorine are generally preferred.
Suitable groups and substituents on the groups may be selected from those described anywhere in the spécification.
The term substituted, as used herein, means that any one or more hydrogens on 20 the designated atom is replaced with a sélection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. The term substituted, as used herein, means that any one or more hydrogens on the designated atom is replaced with a sélection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the 25 substitution results in a stable compound.
“Pharmaceutically acceptable salts” refer to dérivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, minerai or organic acid salts of the basic residues. Such conventional non-toxic salts 30 include, but are not limited to, those derived from inorganic and organic acids selected from 1, 2-ethanedisulfonic, 2-acetoxybenzoic, 2-hydroxyethanesulfonic, acetic, ascorbic, benzenesulfonic, benzoic, bicaibonic, carbonic, citric, edetic, ethane disulfonic, ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, 11 glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodide, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methanesulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicyclic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartane, and toluenesul fonic.
Prodrug is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biological ty active compound described herein. Thus, the term prodrug refera to a precursor of a biologically active compound that is pharmaceutically acceptable. A prodrug may be inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis. The prodrug compound often o fiers advantages of solubility, tissue compatibility or delayed release in a mammalîan organism (Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)). The term prodrug is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalîan subject. Prodrugs of an active compound, as described herein, may be prepared by modifying functional groups présent in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound.
The term ‘optional’ or ‘optionally’ means that the subséquent described event or circumstance may or may not occur, and the description includes instances where the event or circumstance occur and instances in which it does not For example, ‘optionally substituted alkyl’ means either ‘alkyl’ or ‘substituted alkyl*. Further an optionally substituted group means unsubstituted.
Unless otherwise stated in the spécification, structures depicted herein are also meant to include compounds which difier only in the presence of one or more isotopically enriched atoms.
Particularly usefui compounds may be selected from but not limited to;
Table-1: List of compounds as DPP-IV inhibitors
Compounds Structures IUPAC Na mes
1 '-Ο/ Ο (2R,3S,5R)-2-(2,5-<iifluorophenyl)-5-(5(methylsulfonyl)hexahydropyrrolo[3,4c]pyrrol-2( 1 H)-yI)tetrahydro-2H-pyran-3amine
2 F Μ! Γ ' feocr (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(7(methylsulfonyl)-2,7-diazaspiro[4.4]nonan-2yl)tetrahydro-2H-pyran-3-amine
3 F ιί Γ2 r (2R,3S,5R)-2-(2,5-difluorophenyl)-5(tetrahydro-1 H-furo[3,4-c]pyrrol-5(3H)yl)tetrahydro-2H-pyran-3 -amine
4 F A JC1 ^-Qh (2R,3S,5R)-2-(2,5-difluorophenyl)-5- (hexahydropyirolo [3,4-c]pyrrol-2( 1H)yl)tetrahydro-2H-pyran-3-amine
5 F ii i1 (2R3S,5R)-2-(2,5-difluorophenyl)-5-(5- ((tri fluoromethyl)sul fonyl)hexahydropyrrol o[3, 4-c]pyrrol-2(lH)-yl)tetrahydro-2H-pyran-3amine
6 fe ô'° (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(5(phenylsul fonyl)hexahydropyrroïo[3,4c]pyrrol-2( 1 H)-yl)tetrahydro-2H-pyran-3amine
7 F ΙιΊ ï”2 «Ύ 5-((3R,5S,6R)-5-amino-6-(2,5difluorophenyl)tetrahydro-2H-pyran-3-yl)-N,Ndimethylhexàhydropyrrolo[3,4-c]pyrrole2(lH)-sulfonamide
8 F il ï”2 o' (2R,3 S,5 R)-2-(2,5-difluorophenyl)-5-(5(methylsul fonyl)-5,6-dihydropyrrolo[3,4c]pyrrol-2(lH,3H,4H)-yl)tetrahydro-2H-pyran3-amine
9 il F 'Οχ.», <rf 5-((3R,5S,6R)-5-amino-6-(2,5difluorophenyl)tetrahydro-2H-pyran-3-yl)-N,Ndimethyl-3,4,5,6-tetrahydropyTTolo[3,4c]pyrrole-2(l H)-sulfonamide
10 F rv 5-((3 R,5 S ,6R)-5-amino-6-(2,5- di fluorophenyl)tetrahydro-2H-pyran-3 -yl)-2cyclopropyltetrahydropyrTolo[3,4-c]pyrrolel,3(2H,3aH)-dione
11 ÇXO 0 5-((3R,5S,6R)-5-amino-6-(2,5difluorophenyl)tetrahydro-2H-pyran-3-yl)-2benzyltetrahydropyrrolo[3,4-c]pyrrole13(2H,3aH)-dîone
12 X'' 0**0 (2R3S,5R)-2<2,5-difluorophenyl)-5-(5(methylsulfonyl)hexahydro-1 H-pyrrolo[3,4c]pyridin-2(3 H)-yl)tetrahydro-2H-pyran-3 amine
13 K+ (2R3S,5R)-2-(2,5-difluoropheny!)-5-(2- (methylsulfonyî)hexahydro-l H-pyrrolo[3,4c]pyridin-5(6H)-yl)tetrahydro-2H-pyran-3amine
14 F Γιΐ M1j ’ &OO-V (2R,3 S,5R)-2-(2,5-di fl uorophenyl)-5-(8(methylsulfonyl)-2,8-diazaspiro[4.5]decan-2yl)tetrahydro-2H-pyran-3-amine
15 F Π F (2R,3 S,5R)-2-(2,5-di fluorophenyl)-5-( 1 (methylsulfonyl)hexahydropyrrolo[3,4b]pyrrol-5(l H)-yl)tetrahydro-2H-pyran-3amine
16 F fS F <\.z (2R3S,5R)-2-(2,5-difluoropheny!)-5-(5- (methylsulfonyi)hexahydrOpyrrolo[3,4bjpyrrol-l (2H)-yl)tetrahydro-2H-pyran-3amine
17 F (Γί n”2 5-((3R,5S,6R)-5-amino-6-(2,5difluorophenyl)tetrahydro-2H-pyran-3-yl)3,4,5,6-tetrahydro-l H-thieno[3,4-c]pyrrole 2,2di oxide
18 F Γϋ ï2 nQ?njO (2R.3 S,5 R)-5-(5-benzylhexahydropyrrolo[3,4c]pyrrol-2(lH)-yl)-2-(2,5difluorophenyl)tetrahydro-2H-pyran-3-amine
19 F O JC f <3 (2R,3 S,5R)-2-(2,5-difluorophenyl)-5-(( 1 R,5S)6-(methylsulfonyl)-3,6diazabicyclo[3.2.0]heptan-3-yl)tetrahydro-2Hpyran-3-amine
20 F vil ï”2 F £\£τΥ (2R.3 S,5R)-2-(2,5-dif!uorophenyl)-5- ((I R,5R)-3-(methylsulfonyl)-3,6diazabicyclo[32.0]heptan-6-yl)tetrahydro-2Hpyran-3-amine
21 F rîl t1 F ‘’J'n'X K1V N-(2-((3R,5S,6R)-5-ainino-6-(2,5difl uorophenyI)tetrahydro-2H-pyran-3 yl)octahydrocyclopenta[c]pyTrol-5yl)methanesulfonamide
22 F ih 0 (5-((3R,5S,6R)-5-amino-6-(2,5difluorophenyl)tetrahydro-2H-pyran-3-yI)-5,6dihydropyrrolo[3,4-c]pyrrol-2( 1 H,3H,4H)yl)(cyclopropyl)methanone
23 F lil ï”1 o (5-((3R,5S,6R)-5-aniino-6-(2,5difluorophenyl)tetrahydro-2H-pyran-3-yl)-5,6dihydropyrrolo[3,4-c]pyrrol-2( 1 H,3H,4H)yl)(phenyl)methanone
24 F ril ï”1 F ίχΛ,'Χ 0 1 -(5-((3R,5S,6R)-5-amino-6-(2,5difluorophenyl)tetrahydro-2H-pyran-3-yl)-5,6dihydropyrrolo[3,4-c]pyrrol-2( 1 H,3 H,4H)-yl)2-methylpropan-1 -one
25 te., n 0 (5-((3R,5S,6R)-5-amino-6-(2,5difluorophenyl)tetrahydro-2H-pyran-3-yl)-5,6dihydropyrrolo[3,4-c]pyrrol-2(l H,3H,4H)yl)(cyclopentyl)methanone
26 te (5-((3 R,5 S,6R)-5-amino-6-(2,5difluorophenyl)tetrahydro-2H-pyran-3-yl)-5,6dihydropyrrolo[3,4-c]pyrrol-2(l H3H.4H)yl)(cyclohexyl)methanone
27 F rîi Γ2 tte o O methyl 5-((3R,5S,6R)-5-amino-6-(2,5difluorophenyl)tetrahydro-2H-pyran-3-yl)3,4,5,6-tetrahydiOpynOlo[3,4-c] pyrrol e-2( 1H)carboxylate
28 te O ethyl 5-((3R,5S,6R)-5-amino-6-(2,5difluorophenyl)tetrahydro-2H-pyran-3-yl)3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol e-2 ( 1H)carboxylate
29 F A Γ2 o-ter, (2R^S,5R)-2-(2,5-difluorophenyl)-5-(5((trifluoromethyl)sulfonyl)-5,6dihydropyrrolo[3,4-c]pyrrol-2(l H,3H,4H)yl)tetrahydro-2H-pyran-3-amine
30 F Cji Jl’ Οι o ^N;O o (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(5- (ethyIsulfonyl)-5,6-dihydropyrrolo[3,4c]pyrrol-2( 1 H,3H,4H)-yl)tetrahydro-2H-pyran3-amine
31 F °^ΑΝ-Λ. ter? îr (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(5(isopropylsulfonyl)-5t6-dihydropyrrolo[3,4c]pyrrol-2(l H,3H,4H)-yl)tetrahydro-2H-pyran3-amine
32 F O Jl’ F O^Ln^. rfO (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(5(phenylsulfonyl)-5,6-dihydropyrrolo[3,4c]pyrrol-2( 1 H,3H,4H)-yl)tetrahydro-2H-pyran3-amine
33 (2R,3S,5R)-2-(2,5-diiluoropheny])-5-(5-((4fiuorophenyl)sulfonyl)-5,6-dihydropyrrolo[3,4c]pyrrol-2(lH,3H,4H)-yl)tetrahydro-2H-pyran3-amîne
34 4-((5-((3R,5S,6R)-5-amino-6-(2,5difluorophenyl)tetrahydro-2H-pyran-3-yl)-5,6dihydropyrrolo[3,4-c]pyrrol-2( 1 H,3 H,4H)yl)sulfonyl)benzonitri!e
35 (2R.3 S,5 R)-2-(2,5-di fluorophenyl)-5-(5-((4(tri fluoromethoxy)phenyl )sul fonyl)-5,6dihydropyrrolo[3,4-c]pyrrol-2(l H,3H,4H)yl)tetrahydro-2H-pyran-3-amine
36 fe., Μ (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(5-((2,4difluorophenyl)sulfonyl)-5,6dihydropyrrolo[3,4-c]pynOl-2(l H,3H,4H)yl)tetrahydro-2H-pyran-3-amine
37 fe. fe. (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(5-tosyl- 5,6-dihydropyrrolo[3,4-c]pyTTOl-2(lH,3H,4H)yl)tetrahydro-2H-pyran-3-amine
38 fe. fe (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(5-((4methoxyphenyl)sul fonyl)-5,6dihydropyrrolo [3,4-c]pyrrol-2( 1 H,3 H,4H)yl)tetrahydro-2H-pyran-3-amine
39 fe. (2R3S,5R)-2-(2,5-difluorophenyl)-5-(5-((4isopropylphenyl)sul fonyl)-5,6dihydropyTrolo[3,4-c]pyrrol-2(lH,3H,4H)yl)tetrahydro-2H-pyran-3 -amine
40 fe. fe (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(5-((4(trifluoromethyl )phenyl)sul fony1)-5,6dihydropyrrolo[3,4-c]pyiTol-2( 1 H,3H,4H)yl)tetrahydro-2H-pyran-3 -amine
41 F Π Γ Οά Ο 1 -(5-((3 R,5S,6R)-5-amino-6-(2,5difluorophenyl)tetrahydro-2H-pyran-3-yl)-5,6dihydropynolo[3,4-c]pyiTOl-2( 1 Η,3 Η,4Η)yl)ethanone
42 F A Ï’ (2R3S,5R)-2-(2,5-difluorophenyl)-5-(5(isobutylsulfonyl)-5,6-dihydropyrrolo[3,4c]pyrrol-2(IH,3H,4H)-yl)tetrahydro-2H-pyran3-amine
43 feu '-Ck ο 5-((3R,5S,6R.)-5-amino-6-(2,5-difluorophenyl) tetrahydro-2H-pyran-3-yl) hexahydro-1 Hthieno[3,4-c]pyrrole 2,2-dioxide
44 (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(5,6dihydropyrrolo[3,4-c]pyrrol-2( 1H3 H,4H)yl)tetrahydro-2H-pyran-3-arnine
45 ΦΛ η ί o-Aq^ ç ΝΗ β 0 5-((3R,5S,6R)-5-amino-6-(2,5difluorophenyl)tetrahydro-2H-pyran-3-yl)-NphenyI-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole2( 1 H)-carboxamide
46 Λ Λ TO.. %ς N-((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(5(methylsulfonyl)-5,6-dihydropyrrolo[3,4c]pyrrol-2(lH,3H,4H)-yl)tetrahydro-2H-pyran3-yl)acetamide
47 F 0 Φύ A>^ N-((2R,3S,5R)-5-(5-acetyl-5,6dihydropyrrolo[3,4-c]pyrrol-2( 1H ,3 H,4H)-yl)2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3yl)acetamide
48 '-Οφ. ο 5-((3R,5S,6R)-5-amino-6-(2,5difluorophenyl)tetrahydro-2H-pyran-3-yl)3,4,5,6-tetrahydropyrrolo [3,4-c]pyrrol e-2( 1H)caibaldehyde
49 fe (2R,3S,5R)-2-(2,5*<iifluorophenyl)-5-(5-(N-(4methylbenzenesul fonyl)-SmethyIsulfonimidoyl)-5,6-dihydropyrrolo[3,4c]pyrrol-2(l H,3 H,4H)-yl )tetrahydro-2H-pyran3-amine
50 F LÎI V’ Ο 1 -(5-((3 R,5S, 6R)-5-amino-6-(2,5difluorophenyl)tetrahydro-2H-pyran-3-yl)-5,6dihydropyrrolo[3,4-c]pyrrol-2( 1 H,3 H,4H)-yl)2,2,2-trifIuoroethanone
Or pharmaceutically acceptable salts of any of the compounds above.
Following is a list of abbreviations used in the description of the préparation of the compounds of the présent invention:
ACN : Acetonitrile
AIBN : 2-2'-azobisisobutyTonitrile
BOC : tert-Butyloxy carbonyl
CS2CO3 : Césium carbonate
DBU : l,8-Diazabicyclo[5.4.0]undac-7-ene
DCM : Dichloro methane de : diastereomeric excess
DIEA : Diisopropyl ethyl amine
DIPE : Diisopropyl ether
DMA : Ν,Ν-Dimethyl acetamide
EtOH : Ethanol h : hours
HBr : Hydrobromic acid
HCl : Hydrochloric acid
HPLC : High performance liquid chromatography
IPA : Isopropyl alcohol
MeOH : Methanol
NaiCOj : Sodium carbonate
Na2S20j : Sodium thiosulfate
Na2SO4 : Sodium sulfate —
NaBHi : Sodium borohydride
NaHCO3 : Sodium bicaibonate/sodium hydrogen carbonate
NaHSO3 : Sodium hydrogen sulfite
NaOH : Sodium hydroxide
PCC : Pyridinium chlorochromate
PDC : Pyridinum dichromate
PTSA : p-Toluene sulphonic acid
TFA : Trifluoro acetic acid
THF : Tetrahydrofuran
TLC : Thin layer chromatography
The novel compounds of the présent invention were prepared using the reactions and techniques described below, together with conventîonal techniques known to those skilled in the art of organic synthesis, or variations thereon as appreciated by those skilled in the art
The reactions can be performed in solvents appropriate to the reagents and materials employed and are suîtable for the transformations being effected. Preferred methods include, but not limited to those described below, where ail symbols are as defined earlier unless and otherwise defined below.
The compounds of the formula (I) can be prepared as described in schemes below along with suîtable modifications/variations which are well within the scope of a person skilled in the art.
Substituted benzaldehyde (1) can be treated with nitromethane in the presence of appropriate base to give compound (2) or can be prepared by the method reported in literature (for e.g. in WO 10/056708, WO 11/028455, WO 13/003250, US 13/8415297, WO 13/122920 & BMCL., 23(19), 5361-5366, 2013) along with their suîtable modifications as may be necessary. Compound (2) can be oxidized to compound (3) using suîtable oxidizing agents such as Desmartine periodinane, Jone’s reagent, Swem oxidation, Pyridinium dicromate (PDC), Pyridinium chlorocromate (PCC) etc. Compound (3) can be treated with 3-Iodo-2-(iodomethyl)-prop-l-ene using appropriate base to give nitro pyrane (4), which upon subséquent réduction of endocyclic double bond and treatment with appropriate base followed by crystallization provided transpyrane (5). Nitro pyrane (5) can conveniently be reduced by variety of methods familiar to those skilled in the art Chiral resolution of resulting amino pyrane (6) followed by its Boc protection provide compound (7), which upon oxidation in suitable System facilitated the formation of intermediate-1.
Scheme-1:
Ar—CHO qîjNOj
OH o
JL·
Zn-HCl
1. NaBH*
2. DBU
3. PiasiCTcomer scperation
1. Chiral resolution
2. BOC-anhydride
RuCI3.3H2O
NaIO4
Intermediate-1
Intermediate-1 and the substituents representing R2 présent in the compounds of general formula (I) are separately known in the literature or can be conveniently 10 prepared by variety of methods familiar to those skilled in art or by methods described in the literature (for e.g. in Bioorg. Med. Chem. Lett., 19, 1682-1685, 2009; Heterocycles 41, 1291-1298, 1995; JOC 46,2757-2764, 1981), CN 101619064 (2010), WO 101654 (2012), WO 153554 (2009) including their suitable variations).
Novel compounds of general formula (I) of the présent invention can be prepared by treating intermediate-1 with the appropriate substituent R2. Further, R2 can also be prepared using the methods available in the literature or can be prepared by various methods known to those skilled in art (WO 2010/056708, WO 2011/028455, WO 2013/003250, US 2013/8415297, WO 2013/122920 & BMCL., 23(19), 5361-5366, 2013etc.). A synthetic route to compound of présent invention is given in Scheme-2.
Scheme-2:
Intermediate-1
1. Reductivc amination
2. Boc-deprotection
As illustrated in Scheme-2, the compounds of the présent invention with structural formula (I) can be prepared by reductive amination of Intermediate-1 (obtained from the Scheme-1), with substituent-R2 using appropriate reagent such as decaborane, sodiumtriacetoxy borohydride or sodium cyanoborohydride in solvents such as methanol, éthanol, tetrahydrofuran, dichloromethane, Ν,Ν-dimethyl acetamide 10 or N, N-dimethyl formamide. Upon removal of Boc group either by treatment with trifluoroacetic acid, 4N HCl in dioxane or by passing HCl gas in to the reaction solution provides the compounds of the general formula (I). Compounds of the présent invention can be isolated either as free amine form or as a sait corresponding to the acid used such as trifluoroacetic acid, hydrochloric acid, hydrobromic acid, oxalic acid, 15 maleic acid, fumerie acid, succinic acid, p-toluene sulfonic acid or benzene sulfonic acid. The compounds can be purified where ever required, by recrystallization, trituration, précipitation, préparative thin layer chromatography, flash chromatography or by préparative HPLC method.
The compounds of the présent invention can be used either alone or in 20 combination with one or more therapeutic agents selected from insulin, insulin dérivatives and mimetics, insulin secretagogues, insulin sensitizers, biguanide agents, alpha-glucosîdase inhibitors, insulinotropic sulfonylurea receptor ligands, meglitinides, GLP-1, GLP-1 analogs, DPP-IV inhibitors, GPR-119 activators, sodium-dependent glucose co-transporter (SGLT2) inhibitors, PPAR modulators, non-glitazone type 25 PPAR delta agonist, HMG-CoA reductase inhibitors, cholesterol-lowering drugs, rennin inhibitors, anti-thrombotic and anti-platelet agents and anti-obesity agents or pharmaceutically acceptable salts thereof. Such use will dépend on the condition of the patient being treated and is well within the scope ofa skilled practitioner. ___
The invention is further illustrated by the following non-limiting exemples which describe the preferred way of carrying out the présent invention. These are provided without limiting the scope of the présent invention in any way.
*H NMR spectral data given in the examples (vide infra) are recorded using a 400 MHz spectrometer (Bruker AVANCE-400) and reported in δ scale. Until and otherwise mentioned the solvent used for NMR is CDCI3 using TMS as the internai standard.
Synthesis of Intermediate-1: tert-butyl ((2R,3S)-2-(2.5-difluorophenyl)-5oxotetrahydro-2H-pyran-3-yl)carbamate
Step-1: l-(2.5-difluorot>henvl)-2-nitroethanol (2)
To a solution of NaOH (25.3 g) in Water and MeOH at 0 °C was added a solution of 2,5-difluorobenzaldehyde (1, 57.3 ml) and nitromethane (34.2 ml) in MeOH drop wise, over a period of 30 min. After completion of reaction, reaction mixture was neutralized with glacial CH3COOH. Ethyl acetate was added and the layers separated. The organic layer was washed successively with aqueous sat.Na2CO3 solution, and saturated brine solution. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to afford 2 (112 g, 97 % yield) that was used without further purification in next step.
’ll NMR: (CDCh, 400 MHz): δ 7.31-7.33 (m, IH), 7.08-7.01 (m, 2H), 5.73 (dd, IH, J/=9.2Hz, Jy= 2.4Hz), 4.65 (dd, IH, J/=13.6Hz, Λ=2.4Ηζ), 4.53 (dd, IH, J/= 9.2Hz, Λ= 13.6Hz), 2.96 (bs, IH); ESI-MS: (+ve mode) 204.1 (M+H)+ (100 %); HPLC: 99.2 %.
Sten-2: l-(2.5-difluorophenyh-2-nitroethanone (3) l-(2,5-difluorophenyl)-2-nitroethanol (2, 100 g) was dissolved in Acetone and cooled to 0-5 °C. Jones reagent was added drop wise to it in such a way that reaction température should not rise above 10 °C. After completion of reaction, reaction mixture was cool to 0 °C and IPA was added drop wise to quench excess of Jones reagent. Solid — residue precipitated was filtered and washed with acetone. Combined filtrate was evaporated to dryness to give light green oil, cooled it in ice bath and added 1.0 L of cold water, white solid precipitated. The solid obtained was filtered, washed with water and dried to get 3 (67 g, 67.7 % yield).
’H NMR: (DMSCWrt, 400 MHz): δ 7.75-7.64 (m, 2H), 7.55-7.49 (m, IH), 6.30 (d, 2H, J=2.8Hz); ESI-MS: (+ve mode) 201.1 (M+H)+ (70 %); HPLC: 98.3 %.
Steo-3:6-(2.5-difluoroDhenvl)-3-methy1ene-5-nitro-3.4-dihydro-2H-pyran (4) l-(2,5-difluorophenyl)-2-nitroethanone (3, 56.3g) and 3-iodo-2(iodomethyl)prop-l-ene (90.5 g) were dissolved in DMA at 25 °C. To it added CS2CO3 (210 g) in a single portion and stirred for 4h at 25-30 °C. After completion of reaction, reaction mixture was filtered through hy-flow, washed with DIPE. Filtrate was dumped in cold IN HCl solution (1.75 L), extracted with DIPE (2X 850 ml), combined extracts were washed with brine, separated and evaporated to dryness. Oily residue obtained was stirred in cold IPA, solid precipitated was filtered, washed and dried to get 4 (37.3g, 53% yield) as light yellow solid.
’H NMR: (CDClj, 400 MHz): δ 7.14-7.03 (m, 3H), 5.37 (s, IH), 5.28 (s, IH), 4.61 (s, IH), 3.60 (t, 2H, J=1.6Hz); ESI-MS: (+ve mode) 254.1 (M+H)+ (50 %), 271.0 (M+Na)+(90 %); HPLC: 99.3 %.
Steo-4: rrgny-2-(2.5-difluorophenyl)-5-methylene-3-nitrotetrahydro-2H-pyran (5)
6-(2,5-difluorophenyI)-3-methylene-5-nitro-3,4-dihydro-2H-pyran (4, 35g) was dissolved in MeOH (525ml). to it added NaBH» (15.7g) portion wise maintaining température 0-5 °C over a period of 30 min. Stirred the reaction mixture for 30 min at 0-5 °C, quenched with drop wise addition of 6N aqueous HCl solution. To the reaction mixture, cold water (1.05 L) was added, with stirring at 0 °C to get white solid. Solid was filtered, washed with water and dried to get 2-(2,5-difluorophenyl)-5-methylene-3nitrotetrahydro-2H-pyran (30.7g) as a mixture of diastereomers (trans:cis:65:35).
Product thus obtained was dissolved in IPA (92 ml) by heating it to 90 °C, from which inwis-2-(2,5-difluorophenyl)-5-methylene-3-nitrotetrahydro-2H-pyran was crystallized upon graduai cooling. Crystalline product was filtered, washed with IPA and dried to get rranr-2-(2,5-difluorophenyl)-5-methylene-3-nitrotetrahydro-2H-pyran (16.9g). Filtrate was evaporated to dryness, residue obtained was dissolved in THF,
DBU was added, stirred for 15h at 25 °C. Reaction mixture was evaporated to dryness and extracted with ethyl acetate. Combined organic layer was washed with IN HCI solution, water and brine solution. Organic layer was evaporated to dryness to get diasteriomeric mixture of 2-(2,5-difluorophenyl)-5-methylene-3-nitrotetrahydro-2Hpyran (13.4g), which was further treated with IPA as above to get trans-2-(2,5difluorophenyl)-5-methylene-3-nitrotetrahydro-2H-pyran (7.4g, 29 mmol).
/nms-2-(2,5-difluorophenyI)-5-methylene-3-mtrotetrahydro-2H-pyran (24.3g) obtained was further dissolved in IPA by heating it to 90 °C. This was subsequently allowed to cool gradually to room température and the crystalline product was filtered, washed with cold IPA and dried to get rra?is-2-(2,5-difluorophenyl)-5-methylene-3nitrotetrahydro-2H-pyran as a white crystals (5,20.8g, 59% yield).
’H NMR: (CDClj, 400 MHz): δ 7.14-7.10 (m, IH), 7.06-6.99 (m, 2H), 5.11 (s, IH), 5.09 (s, IH), 5.06 (d, 2H, J= 92Hz), 4.76 (ddd, IH, J/=5.6Hz, Λ=9.6Ηζ, Jj=l 4.0Hz), 4.38 (d, IH, 12.4Hz), 4.24 (d, IH, J= 12.4Hz ), 3.09 (d, 2H, J=8.0Hz); ESI-MS: (+vemode) 256.1 (M+H)+ (100 %); HPLC: 99.7 %.
Steo-5: rrflns-2-(2.5-difluorophenyl)-5-methylenetetrahvdro-2H-pvran-3-amine (6)
To a vigorously stirred suspension of trans-2-(2,5-difluorophenyl)-5-methylene3-nitrotetrahydro-2H-pyran (5, 20.5 g) and zinc (61.9 g) in EtOH was added 6 N HCl solution drop wise and stirred for lh at 0 °C. After completion of reaction, reaction mixture was treated with DCM and ammonia solution. The resulting solid was filtered and washed with DCM. In the filtrate, organic layer was separated and washed with water, saturated brine, dried over anhydrous Na2SO4 and evaporated to yield trans-2(2,5-difluorophenyl)-5-methylenetetrahydro-2H-pyran-3-amine as an off white solid (6,
17.4 g, 97% yield).
’H NMR: (CDClj, 400 MHz): δ 7.26-7.14 (m, IH), 7.05-6.93 (m, 2H), 4.92 (dd, 2H,
1.6 Hz, J2= 5.2 Hz), 4.36 (d, IH, J=9.2 Hz), 4.30 (dd, IH, Λ=1.6Ηζ, Λ=12.8Ηζ), 4.27 (d, IH, J=12.8 Hz), 2.85-2.73 (m, 2H) 2.22-2.16 (m, IH); ESI-MS: (+ve mode) 226.3 (M+H)+ (100 %); HPLC: 94.9 %.
Step-6: tert-butyl f(2R.3S)-2-(2.5-difluorophenvl)-5-methv1enetetrahydro-2H-pvran-3yl) carbamate (7)
D(-) Tartane acid (12.5g) was dissolved in methanol to get a clear solution, to it was added a solution of frflas-2-(2,5-difluorophenyl)-5-methylenetetrahydro-2Hpyran-3-amine (6,17 g) dissolved in MeOH (59.5ml) at 25 °C and the reaction mixture was stirred for 15h at 25 °C. The solid was fïltered, washed with methanol and dried. Solid thus obtained was suspended in MeOH (119 ml) and refluxed for Ih, & cooled gradually to 25 °C and stirred for 15h. The obtained solid was fïltered, washed with MeOH and dried to get (2R,3S)-2-(2,5-difluorophenyl)-5-methylenetetrahydro-2Hpyran-3-amine as a tartrate sait (14.2g).
The tartrate sait was dissolved in ACN and water, to it added Na2COj (10g) portion wise at 25-30 °C. Reaction mixture was cooled to 0-5 °C and Boc-anhydride (9.9g) was added. Reaction mixture was stirred for 2h, concentrated to remove ACN, to the residue obtained was added ice cold water (150ml) and stirred for 30 min. The solid precipitated was fïltered, washed with water and dried to get tert-butyl ((2R,3S)-2-(2,5difluorophenyl)-5-methylenetetrahydro-2H-pyran-3-yl) carbamate as a white solid (7, 12.06g, 49% yield).
’H NMR: (CDClj, 400 MHz): Ô 7.20-7.30 (m, IH), 6.93-6.99 (m, 2H), 4.95 (d, 2H, J=
10.4 Hz), 4.47(d, 2H, J= 9.2 Hz), 4.30 (dd, IH, J/= 12.8 Hz, J2= 1.60 Hz), 4.06 (d, IH, 12.8 Hz), 3.70 (d, IH, J= 8.4 Hz), 2.83 (dd, IH, J}= 12.8 Hz, 4.0 Hz), 2.27 (t,
IH, J= 12.4 Hz), 1.26 (s, 9H); ESI-MS: (+ve mode) 326.5 (M+H)+ (100 %); HPLC:
96.4 %.
Step-7: tert-butyl ((2R.3S)-2-(2.5-difluorophenyl)-5-oxotetrahydro-2H-pyran-3vDcarbamate (Intermediate-1)
Tert-butyl ((2R,3S)-2-(2,5-difluorophenyl)-5-methylenetetrahydro-2H-pyran-3yl) carbamate (7, 10g) was dissolved in DCM and ACN, to it added solution of NaIO4 (19.75g) dissolved in water (150ml) followed by RuCh 3H2O (160mg) at 25 °C. Reaction mixture was stirred for 3h. After completion of reaction, diluted it with DCM and added water (150ml), layers were separated and aqueous layer was extracted with DCM. Combined organic layer was washed with 10% aqueous Na2S2O2 solution, water and brine. Organic layer was evaporated to dryness to get tert-butyl ((2R,3S)-2-(2,5difluorophenyl)-5-oxotetrahydro-2H-pyran-3-yl)caibamate as a white crystalline powder (8.5g, 84% yield). y;— *H NMR: (CDClj, 400 MHz): δ 7.20-7.30 (m, IH), 6.96-7.04 (m, 2H), 4.83 (d, IH, J=
8.0 Hz), 4.61(m, IH), 4.29 (dd, IH, J/= 16.4 Hz, Jy= 1.60 Hz), 4.11 (d, IH, J= 16.4
Hz), 3.02-3.07 (m, IH), 2.60-2.80 (m, IH), 1.30 (s, 9H); ESI-MS: (+ve mode) 328.4 (M+H)+ (40 %); HPLC: 98.9 %.
Synthesis of substituent Λ2 [hexahydro-lH-furo[3,4-c]pyrrole; (2a)] hnCO
Synthesis of substituent R2 (hexahydro-lH-furo[3,4-c]pyrrole; 2a) was carried out as shown in Scheme-3 and the stepwise procedure is depicted below:
Scheme-3:
Pd/C, H2 Ethanol
H\X>
Substitated R1 (2a)
Step-1: l-Benzvl-pvTro1idine-3.4-dîcarboxylic add dimethyl ester (10)
N-benzyl-l-methoxy-N-((trimethylsilyl)methyl)methanamine (8, 21.4g) and dimethyl maleate (9, 10g) were dissolved »n DCM (200 ml). To the reaction mixture TFA (0.54ml, 6.94mmol) was added and stirred for 3 h. After completion of reaction, reaction mixture was neutralized with saturated NaHCOj solution (100 ml). Organic layer was washed with water, brine solution, dried over anhydrous Na^SOi and evaporated under reduced pressure to get l-Benzyl-pyrrolidine-3,4-dicarboxylic acid dimethyl ester (10) as a light yellow color oil (16.7g, 87% yield).
’H NMR: (CDClj, 400 MHz): δ 7.25-7.13 (m, 5H), 3.72 (s, 2H), 3.58 (s, 6H), 3.263.20 (m, 2H), 3.08-3.04 (m, 2H), 3.04-2.63 (m, 2H); ESI-MS: (+ve mode) 277.9 (M+H)+ (60 %), 299.9 (M+Na) (80 %).; HPLC: 90 %.
Step-2: (l-BenzylDyrrolidîne-3.4-divl)dimethanol (11) l-Benzyl-pyrrolidine-3,4-dicarboxylic acid dimethyl ester (10, 15g), dissolved in THF (30 ml) was added to a suspension of L1AIH4 (4.3g) and stirred for 2h at 25 °C. Reaction mixture was quenched with water (2 ml) and 2N NaOH solution (2 ml). The reaction mixture was filtered, dried over anhydrous Na2SO4 and evaporated under reduced pressure to get (l-Benzylpyrrolidine-3,4-diyl)dimethanol (11) as a yellow color oil (11.6 g, 97% yield).
’ll NMR: (CDClj, 400 MHz): δ 7.25-7.13 (m, 5H), 3.67 (s, 2H), 3.64-3.47 (m, 4H), 2.70-2.65 (m, 2H), 2.44-2.39 (m, 2H), 2.15-2.1 l(m, 2H); ESI-MS: (+ve mode) 222.1 (M+H)+ (85%); HPLC: 94 %.
Sten-3: 5-Benzvl-hexahydro-fijrol3.4-c)nyiTo1e (12)
A mixture of l-Benzylpyrrolidine-3,4-diyl)dimethanol (11, 10g) and PTSA (1.94g) in dry toluene (100 ml) was refluxed at 140 °C for 16h. The reaction mixture was cooled and basified with IN NaOH solution (100 ml), organic layer was separated off, washed with water, brine solution and dried to yield 5-Benzyl-hexahydro-furo[3,4c]pyrrole (12) as an oil (5.9 g, 64% yield).
*H NMR: (CDClj, 400 MHz): δ 7.05-7.23 (m, 5H), 3.77-3.67 (s, 4H), 3.49 (s, 2H), 2.27-2.25 (m, 4H) 2.26-2.25 (m, 2H); ESI-MS: (+ve mode) 204.2 (M+H)+ (89%); HPLC: 84 %.
Step-4; hexahvdro-lH-furor3.4-c1r>vrrole (2a)
5-Benzyl-hexahydro-furo[3,4-c]pyrrole (12, 5g) was dissolved in EtOH (50 ml) and hydrogenated in presence of 10 % Pd/C (0.5 g) at 60 psi. Filtered the reaction mixture was filtered, evaporated to dryness to get hexahydro-lH-furo[3,4-c]pyrrole (2a) as a colorless oil (2.56g, 92% yield). — ’H NMR: (CDa3, 400 MHz): δ 3.67-3.58 (m, 4H) 3.43-3.33 (m, 2H), 2.97-2.88 (m, 4H); ESI-MS: (+ve mode) 113.8 (M+H)+ (55%); GC: 92 %.
Synthesis of substituent R2: [(3,4,5,6-tetrahydro-lH-thieno[3,4-c]pyrrole 2,2dioxide hydrobromide: (2b)]
U-HBr
Synthesis of substituent R (3,4,5,6-tetrahydro-lH-thieno[3,4-c]pyrrole 2,2dioxide hydrobromide; (2b) was carried out as shown in Scheme-4 and the stepwise procedure is depicted below:
Scheme-4:
110 OH \ / SOj in methanol, HBr \ / Hydroquinone _ H Br·—k y—Br AIBN.NBS
/ \ o o o''o
13 14 15 16
Bz-NHj
U HBr Cbz / Bn I
.N
\__( HBr in acetic acid Q Cbz-Cl \ /
Q ’ 0 o Q O 0 Q o o
Substituer! R1 (2b) 18 17
Steo-1:2.3-dimethylbuta-l,3-<iiene (14)
To 2,3-dimethylbutane-2,3-diol (13,85g), 48% aqueous HBr was added to get the colorless solution. Mixture was ffactionally distilled, washed twice with water and dried over anhydrous CaCI2. Mixture was redistilled and the fraction of 69-70 °C was collected to get 2,3-dimethylbuta-l,3-diene (14,38g. 64%yield).
*H NMR: (CDClj, 400 MHz): δ 5.06 (2H, s), 4.97 (2H, s), 1.92 (6H, s); ESI-MS: (+ve mode) 83.3 (M+H)+ (70 %).
Step-2: 3.4-dimethvl-2.5-dihydrothiophene 1.1-dioxide (15)
A mixture of hydroquinone (492mg) and 2,3-dimethylbuta-l,3-diene (14, 31.96 ml) was placed in sealed tube and a solution of sulfur dioxide in MeOH (140 ml) was added. Reaction mixture was heated at 85 °C for 4 h and cooled to room température. Crystals obtained was filtered, washed with cold methanol and dried to get 3,4dimethyl-2,5-dihydrothiophene 1,1-dioxide (15) as white crystalline solid (30 gm, 72% 10 yield).
’H NMR: (CDClj,400 MHz): δ 3.73 (4H, d, J= 1.2 Hz), 1.78 (6H, t, J= 1.2 Hz); ESIMS: (+ve mode) 147.2 (M+H)+ (70 %), 169.1 (M+Na)+ (40%).
Steo-3: 3.4-bis(bromomethyl)-2.5-dihydrothiophene I.l-dioxideil6)
A mixture of 3,4-dimethyl-2,5-dihydrothiophene 1,1-dioxide (15, 20g), 1bromopyrrolidine-2,5-dione (53.5g), and AIBN (400mg) in CHClj was heated for 15 hr. After completion of reaction, filtrate was evaporated under reduced pressure. The residue obtained was recrystallize from methanol to get 3,4-bis(bromomethyl)-2,5dihydrothiophene 1,1-dioxide as a white crystals (16,19 g, 45% yield).
’H NMR: (CDClj, 400 MHz): δ 4.06 (4H, s), 4.01 (4H, s); ESI-MS: (+ve mode) 303.8 (M+H)+ (90 %), 305.7 (M+2H)+ (70%).
Sten-4: 5-benzyl-3.4.5.6-tetrahydro-lH-thienor3.4-clDyrro1e 2.2-dioxide (17)
Mixture of 3,4-bis(bromomethyl)-2,5-dihydrothiophene 1,1-dioxide (16, 12g) and phenylmethanamine (10.84ml) in acetonitrile was stirred at 25 °C for 2 hr. After completion of reaction, solvent was removed under reduced pressure, ethyl acetate and IN NaOH were added, organic layer was separated and aq layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous NajSO4 and concentrated under reduced pressure to give 5-benzyl-3,4,5,6-tetrahydro30 lH-thieno[3,4-c]pyrrole 2,2-dioxide (17) as a solid compound (3.7 g, 38% yield).
’H NMR: (CDClj. 400 MHz): δ 7.34-7.29 (5H, m), 3.88 (2H, s), 3.77 (4H,s), 3.61 (4H, s); ESI-MS: (+ve mode) 250.3 (M+H)+ (100 %).
Step-5: benzyl 4.6-dihydro-lH-thienor3.4-clnyrrole-5(3H)-carboxylate 2,2-dioxide (18) A mixture of 5-ben2yI-3,4,5,6-tetrahydro-lH-thieno[3,4-c]pyrrole 2,2-dioxide (17, 3.6g) and CBZ-C1 (13.5 ml) in toluene was stirred for 3 hr. After completion of reaction, diethyl ether was added till solid precipitated out. Solid was fîltered and dried under reduced pressure to get benzyl 4,6-dihydro-lH-thieno[3,4-c]pyrro!e-5(3H)carboxylate 2,2-dioxide (18,2.7 g, 64% yield).
'H NMR: (CDClj, 400 MHz): Ô 7.38-7.35 (5H, m), 5.19 (2H, s), 4.31 (4H, s), 3.88 (4H, d, J = 13.6 Hz); ESI-MS: (+ve mode) 294.4 (M+H)+ (80 %).
Sten-6: 3.4.5.6-tetrahydro-1H-thienor3.4-clDvrro1e 2.2-dioxide hvdrobromide (2b)
To a solution of benzyl 4,6-dihydro-lH-thieno[3,4-c]pyiTole-5(3H)-carboxylate 2,2-dioxide (18, 3.7 g) in glacial acetic acid, HBr in glacial acetic acid was added and the reaction mixture was stirred at 25 °C for 3h. After completion of reaction, diethyl ether was added to afford sticky solid, solvent was decanted and added minimum amount of methanol to get the crystalline solid as 3,4,5,6-tetrahydro-lH-thieno[3,4cjpyrrole 2,2-dioxide hydrobromide as a hydrobromide sait (2b,1.5 g, 50% yield).
’H NMR: (CDClj, 400 MHz): δ 9.43 (2H, bs), 4.08 (4H, s), 4.02 (4H, s); ESI-MS: (+vemode) 160.4 (M+H)+ (88 %).
The other groups representing R2 as described elsewhere in the spécification were sourced commercially or were prepared either by similar processes as described above with suitable modifications as are necessary which are within the scope of a skilled person or prepared following literature processes. Such literature processes including suitable variations thereof are incorporated herein as référencés.
Synthesis of Compound 1: (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(5-(methylsulfonyl)hexahydro-pyrrolo[3,4-c]pyrrol -2 (IH)-yl) tetrahydro~2H-pyran-3-amine
Step-1: Synthesis of tert-butyl ((2R.3S,5R)-2-(2.5-difluorophenyn-5-(5(methylsulfonvD-hexahydropyrrolo r3.4-clpyrrol-2flH)-vl)tetrahvdro-2H-nvran-3vDcarbamate
Under nitrogen atmosphère ((2R,3S)-2-(2,5-difluorophenyl)-5-oxotetrahydro-2Hpyran-3-y 1) carbamate (Intermediate-1; 250mg) and 5(methylsulfonyl)octahydropyTrolo[3,4-c]pyTrol-2-ium 4-methylbenzenesulfonate (substituent-R2; 172mg) was dissolved in anhydrous DMA to get the pale yellow clear solution. Reaction mixture was cool to 0-5 °C and sodiumtriacetoxyborohydride (21 lmg) was added. The reaction mixture was stirred at 0-5 °C for 2h, poured in ice cold water, solid precipitated was filtered, washed with water and dried to get the title compound as a white solid (234mg, 61% yield).
Step-2: Synthesis of (2R. 3S. 5R)-2-(2.5-difluorophenyl)-5-(5-fmethyÎsulfonyhhexahvdro-pyrrolor3.4-clpvrro1-2 (lH)-vl) tetrahvdro-2H-pyran-3-amine
Compound of step-1 (tert-butyl ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(5(methylsulfonyl) hexahydropyrrolo [3,4-c]pyrrol-2(lH)-yl)tetrahydro-2H-pyran-3yl)carbamate; 210mg) was treated with HCl in dioxane solution at 15-25 °C for 2h. Solvent was removed under reduced pressure and water was added to get clear solution, which was extracted with DCM. Aqueous layer was basifîed with saturated aqueous NaHCOj solution and extracted with DCM. Combined organic layer was washed with water (50ml), evaporated to get (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(5(methylsulfonyl)hexahydropyrrolo[3,4-c]pyrrol-2 (lH)-yl) tetrahydro-2H-pyran-3amine as a white solid (160mg, 95% yield).
’H NMR: (CD3OD, 400 MHz): 7.31-7.27 (m, IH), 7.24-7.20 (m, 2H), 4.68 (d, IH, J= 10Hz), 4.464.42 (m, IH), 3.98-3.96 (m, IH), 3.87-3.83 (m, IH), 3.77 (t, IH, J= 10.8Hz), 3.71-3.67 (m, IH), 3.62-3.56 (m, IH), 3.41-3.33 (m, 4H), 3.30-3.23 (m, 4H), 2.95 (s, 3H), 2.78-2.69 (m, IH), 2.15 (q, IH, J= 11.6Hz); ESI-MS: (+ve mode) 402.0 (M+H)+ (100 %), 423.8 (M+Na)+ (50%); HPLC: 98.2 %.
Synthesis of Compound 2: (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(7-(methylsulfonyl)-
2,7-diazaspiro [4.4]-nonan-2-yl) tetrahydro-2H-pyran-3-amine
F
Step-1: Synthesis of______tert-butyl f(2R.3S.5R)-2-(2.5-difluoTOphenyl)-5-(7(methylsulfonyl)-2.7-diazaspiror4.41 nonan-2-yl)tetrahydro-2H-pyran-3-yl)carbamate Under inert atmosphère ((2R,3S)-2-(2,5-difluorophenyl)-5-oxotetrahydro-2Hpyran-3-yl)carbamate (Intermediate-1; 250mg) and 2-(methylsulfonyl)-2,7diazaspiro[4.4] nonane (substituent-R2; 172mg) were dissolved in anhydrous MeOH, Decaborane (28mg) was added to this reaction mixture at 25-30 °C and stirred for 15h. MeOH was removed from the reaction mixture and residue obtained was purified by column chromatography using 0 to 2% MeOH in DCM as an eluent system to get the title compound as a white solid (264mg, 67% yield).
Step-2: Synthesis of (2R.3S,5R)-2-(2.5-difluorophenvl)-5-(7-(methylsulfonvl)-2.7diazaspiror4.41nonan-2-yl) tetrahvdro-2H-pyran-3-amine
Compound of step-1 (tert-butyl ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(7(methylsulfonyl)-2,7-diazaspiro[4.4] nonan-2-yl)tetrahydro-2H-pyran-3-yl)carbamate; 250mg) was dissolved in DCM, to it TFA was added and stirred at 25 °C for 2h. After completion of reaction, mixture was evaporated to dryness and residue obtained was neutralized with 2.5% ammonium hydroxide, solvents were removed under reduced pressure and residue was triturated with diethyl ether to get the title compound as a white powder (189mg, 94% yield).
’H NMR: (CDjOD,400 MHz): 7.33-7.25 (m, 3H), 4.85-4.82 (d, IH, J= 10.4Hz), 4.514.49 (d, 2H, J= 6.8Hz), 3.84-3.82 (m, 2H), 3.78-3.67 (m, 4H), 3.51 (t, 2H, J= 6.8Hz), 3.43-3.35 (m, 2H), 3.07 (s, 3H), 2.89-2.86 (m, IH), 2.25-2.19 (m, 2H), 2.17-2.08 (m, 3H); ESI-MS: (+ve mode) 416.1 (M+H)+ (100 %); HPLC: 982 %.
Synthesis of Compound 3: (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(tetrahydro-lHfuro[3,4-c]pyrrol-5(3H)-y!)tetrahydro-2H-pyran-3-amine
Step-1: Synthesis of tert-butyl (f2R.3S.5R)-2-(2.5-difluorophenvl)-5-(tetrahydro-lHfuror3.4-clpyrrol-5f3H)-yl)tetrahvdro-2H-pyran-3-yl)cafbamate
Hexahydro-lH-furo[3,4-c]pyrrol-5-ium 4-methylbenzenesulfonate (substituentR ; 445mg) was dissolved in DMA, Intermediate-1 (150mg) and DIEA (556mg) were added to it and the solution was stirred for 30 min. Glacial CH3COOH (413mg) was added to this mixture and stirred at 25 °C for 15min. Sodium cyanoborohydride was added and stirred for 3h. Reaction mixture was cooled and added to a mixture of ethyl acetate) and saturated aqueous NaHCOj solution. Organic layer was washed with water, brine, dried over anhydrous Na2SO4, filtered and evaporated to dryness to give diastereomeric mixture of the title compound, which was purified by flash column chromatography using 0-3% methanol in DCM as an eluent system to get tert-butyl ((2R,3 S,5R)-2-(2,5-difluorophenyl)-5-(tetrahydro-1 H-furo[3,4-c]pyrrol-5 (3 H)yl)tetrahydro-2H-pyran-3-yl)caibamate as a white solid (132mg, 67%yield).
Step-2: Synthesis of (2R.3S.5R)-242.5-difluorophenv1)-5-(tetrahydro-lH-fi]roF3.4c1pyrro1-5f3H)-yh tetrahydro-2H-pyran-3-amine
Compound of the step-1 (tert-butyl ((2R,3S,5R)-2-(2,5-difluorophenyl)-5(tetrahydro-lH-furo[3,4-c]pynol-5(3H)-yl)tetrahydro-2H-pyran-3-yl)carbamate; 132mg) was dissolved in anhydrous MeOH to get the clear solution. HCl gas was bubbled through this solution for 2h. Solvent was removed under reduced pressure and residue was dissolved in water, basifîed with saturated aqueous NaHCO3 solution and extracted with DCM. Combined organic layer was washed with water and saturated brine solution, evaporated to dryness to get the 2R,3S,5R-2-(2,5-difluorophenyl)-5(tetrahydro-lH-furo[3,4-c]pyirol-5(3H)-yl) tetrahydro-2H-pyran-3-amine as a white solid (98mg, 97% yield).
'H NMR: (CD3OD, 400 MHz): 7.18-7.19 (m, IH), 7.13-7.11 (m, 2H), 4.55-4.54 (d, IH, J= 10.4Hz), 4.3 (m, IH), 3.77-3.74 (m, 2H), 3.63-3.62 (m, 2H), 3.60-3.56 (m, 5H), 3.04-3.03 (m, 4H), 2.6-2.7 (m, 2H), 1.97-1.94 (m, IH); ESI-MS: (+ve mode) 324.9 (M+H)+ (100 %), 347 (M+ Na)+ (25%); HPLC: 96.6 %.
Using either of the above procedures, following additional compounds were prepared by suitable reductive amination of intermediate-1 with appropriate substituent R2 followed by άτ-* removal of amine protecting group.
Compound 4: (2R,3S,5R)-2-(2,5-difIuorophenyl)-5-(hexahydropyrro!o[3,4-c]pyrrol2(lH)-yl)tetrahydro~2H~pyran~3~amine
’H NMR: (CDjOD. 400 MHz): 729-727 (m, IH), 723-720 (m, 2H), 4.64 (d, IH, J= 10.4 Hz), 4.38-4.35 (dd, IH, Jf= 2.4Hz, Λ= 10.4Hz), 3.69 (t, IH, J= 11Hz), 3.57-3.53 (m, 4H), 3.34-3.30 (m, 8H), 2.68-2.65 (m, IH), 2.04 (q, IH, J = 11.6 Hz); ESI-MS: (+ve mode) 323.9 (M+H)+ (100 %), 345.9 (M+Na)+ (20%); HPLC: 98.6 %.
Compound 5: (2R,3S,5R)-2-(2.5-difluorophenyl)-5-(5-((trifluoromethyl)sulfonyl) hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)tetrahydro-2H-pyran-3-amine
’H NMR: (CDjOD 400 MHz): δ 7.45-7.43 (m, IH), 724-7.19 (m, 2H), 4.80-4.72 (m, IH), 4.47-4.30 (m, IH), 3.93-3.82 (m, 2H), 3.60-3.81 (m, 6H), 328-3.18 (m, 2H), 3.082.93 (m, 2H), 2.71-2.52 (m, 2H), 223-2.08 (m, IH); ESI-MS: (+ve mode) 456.0 (M+H)+ (100 %); HPLC: 95.0 %.
Compound 6: (2R,3S,5R)~2-(2,5-difluorophenyl)-5-(5(ph enyhulfonyl)hexahydropyrrolo[3,4-c]pyrrol-2(l H)-yl) tetrahydro-2H-pyran-3amine
’H NMR: (CDjOD, 400 MHz): δ 7.85-7.82 (m, 2H), 7.73-7.64 (m, 3H), 7.31-728 (m, IH), 724-721 (m, 2H), 4.66-4.64 (m, IH), 4.42-4.39 (m, IH), 3.81-3.72 (m, 3H), 3.693.66 (m, 2H), 3.39-3.36 (m, 2H), 3.06-3.00 (m, 4H), 2.95-2.83 (m, 2H), 2.73-2.70 (m, IH), 2.05-2.02 (m, IH); ESI-MS: (+ve mode) 464.0 (M+H)+ (100 %); HPLC: 95.68 %.
Compound 7: 5-((3R,5S, 6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3yl)-N,N-dimethylhexahydropyrrolo[3,4-c]pyrrole-2(lH)-sulfonamide
Z* 'h NMR: (CDjOD, 400 MHz): 7.29-7.26 (m, IH), 7.24-7.21 (m, 2H), 4.67-4.65 (m, IH 4.45-4.43 (m, 2H), 3.93-3.32 (m, 2H), 3.77-3.72 (m, IH), 3.69-3.66 (m, IH), 3.613.55 (m, 2H), 3.36 (s, 3H), 3.30-329 (s, 3H), 2.88 (s, 6H), 2.77-2.74 (m, IH), 2.14-2.07 (m, IH); ESI-MS: (+ve mode) 431.1 (M+H)+ (100 %), 453 (M+Na)+; HPLC: 97.50 %.
Compound 8: (2R, 3S,5R)-2-(2,5-difluorophenyl)-5-(5-(methylsulfonyl)-5,6dihydropyrroîo [3,4-c]pyrrol-2(lH,3H,4H)-yl)tetrahydro-2H-pyran-3-amine
F
’H NMR: (CDjOD. 400 MHz): 7.32-7.28 (m, IH), 7.26-7.23 (m, 2H), 4.77 (d, IH, J= 10Hz), 4.32(dd, IH, Jt= 2.0Hz, J2= 10.8Hz), 4.19 (s, 4H), 3.89-3.83 (m, 4H), 3.703.65 (m, IH), 3.61 (t, IH, J= ll.6Hz), 3.53-3.46 (m, IH), 3.04 (s, 3H), 2.65-2.62 (dd, IH, Jr 1.2Hz, Jf= 12Hz), 1.84 (q, IH, J « 12 Hz); ESI-MS: (+ve mode) 400.0 (M+H)+ (100 %); HPLC: 99.4 %.
Compound 9: 5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3yï)-N,N-dimethyl-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(lH)-sulfonamide
’H NMR: (CDjOD, 400MHz) :- 725-722 (m, IH), 7.18-7.13 (m, 2H), 4.41 (d, 9.6
Hz, IH), 422-4.19 (m, IH), 4.11 (s, 4H), 3.59 (s, 4H), 3.37 (t, J = 10.8 Hz, IH), 3223.14 (m, IH), 3.05-2.95 (m, IH), 2.82 (s, 6H), 2.50-2.41 (m, IH), 1.55 (q, J = 12.0 Hz, IH). ESI-MS: (+ve mode) 429.15 (100*) (M+H)+ ; HPLC: 95.18 %.
Compound 10: 5-((3R.5S,6R)-5-amino-6~(2,5-difluorophenyl)tetrahydro-2H-pyran-3yï)-2-cyclopropyltetrahydropyrroîo[3,4-c]pyrrole-l,3(2H,3aH)-dione ’H NMR: (CD3OD, 400MHz) 730-726 (m, IH), 723-7.18 (m, 2H), 4.53 (d, J =
10.0 Hz, IH), 427-423 (m, IH), 3.48-3.41 (m, 2H), 3.38-3.31 (m, 2H), 329-321 (m, 2H), 2.77-2.69 (m IH), 2.65-2.61 (m, 2H), 2.60-2.54 (m, IH), 2.53-2.49 (m, IH), 1.65 (q, J = 12.0 Hz, IH), 1.92-0.87 (m, 4H). ESI-MS: (+ve mode) 391.9 (100%) (M+H)+ ; HPLC: 98.30 %.
Compound 1 1: 5-((3 R, 5S, 6R)-5-amino-6-(2,5-difluoroph enyl)tetrahydro-2H-pyran-3yl)-2-benzyltetrahydropyrrolo[3,4-c]pyrroîe-l,3(2H,3aH)-dione ’H NMR: (CD3OD, 400 MHz): 7.35-7.30 (m, 6H), 7.21-720 (m, 2H), 4.66 (s, 2H), 4.55 (d, IH, J= 10Hz), 4.27-4.25 (m, IH), 3.48-3.44 (m, 2H), 3.42-3.36 (m, 4H), 2.802.74 (m, IH), 2.69-2.68 (m, 2H), 2.55-2.52 (m, IH), 1.66 (q, IH, J= 11.6 Hz); ESIMS: (+ve mode) 441.9 (M+H)+ (100 %); HPLC: 97.2%.
Compound 12: (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(5-(methylsulfonyl)hexahydro-lHpyrrolo[3,4-c]pyridin-2(3H)-yl)tetrahydro-2H-pyran-3-amine ’H NMR: (CDjOD 400 MHz): 7.26-7.23 (m, 3H), 4.66-4.63 (m, IH), 3.58-3.48 (m, 7H), 3.31 (s, 3H), 3.13-3.14 (m, 2H), 2.95 (m, IH), 2.94-2.66 (m, 3H), 2.24-2.22 (m, 15 IH), 2.09-2.05 (m, 3H), 1.89-1.94 (m, IH); ESI-MS: (+ve mode) 416.07 (M+H)+ (100 %); HPLC: 95.3 %.
Compound 13: (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)hexahydro-lHpyrrolo [3,4-c]pyridin-5(6H)-yl)tetrahydro-2H-pyran-3-amine ’H NMR: (CD3OD 400 MHz): 7.29-7.36 (m, 3H), 4.61-4.63 (m, IH), 3.48-3.37 (m, 7H), 3.34 (s, 3H), 3.13-3.14 (m, 2H), 2.98 (m, IH), 2.94-2.61 (m, 3H), 2.24-2.22 (m, IH), 2.05-2.01 (m, 3H), 1.91-1.84 (m, IH); ESI-MS: (+ve mode) 416.07 (M+H)+ (100 %); HPLC: 96.6 %.
Compound 14: (2R,3S,5R)-2-(2,5-difuorophenyl)-5-(8-(methylsulfonyl)-2,8diazaspiro[4.5]decan -2-yl)tetrahydro-2H-pyran-3-amine ’H NMR: (CD3OD, 400 MHz): 7.30-7.28 (m, IH), 7.26-7.22 (m, 2H), 4.74-4.71 (m, 30 IH), 4.30-4.24 (m, IH), 3.87-3.84 (m, 2H), 3.75-3.61 (m, 2H), 3.61 (s, 3H), 3.58-3.60 (m, 2H), 3.31-3.30 (m, 2H), 3.26-322 (m, 3H), 2.97-2.84 (m, 4H), 2.20-2.10 (m, 2H), 2.04-1.95 (m, IH), 1.93-1.82 (m, IH); ESI-MS: (+ve mode) 464.0 (M+H)+ (100 %); HPLC: 95.32%.
15:
(2R.3S.5R)-2-(2,5-difluorophenyl)-5-(I(methylsulfonyl)hexahydropyrrolo[3,4-b]pyrrol-5(lH)-yl)tetrahydro-2H-pyran-3 amine ’H NMR: (CD3OD, 400 MHz): 7.30-726 (m, IH), 7.22-7.20 (m, 2H), 4.67^.65 (d, IH, J = 10Hz), 4.44-4.38 (m, 2H, 3.85-3.82 (m, IH), 3.76-3.71 (m, IH), 3.64-3.46 (m, 6H), 3.33-3.29 (m, 2H), 2.97 (s, 3H), 2.76-2.72 (m, IH), 2.28-2.22 (m, IH), 2.13 (q, IH, J= 12 Hz), 1.96-1.92 (m,lH); ESI-MS: (+ve mode) 402.1 (M+H)+ (100 %), 424.1 (M+Na)+ (10 %),; HPLC: 95.6 %.
Compound 16: (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(5(methylsulfonyI)hexahydropyrrolo[3,4-b]pyrrol-l(2H)-yl)tetrahydro-2H-pyran-3amine *H NMR: (CDjOD, 400 MHz): 7.29-7.27 (m, IH), 7.23-7.20 (m, 2H), 4.65-4.63 (m, 2H), 4.47-4.44 (m, IH), 4.14-4.10 (m, IH), 3.66-3.48 (m, 4H), 3.48-3.43 (m, 4H), 3.31325 (m, IH), 2.69 (s, 3H), 2.65-2.62 (m, IH), 2.42-2.32 (m, IH), 2.01-1.98 (m, IH), 1.89-1.78 (m, IH); ESI-MS: (+ve mode) 402.1 (M+H)+ (100 %), 424 (M+Na)+; HPLC: 97.55 %.
Compound 17: 5~((3R,5S,6R)-5-amino-6-(2,5-difluoropheny!)tetrahydro-2H-pyran-3yl)-3,4,5,6-tetrahydro-lH-thieno[3.4-c]pyrrole 2,2-dioxide ’H NMR: (CDjOD, 400 MHz): 7.30-7.328 (m, IH), 7.24-7.20 (m, 2H), 4.66-4.65 (d, IH, J =10 Hz), 4.40-4.38 (t, IH, J= 6.8 Hz), 4.19-4.14 (m, 4H), 3.95-3.90 (m, 4H), 3.71-3.58 (m, 3H), 2.65-2.62 (m, IH), 2.00 (q, IH, J= 12 Hz); ESI-MS: (+ve mode) 371.0 (M+H)+ (100 %), 393.1 (M+ Na)+ (55%); HPLC: 96.75 %.
Compound 18: (2R,3S,5R)-5-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)-2(2.5-difluorophenyl)tetrahydro-2H-pyran-3-amine *H NMR: (CDjOD, 400 MHz): δ 7.51-7.49 (m, 5H), 7.25-7.23 (m, IH), 7.22-7.20 (m, 2H), 4.59 (d, IH, J= 10Hz), 439 (s, 2H), 4.37-4.34 (m, IH), 3.98-3.95 (m, IH), 3.883.83 (m, IH), 3.77 (t, 1H,^= 10.8Hz), 3.34-3.31 (m, 8H), 3.06-3.02 (m, 2H), 2.57-2.54 (m, IH), 1.91-1.87 (q, IH, J= 11.6Hz); ESI-MS: (+ve mode) 414.2 (M+H)+ (100 %); HPLC: 96.32%.
Compound 19: (2R,3S,5R)-2-(2,5-difîuorophenyl)-5-(6-(methylsulJbnyl)-3,6diazabicyclo[3.2.0] heptan~3-yl)tetrahydro-2H~pyran-3-amine
’H NMR: (CDjOD 400 MHz): δ 7.31-7.29 (m, IH), 7.25-7.21 (m, 2H), 5.00-4.97 (m, IH), 4.68 (d, IH, J= 10.0 Hz), 4.44-4.40 (m, IH), 4.18 (t, IH, J = 8.4 Hz), 3.81-3.76 (m, 2H), 3.71 (d, IH, J= 11.2 Hz), 3.65-3.62 (m, IH),3.59-3.56 (m, IH), 3.39-3.35 (m, 2H), 3.12-3.04 (m, IH), 3.02 (s, 3H), 3.00-2.94 (m, IH), 2.74-2.72 (m, IH), 2.10 (q, IH, J = 12.0 Hz).; ESI-MS: (+ve mode) 388.10 (100%) (M+H)+, 410.05 (M+Na)+ (20%); HPLC: 96.02%.
Compound 20: (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(3-(methylsulfonyl)-3,6diazabicyclo[3.2.0] heptan-6-yl)tetrahydro-2H-pyran-3-amine
’H NMR: (CDîOD, 400 MHz): δ 7.34-7.32 (m, IH), 7.29-7.26 (m, 2H), 5.01-4.98 (m, IH), 4.68 (d, IH, J= 10.0 Hz), 4.44-4.40 (m, IH), 4.284.21 (m,lH), 3.98-3.83 (m, 2H), 3.74-3.70 (m, 2H), 3.65-3.59 (m, IH), 3.55-3.48 (m, 2H), 3.33-3.29 (m, 2H), 3.07 (s, 3H), 2.61-2.58 (m, IH), 1.88-1.79 (m, IH).; ESI-MS: (+ve mode) 388.15 (100%) (M+H)+, 410.10 (M+Na)+ (10%); HPLC: 97.49 %.
Compound 21: N-(2-((3R,5S, 6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-
3-yl)octahydrocyclopenta[c]pyrrol-5-yl)methanesulfonamide ’H NMR: (CD3OD, 400 MHz): δ 7.20-7.17 (m, IH), 7.14-7.11 (m, 2H), 4.56 (d, IH, J = 10.0 Hz), 4.34-4.31 (m, IH), 3.66-3.61 (m, 3H), 3.51-3.45 (m, 4H), 2.89-2.87 (m, 4H), 2.82-2.81 (m, 2H), 2.65-2.62 (m, IH), 2.22-2.19 (m, 2H), 2.09-1.99 (m, IH), 1.511.48 (m, 2H); ESI-MS: (+ve mode) 416.05 (M+H)+ (100%); HPLC: 96.02 %.
Compound 22: (2R,3S,5R)-5-(5-(cyclopropanecarbonyl)-5,6-dihydropyrrolo[3,4· c]pyrrol-2(lH,3H,4H)-yI)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-amine
F
’H NMR: (CDjOD, 400 MHz): 7.04-6.98 (m, 3H), 4.55-4.45 (m, IH), 4.40-4.30 (m, 2H),4.18-4.15 (m, IH),4.08-4.07 (m, 2H), 3.54-3.53 (m, 4H), 3.40-3.38 (m, IH), 3.253.20 (m, IH), 2.85-2.75 (m, IH), 2.40-2.22 (m, IH), 1.75-1.60 (m, IH), 1.55-1.40 (m, IH), 0.83-0.81 (m, 2H), 0.78-0.75 (m, 2H); ESI-MS: (+vemode) 390.15 (M+H)+ (100 %); HPLC: 95.86 %.
Compound 23: (5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3yl)~5,6-dihydropyrrolo[3,4~c]pyrrol-2(lH,3H,4H)~yl)(phenyl)methanone
’H NMR: (CD3OD, 400 MHz): δ 7.59-7.47 (m, 5H), 7.32-7.28 (m, IH), 7.26-7.22 (m, 2H), 4.72 (d, IH, J= 10.4 Hz), 4.48-4.43 (m, 3H), 4.33-4.29 (m, 4H), 4.23-4.21 (m, 2H), 3.91-3.87 (m, IH), 3.76 (t, IH, J= 10.8 Hz), 3.66-3.60 (m, IH), 2.79-2.75 (m, IH), 2.08 (q, IH, J= 11.6 Hz); ESI-MS: (+ve mode) 426.15 (M+H)+ (100%), 464.35 (M+K)+ (10%); HPLC: 95.70 %.
Compound 24: l-(5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-
3-yl)-5,6-dihydropyrrolo[3,4-c]pyrrol-2(1 H, 3H,4H)-yl)-2-methylpropan-l -one
F
O ’H NMR: (CDjOD, 400 MHz): δ 7.28-7.24 (m, IH), 7.20-7.14 (m, 2H), 4.47 (d, IH, J = 9.6 Hz), 4.36 (s, 2H), 425^22 (m, IH), 4.16 (s, 2H), 3.63 (s, 4H), 3.41 (t, IH, J = 10.8 Hz), 3.36-327 (m, IH), 3.08-3.05 (m, IH), 2.78-2.73 (m, IH), 2.52-2.49 (m, IH), 1.61 (q, IH, J - 11.6 Hz), 1.12 (d, 6H, J = 6.4 Hz); ESI-MS: (+ve mode) 39220 (100%) (M+H)+; HPLC: 95.48 %.
Compound 25: (5-((3R,5S,6R)-5-armno-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3yl)-5,6-dihydropyrrolo[3,4-cJpyrro 1-2(1 H, 3H,4H)-yl) (zyclopentyl)methanone
o ’H NMR: (CDjOD 400 MHz): 7.32-7.26 (m, IH), 7.25-7.22 (m, 2H), 4.70 (d, IH, J = 10 Hz), 4.47-4.44 (m, 3H), 4.25-4.23 (m, 5H), 3.76-3.73 (m, IH), 3.65-3.62 (m, 3H), 2.95-2.89 (m, IH), 2.85-2.75 (m, IH), 2.00 (q, IH, J = 11.6 Hz), 1.95-1.90 (m, 2H), 1.78-1.77 (m, 4H), 1.67-1.64 (m, 2H); ESI-MS: (+ve mode) 418.2 (M+H)+ (100 %), 440.3 (M+Na)+; HPLC: 95.64 %.
Compound 26: (5-((3R.5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3yl)~5,6-dihydropyrrolo[3,4-c]pyrrol-2(!H,3H,4H)-yl)(cyclohexyl)methanone
’H NMR: (CDjOD, 400 MHz): 7.33-7.30 (m, IH), 7.25-7.19 (m, 2H), 4.51 (d, IH, J = 92 Hz), 4.41 (s, 2H), 4.3(M.27 (m, IH), 4.20 (s, 2H), 3.68 (s, 4H), 3.48-3.40 (m, IH), 3.09-3.08 (m, lH)2-53-2.50 (m, IH), 1.88-1.76 (m, 5H), 1.66-1.63 (m, IH), 1.57-1.48 (m, 3H), 1.46-1.34 (m, 4H); ESI-MS: (+ve mode) 4322 (M+H)+ (100 %); HPLC: 95.2 %.
Compound 2 7: (2R. 3S. 5R)-2-(2,5-difluorophenyl)-5-(5-(methoxycarbonyl)-5,6dihydropyrrolo- [3,4-c]pyrro!-2(lH,3H, 4H)-yl)tetrahydro-2H-pyran-3-amine
F
II o ’H NMR: (CDjOD. 400 MHz): 7.31-725 (m, 3H), 4.71 (d, IH, J= 10.4 Hz), 4.434.39 (m, IH), 423- 421 (m, 4H), 420-4.19 (m, 4H), 3.76 (s, 3H), 3.69-3.64 (m, 2H), 3.54-3.50 (m, IH), 2.72-2.70 (m, IH), 2.06-2.03 (m, IH),; ESI-MS: (+vemode) 380.10 (M)+ (100 %); HPLC: 95.07 %.
Compound 28: (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(5-(elhoxycarbonyl)-5,6dihydropyrrolo[3,4-c]pyrrol-2(lH,3H,4H)-yl)tetrahydro-2H-pyran-3-amine
*H NMR: (D20.400 MHz): 7.34-725 (m, 3H), 4.86 (d, IH, J= Î0.4 Hz), 4.49-4.38 (m, IH), 426-423 (m, 4H), 421-4.19 (m, 4H), 4.16 (q, 2H, J=7.2 Hz ), 4.10-4.07 (m, IH), 3.85-3.74 (m, 2H), 2.83-2.85 (m, IH), 2.15-2.06 (m, IH), 128 (t, 3H, J= 14.4 Hz); ESI-MS: (+ve mode) 394.15 (M)+ (100 %); HPLC: 95.72 %.
Compound 29: (2R*3S,5R)-2-(2,5-difluorophenyl)-5~(5-((trifluoromethyl)sulfonyl)-5,6dihydropyrrolo [3,4-c] pyrrol-2(lH,3H,4H)-yl)tetrahydro-2H-pyran-3-armne _
’H NMR: (CDjOD, 400 MHz): 7.30-727 (m, IH), 725-7.21 (m, 2H), 4.49 (d, IH, J= 10 Hz), 4.40 (s, 4H), 4.28-4.26 (m, IH), 3.72-3.67 (m, 4H), 3.46-3.44 (m, IH), 3.313.30 (m, IH), 3.11-3.06 (m, IH), 2.53-2.50 (m, IH), 1.67-1.58 (m, IH); ESI-MS: (+ve mode) 454.1 (M+H)+ (100 %); HPLC: 96.5 %.
Compound 30: (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(5-(ethylsulfonyl)-5,6dihydropyrrolo[3,4-c]pyrrol-2(lH,3H,4H)-yl)tetrahydro-2H-pyran~3-amine
F
’H NMR: (CDjOD. 400 MHz): Ô 7.32-7.29 (m, IH), 726-723 (m, 2H), 4.72 (d, IH, J = 10.4 Hz), 4.46-4.44 (m, IH), 4.30-422 (m, 8H), 3.91-3.86 (m, IH), 3.76 (t, IH, J = 11.0 Hz), 3.66-3.60 (m, IH), 3.18 (q, 2H, J= 7.2 Hz), 2.78-2.75 (m, IH), 2.09 (q, IH, J = 11.6 Hz), 1.37 (t, 3H, J = 72 Hz); ESI-MS: (+ve mode) 414.1 (100%) (M+H)+; HPLC: 95.48 %.
Compound 31: (2R,3S,5R)-2-(2.5-difluorophenyl)-5-(5-(isopropylsulfonyl)~5,6· dihydropyrrolo [3,4~c]pyrrol-2(l H, 3H,4H)-yl)tetrahydro-2H-pyran-3-amine
’H NMR: (CD3OD, 400 MHz): δ 725-7.22 (m, IH), 7.18-7.14 (m, 2H), 4.42 (d, IH, J = 9.6 Hz), 4.23-420 (m, 5H), 3.60 (s, 4H), 3.49-3.35 (m, 2H), 3.24-3.18 (m, IH), 3.063.00 (m, IH), 2.46 (d, IH, J= 12.0 Hz), 1.35 (q, IH, J= 11.6 Hz), 1.35 (d, 6H, J= 6.8 Hz); ESI-MS: (+ve mode) 42820 (100%) (M+H)+; HPLC: 95.52 %.
Compound 32: (2R. 3S, 5R)~2-(2,5-difluorophenyl)-5-(5-(phenylsuîfonyl)-S, 6dihydropyrrolo[3,4-c]pyrrol-2(lH,3H,4H)-yl)tetrahydro-2H-pyran-3-amine
’H NMR: (CD3OD, 400 MHz): 7.89-7.87 (m, 2H), 7.70-7.59 (m, 3H), 7.27-720 (m,
3H), 4.65-462 (m, IH), 4.35-4.32 (m, IH), 420-4.10 (m, 4H), 4.09-4.00 (m, 4H), 3.72
3.57 (m, 3H), 2.67-2.65 (m, IH), 1.96-1.93 (m, IH); ESI-MS: (+ve mode) 462.15 (M+H)+ (100 %), 484.10 (M+Na)+ (25%); HPLC: 96.69 %.
Compound 33: (2R,3St5R)-2-(2,5-difluorophenyl)-5-(5-((4-fluorophenyl)sulfonyl)-5,6dihydropyrrolo[3,4-c]pyrrol-2(lH,3H,4H)-yl)tetrahydro-2H-pyran-3-amine
*H NMR: (CDjOD 400 MHz): 8.00-7.96 (m, 2H), 7.42-7.38 (m, 2H), 7.29-7.25 (m, IH),
7.23-7.18 (m, 2H), 4.44 (d, IH, J= 10 Hz), 4.21-4.19 (m, IH), 4.16 (s, 4H), 3.54-3.53 (m, 5H), 325-3.20 (m, IH), 3.02-3.00 (m, IH), 2.44-2.437 (m, IH), 1.56-1.53 (m, IH); ESI-MS: (+ve mode) 480.2 (M+H)+ (100 %); HPLC: 95.5 %.
Compound 34:4-((5-((3R,5S,6R)-5-amino-6~(2,5-difluorophenyl)tetrahydro-2II-pyran3-yl)-5,6-dihydropyrrolo[3,4-c]pyrrol-2(lH,3H,4H)-yl)sulfonyl)benzonitrile
’H NMR: (CDjOD, 400 MHz): δ 8.07 (dd, 2H, 2.0 Hz, Λ= 6.8 Hz), 8.01 (dd, 2H,
Λ= 2.0 Hz, J/= 6.8 Hz), 7.30-7.22 (m, 3H), 4.69 (d, IH, J= 10.0 Hz), 4.40-4.36 (m, IH), 4.23-4.17 (m, 8H), 3.88-3.84 (m, IH), 3.71 (t, IH, J= 10.8 Hz), 3.63-3.57 (m, IH), 2.74-2.71 (m, IH), 2.07 (q, IH, J = 12.0 Hz); ESI-MS: (+ve mode) 487.15 (M+H)+ (100%); HPLC: 96.23 %.
Compound 35: (2R,3S,5R)-2-(2,5-difhiorophenyl)-5-(5-((4-(trifluorometho.xy) phenyl)sulfonyl)-5,6-dihydropyrrolo[3,4-c]pyrro 1-2(1 H, 3 H, 4H)-yl) tetrahydro-2Hpyran-3-amine
’H NMR: (CDjOD, 400 MHz): δ 7.99 (d, 2H, J = 8.8 Hz), 7.51 (d, 2H, J = 8.4 Hz), 723-720 (m, IH), 7.17-7.13 (m, 2H), 4.40 (d, IH, J= 10.8 Hz), 4.15-4.12 (m, 5H), 3.49 (s, 4H), 3.36-3.33 (m, IH), 322-3.18 (m, IH), 2.99-2.93 (m, IH), 2.42-2.39 (m, IH), 1.50 (q, IH, J = 11.2 Hz); ESI-MS: (+ve mode) 546.25 (100%) (M+H)+; HPLC: 96.75 %.
Compound 36: (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(5-((2,4-difluorophenyl)sulfonyl)-
5,6-dihydropyrrolo[3,4-c]pyrrol-2(lH,3H,4H)-yl)tetrahydro-2H-pyran-3-amine
F
’H NMR: (CDCb, 400 MHz): 7.96-7.90 (m, IH), 7.15-7.11 (m, IH), 7.06-7.69 (m, 4H), 4.20-4.12 (m, 6H), 3.59 (s, 4H), 3.31 (t, IH, J = 10.8 Hz), 2.94-2.89 (m, IH), 2.84-2.78 (m, IH), 2.37-2.33 (m, IH), 1.36 (q, IH, 12 Hz); ESI-MS: (+ve mode) 498.15 (M+H)+ (100 %), 520.20 (M+Na)+; HPLC: 96.95 %.
Compound 3 7: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(5-tosylhexahydrocyclo penta[c]pyrrol-2(lH)-yl)tetrahydro-2H-pyran-3-amine
’H NMR: (CDjOD, 400 MHz): 7.76-7.74 (d, 2H, 8.0 Hz), 7.43-7.41 (d, 2H, J= 8.0 Hz), 7.27-7.20 (m, 3H), 4.65-4.62 (m, IH), 4.33-4.31 (m, IH), 4.16-4.05 (m, 8H), 3.783.70 (m, IH), 3.64-3.55 (m, 2H), 2.67-2.65 (m, IH), 2.42 (s, 3H), 1.97-1.94 (m, IH) ; ESI-MS: (+ve mode) 476.20 (M+H)+ (100 %); HPLC: 95.16 %.
Compound 38: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(5-((4-methoxyphenyl)sulfonyl)-
5,6-dihydropyrrolo[3,4-c]pyrrol-2(lH,3H,4H)-yl)tetrahydro-2H-pyran-3-amine
F
*H NMR; (CDjOD, 400 MHz): 7.84-7.81 (m, 2H), 7.29-7.22 (m, 3H), 7.15-7.12 (m, 2H), 4.68 (d, IH, J= 10.4 Hz), 4.37-4.33 (m, IH), 4.17- 4.1 (m, 8H), 3.88 (s, 3H), 3.80-3.78 (m, IH), 3.68-3.61 (m,2H), 2.72-2.68 (m, IH), 2.06-1.99 (m, IH),; ESI-MS: (+ve mode) 492.2 (M+H)+ (100 %); HPLC: 95.67 %.
Compound 39: (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(5-((4-methoxyphenyl)sulfonyl)-
5,6-dihydropyrrolo[3,4-c]pyrroï-2(lH,3H,4H)-yl)tetrahydro-2H-pyran-3-amine
’H NMR: (CDjOD 400 MHz): 7.81 (d, 2H, J= 8.4 Hz), 7.50 (d, 2H, J= 8.4 Hz),7.297.21 (m, 3H), 4.50’(d, IH, 10 Hz), 436-4.31 (m, IH), 4.17- 4.19 (m, 4H), 4.013.97 (m, 4H), 3.62- 3.55 (m, 3H), 3.31-3.01 (m, IH), 2.63-2.61 (m, IH), 1.93-1.90 (m,
IH), 1.30 (d, 6H, J = 6.8 Hz); ESI-MS: (+ve mode) 50425 (M)+ (100 %); HPLC: 97.13 %.
Compound 40: (2R,3S,5R)-2-(2,5~difluorophenyl)-5-(5~((4-(trifluoromethyl) phenyl)sulfonyl)-5,6-dihydropyrrolo[3,4-c]pyrrol-2(lH.3H,4H)-yl)tetrahydro-2Hpyran-3-amine
'H NMR: (CDjOD, 400 MHz): δ 8.11 (d, 2H, 8.4 Hz), 7.97 (d, 2H, J= 8.4 Hz),
729-721 (m, 3H), 4.67 (d, IH, J= 10.0 Hz), 4.37^.34 (m, IH), 4.27-4.23 (m, 4H), 4.12-4.09 (m, 4H), 3.79-3.72 (m, IH), 3.65 (t, IH, J= 10.8 Hz), 3.58-3.57 (m, IH), 2.68-2.65 (m, IH), 2.00 (q, IH, 11.6 Hz); ESI-MS: (+ve mode) 530.25 (M+H)+ (100%); HPLC: 95.73 %.
Compound 41: (2R,3S,5R)-5-(5-acetyl-5,6-dihydropyrrolo[3,4-c]pyrrol-2(lH,3H,4H)yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-amine
F
o 'H NMR: (CD3OD, 400 MHz): 7.20-7.09 (m, 3H), 4.58 (s, IH), 4.30-428 (m, 2H), 420-4.10 (m, 3H), 3.63-3.61 (m, 4H), 3.40-3.35 (m, IH), 2.97-2.94 (m, 2H), 2.42-2.38 (m, IH), 2.13 (s, 3H) 2.10-2.08 (m, IH) ; ESI-MS: (+ve mode) 364.10 (M+H)+ (100 %); HPLC: 96.52%.
Compound 42: (2R.3S, 5R)-2-(2,5-difluorophenyl)-5-(5~(isobutylsu!fonyl)-5,6dihydropyrrolo[3,4-c]pyrrol-2(lH,3H,4H)-yl)tetrahydro-2H-pyran-3-amine
‘il NMR: (CD3OD, 400MHz) :- 7.31-727 (m, IH), 7.24-720 (m, 2H), 4.67 (d, IH, J= 10.0 Hz), 4.42-4.40 (m, IH), 422 (s, 4H), 4.16-4.12 (m, 4H), 3.77-3.72 (m, IH), 3.70 (t, IH, J= 10.8 Hz), 3.61-3.56 (m, IH), 2.99 (d, 2H, J= 6.8 Hz), 2.73-2.70 (m, IH), 2.24 (hep, IH, J= 6.4 Hz), 2.02 (q, IH, J = 11.6 Hz), 1.11 (d, 6H, J= 6.8 Hz). ESIMS: (+ve mode) 442.15 (M+H)+ (100 %); HPLC: 98.12 %.
Compound 43: 5~((3R,5S,6R)-5-amino-6-(2,5-difluorophenyI) yl) hexahydro-lH-thieno[3,4-c]pyrrole 2,2-dtoxide tetrahydro-2H-pyran-345
F
'H NMR: (D2O, 400MHz) δ 7.35-7.28 (m, 3H), 4.86 (d, IH, J= 10.4Hz), 4.53-4.51 (m, IH), 4.14-4.05 (m, 2H), 3.86-3.74 (m, 3H), 3.60-3.52 (m, 2H), 3.47-3.43 (m, 4H), 334 (d, 2H, 14Hz), 2.90-2.88 (m, IH), 2.14-2.11 (m, IH). ESI-MS: (+ve mode)
373.1 (M+H)+ (100 %); HPLC: 95.61 %.
Compound 44: (2R,3S,5R)-2-(2,5-difuorophenyl)-5-(5.6-dihydropyrrolo[3.4-c]pyrrol2(lH,3H,4H)-yl)tetrahydro-2H-pyran-3-amine
NH *H NMR: (D2O,400MHz) δ7.34-7.25 (m, 3H), 4.87 (d, IH, J= I2Hz), 4.52-4.48 (m, IH), 4.43-4.40 (m, 4H), 4.24 (s, 4H), 4.13-4.09 (m, IH), 3.82 (t, IH, J= 11.2 Hz), 3.78-3.74 (m, IH), 2.88-2.85 (m, IH), 2.13 (q, IH, J= 12Hz). ESI-MS: (+ve mode)
322.1 (M+H)+ (100 %); HPLC: 95.44 %.
Compound 45: 5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3yl)-N-phenyl-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxamide o
’H NMR: (CD3OD, 400MHz) :- δ 730-7.21 (m, 7H), 7.04 (t, IH, J= 7.4Hz), 4.73 (d, IH, J= 10.4Hz), 4.45-4.43 (m, IH), 4.29-4.26 (m, 8H), 3.93-3.90 (m, IH), 3.76 (t, IH, J= I0.8Hz), 3.67-3.60 (m, IH), 2.82-2.79 (m, IH), 2.08 (q, IH, J= 12Hz). ESI-MS: (+ve mode) 441.1 (M+H)+ (100 %); HPLC: 96.20 %.
Compound 46: N-((2R,3S,SR)-2-(2,5-difluorophenyl)-5-(5~(methylsulfonyl)~5,6dihydropyrrolo[3,4-c]pyrrol-2(lH,3H,4H)-yl)tetrahydro-2H-pyran-3-yl)acetamide ’H NMR: (CDClj, 400MHz) :- δ 7.28-7.19 (m, IH), 7.00-6.92 (m, 2H), 5.45 (d, IH, J= 9.2Hz), 438 (d, 1H,J= 10Hz), 4.22-4.18 (m, IH), 4.14 (s, 4H), 4.12-4.03 (m, IH), 3.55 (s, 4H), 336 (t, IH, J= 10.8Hz), 3.01-2.94 (m, IH), 2.86 (s, 3H), 2.48-2.44 (m, IH),
1.82 (s, 3H), 1.50 (q, IH, J= 11.6Hz). ESI-MS: (+ve mode) 442.1 (M+H)+ (100 %); HPLC: 96.44 %.
Compound 47: N-((2R,3S,5R)-5-(5-acetyl-5,6-dihydropyrrolo[3,4-c]pyrrol2(lH,3H,4H)-yl)-2-(2,5-difluorophenyl)tetrahydro-2H~pyran-3-yl)acetamide
o ’H NMR: (CDClj, 400MHz) :- δ 7.24-7.19 (m, IH), 7.00-6.93 (m, 2H), 5.43 (d, IH, J= 10 9.2Hz), 439 (d, IH, J= 10Hz), 4.20 (s, 5H), 4.09-4.07 (m, IH), 3.57 (s, 4H), 337 (t,
IH, 10.8Hz), 3.01-2.95 (m, IH), 2.49-2.45 (m, IH), 2.07 (s, 3H), 1.83 (s, 3H), 1.48 (q, IH, J= 11.6Hz). ESI-MS: (+vemode) 406.1 (M+H)+ (100 %); HPLC: 96.44 %.
Compound 48: 5-((3R,5S,6R)~5~amino~6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3yl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(lH)-carbaldehyde
cuo ’H NMR: (CDjOD, 400MHz) δ 8.25 (s, IH), 731-7.28 (m, IH), 7.24-7.20 (m, 2H), 4.71 (d, IH, J= 10.0 Hz), 4.46-4.42 (m, 3H), 4.31-4.23 (m, 6H), 3.89-3.85 (m, IH), 3.76 (t, IH, J= 10.8Hz), 3.65-3.59 (m, IH), 2.78-2.75 (m, IH), 2.08 (q, IH, J= 11.6 Hz).; ESI-MS: (+ve mode) 350.1 (M+H)+ (100 %); HPLC: 98.78 %.
Compound 49: (2R,3S,5R)-2-(2,5-difîuorophenyl)-5-(5-(N-(4-methylbenzenesulfonyl)S-methylsulfonimidoyl)-5,6-dihydropyrrolo[3,4-c]pyrrol-2(lH,3H,4H)-yl)îetrahydro25 2H-pyran-3-amine
F
’H NMR: (CDjOD, 400MHz) :- δ 7.80 (d, 2H, J= 8.0Hz), 736 (d, 2H, J= 8.0Hz), 731-7.29 (m, IH), 724-7.21 (m, 2H), 4.70 (d, 1 H, J = 10.0 Hz), 4.41 (d, IH, J= 30 8.0Hz), 434-431 (m, 4H), 4.15 (s, IH), 3.74-3.70 (m, 2H), 3.64-3.58 (m, IH), 3.24 (s,
3H), 2.74-2.71 (m, IH), 2.42 (s, 3H), 2.05 (q, IH, J= 11.6 Hz).; ESI-MS: (+ve mode)
553.2 (M+H)+ (100 %); HPLC: 9739 %.
Compound 50: l-(5-((3R,5S,6R)-5-amino-6-(2,5-difuorophenyl)tetrahydro-2H-pyran3-yl)-5,6-dihydropyrrolo[3,4-c]pyrrol-2(IH,3H,4H)-yl)-2,2,2-trifluoroethanone
» ’ll NMR: (CDjOD, 400MHz) :- δ7.31-7.27 (m, IH), 7.24-7.20 (m, 2H), 4.70 (d, IH, J = 10.0 Hz), 4.57 (s, 2H), 4.44-4.39 (m, 3H), 4.21 (s, 4H), 3.82-3.69 (m, 2H), 3.64-3.57 (m, IH), 2.75-2.72 (m, IH), 2.04 (q, IH, J = 11.6 Hz).; ESI-MS: (+ve mode) 418.2 (M+H)+ (100 %); HPLC: 99.18 %.
Using the above procedures, following compounds (Table-2) can be prepared by accompnying reductive amination of intermedîate-1 with appropreate substituent R followed by removal of amine protecting group.
Table-2:
Compounds Structures IUPAC Names
51 NH, (2R,3S,5R)-5-(5- (cyclopropylsulfonyl)hexahydropyrrolo[3 ,4-c]pyrrol-2(lH)-yl)-2-(2,5- d i fluorophenyl )tetrahydro-2 H-pyran-3 amine
52 F fi! /γ (2R,3S,5R)-2-(2,5-difluorophenyl )-5-(5(isopropylsulfonyl)hexahydropyrrolo[3,4 -c]pyrrol-2( 1 H)-yl)tetrahydro-2H-pyran3-amine
53 F ίη (2R,3S,5R)-2-(2,5-difïuorophenyl)-5-(5(isobutylsulfonyl)hexahydropyrrolo[3,4c]pyrrol-2( 1 H)-yl)tetrahydro-2 H-pyran3-amine
54 A (2R,3S,5R)-5-(5- (cyclopropylmethyl)hexahydropyrrolo[3, 4-c]pyrrol-2(lH)-yl)-2-(2,5difluorophenyI)tetrahydro-2H-pyran-3amine
55 F (ιΊ ï”2 o (5-((3R,5S,6R)-5-amino-6-(2,5difluorophenyl)tetrahydro-2H-pyran-3yl)hexahydropyirolo[3,4-c]pyrrol-2( 1H)yl)(cyc!opropyl)methanone
56 ‘-Ογκ o methyl 5-((3R,5S,6R)-5-amîno-6-(2,5di fluorophenyl)tetrahydro-2H-pyran-3 yl)hexahydropyrrolo[3,4-c]pyrrole2(lH)-caiboxylate
57 F îj ï2 (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(5methylhexahydropyrrolo[3,4-c]pyrrol 2(1 H)-yl)tetrahydro-2H-pyran-3-amine
58 (2R,3 S,5 R)-5-(5-(cyclopropylmethyl)5,6-dihydropyKolo[3,4-c]pyrrol2(lH,3H,4H)-yl)-2-(2,5difluorophenyl)tetrahydro-2H-pyran-3amine
59 ΙίΊ T1 (2R,3 S,5R)-2-(2,5-di fluorophenyl)-5 -(5methyl-5,6-dihydropyrrolo[3,4-c]pyrrol2(lH,3H,4H)-yl)tetrahydro-2H-pyran-3amine
60 A.. Q) (2R,3S,5R)-5-(5-(cyclopropylsulfonyl)5,6-dihydropyrrolo[3,4-c]pyrrol2(lH,3H,4H)-yl)-2-(2,5difluorophenyl)tetrahydro-2H-pyran-3amine
61 fi6! H]N 0 l-(5-((3R,5S,6R)-5-amino-6-(2,5difluorophenyl)tetrahydro-2H-pyran-3yl)-5,6-dihydropyrrolo[3,4-c]pyrrol2(1 H,3H,4H)-yl)-3-methy!butan-l -one
62 F ul ï”’ „4? ° V-NH 2-((3R,5S,6R)-5-amino-6-(2,5difluoropheny])tetrahydro-2H-pyran-3yl)tetrahydropyrrolo[3,4-c] pyrrol el,3(2H,3aH)-dione
63 k y™ o 5-((3R,5S,6R)-5-amino-6-(2,5difluorophenyl)tetrahydro-2H-pyran-3yl)tetrahydropyrrolo[3,4-c] pyrrol el,3(2H,3aH)-dione
64 te 5-((3R,5S,6R)-5-amino-6-(2,5difluorophenyl)tetrahydro-2H-pyran-3yl)-2-methyltetrahydropyrrolo[3,4c]pyrrole-1,3 (2H,3 aH)-dione
65 te iï 5-((3R,5S,6R)-5-amino-6-(2,5difluorophenyl)tetrahydro-2H-pyran-3yi>2- (methylsul fonyl)tetrahydropyrrolo[3,4c] pyrrole-1,3(2H,3 aH)-di one
66 F |Γί ^2 A 5-((3R,5S,6R)-5-amino-6-(2,5difluorophenyI)tetrahydro-2H-pyran-3yl)-2- (cyclopropylsulfonyl)tetrahydropyrrolo[3 ,4-c]pyrrole-1,3 (2 H,3aH)-dione
67 a JC Axr (2R,3S,5R)-2-(2,5-difluorophenyl)-5- (2,7-diazaspiro[4.4]nonan-2yl)tetrahydro-2H-pyran-3 -amine
68 F A JC Αχί (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(7methyl-2,7-diazaspiro[4.4]nonan-2y!)tetrahydro-2H-pyran-3-amine
69 F A î1 r tecr? (2R,3S,5R)-5-(7-(cyclopropylmethy])- 2,7-diazaspiro[4.4]nonan-2-yl)-2-(2,5difluorophenyl)tetrahydro-2H-pyran-3amine
70 te. (2 R,3 S,5R)-5-(7-(cyclopenty Isul fonyl)2,7-diazaspiro[4.4]nonan-2-yl)-2-(2,5difluorophenyl)tetrahydro-2H-pyran-3amine
71 F Cj JC ^00'^7 (2R,3S,5R)-5-(7-(cyclopropylsuIfonyl)’ 2,7-diazaspiro[4.4]nonan-2-yl)-2-(2,5difluorophenyl)tetrahydro-2H-pyran-3amine
72 F ό Γ v τη v 1 °Αχτ° (2R3S,5R)-2-(2,5-difluorophenyl)-5-(7(isopropylsulfonyI)-2,7diazaspiro[4.4] nonan-2-yi)tetrahydro2H-pyran-3-amine
73 Ψδ (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(7((trifluoromethyl)suIfonyl)-2,7diazaspiro [4.4]nonan-2-yl)tetrahydro2H-pyran-3 -amine
74 fe„ (2R,3S,5R)-2-(2,5-(Jifluorophenyl)-5(hexahydro-1 H-pyrrolo[3,4-c]pyridin2(3 H)-yl)tetrahydro-2H-pyran-3-amine
75 fe„ (2R,3S,5R)-2-(2,5-difluorophenyl )-5-(5methylhexahydro-1 H-pyrrolo[3,4c]pyridin-2(3H)-yl)tetrahydro-2H-pyran3-amine
76 fe fev (2R3S,5R)-5-(5(cyclopropylmethyl)hexahydro-l Hpyrrol o[3,4-c]pyridin-2(3 H)-yl)-2-(2,5difluorophenyl)tetrahydro-2 H -pyran-3 amine
77 K> (2R,3S,5R)-5-(5- (cyclopropylsul fonyl)hexahydro-1Hpyrrolo[3,4-c]pyridin-2(3H)-yl)-2-(2,5difluorophenyl)tetrahydro-2H-pyran-3amine
78 f il (2R3S,5R)-2-(2,5-difluorophenyl)-5-(5(isopropyl sul fonyl)hexahydro-1HpyTrolo[3,4-c]pyridin-2(3H)yl)tetrahydro-2H-pyran-3 -amine
79 F 1Î1 Π”2 ' fe-t l-(2-((3R,5S,6R)-5-amino-6-(2t5difluorophenyl)tetrahydro-2H-pyran-3yl)hexahydro-1 H-pyrrolo [3,4-c] pyridin5(6H)-y!)-2-methylpropan-l -one
80 F |Γί 1011 (2fC3S,5R)-2-(2,5-difluorophenyl)-5’(5(isobutylsulfonyl)hexahydro-l Hpyrrolo[3,4-c] pyridin-2(3 H)yl)tetrahydro-2H-pyran-3-amine
81 F ίι ï”’ ' CO (2 R,3 S,5R)-2-(2,5-di fl uorophenyl)-5(hexahydro-1 H-pyrrolo[3,4-c]pyridin5(6H)-yl)tetrahydro-2H-pyran-3-amine
82 F fil Γ’ 1 °Ax>- (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2methylhexahydro-1 H-pyrrolo[3,4c]pyridin-5(6H)-yl)tetrahydro-2H-pyran3-amine
83 F ΙΪΊ f”2 (2R3S,5R>5-(2(cyclopropylmethyl)hexahydro-l Hpyrrolo(3,4-c]pyridin-5(6H)-yl)-2-(2,5difluorophenyl)tetrahydro-2H-pyran-3amine
84 F f] ï’ (2R,3S,5R)-5-(2(cyclopropylsulfonyl)hexahydro-l Hpyrrolo[3,4-c]pyridin-5(6H)-yl)-2-(2,5difluorophenyl)tetrahydro-2H-pyran-3amine
85 F îj r (2R,3S,5R)-5-(2(cyclopentylsulfonyl)hexahydro-1Hpyrrolo[3,4-c]pyridin-5(6H)-yI)-2-(2,5difluorophenyl)tetrahydro-2H-pyran-3amine
86 fe, ^b- (2R,3 S,5R)-2-(2,5-di fluorophenyl)-5(4,5,6,7-tetrahydro-l H-pyrrolo[3,4c]pyridin-2(3 H)-yl)tetrahyd ro-2 H -pyran3-amine
87 Φ-Λ ^b- (2R,3 S,5 R)-2-(2,5-difluorophenyl)-5-(5methyl-4,5,6,7-tetrahydro-l Hpyrrolo[3,4-c]pyridin-2(3 H)yl)tetrahydro2H-pyran-3 -amine
88 F fl ' fe.y (2R.3 S,5R)-5-(5-(cycl opropylmethyl)4,5,6,7-tetrahydro-1 H-pyrrolo[3,4c]pyridin-2(3H)-yl)-2-(2,5difluorophenyl)tetrahydro-2H-pyran-3amine
89 F ΙίΊ Y2 (2R,3S,5R)-5-(5-(cyclopropylsulfonyl)4,5,6,7-tetrahydro-1 H-pyrrolo[3,4c]pyridin-2(3H)-yl)-2-(2,5difluorophenyl)tetrahydro-2H-pyran-3amine
90 ί] Τ’1’ (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(5(isopropylsulfonyl)-4,5,6,7-tetrahydro- 1 H-pyrTolo[3,4-c]pyridin-2(3H)yl)tetrahydro-2H-pynm-3 -amine
91 F ΝΗ, ώ·^+ (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(5(methylsulfonyl)-4,5,6,7-tetrahydro-l Hpyrrolo[3,4-c]pyridin-2(3H)yl)tetrahydro-2H-pyran-3-amine
92 F ίΊ Τ’’ l-(2-((3R,5S,6R)-5-amino-6-(2,5difluorophenyl)tetrahydro-2H-pyran-3yl)-2,3(6,7-tetrahydro-l H-pyrrolo[3,4c]pyridin-5(4H)-yl)-2-methylpropan-1 one
93 F (Γί 'ùw (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(5(isobutylsulfonyl)-4,5,6,7-tetrahydro-1Hpyrrolo[3,4-c]pyridin-2(3 H)yl)tetrahydro-2H-pyran-3-amine
94 F ΙίΊ Y1 (2R,3S,5R)-2-(2,5-difluorophenyl)-5(2,3,6,7-tetrahydro-l H-pyrrolo[3,4c]pyridin-5(4H)-yI)tetrahydro-2H-pyran3-amine
95 F ίίΊ Υ”1 T oj.^. (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2methyl-2,3,6,7-tetrahydro-l Hpyrrolo[3,4-c]pyridin-5(4H)yl)tetrahydro-2H-pyran-3-amine
96 fe F (2R,3S,5R)-5-(2-(cyclopropylmethyl)2,3,6,7-tetrahydro-1 H-pyrrolo[3,4c]pyridin-5(4H)-yl)-2-(2,5difluorophenyl)tetrahydro-2H-pyran-3amine
97 F |Γί Y”2 (2 R,3 S ,5 R)-5-(2-(cyclopropylsul fonyl)2,3,6,7-tetrahydro-1 H-pyrrolo[3,4c]pyridin-5(4H)-yl)-2-(2,5difluorophenyl)tetrahydro-2H-pyran-3 amine
98 F ιΓί r Ϋΐ\χ>ΐ-Ό (2R,3S,5R)-5-(2-(cyclopentylsulfonyl)2,3,6,7-tetrahydro-lH-pyTrolo[3,4c]pyridin-5(4H)-yl)-2-(2,5difluorophenyl)tetrahydro-2H-pyran-3amine
99 F il Τ’3 (2R3S,5R)-2-(2,5-difluorophenyl)-5-(2- (methyisulfonyI)-2,3,6,7-tetrahydiO-1Hpyrrolo[3,4-c]pyridin-5(4H)yl)tetrahydro-2H-pyran-3-amine
100 F il ï”1 (2R,3S,5R)-2-(2,5-difluorophenyl)-5(tetrahydro-1 H-thieno[3,4-c]pyrrol5(3H)-yl)tetrahydro-2H-pyran-3-amine
101 F il Γ % (2R,3S,5R)-2-(2,5-difluorophenyl)-5(1 H-thieno[3,4-c]pyrrol-5(3H,4H,6H)’ yl)tetrahydro-2H-pyran-3-amine
102 Φ'Λ T (2 R,3 S,5R)-2-(2,5-di fl uorophenyl)-5(hexahydropyrrolo[3,2-b]pyrrol-l (2H)y!)tetrahydro-2H-pyran-3-amine
103 lîi V”1 (2R,3 S,5 R)-2-(2,5-difluorophenyl)-5-(4methylhexahydropyrrolo[3,2-b] pyrrol1 (2H)-yl)tetrahydro-2H-pyran-3-amine
104 ij ï1’3 (2R,3S,5R)-5-(4- (cyclopropylmethyl)hexahydropyrrol o[3, 2-b]pyTTol-1 (2H)-yl)-2-(2,5difluorophenyl)tetrahydro-2H-pyran-3amine
105 F Cj Γ °^'n'O / LZ /o (2 R3 S,5R)-2-(2t5-di fluorophenyl)-5-(4(methylsulfonyl)hexahydropyrrolo[3,2bjpyrrol-1 (2H)-yI)tetrahydro-2 H-pyran3-amine
106 F il ï”1 n\^ LV feo (2R,3S,5R)-5-(4(cyclopropylsulfonyl)hexahydropyrrolo[3 ,2-b]pynOl-l(2H)-yl)-2-(2,5difluorophenyl)tetrahydro-2H-pyran-3amine
107 F (S N»! r o* Y (2R,3 S,5 R)-2-(2,5-difluorophenyl)-5-(4(isopropylsulfonyl)hexahydropyrrolo[3,2 -b]pyrrol-l (2H)-yl)tetrahydro-2H-pyran3-amine
108 F il m’ F O'N'Çl.J’ (2R3S,5R)-5-(4(cyclopentylsulfonyl)hexahydropyrrolo[3 «2-blpyrrol-l (2H>yl)-2-(2,5difIuorophenyl)tetrahydro-2H-pyran-3amine
109 F A l”1 1 °ΑΡχ° l-(4-((3R,5S,6R)-5-amino-6-(2,5dif!uorophenyI)tetrahydro-2H-pyran-3yl)hexahydropyrrolo[3,2-b]pyiTol-l (2H)yl)-2-methy!propan-l -one
110 F O T * θ''-^N''V-N^O A (4-((3R,5S,6R)-5-amino-6-(2,5difluorophenyI)tetrahydro-2 H-pyran-3 yl)hexahydropyrrolo[3,2-b]pynOl-1 (2H)yl)(cyclopropyl)m ethanone
111 F O Jk’ J ‘^XpŸ'v 4-((3R,5S,6R)-5-amino-6-(2,5difluorophenyl)tetrahydro-2H-pyran-3yl)-N-cyclopiOpylhexahydropyrrolo[3,2b]pyrrole-l(2H)-caiboxamide
112 N y,NH (2R3S,5R)-2-(2,5-difluorophenyl)-5(2,3,5,6-tetrahydropyrrolo[3,2-b]pyrrol1 (4H)-yl)tetrahydro-2H-pynm-3-amine
113 Φ-Λ T ^Spk (2R3S,5R)-2-(2,5-difliiorophenyl)-5-(4methyl-2,3,5,6-tetrahydropyrrolo[32bjpyrrol-l (4H)-yl)tetrahydro-2H-pyran3-amine
114 il f”* (2R3 S,5 R)-5-(4-(cyclopropylmethyl)- 2,3,5,6-tetrahydropyrTolo[3,2-b]pyrroIl(4H)-yl)-2-(2,5- difluorophenyl)tetrahydro-2H-pyran-3amine
115 F f] 11 * ΟγΟ^ uy /m (2R3 S,5R)-2-(2,5-di fluorophenyl)-5-(4(methylsulfonyl)-2,3,5,6tetrahydropyrrolo[3,2-b]pyiTol-l(4H)yl)tetrahydro-2H-pyran-3 -amine
'-t/'
116 F O ï”’ LV <f*o (2R3S,5R)-5-(4-(cyclopropylsulfonyl)- 2,3,5,6-tetrahydropyrrolo[3,2-b]pyrroll(4H)-yl)-2-(2,5- difluorophenyl)tetrahydro-2H-pyran-3amine
117 F rS nh, rQ'sp o* y (2R2S,5R)-2-(2,5-difluorophenyl)-5-(4(isopropylsulfonyl)-2,3,5,6tetrahydropyTrolo[32-b]pyrrol-1 (4H)yl)tetrahydro-2H-pyran-3-amine
118 F lil i1 ^°Ό (2R3 S,5R)-5-(4-(cyclopentylsul fonyl)- 2,3,5,6-tetrahydropyrroîo[3,2-b]pyrrolI(4H)-yl)-2-(2,5- difIuorophenyl)tetrahydro-2H-pyran-3amine
119 F ΙΐΊ t”1 F l-(4-((3R,5S,6R)-5-ammo-6-(2,5difIuorophenyl)tetrahydro-2H-pyran-3yl)-2,3,5,6-tetrahydropyrrolo[32bjpyrrol-1 (4H)-yl)-2-methylpropan-1 one
120 F Cj JC F O---J*N-^?N^O (4-((3R,5S,6R)-5-amino-6-(2,5difluorophenyl)tetrahydro-2H-pyran-3yl)-2,3,5,6-tetrahydropyrrolo[ 3,2b]pyrrol-l(4H)yl)(cyclopropyl)methanone
121 F A Jl’ 4-((3R,5S,6R)-5-amino-6-(2,5difluorophenyI)tetrahydro-2H-pyran-3yl)-N-cyclopropyl-2,3,5,6tetrahydropynOlo[3,2-b]pyrrole-1 (4H)carboxamide
122 A (2R,3S,5R.)-2-(2,5-difIuorophenyl)-5-(5methylhexahydropyrrolo[3,4-b] pyrrol1 (2H)-yl)tetrahydro-2H-pyran-3-ainÎne
123 Ιίι ï”1 ΙΑΙ,.Ι. T (2R3S,5R)-5-(5(cyclopropylmethyl)hexahydropyrrolo[3, 4-b]pyrroî-l (2H)-yl)-2-(2,5difluorophenyl)tetrahydro-2H-pyran-3amine
124 F Δ P o a ^<·\ 's^ I Γ 1 /-N '0 (2R,3S,5R)-5-(5(cyclopropylsulfonyï)hexahydropyrrolo[3 ,4-b]pyrrol-l (2H)-yl)-2-(2,5difluorophenyl)tetrahydro-2H-pyran-3amine
125 ό-Λ ’ °-AX> (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(5(îsopropylsul fonyl)hexahydropyrrolo[3,4 -bJpyiroM (2H)-yl)tetrahydro-2H-pyran3-amine
126 F Π ϊ”! Μ-. Λ V’ (2R,3S,5R)-2-(2,5-difluorophenyI)-5-(5((trifluoromethy])sulfonyl)hexahydropyrr oIo[3,4-b]pyrroM(2H)-y])tetrahydro-2Hpyran-3-amine
127 F ΓιΊ f,c Wl y-A F °ΑΡ 1 -(1 -((3R,5S,6R)-5-amino-6-(2,5di fluorophenyl )tetrahydro-2H-pyran-3yl)hexahydropyTrolo[3,4-b]pyrrol-5(l H)yl)-2,22’trifluoroethanone
128 F ίίΊ F 111 /N ° ί Μ-φ (1-((3 R,5S,6R)-5-amino-6-(2,5di fl uorophenyl)tetrahydro-2H-pyran-3yl)hexahydropyrrolo[3,4-b]pyrrol-5(l H)yl)(cyclopropyl)methanone
129 F ώ Γ Çf (2R,3S,5R)-2-(2,5-difluorophenyl)-5’(5(isobutylsulfonyl)hexahydropyrrolo[3,4b]pyrrol-l (2H)-yl)tetrahydro-2H-pyran3-amine
130 F ίι F (2R,3S,5R)-2-(2,5-difluorophenyl>5-(5methyl-2,3,5,6-tetrahydropyTrolo[3,4b]pyrrol-1 (4H)-yl)tetrahydro-2H-pyran3-amine
131 Ô..T (2R,3 S,5 R)-5-(5-(cyclopropylmethyl)- 2,3,5,6-tetrahydropyrrolo[3,4-b]pyrrol1 (4H)-yI)-2-(2,5- d ifluorophenyl)tetrahyd ro-2 H-pyran-3 amine
132 F fS F θνΛ Yô^° (2R,3 S,5 R)-5-(5-(cyc!opropylsulfonyl)- 2,3,5,6-tetrahydropyrrolo[3,4-b]pyrroll(4H)-yl)-2-(2,5- difluorophenyl)tetrahydro-2H-pyran-3amine
133 F ό..Γ °A 1 ' 1 Λ~Ν Ο ί «Οφ (2R,3S,5R)-2-(2,5-difluorophenyl )-5-(5(isopropylsulfonyl)-2,3,5,6tetrahydropyrro]o[3,4-b]pyrT01-1 (4H )yl)tetrahydro-2H-pyran-3-amine
134 F A ί1 „ (2R,3 S,5R)-2-(2,5-di fl uorophenyl)-5-(5((trifluoromethyl)sulfonyl)-2,3,5,6tetrahydropyrrolo[3,4-b]pyrrol-l (4H)yl)tetrahydro-2 H-pyran-3 -amine
135 F ΙΪΊ i’ V l-(l-((3R,5S,6R)-5-amino-6-(2,5difluorophenyl)tetrahydro-2 H-pyran-3 yl)-2,3-dihydropyrrolo[3,4-b]pyrrol5( 1 H,4H,6H)-yl)-2,2,2-trifluoroethanone
136 T I 1 /'N υ (1 -((3R,5S,6R)-5-amino-6-(2,5difluorophenyl)tetrahydro-2 H-pyran-3 yl)-2,3 -dihydropyrrolo[3,4-b]pyrrol5(1 H,4H,6H)-yl)(cyclopropyl)methanone
137 άτ (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(5(isobutylsulfonyl)-2,3,5,6tetrahydropyrrolo[3,4-b]pyrrol-l (4H)yl)tetrahydro-2H-pyran-3 -amine
138 \«p u—**. (2R,3 S,5 R)-2-(2,5-di fluorophenyl)-5-(5(methylsul fonyl)-23,5,6tetrahydropyrrolo[3,4-b]pyrrol-l (4H)yl)tetrahydro-2H-pyran-3 -amine
139 A. Q? (2R,3 S,5 R)-2-(2,5-difluorophenyl )-5-( 1 methyl-3,4-dihydro-1 H-pyrrolo[3,4b]pyridin-6(2H,5H,7H)-yl)tetrahydro2H-pyran-3 -amine
140 F ΙΪΊ i”2 Qj (2R,3 S,5 R)-5-( 1 -(cyclopropylmethyl)3,4-dihydro-1 H-pyrrolo[3,4-b]pyridin6(2H,5H,7H)-yl)-2-(2,5- di fl uorophenyl)tetrahydro-2H-pyran-3 amine
141 ij NH» (2R,3 S,5R)-2-(2,5-difluorophenyl)-5-( 1 isopropyl-3,4-dihydro-1 H-pyrrolo[3,4b]pyridin-6(2H,5H,7H)-yl)tetrahydro2H-pyran-3-amine
142 F It) N”2 T ÏjL %' (2R,3 S,5R)-2-(2,5-difluorophenyl)-5-( 1 (methylsulfonyl)-3,4-dihydro-1 Hpyrrolo[3,4-b]pyridin-6(2H,5H,7H)yI)tetrahydro-2H-pyran-3 -amine
U—
143 (2R,3 S,5R)-5-( 1 -(cyclopropylsulfonyl)3,4-dihydro-l H-pyrrolo[3,4-b]pyridin6(2H,5H,7H)-yl)-2-(2,5difluorophenyl)tetrahydro-2H-pyran-3amine
144 (2R,3 S,5R)-2-(2,5-difluorophenyl)-5-( 1 (isopropylsulfonyl)-3,4-dihydro-1Hpyrrolo[3,4-b]pyridin-6(2H,5H,7H)yl)tetrahydro-2H-pyran-3 -amine
145 |Γί μ<1 ι ό (2R,3 S,5R)-2-(2,5-difluorophenyl)-5-( 1 (isobutylsulfonyl)-3,4-dihydro-1Hpyrrolo[3,4-b]pyridin-6(2H,5H,7H)yl)tetrahydro-2H-pyran-3-amine
146 «-X >Ο l-(6-((3R,5S,6R)-5-amino-6-(2,5difIuorophenyl)tetrahydro-2H-pyran-3yl )-2,3,4,5,6,7-hexahydro-1Hpyrrolo[3,4-b]pyridin-l -yl)-2methylpropan-1 -one
147 (^.. rh (6-((3R,5S,6R)-5-amino-6-(2,5difluorophenyl)tetrahydro-2H-pyran-3yl)-2,3,4,5,6,7-hexahydro-l Hpyrrolo[3,4-b]pyridin-l yl)(cyclopropyl)methanone
148 ί 'V methyl 6-((3R,5S,6R)-5-amino-6-(2,5di fluorophenyl)tetrahydro-2H-pyran-3 yl)-2,3,4,5,6,7-hexahydro-1H- pynolo [3,4-b]pyridine-1 -carboxylate
149 F |Γί F °xX*N-x / (2R,3 S,5 R)-2-(2,5-di fluorophenyl )-5-(1methylhexahydrü-1 H-pyrrolo[3,4b]pyridin-6(2H)-yl)tetrahydro-2H-pyran3-amine
150 F n y1’ T* ίΟ^Ν\ > Qj (2R,3S,5R)-5-(l(cyclopropylmethyl)hexahydro-1Hpyrrolo[3,4-b]pyridin-6(2H)-yl)-2-(2,5difluorophenyl)tetrahydro-2H-pyran-3amine
151 F |Γί 14111 (2R,3 S,5R)-2-(2,5-difluorophenyl)-5-( 1 isopropylhexahydro-1 H-pyrrolo[3,4b]pyridin-6(2H)-yl)tetrahydro-2H-pyran3-amine
ΙΛ^\
152 Ιίι ï”1 l YjL (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(l(methylsul fonyl)hexahydro-1Hpyrrolo[3,4-b]pyridin-6(2H)yl)tetrahydro-2H-pyran-3-amine
153 |Γί (2R3S,5R>5-(1(cyclopropylsulfonyl)hexahydro-1Hpyrrolo[3,4-b]pyridin-6(2H)-yl)-2-(2,5difluorophenyI)tetrahydro-2H-pyran-3amine
154 (2R»3S,5R)-2-(2,5-difluorophenyl)-5-(l(isopropylsulfonyl)hexahydro-l HpyTrolo[3,4-b]pyridin-6(2H)yl)tetrahydro-2H-pyran-3-amine
155 (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(l(isobutylsulfonyl)hexahydro-l Hpyrrolo[3,4-b]pyridin-6(2H)yl)tetrahydro-2H-pyran-3-amine
156 F θΊ p 'ù·^ l-(6-((3R,5S,6R)-5-amino-6-(2,5d i fluorophenyl)tetrahydro-2H-pyran-3 yl)octahydro-l H-pyrrolo[3,4-b]pyridin1 -yl)-2-methyl propan-1 -one
157 F ΐίΊ VH= τ rS 93 (6-((3 R,5S ,6R)-5-amino-6-(2,5di fl uorophenyl)tetrahydro-2H-pyran-3 yljoctahydro-1 H-pyrrolo [3,4-b]pyrid in1 -yl)(cyclopropyl)methanone
158 F Γί wi» tA </ ,O.^ methyl 6-((3R,5S,6R)-5-amino-6-(2,5difluorophenyl)tetrahydro-2H-pyran-3yl)octahydro-1 H-pyrrolo[3,4-b] pyridine1-carboxylate
159 ΪΊ *”> Yx\f (2R,3S,5R)-2-(2,5-difluorophenyl)-5-( 1 methylhexahydropyrrolo[3,4-b]pyrrol5(1 H)-yl)tetrahydro-2H-pyran-3-amine
160 Φ-Λ (2R,3S,5R)-5-(l- (cyclopropylmethyl)hexahydropyrrolo[3, 4-b]pyrrol-5(l H)-yl )-2-(2,5- di fluorophenyl)tetrahydro-2 H-pyran-3 amine
161 F il i™1 (2 R,3 S,5R)-2-(2,5 -di fluorophenyl )-5-( 1 isopnopylhexahydropynOlo[3,4-b]pyrrol5( 1 H)-yl)tetrahydro-2H-pyran-3-amine
162 F ΙΪΊ T ’il A (2R,3S,5R>5-(1- (cyclopropylsul fonyl)hexahydropyrrolo [3 ,4-b]pyirol-5(lH)-yl)-2-(2,5difluorophenyl)tetrahydro-2H-pyran-3amine
163 te„s.>- ° (2 R,3 S,5R)-2-(2,5-di fl uorophenyl)-5-( 1 (isopropylsulfonyl)hexahydropyrrolo[3,4 -b]pyrrol-5(l H)-yl)tetrahydro-2H-pyran3-amine
164 F fil V”2 F ώ (2R,3S,5R)-5-(l(cyclopentylsulfonyl)hexahydropyTrolo[3 ,4-b]pyrrol-5(lH)-yl)-2-(2,5difluorophenyl)tetrahydro-2H-pyran-3amine
165 F fi] ï”1 T'O^L· l-(5-((3R,5S,6R)-5-amino-6-(2,5difluorophenyl)tetrahydro-2H-pyran-3yl)hexahydropynOlo[3,4-b]pyrrol-1 (2H)yl)propan-l-one
166 F [il Y”3 (5-((3 R,5S,6R)-5-amino-6-(2,5difluorophenyl)tetrahydro-2H-pyran-3yl)hexahydropyrrolo[3,4-b]pyrrol-l (2H)yl)(cyclopropyl)m ethanone
167 F fil 141,3 5-((3R,5S,6R)-5-amino-6-(2,5difluorophenyl)tetrahydro-2H-pyran-3yl)-N-cyclopropylhexahydropyrrolo[3,4b]pyrrol e-1 (2H)-caiboxamide
168 F [η NHj (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(l methyl-2,3-dihydropynOlo[3,4-b]pyrrol5( 1 H,4H,6H)-yl)tetrahydro-2H-pyran-3amine
169 te f F > Qj (2R3 S,5 R)-5-( 1 -(cycl opropylmethyl)2,3-dihydropyTTolo[3,4-b]pyrrol5(lH,4H,6H)-yl)-2-(2,5difluorophenyl)tetrahydro-2H-pyran-3amine
170 fil (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(lisopropyl-23-dihydropyrrolo[3,4b]pyrrol-5(l H,4H,6H)-yl)tetrahydro-2Hpyran-3-amine
171 F f] i2 (2 R,3 S,5 R)-2-(2,5-difluorophenyl)-5-(4methyl-2,3,4,5,6,7-hexahydro-1 Hpyrrolo[3,2-b]pyridin-1 -yl)tetrahydro2H-pyran-3-amine
172 F ij ï”3 (2R3 S, 5 R)-5-(4-(cyclopropylmethyl)- 2,3,4,5,6,7-hexahydro-1 H-pyrrolo[3,2b]pyridin-l -yl)-2-<2,5difluorophenyl)tetrahydro-2H-pyran-3amine
173 F il Τ’3 (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(4isopropyt-2,3,4,5,6,7-hexahydro-1Hpyrrolo[3,2-b]pyridin-l -yl)tetrahydro2H-pyran-3-amine
174 F fi] i”’ o methyl l-((3R,5S,6R)-5-amino-6-(2,5di fluorophenyl )tetrahydro-2H-pyran-3yl)-23,6,7-tetrahydro-lH-pyrrolo[3^b]pyridine-4(5H)-carboxylate
175 F ίιΊ V”3 J û.Np OAO (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(4(methylsulfonyl)-2,3,4,5,6,7-hexahydro1 H-pyrrolo[3,2-b]pyridin-1 yl)tetrahydro-2 H-pyran-3 -amine
176 F îj T1’ (2R,3 S,5 R)-5-(4-(cyclopropylsuï fonyl )23.4,5,6,7-hexahydro-lH-pyrrolo[32bjpyridin-1 -yl)-2-d(2,5- di fl uorophenyl)tetrahydro-2H-pyran-3amine
177 F f] i*3 (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(4(isopropylsulfonyl)-2,3,4,5,6,7hexahydro-1 H-pyrrolo[3,2-b]pyridm-1 yl)tetrahydro-2H-pyran-3 -amine
178 F i] i”’ r (2R,3S,5R)-5-(4-(cyc]opentylsulfonyl)2,3,4,5,6,7-hexahydro-l H-pyrrolo[3,2bjpyridin-1 -yl)-2-(2,5- difluorophenyl)tetrahydro-2H-pyran-3amine
179 F lit Y”1 f CU-Q l-(l-((3R,5S,6R)-5-amino-6-(2,5difluorophenyl)tetrahydro-2H-pyran-3yl)-2,3,6,7-tetrahydro-l H-pyrrolo[3,2b]pyndin-4(5H)-yl)ethanone
180 F [ii Y”1 l-(l-((3R,5S,6R)-5-amino-6-(2,5difluorophenyl)tetrahydro-2H-pyran-3yl)-2,3,6,7-tetrahydro-l H-pyrrolo[32b]pyridin-4(5H)-yl)-3-methylbutan-l -one
181 F [il Y”1 ‘ F Ly y-*» o l-((3R,5S,6R)-5-amino-6-(2,5difluorophenyl)tetrahydro-2H-pyran-3yl)-N-cyclopiOpyl-2,3,6,7-tetrahydro-lHpyrrolo[3,2-b] pyridine-4(5H)carboxamide
182 F il Y1’1 ' ^OC”- (2R3S,5R)-2-(2,5-difluorophenyl)-5-(8methyl-2,8-diazaspiro[4.5]decan-2yI)tetrahydro-2H-pyran-3-amine
183 F il Y”1 (2R,3 S,5 R)-5-(8-(cyclopropylmethyl)- 2,8-diazaspiro[4.5]decan-2-yl)-2-(2,5difluorophenyl)tetrahydro-2H-pyran-3amine
184 F il 14,11 (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(8isopropyl-2,8-diazaspiro(4.5]decan-2yl)tetrahydro-2H-pyran-3 -amine
185 F il Y”1 Axx l-(2-((3R,5S,6R)-5-amino-6-(2,5difluorophenyl)tetrahydro-2H-pyran-3yl)-2,8-diazaspiro[4.5]decan-8yl)ethanone
186 F Cj JL1 ’θ'ΟΟ'Γ (2-((3R,5S,6R)-5-amino-6-(2,5difluorophenyl)tetrahydro-2 H-pyran-3 yl)-2,8-diazaspiro[4.5]decan-8yl)(cyclopropyl)methanone
187 F fil T2 °Aoo-H (2R,3S,5R)-5-(8-(cycIopropy!sulfonyl)- 2,8-diazaspiro[4.5]decan-2-yl)-2-(2,5difluorophenyl)tetrahydro-2H-pyran-3 amine
U_x—
188 F liS f1 .A. T (2R,3 S,5 R)-2-(2,5-difluorophenyl)-5-(8(isopropylsulfonyl)-2,8diazaspiro[4.5]decan-2-yl)tetrahydro-2Hpyran-3-amine
189 ^oo-K*'”· 4-((2-((3R,5S,6R)-5-amino-6-(2,5difluorophenyl)tetrahydro-2H-pyran-3yl)-2,8-diazaspiro[4.5]decan-8yi)sulfonyl)benzonitrile
190 |fj ï1’1 T methyl 2-((3R,5S,6R)-5-amino-6-(2,5di fluorophenyl )tetrahydro-2H-pyran-3 yl)-2,8-diazaspiro[4.5]decane-8caiboxylate
191 F A ï”1 F Q> (2R,3 S,5 R)-2-(2,5-d ifluorophenyl)-5-(2methyl-2t8-diazaspiro[4.5]decan-8yl)tetrahydro-2H-pyran-3-amine
192 F A F1 ' Q>-o (2R,3 S,5 R)-5-(2-cyclopenty 1-2,8diazaspiro[4.5]decan-8-yl)-2-(2,5difluorophenyl)tetrahydro-2H-pyran-3amine
193 F Π ï”’ (2R,3S,5R)-2-(2,5-difluorophenyI)-5-(2isopropyl-2,8-diazaspiro[4.5]decan-8yl)tetrahydro-2H-pyran-3-amine
194 F A Ï1 Ai (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2(methylsul fonyl)-2,8diazaspiro[4.5]decan-8-yl)tetrahydro-2Hpyran-3-amine
195 F A Γ A-B (2R,3 S,5 R)-5-(2-(cyclopropylsul fonyl)2,8-diazaspiro[4.5]decan-8-yl)-2-(2,5difluorophenyl)tetrahydro-2H-pyran-3amine
196 F A Γ (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2(isopropylsul fonyl)-2,8 diazaspiro[4.5]decan-8-yl)tetrahydro-2Hpyran-3-amine
197 4-((8-((3R,5S,6R)-5-amino-6-(2,5difluorophenyl)tetrahydro-2H-pyran-3yl)-2,8-diazaspiro[4.5]decan-2yl)sulfonyl)benzonitrile
198 F |Γί ï”3 l-(8-((3R,5S,6R)-5-amino-6-(2,5dî fluorophenyl)tetrahydro-2 H-pyran-3 yl)-2,8-diazaspiro[4.5]decan-2yl)ethanone
199 F il T1 (8-((3R,5S,6R)-5-amino-6-(2,5difIuorophenyl)tetrahydro-2 H-pyran-3 yl)-2,8-diazaspiro[4.5]decan-2yl)(cyclopropyl)methanone
200 1-(8-((3 R,5 S,6R)-5-amino-6-(2,5di fluorophenyl)tetrahydro-2 H-pyran-3 yl)-2,8-diazaspiro[4.5]decan-2-yl)-2methylpropan-1 -one
201 F îj Γ'2 methyl 8-((3R,5S,6R)-5-amino-6-(2,5difluorophenyl)tetrahydro-2H-pyran-3yI)-2,8-diazaspiro[4.5]decane-2cafboxylate
202 A t*1* MiX 8-((3R,5S,6R)-5-amino-6-(2,5difluorophenyI)tetrahydro-2H-pyran-3yI)-N-cyclopropyl-2,8diazaspiro[4.5]decane-2-carboxamide
203 Φά Ao·^7 8-((3R,5S,6R)-5-amino-6-(2,5difluorophenyl)tetrahydro-2H-pyran-3yl)-N-(4-fluorophenyl)-2,8diazaspiro[4.5]decane-2-carboxamide
204 F Π ï”1 (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(6methyl-3,6-diazabîcyclo[3.2.0]heptan-3yl)tetrahydro-2H-pyran-3-amine
205 (2 R.3S.5 R)-5-(6-(cyclopropylmethyl)3,6-diazabicyclo[3.2.0]heptan-3-yl)-2(2,5-difluorophenyl)tetrahydro-2Hpyran-3-amine
206 te (2R3S,5R)-2<2,5-difluorophenyl)-5-(6isopropyl-3,6-diazabicyclo[3.2.0]heptan3-yl)tetrahydro-2H-pyran-3-amine
207 F A F 1 -(3-((3R,5S,6R)-5-amino-6-(2,5difluorophenyl)tetrahydro-2H-pyran-3yl)-3,6-diazabicyclo[3.2.0]heptan-6yl)ethanone
208 F ίίΊ F A (3-((3R,5S,6R)-5-amino-6-(2,5difluorophenyl)tetrahydro-2H-pyran-3yl)-3,6-diazabicyclo[3.2.0]heptan-6yl)(cyclopropyl)methanone
209 |Γί N”1 (2R,3S,5R)-5-(6-(cyclopropylsulfonyl)3,6-diazabicyclo[3.2.0]heptan-3-yl)-2(2,5-difluorophenyl)tetrahydro-2Hpyran-3-amine
210 F Γί ώ0Α< (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(6(isopropyIsulfonyl)-3,6diazabïcyclo[3.2.0]heptan-3yl)tetrahydro-2 H-pyran-3 -amine
211 F il (2R3S,5R)-2-(2,5-difluorophenyl)-5-(6- (isobuty!sulfonyl)-3,6diazabicyclo[3.2.0] heptan-3 yl)tetrahydro-2H-pyran-3 -amine
212 F ΙίΊ ϊ”1 Λ isopropyl 3-((3R,5S,6R)-5-amino-6-(2,5difluorophenyl)tetrahydro-2H-pyran-3yl)-3,6-di azabicycl o[3.2.0]heptane-6caiboxylate
213 F |Γί ι”1 methyl 3-((3 R,5 S,6R)-5-amîno-6-(2,5- di fluorophenyl)tetrahydro-2 H-pyran-3 yI)-3,6-diazabicyclo [3.2.0]heptane-6carboxylate
214 F Ο JC ' °^Ν-\ y teteo 3-((3R,5S,6R)-5-amino-6-(2,5- di fluorophenyl)tetrahydro-2 H-pyran-3 yl)-N-methyl-3,6- diazabicyclo[3.2.0]heptane-6carboxamide
215 F - 3-((3R,5SJ6R)-5-amino-6-(2,5difluorophenyl)tetrahydro-2H-pyran-3y!)-N-cyclopropyl-3,6diazabicyclo[3.2.0]heptane-6carboxamide
216 F iil NH1 T ίΧφ- (2R,3 S,5 R)-2-(2,5-di fluorophenyl)-5-(3 methyl-3,6-diazabicyclo[3.2.0]heptan-6yl)tetrahydro-2H-pyran-3-amine
217 F Ô..T y T (2R,3S,5R)-5-(3-(cyclopropylmethyl)3,6-diazabicyclo[32.0]heptan-6-yl)-2(2,5-difluorophenyl)tetrahydro-2Hpyran-3-amine
218 F |Γί V’ -A. T οΛ,-βΛ (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(3isopropyl-3,6-diazabicyclo[3.2.0]heptan6-yl)tetrahydro-2H-pyran-3-amine
219 F ÇLA 1 -(6-((3 R,5S,6R)-5-amino-6-(2,5difluorophenyl)tetrahydro-2 H -pyran-3 yl)-3,6-diazabicyclo[3.2.0]heptan-3yl)ethanone
220 F (ίΊ Ï”1 τ^’’ (Ά| F °^γΰ·Λ (6-((3R,5S,6R)-5-amino-6-(2,5di fl uorophenyl )tetrahydro-2H-pyran-3yl>3,6-diazabicyclo[3.2.0]heptan-3yl)(cyclopropyl)methanone
221 y 1 -(6-((3R,5S,6R)-5-amino-6-(2,5difluorophenyl)tetrahydro-2 H-pyran-3 yl)-3,6-dia2abi cyclo[3.2.0]heptan-3-yl)2-methylpropan-1 -one
222 o- F °^*ν^ΟΝΑ methyl 6-((3R,5S,6R)-5-amino-6-(2,5difluorophenyl)tetrahydro-2H-pyran-3yl)-3,6-diazabicyclo[3.2.0]heptane-3carboxylate
223 F iil V01 LJ-..X o-4 cyclopropyl 6-((3R,5S,6R)-5-amino-6(2,5-difluorophenyl)tetrahydro-2Hpyran-3-yl)-3,6- diazabicyclo[3.2.0]heptane-3 -carboxylate
224 F ΙΪΊ V1’1 -r> ο λ * A (2R,3S,5R)-5-(3-(cyclopropylsulfonyl)3,6-diazabicyclo[3.2.0]heptan-6-yl)-2(2,5-difluorophenyl)tetrahydro-2Hpyran-3-amine
225 F A t”1 V A o / F “AoV (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(3- (isopropylsulfonyl)-3,6diazabicyclo[3.2.0]heptan-6yl)tetrahydro-2H-pyran-3-amine
226 F A NHi (2R,3S,5R)-5-(3-(cyclopentylsulfonyl)- 3,6-diazabicyclo[3.2.0]heptan-6-yl)-2(2,5-difluorophenyl)tetrahydro-2Hpyran-3-amine
227 4-((6-((3R,5S,6R)-5-amino-6-(2,5difluorophenyl)tetrahydro-2H-pyran-3yl)-3,6-diazabicyclo[3.2.0]heptan-3yl)sulfonyl)benzonitrile
228 F A NHj HN- F 6-((3 R,5 S,6R)-5-amino-6-(2,5difluorophenyl)tetrahydro-2H-pyran-3 yl)-N-methyl-3,6- diazabicyclo[3.2.0]heptane-3 carboxamide
229 F γΊι r ° v* N-(2-((3R,5S,6R)-5-amino-6-(2,5di fl uorophenyl)tetrahydro-2H-pyran-3 yl)octahydrocyclopenta[c]pyrrol-5yl)cyclopropanesul fonamide
230 F r^il N-(2-((3R,5S,6R)-5-amino-6-(2,5difluorophenyl)tetrahydro-2H-pyran-3yl)octahydrocyclopenta[c]pyrrol-5yl)propane-2-sulfonamide
231 A n N-(2-((3R,5S,6R)-5-amino-6-(2,5difluorophenyl)tetrahydro-2H-pyran-3yl)octahydrocyclopenta[c]pyrrol-5yl)cyclopentanesuifonamide
232 fe rv l-(2-((3R,5S,6R)-5-amino-6-(2,5- difluorophenyl) tetrahydno-2H-pyran-3yl)octahydrocyclopenta[c] pyrrol-5-yl)-3(4-fluorophenyl)urea
233 F rïl ï”3 1-(2-((3 R,5S,6R)-5-amino-6-(2,5difluorophenyl)tetrahydro-2 H -pyran-3yl)octahydrocyclopenta[c] pyrrol-5-yl)-3 cyclopropyl urea
234 Al 'A. O*A N-(2-((3R,5S,6R)-5-amino-6-(2,5difluorophenyl)tetrahydro-2H-pyran-3 yl)octahydrocyclopenta[c]pyrrol-5yl)acetamide
235 K.· As N-(2-((3R,5S,6R)-5-amino-6-(2,5difluorophenyl) tetrahydro-2H-pyran-3y1)octahydrocyclopenta[c] pyrrol-5- yl )cyclopropanecaiboxamide
236 fe N-(2-((3R15S,6R)-5-amino*6-(2,5difluorophenyl)tetrahydro-2H-pyran-3yl)octahydrocyclopenta[c]pyTrol-5yl)isobutyramide
237 A,, 2-((3R,5S,6R)-5-amino-6-(2,5difluorophenyl)tetrahydro-2H-pyran-3yl)-Nisobutyloctahydrocyclopenta[c]pyrrol-5amine
238 A„ Av 2-((3R,5S,6R)-5-amino-6-(2,5di fl uorophenyl)tetrahydro-2H-pyran-3 yl)-N-ethyloctahydrocyclopenta[c]pyrrol5-amine
239 v?· (2R,3S,5R)-2-(2,5-difluorophenyl)-N5(2-methyloctahydrocyclopenta[c]pyrrol5-yl)tetrahydro-2H-pyran-3,5-diamine
240 Ai, a (2RJS,5R)-N5-(2- (cyclopropylmethyl)octahydrocyclopenta [c]pyrrol-5-yl)-2-(2,5- difluorophenyl)tetrahydro-2H-pyran-3,5diamine
241 F A w _ x Ύ 'fe r/j ° l-(5-(((3R,5S,6R)-5-amino-6-(2,5difluorophenyl)tetrahydro-2H-pyran-3yl)amino)hexahydrocyclopenta[c] pyrrol2(1 H)-yl)ethanone
242 Λ r- z-î r-AN^0 ' ‘Λ-0'' (5-(((3R,5S,6R)-5-amino-6-(2,5difluorophenyl)tetrahydro-2H-pyran-3yl)amino)hexahydrocyclopenta[c] pyrrol2(1 H)-yl)(cyclopropyl)methanone
243 F fAi NU, ?'ÙxP'° (2R,3S,5R)-N5-(2- (cyclopropylsulfonyl)octahydrocyclopent a[c]pyrrol-5-yl)-2-(2,5- di fluorophenyl)tetrahydro-2H-pyran-3,5-
H—
diamine
244 F NH, θ'< rùxP'0 (2R,3S,5R)-2-(2,5-difluorophenyl)-N5(2- (methylsul fonyl)octahydrocyclopenta[c] p yrrol-5-yl)tetrahydro-2 H-pyran-3,5diamine
245 Φ--Λ (2R,3S,5R)-N5-(2- (cyclopentylsulfonyl)octahydrocyclopent a[c]pyrrol-5-yl)-2-(2,5- difluorophenyl)tetrahydro-2H-pyran-3,5diamine
246 F ôuç Γ<Λ>' methyl 5-(((3R,5S,6R)-5-amino-6-(2,5difluorophenyl)tetrahydro-2H-pyran-3yl)amino)hexahydrocyclopenta[c]pyrrole -2(1 H)-carboxylate
247 F O JC F O-—J*N-< A' o 5-((3R,5S,6R)-5-amino-6-(2,5difluorophenyl)tetrahydro-2H-pyran-3yl)-N-methyl-3,4,5,6tetrahydropyrrolo[3,4-c]pyrrole-2( 1H)carboxamide
248 •fe. L-O/ cfe (2R,3S,5R)-5-(5- (methylsul fonyl)hexahydropyrTolo[3,4c]pyrrol-2(l H)-yl)-2-(2,3,5tri fluorophenyl )tetrahydro-2H-pyran-3amine
249 F il V o7 (2R,3S,5R)-5-(5-(methylsulfonyl)-5,6dihydropyTTolo[3,4-c]pyrrol2(lH,3H,4H)-yl)-2-(2,3,5trifluorophenyl)tetrahydro-2H-pyran-3amine
250 ii r ’YÔ.^ (2R,3S,5R)-5-(tetrahydro-lH-fÎiro[3,4c]pyrrol-5(3H)-yl)-2-(2,3,5trifluorophenyl)tetrahydro-2H-pyran-3amine
251 fe fel.» 0 5-((3R,5S,6R)-5-amino-6-(2,3,5trifluorophenyl)tetrahydro-2H-pyran-3yl)hexahydro-1 H-thieno[3,4-c]pyrrole 2,2-dioxide
U70
252 As 5-((3R,5S,6R)-5-amino-6-(2,3,5trifluorophenyl)tetrahydro-2H-pyran-3yl)-3,4,5,6-tetrahydro-l H-thieno[3,4cjpyrrole 2,2-dioxide
253 F il ï1 (2R,3S,5R)-5-(5,6-dihydropyrrolo[3,4c]pyrrol-2(lH,3H,4H)-yl)-2-(2,3,5trifluorophenyl)tetrahydro-2H-pyran-3amine
254 nS fe, NH (fe (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(5(Smethylsulfonimidoyl)hexahydropyrrolo[3 ,4-c]pynol-2( 1 H)-yl)tetrahydro-2Hpyran-3-amine
255 fe (2R3 S,5R)-2-(2,5-difluorophenyl)-5-( 1 (SmethyIsu1fonimidoyl)hexahydropyTTolo[3 ,4-b]pyrrol-5( 1 H)-yl)tetrahydro-2Hpyran-3-amine
256 t fe (2R,3S,5R)-2-(2,S-difIuorophenyI)-5-(5(2,2,2- trifluoroethyl)h exahydropyrroto[3,4c]pyrroï-2(lH)-yl)tetrahydro-2H-pyran3-amine
257 F fej F3 Q-· feN NH (Τ' (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(5- (S-methylsu!fonimidoy!)-5,6dihydropyrrolo[3,4-c]pyrroi- 2(IH, 3H,4H)-yl)tetrahydro-2H-pyran-3 amine
Tesftne of Compounds of the invention
In vitro DPP-IV inhibitory activity using enzymatic assay:
In vitro enzyme (DPP-IV) inhibitory activity was determined using fluorescence5 based assay (Anal. Biochem., 200, 352, 1992). The Gly-Pro-AMC was used as a substrate (which is cleaved by the enzymes to release the fluorescent AMC) and soluble human proteins (DPP-IV enzyme) produced in a baculovirus expression system (Life Technologies) was used as the enzyme source. The H-Gly-Pro-AMC (200 μΜ) was incubated with DPP-IV enzyme in the presence of various concentrations (30 & 100 nM) of test compounds. Reaction was carried out at pH 7.8 (HEPES buffer 25 mM containing 1.0% BSA, 140 mM NaCI, 16 mM MgCI2,2.8% DMSO) in a total volume of 100 μΐ at 25 °C for 30 min., in the dark. Reaction was terminated with acetic acid (25 μΐ of 25% solution). Activity (fluorescence) was measured using Spectra Max fluorometer (Molecular Devices, Sunnyvale CA) by exciting at 380 nm and émission at
460 nm. In-vitro DPP-IV inhibitory activity of some of the représentative compounds are listed in Table-3.
Table-3: In vitro DPP-IV inhibitory activity of test compounds
Compounds % In-vitro DPPIV Inhibition
ICse
1 ++
2 +++
3 +
4
5
6 +
7 +++
8 +++
9 +++
10 +
11 +
12 +
13 +++
14 +
15
16 +
17 +++
18 +
19 +
20 +
21 +
22 ++
23 ++
24 ++
25 -H-
26 ++
27 +++
28 +++
29 ++
30 +++
31 +++
32 +++
33 -H-
34 +++
35 -H-
36 +++
37 -H-
38 +++
39 +++
40 ++
41 +
42 ++
43 ++
44 ++
45 +++
46 +
47 +
48 +++
49 +++
50 +++
+ indieates IC» <100 nM; ++ indieates IC» < 30 nM and +++ indieates IC» <10 nM; DPP-IV inhibitory activity determined by fluoresccnce-bascd assay, fluorescence measured using Spectra Max fluorometer (Molecular Déviées, CA) by exciting at 380 nm and émission et 460 nm.
In vivo effïcacy studies:
a) Démonstration of in vivo effïcacy (antihyperglycaemicf antidiabetic activity) of test compounds in C57BL/6J mice, oral routes of administration.
Animais
Acute single dose 120-min time-course experiments were carried out in male
C57BL/6J mice, âge 8-12 weeks, bred in-house. Animais were housed in groups of 6 animais per cage, for a week, in order to habituate them to vivarium conditions (25 ± 4 °C, 60-65 % relative humidity, 12:12 h light: dark cycle, with lights on at 7.30 am). Ail the animal experiments were carried out according to the intemationally valid guidelines following approval by the ‘Zydus Research Center animal ethical committee*.
Procedure
The in- vivo glucose lowering properties of the test compounds were evaluated in
C57BL/6J (mild hyperglycémie) animal models as described below. Two days prior to the study, the animais were randomized and divided into groups (n = 6), based upon their fed glucose levels. On the day of experiment, food was withdrawn from ail the cages, water was given ad-libitum and were kept for ovemight fasting. Vehicle (normal saline) / test compounds were administered orally, on a body weight basis. Soon after the 0 min. blood collection from each animal, the subséquent blood collections were done at 30, 60 and 120 or upto 240 min., via retro-orbital route, under light ether anesthésia (Diabètes Obesity Metabolism, 7,307,2005; Diabètes, 52,751,2003).
Blood samples were centrifuged and the separated sérum was immediately subjected for the glucose estimation. Sérum for insulin estimation was stored at -70 °C until used for the insulin estimation. The glucose estimation was carried out with DPEC-GOD/POD method (Ranbaxy Fine Chemicals Limited, Diagnostic division, India), using Spectramax-190, in 96-microwell plate reader (Molecular devices
Corporation, Sunnyvale, California). Mean values of duplicate samples were calculated using Microsoft excel and the Graph Pad Prism software (Ver 4.0) was used to plot a 0 min base line corrected line graph, area under the curve (0-120 min AUC) and base line corrected area under the curve (0 min BCAUC). The AUC and BCAUC obtained from graphs were analyzed for one way ANOVA, followed by Dunnett’s post test, using
Graph Pad prism software. Changes in the blood glucose levels, with selected compounds are shown in Table-4. —
Table-4: in vivo anti-diabetic activity of test compounds, in mice
Compounds In vivo OGTT C57; % Glucose change
1 -2250+45
2 -25.70+1.8
3 -27.60+1.6
4 -1650+3.8
5 -7.60+1.3
6 -730+1.6
7 -7.90+1.2
8 -49.10+3.6
9 -34.70±4.4
10 -12.50+1.3
11 -25.60+32
12 -9.80+15
13 -26.40+1.6
14 -14.20+3.4
15 -42.03±1.8
16 -29.40+6.8
17 -2730+33
18 -12.60+4.0
19 -20.60+3.0
20 -8.40±1.7
21 -15.02+4.0
22 -25.10+2.0
23 -22.01+12
24 -18.90+5.7
25 -1220+25
26 -20.10+1.4
27 -13.70±12
28 -35.02+6.1
29 -27.70+3.1
30 -35.01+1.4
31 -28.10+32
32 -25.30+3.9
33 -16.80+1.6
34 -30.10±3.4
35 -20.50+3.8
36 -22.20+2.5
37 -25.05+32
38 -22.04±2.6
39 -25.08±3.6
40 -14.01±1.5
41 -6.04+2.6
42 -25.05+2.8
43 -15.50+3.6
44 -12.50+1.5
45 -34.9+4.4
46 -9.3+3.8
47 8.6+5.9
48 -38.5+1.5
50 -30.02±1.4
Acute single dose 120-min tûne-course expérimenta, in male C57BL/6J mice (in vivo glucose réduction), with test compounds; n=6, ail values are Mean ± SEM; Test compounds administered via oral route of administration, dose 0.3 mg/kg, po.
Pharmacokinetic study in Wistar rats
The pharmacokinetic parameters of test compounds were determined in male wistar rats (n=6). Briefly, test compounds were administered orally / iv on a body weight basis 5 to ovemight fasted rats. Serial blood samples were collected in microcentrifuge tubes containing EDTA at pre-dose and post-dose after compounds administration, over a period of 168 hrs. Blood was collected at various time points and centrifuged at 4 °C. The obtained plasma was frozen, stored at -70 °C and the concentrations of compounds in plasma were determined by the LC-MS/MS (Shimadzu LC 1 OAD, USA), using YMC 10 hydrosphère Cjg (2.0 x 50 mm, 3 pm) column (YMC Inc., USA). The pharmacokinetic parameters, such as Tmax, tj/2, Kel, AUC and %F were calculated using a noncompartmental model of WinNonlin software version 5.2.1. PK parameters of représentative test compounds are shown in Table-5.
TabIe-5: Pharmacokinetic (PK) parameters of test compounds in rats
Compounds Cmax (ng/ ml) ti/2(h) AUC (h.ng/ml)
1 148.25±34.17 33.30+2.07 88829+129.47
3 300.78+4427 4820+11.05 2967.69+1070.68
8 459.04±52.17 59.48±6.44 4751.59+646.66
17 418.83±45.50 32.46+5.91 1554.33±114.41
•Vehicle : TweenSO: PEG400:0.5% Na-CMC in purified water :: 5:5:90, v/v/r, n=6; Mcan+SD; Dose: 2 mg/kg, orally
The novel compounds of the présent invention can be formulated into suîtable pharmaceuticaily acceptable compositions by combinîng with suîtable excipients by techniques and processes and concentrations as are well known.
The compounds of Formula (I) or pharmaceutical compositions containing them are usefiil as antidiabetic compounds suîtable for humans and other warm blooded animais, and may be administered either by oral, topical or parentéral administration.
The novel compounds of the présent invention can be formulated into suîtable pharmaceuticaily acceptable compositions by combining with suîtable excipients by techniques and processes and concentrations as are well known. Thus, a pharmaceutical composition comprising the compounds of the présent invention may comprise a suîtable binder, suîtable bulking agent &/or diluent and any other suîtable agents as may be necessary. Optionally, the pharmaceutical composition may be suitably coated with suîtable coating agents.
The compounds of the présent invention (I) are DPP-IV inhibitors and are useful in the treatment of disease states mediated by DPP-IV enzyme, preferably diabètes and related disorders.
The quantity of active component, that is, the compounds of Formula (I) according to this invention, in the pharmaceutical composition and unit dosage form thereof may be varied or adjusted widely depending upon the particular application method, the potency of the particular compound and the desired concentration. Generally, the quantity of active component will range between 0.5% to 90% by weight of the composition,
While the présent invention has been described in terms of its spécifie embodiments, certain modifications and équivalents will be apparent to those skilled in the art and are intended to be included within the scope of the présent invention.
-CAMEROUN

Claims (13)

  1. We claim
    1. Compound having the structure of general formula (I) (l)
    Wherein:
    5 R1 at each occurrence is independently selected from hydrogen, halo, cyano, nitro, hydroxyl, optionally substituted groups selected from amino, alkyl, C2^ alkenyl, C2_6 alkynyl, Cw alkoxy, alkenoxy, C« alkynyloxy, cycloalkoxy, aryl, cycloalkyl, carbocycle, heterocyclyl, heteroaryl, heterocycloalkyl, cycloalkyl(Ci_6)alkyl, heterocycloalkyl(C|^)alkyl, aralkyl, heteroarylalkyl, aryloxy, heteroaryloxy, heterocyclyloxy groups; R2 is selected from ÎO the following bicyclic non-aromatic ring Systems:
    Wherein R3 at each occurrence is independently selected from hydrogen, halo, haloalkyl, cyano, optionally substituted groups selected from amino, Ct^ alkyl, C2_é
    Λ alkenyl, Cm alkynyl, aryl, cycloalkyl, carbocycle, heterocycloalkyl, cycloalkyl(Ci_ 6)alkyl, heterocycloalkyl(C|^)alkyl, S(O)„ S(O)o(Ci^)alkyl, S(O)B(C|.e)aiyl, S(O)nNH2, S(O)oNH(Ci_6)alkyl, S(O)nNHcycloalkyl, S(O)nNHaryl, S(O)nNIIheteroaryl, (C|. 6)alkylamino, nitro, COOÎCM)alkyl, S((O)=NH)-alkyl. S((O)=NH)-aryl, S((O)=NH)cycloalkyl, S((O)=NH)-hetroaryl, S((O)=N-alkyl)-alkyl, S((O)=N-alkyl)-aryl, S((0)=N-alkyJ)-cycloalkyJ, S((O)=N-aIkyl)-hetroaryl, S((O)=N-aryl)-alkyl, S((O)=Naryl)-aryl, S((0)=N-aryl)-cyctoalkyl, S((O)=N-aryl)-hetroaryl, S((O)=N-(SO2-aIkyl))alkyl, S((O)=N-(SO2-alkyl))-aryl, S((O)=N-(SO2-alkyl))-cycloalkyl, S((O>N-(SO2alkyl))-hetroaryl, SitO^N-iSCh-aryli^alkyl, S((O)=N-(SO2-aryl))-aryl, S((O)=N(SOî-arylJJ-cycloalkyl, S((0)=N-(SO2-aryl))-hetroary!, C(O), C(O)NH(C1J6)alkyl groups;
    n = 0,1,2,3,4,5,6,7; p = 1-3; X = -CH2-NR4,0, S;
    R4 îs independently selected from hydrogen, halo, amino, cyano, nitro, (CM)alkyl, (Ci. e)alkylcarbonyt, (C2^)alkenyl, (C2^)alkynyl, -(CH2)nCOO(CI4)alkyl, -(CH2)nCOOH, C(=O)CH2alkyl, -C(=O)CH2aryl, -C(=O)CH2heteroaiyl, (CHâ^l, (CH2)nheteroaryl, (CH2)B-N-heteroaryl, (CH2)B-N-heterocyclyl, S(O)„, S(O)^iryl, StO^lkyl, S(O)n(Cb 6)alkyl, S(O)„(C^)aryl, S(O)nNH2, S(OXNH(Cw)alkyl groups.
  2. 2. The compound as elaimed in claim 1 wherein R1 at each occurrence is independently selected from hydrogen, halo, cyano, optionally substituted groups selected from amino, Cm alkyl, Cm alkenyl, Cm alkynyl, aryl, cycloalkyl, carbocycle, heterocycloalkyl, cycloalkyl(CM)alkyl, heterocycloalkyl(CM)alkyl groups.
  3. 3. The compound as elaimed in claim 1 wherein the substituents on R1 are independently selected from hydroxy, (CM)alkoxy, halo, cyano, amino, (CM)alkylamino, nitro, COO(CM)alkyl. S(O)o, S(O)^1I2, S(O)„NH(CM)alkyl, C(O); C(O)NH(CM)alkyl groups.
  4. 4. The compounds elaimed in claim 1, wherein R4 is independently selected from hydrogen, halo, amino, cyano, nitro, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2.COOH, -C(=O)CH2-methyl, -C(=O)CH2-phenyl, S(O)2phenyl, S(O)2-methyl, S(O)2NH2, S(O)2NH-methyl groups.
  5. 5. The compound as elaimed in any preceding claims, wherein when Rj is substituted, the substituents on Rj arc selected from hydrogen, halo haloalkyl, amino, cyano, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, -CH2. COOH, -C(=O)-O-methyl, -C(=O)-O-trifluromethyl, -C(=O)-O-ethyl, -C(=O)-O80 phenyl, -C(=O)-NH-mcthyl, -C(=O)-NH-ethyI, -C(=0)-NH-propyl, -C(=O)-NHcyclopropyl, -C(=O)-NII-phenyl,-C(=O)-NH-trfluromethyl, -C(=O)-methyl, -C(=O)cthyl, -C(=O)CH2-methyl, -C(=OX?H2-phenyl, S(O)2-phenyl, S(O)2-methyl, S(O)2ethyl, S(O)rpropyl, S(O)rbutyl, S(O)rcyclopropyl, S(O)2-cyclobutyl, S(O)25 cyclopentyl, S(O)j-cyc!ohexyl, S(O)2-phenyl, S(O)2-flurophenyl, S(O)2-cynophenyI,
    S(O)ïNHî, S(OhNH-methyl, S(O)2NH-ethyl, S(O)2NH-propyI, S(O)2NH-butyl, S(O)îNH-pentyl, S(0)2NH-cyclopropyl, S(O)2NH-cyclobutyl, S(O)2NH-cyclopentyl, S(O)îNH-cyclohexyl, S(O)2NH-phcnyl, S((O)=NH)-methyl, S((O>NH)-ethyl, S((O)=NH>phenyl, S((O)=NH)-cyclopentyl, S((O}=NH)-pyridine, S((O)=N-methyl)10 methyl, S((O)=N-methyl)-phenyl, S((O)=N-ethyl)-cyclopropyl, S((O)=N-methyI)pyridine, S((O)=N-phenyl)-methyl, S((O)=N-phenyl)-phenyl, S((O)=N-phenyl>cyclopentyl, S((O)=N-phenyl)-pyridine, S((O)=N-(SO2-methyl))-methyl, S((O)=N(SOrmethyl))-phcnyl, SfCO^N-fSOi-ethyl^-cyclohexyl, S((O)=N-(SO2-methyl))pyridine, S((O)=N-(SO2-pheny!))-methyl, S((O)=N-(SO2-phcnyl))-phenyl, S((O)=N15 (SOrphenyl))-cyclopentyl, S((O)=N-(SO2-phenyl))-pyri<line.
  6. 6. A compound as claimed in claim 1 selected from the group comprising of:
    U—-17288 'Λ/'
    F il NHl ' F (Tl F ifl MI1 F Îl NHi ^-ly F il ï”’ F ίη nh, T oj.œ_ F A i”* α.ύ F ΙΪΊ ï”2 F <kA O F Π ï”2 Y ^œio F ηΊ '* O-N^\ L Q? fe„ fe., 9> F il t1 fe--^ F il i”1 ' ’%? A ÏH’ 9>h K. F ιΓί *”1
    F ‘'A-b- F il Ï”J ' ^ο> F lii F T A F Μα>Ύ F il F γ F ifj F X ^COfO F il F F fij F Φ-Λ τ αόλ Ô-A T F O JF uy rf'o F il F î&3V A/ q' O F p tpv0 d'y F O JF >P Oo+Q F ii F i O-H-py
    •Λ/—
    ό F> feT F 0, r ' Q 5. ι'Ύ. fe? fe> F M ï”2 F / A |Γί τ ‘γΊ <ϊ fe? F ίΪΊ î2 rù^y- F ffj ΝΠ’ 1 il °*/ 9fe fe F Ôfe^u£^_feo F fil Ï™1 fefe <,> - A^> F il ï2 ï OA fe? F A t”1 t'ÛA» A) F A nh2 Ψ-Λ fe fe ί F F |Γί Kj F |Γί F A ïH’ fefe. x-fe F UhA. k F ίιΊ T2 Tïfe «fe fec NH, fefe
    F A NHï ' 0>-ζ F A NHî ' V Φ'Λ F A NH, ' Av άτ Yùq/ fe F A NHj F A N», F A ï”· F a r v-v F ÎJ Γ YiAA F A NH, ÔaÇ vA F il K3 7 ώο,χ F A ï”1 r F A] NHj r At, A> F (il t”2 ’ Air F Ô..X* y F A -, ’ AiT^
    tA^x·
    F ιΓί NH1 F ίίΊ V”î * τ^ί p7 f °AtA F M ï2 F fil ï”2 Γ Οχ-βΝ-ζ F itS ï”j Τ^Ί o— > F ÎÎJ i2 ΜΑ| ° Λ F il Y1 Ti ° / f «fe^-fe F fil ï”1 T Ο^-βΗ^Ό fe.^ F A ï2 UN- ’ -•feifeo F Π ï’1 ^Ύ·ο F Γυ Τ’2 fel fe F fy F2 fey ofe F fil î”1 feBA F fil Y”1 Ολ [S T1 fe. ofe F Π ï”J i;%fe fe * 12S »
    ιΑ-'93
    te F A “Hz CLqqI- F A F F iS F Ï£Xte^ F (Γί M,‘ θΌι. te„ tex. F A F ' ° Çxo F A X*2 ï θ-ΧΝ-χ o ter F A F i Vil ° F ‘^'cO'V te F O.—XN->. xxv F rll N*1' o ri 141,1 0 Άο o F A F o te 0 te ΧίγΟ F A «h ma X^NyO^ 0
    U__
    F Π F1* tA Χ,ΝγΟ^χ 0 F A NHj ' Qx? cjtep, F A Y7’2 Q?n p F A NHï F “ter F A Y2 Rx? ^0 A ''Ch p °χχ te., tex te., X, te., tei, te * <a>*n-x ter» <%α te, tes? TX te, •x F A Y2 tb νγΐ) o F A Y”2 Ό~> ο. A F A y1 F A NH» X^sX -A. A \,NH
  7. 7. The compound as claimed in any preceding claim preferably selected from the group comprising of:
    F ιΊΐ ϊ1 ο F γΊ( m,j fe) oA fe Άι- F A p O-qqI- F A JL2 F °ANA °sZ A F fS Γ11 θνζ F A mi, o A rfTX. F A «H, fefe-. fe·. ° few F A N>h fejfe’-.-fex, f fe«A ° fe?T Ά °. °^ncO F A Ntl, F ASA aiv ^fe'b F (*« Wj Av 0 F γΊι M,ï ' ° 9\O 0 F A NHî F Mha o A κ?Νγο 0
    fe F A NH, 0 0. O lil Γ* O-> O F A NH, F ANA Ap F Al NHj tA o AA O fe F O''Z*'N'X_ %φ F A v”1 ' Ά A fe r X-S-\ ^o. F Π T* A A A M A A «Ck A Ψά., F A NU, X^N CH, Y o F A nh, Α._/;λ O
  8. 8. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) as claîmed in any of the preceding claims and optionally one or more pharmaceutically acceptable carriers, diluents or excipients.
  9. 9. The pharmaceutical composition which is useful for reducing blood glucose levels for treating type Π diabètes.
  10. 10. Use of a compound of Formula (I) or its pharmaceutical composition according to any of the preceding claims for the manufacture of a médicament for increasing insulin sécrétion for treating type Π diabètes.
  11. 11. A medicîne for the treatment of type II diabètes which comprises administering a therapeutically effective amount of compound of Formula (I) or its pharmaceutical composition as defined in any of the preceding claims to a patient or subject in need thereof.
  12. 12. A pharmaceutical composition comprising the compound of the présent invention in combination with one or more suitable pharmaceutically active agents seiected from insulin, insulin dérivatives and mimetics, insulin secretagogues, insulin sensitizers, biguanide agents, alpha-glucosidase inhibitors, insulinotropîc sulfonylurea receptor ligands, meglitinides, GLP-1, GLP-1 analogs, DPP-IV inhibitors, GPR-119 activators, sodîum-dependent glucose co-transporter (SGLT2) inhibitors, PPAR modulators, nonglitazone type PPAR.delta agonist, HMG-CoA reductase inhibitors, cholesterol- lowering drugs, rennin inhibitors, anti-thrombotic and anti-platelet agents and antiobesity agents or their suitable pharmaceutically acceptable salts.
  13. 13. Use of the compound of formula (I) and a suitable pharmaceutically acceptable agent selected from insulin, insulin dérivatives and mimetics, insulin secretagogues, insulin sensitîzers, biguanide agents, alpha-glucosidase inhibitors, insulinotropic sulfonylurea receptor ligands, meglitinides, GLP-1, GLP-1 analogs, DPP-IV inhibitors, GPR-119 activators, sodium-dependent glucose co-transporter (SGLT2) inhibitors, PPAR modulators, non-glitazone type PPAR.delta agonist, HMG-CoA reductase inhibitors, cholesterol-lowering drugs, rennin inhibitors, anti-thrombotic and anti-platelet agents and anti-obesity agents or their pharmaceutically acceptable salts for the treatment of diabètes and its associated disorders.. IA-''
OA1201500132 2012-10-17 2013-10-17 2-phenyl-5-heterocyclyl-tetrahydro-2H-pyran3-amine compounds for use in the treatment of diabetes and its associated disorders. OA17288A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
IN3030/MUM/2012 2012-10-17

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Publication Number Publication Date
OA17288A true OA17288A (en) 2016-04-29

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