BR112017005859B1 - ALDOSTERONE SYNTHASE INHIBITORS, THEIR USES AND PHARMACEUTICALLY ACCEPTABLE SALTS AND PHARMACEUTICAL COMPOSITION - Google Patents

Abstract

ALDOSTERONE SYNTHASE INHIBITORS, THEIR USES AND PHARMACEUTICAL COMPOSITION. The present invention relates to compounds of formula I: and pharmaceutically acceptable salts thereof, wherein R1, R2 and R3 are as defined herein. The invention further relates to pharmaceutical compositions comprising these compounds, processes for using these compounds in the treatment of various diseases and disorders, processes for preparing these compounds and intermediates useful in these processes.

Description

FIELD OF INVENTION

[0001] This invention relates to heteroaryl compounds that are useful as inhibitors of aldosterone synthase (CYP11B2) and are thus useful for treating a variety of diseases that are mediated or maintained by aldosterone activity, including kidney disease, diabetic nephropathy , cardiovascular diseases and fibrotic disorders. This invention further relates to pharmaceutical compositions comprising these compounds, methods of using these compounds in the treatment of various diseases and disorders, processes for preparing these compounds and intermediates useful in these processes.

BACKGROUND

[0002] Aldosterone is a steroid hormone that has mineralocorticoid activity. It is primarily produced by the adrenal glomerulosa in response to angiotensin II, adrenocorticotropic hormone and increased serum potassium levels. A primary physiological function of aldosterone in the kidney is to maintain sodium and potassium balance by regulating cation exchange (Na+ reabsorption and K+ secretion) in the distal nephron. However, it has also been observed that aldosterone is a pro-inflammatory and pro-fibrotic hormone in blood vessels, the heart and kidneys. The effects of aldosterone on gene expression are mediated via binding to the mineralocorticoid receptor (MR) and a canonical nuclear hormone receptor pathway. However, the hormone also induces rapid nongenomic responses, including acute regulation of the activity of tubular ion transporters, e.g., Na+/H+ players (NHEs), H+- ATPase, ENaC, and Na+/K+ ATPase (D. W. Good, 2007, Hypertension, 49, 728-739). It is likely that some of these effects are mediated by MR-independent pathways. Conversely, MR can bind alternative ligands, including deoxycorticosterone, corticosterone, cortisol, and progesterone. Thus, inhibition of aldosterone synthesis is predicted to have a pharmacodynamic profile distinct from that observed with MR antagonists.

[0003] Aldosterone is synthesized in the zona glomerulosa of the adrenal glands, in which a single enzyme, CYP11B2 (aldosterone synthase), catalyzes the 3-step conversion of 11-deoxycorticosterone (11-DOC) into aldosterone, via corticosterone and 18 -hydroxycorticosterone. The activity of adrenal aldosterone synthase is regulated by Angiotensin II and K+ levels and by media derived from unidentified adipocytes. Low levels of aldosterone synthase have also been detected in the heart in the CNS, although the physiological relevance is uncertain, perhaps related to paracrine effects. Systemic aldosterone is believed to be derived essentially entirely from the adrenals.

[0004] In addition to its function in regulating sodium and potassium balance, aldosterone has been shown to have pro-inflammatory and pro-fibrotic actions in various tissues including the kidney, blood vessels and the heart. The harmful effects of inappropriate aldosterone levels on blood pressure and cardiac, renal, cerebral and vascular function and structure have been widely reported in the literature, including: i) increased sodium retention through induction of the Na+ pump /K+ ATPase in the distal tubules resulting in volume expansion and high blood pressure, ii) endothelial dysfunction, iii) oxidative stress, iv) renal and cardiac hypertrophy, v) fibroblast proliferation and, vi) excessive extracellular matrix synthesis resulting in renal, cardiac and vascular fibrosis.

[0005] The benefits of aldosterone blockade/inhibition include the reduction of renal fibrosis and the improvement of glomerular filtration rate and albuminuria in models of chronic kidney disease (CKD) and diabetic nephropathy. This is supported by preclinical data (e.g., Fiebler et al., 2005, Circulation, 111, 3087-3094; Lea et al., 2009, Kidney International, 75, 936-945). Other benefits reported in the literature include lower blood pressure and end-organ damage (heart, kidney, vessels) in both renin-dependent and salt-sensitive hypertension.

[0006] Although many known effects of aldosterone are mediated through activation of the mineralocorticoid receptor (MR) and much of the evidence favoring its targeting comes from experiments with MR antagonists, effects that are not mediated by MR and mice are reported. Knockouts for MR and aldosterone synthase exhibit different phenotypes (Makhanova et al. 2006, Berger et al. 1998, Funder 2007). These observations also suggest that aldosterone synthase inhibitors may have a different profile and offer advantages when compared to MR antagonists.

[0007] For example, several actions of aldosterone are not inhibited by MR antagonists, including potentially deleterious effects on the vasculature (increased peripheral vascular resistance), the heart (effects on myocardial repolarization) and the endocrine system (secretion of reduced insulin). Furthermore, MR antagonism leads to an increase in circulating aldosterone, predicted to increase aldosterone signaling through non-MR pathways and potentially partially overcome MR blockade itself.

[0008] Current therapy strategies focus on delaying progression and treating conditions fundamental to diabetic nephropathy: blood glucose control and high blood pressure control. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) have shown renal benefit in diabetic patients. So far, representatives of the ACE inhibitor class and the ARB class have been approved for the treatment of diabetic nephropathy. These therapies represent limited benefit for patients with diabetic nephropathy.

[0009] Although the use of ACE inhibitors and ARBs represents the current standard of care for patients with diabetic nephropathy, patients progressively lose renal function while on these medications, as observed in the IDNT studies (E. J. Lewis et al., 2001 , N. Engl. J. Med., 345, 851-860) and RENAAL (B.M. Brenner et al., 2001, N. Engl. J. Med., 345, 861-869), who reported a decrease over time in the estimated glomerular filtration rate, which is an accurate measure of chronic kidney disease progression in patients treated using these conventional methods. In stage 5 chronic kidney disease, renal replacement therapy is required in the form of dialysis or transplant.

[00010] Inhibition of aldosterone synthase can also be predicted to offer advantages as add-on therapy with ACE inhibitors and ARBs. Notably, 25 - 50% of patients receiving these agents experience "aldosterone escape" in which aldosterone levels initially reduced through these treatments eventually return to pre-treatment levels. This phenomenon would not occur with direct inhibition of aldosterone synthase and could increase efficacy in combination therapy.

[00011] There remains a great unmet medical need to treat diabetic nephropathy, halt or regress disease progression by specifically targeting fundamental pathophysiological mechanisms associated with chronic inflammation and fibrosis, regardless of the original cause of the disease and when co-administered. treated with current therapies. The studies described above and in the literature provide evidence that aldosterone synthesis inhibitors will be useful for the treatment of diabetic kidney disease including diabetic nephropathy; non-diabetic kidney disease including glomerulosclerosis, glomerulonephritis, IGA nephropathy, nephritic syndrome and focal segmental glomerulosclerosis (FSGS); cardiovascular diseases including hypertension, pulmonary arterial hypertension, Conn syndrome, systolic heart failure, diastolic heart failure, left ventricular dysfunction, left ventricular stiffness and fibrosis, left ventricular filling abnormalities, arterial stiffness, atherosclerosis, and hyperalcohol-associated cardiovascular morbidity - primary or secondary dosteronism; adrenal hyperplasia and primary and secondary hyperaldosteronism.

BRIEF SUMMARY OF THE INVENTION

[00012] The present invention provides new compounds that inhibit aldosterone synthase and thus are useful for treating a variety of diseases and disorders that can be alleviated by reducing aldosterone levels including kidney disease, diabetic nephropathy, cardiovascular diseases and fibrotic disorders . This invention further relates to pharmaceutical compositions comprising these compounds, methods of using these compounds in the treatment of various diseases and disorders, processes for preparing these compounds and intermediates useful in these processes.

DETAILED DESCRIPTION OF THE INVENTION

[00013] In one embodiment of the invention, compounds of formula I are provided where: R1 is selected from -C(O)NH2, -C(O)NH(CH3) and -CN; R2 is -(X)-R4, where -(X)- is a bond, -CH2- or -O-; and R4 is selected from - H; C1-3alkyl, optionally substituted by one to four groups selected from -F, -OH and -SO2C1-3alkyl; halogen; - CN; - SO2C1-3alkyl; - C(O)N(C1-3alkyl)2; - NHC(O)R5 or -N(CH3)C(O)R5, provided that -(X)- is - CH2- and wherein R5 is selected from C3-6cycloalkyl and C1-3alkyl optionally substituted by one to three groups -F; - NHSO2C1-3alkyl; - CH(cyclopropyl)NHSO2C1-3alkyl; - OCH2C(O)N(C1-3alkyl)2, as long as -(X)- is -CH2-; - S(=O)(=NH)CH3, as long as -(X)- is -CH2-; heterocyclyl selected from tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, 1,1-dioxo[1,2]-thiazine, morpholinyl, oxazolidinyl, piperidinyl, azetidinyl, wherein said heterocyclyl is optionally substituted by one of up to three selected groups of -C(O)C1-3alkyl, halogen, -OH, oxo and C1-3alkyl; -C(O)-heterocyclyl, provided that -(X)- is -CH2, wherein said heterocyclyl is selected from morpholin-4-yl, pyrrolidin-1-yl and piperidin-1-yl, optionally substituted by one or two groups selected from -F and -OH; C3-6cycloalkyl optionally substituted by -CN or -OH; and phenyl, optionally substituted by -SO2NH2; and R3 is H or C1-3alkyl optionally substituted by -OH; or R2 and R3 together form an annealed five-membered cycloalkyl ring optionally substituted by -OH; or a salt or stereoisomer thereof.

[00014] In another embodiment, compounds of formula I are provided which are described in accordance with the previous embodiment and in which R1 is -C(O)NH2 or -CN; R2 is -(X)-R4, where - (X)- is a bond and R4 is selected from - CH3; - CF3; - CHF2; - CH2OH; - CH(OH)CH3; - CH(OH)CF3; - F; -CN; heterocyclyl selected from tetrahydropyranyl and pyrrolidinyl, wherein said heterocyclyl is optionally substituted by one to three groups selected from C1-3alkyl, halogen, -OH and oxo; C3-6cycloalkyl optionally substituted by -CN or -OH; and phenyl, optionally substituted by -SO2NH2; or -(X)- is O and R4 is selected from C1-3alkyl; -CH2SO2C1-3alkyl; and heterocyclyl selected from tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl and azetidinyl, wherein said heterocyclyl is optionally substituted by one to three groups selected from -C(O)C1-3alkyl, halogen, -OH , oxo and C1-3alkyl; or X is (-CH2-) and R4 is selected from -SO2C1-3alkyl; - C(O)N(C1-3alkyl)2; - NHC(O)R5 or -N(CH3)C(O)R5, where R5 is selected from cyclopropyl and C1-3alkyl optionally substituted by one to three -F groups; - OCH2C(O)N(C1-3alkyl)2; - NHSO2C1-3alkyl; -S(=O)(=NH)CH3; heterocyclyl selected from pyrrolidinyl, 1,1-dioxo[1,2]-thiazine, morpholinyl and oxazolidinyl, wherein said heterocyclyl is optionally substituted by one to three groups selected from -C(O)C1-3 alkyl, halogen, - OH, oxo and C1-3alkyl; and -C(O)-heterocyclyl, wherein the heterocyclyl is selected from morpholin-4-yl, pyrrolidin-1-yl and piperidin-1-yl, optionally substituted by one or two groups selected from -F and -OH; and R3 is H or C1-3alkyl optionally substituted by -OH; or a salt or stereoisomer thereof.

[00015] In another embodiment, compounds of formula I are provided which are described in accordance with any of the previous embodiments and wherein R2 is -(X)-R4, wherein -(X)- is a bond and R4 is selected from - CF3; - CHF2; - CH2OH; - CH(OH)CH3; - CH(OH)CF3; - F; -CN; heterocyclyl selected from tetrahydropyranyl and pyrrolidinyl, wherein said heterocyclyl is substituted by one to three groups selected from C1-3alkyl, -F, -OH and oxo; C3-6cycloalkyl, substituted by -CN or -OH; and phenyl, optionally substituted by -SO2NH2; and R3 is H or C1-3alkyl optionally substituted by -OH; or a salt or stereoisomer thereof.

[00016] In another embodiment, compounds of formula I are provided which are described in accordance with any of the previous embodiments and wherein R2 is -(X)-R4, wherein -(X)- is O and R4 is selected from C1-3alkyl; -CH2SO2C1-3alkyl; and heterocyclyl selected from tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl and azetidinyl, wherein said heterocyclyl is optionally substituted by -C(O)C1-3alkyl; and R3 is H or C1-3alkyl optionally substituted by -OH; or a salt or stereoisomer thereof.

[00017] In another embodiment, compounds of formula I are provided which are described in accordance with any of the previous embodiments and wherein R2 is -(X)-R4, wherein X is (-CH2-) and R4 is selected from - SO2C1-3alkyl; - C(O)N(C1-3alkyl)2; - NHC(O)R5 or -N(CH3)C(O)R5, where R5 is selected from cyclopropyl and C1-3alkyl optionally substituted by one to three -F groups; - OCH2C(O)N(C1-3alkyl)2; - NHSO2C1-3alkyl; -S(=O)(=NH)CH3; heterocyclyl selected from pyrrolidinyl, 1,1-dioxo[1,2]-thiazine, morpholinyl and oxazolidinyl, wherein said heterocyclyl is optionally substituted by one to two groups selected from oxo and C1-3 alkyl; and -C(O)-heterocyclyl, wherein the heterocyclyl is selected from morpholin-4-yl, pyrrolidin-1-yl and piperidin-1-yl, optionally substituted by one or two groups selected from -F and -OH; and R3 is H or C1-3alkyl optionally substituted by -OH; or a salt or stereoisomer thereof.

[00018] In another embodiment, compounds of formula I are provided that are described in accordance with any of the previous embodiments and in which R1 is -C(O)NH2; or a salt or stereoisomer thereof.

[00019] In another embodiment, compounds of formula I are provided that are described according to any of the previous embodiments and in which R1 is -CN; or a salt or stereoisomer thereof.

[00020] In another aspect of the invention, there is provided a compound of general formula I or a stereoisomer or a pharmaceutically acceptable salt thereof for use in a therapeutic method that is described previously and subsequently herein.

[00021] Table 1 shows representative compounds of the invention that can be produced using the methods described in the general synthetic schemes, examples and methods known in the art. Table 1

[00022] In one embodiment, the invention relates to a compound selected from the group consisting of compounds 1-62 represented in Table 1 above and pharmaceutically acceptable salts and stereoisomers thereof.

[00023] In another embodiment, the invention relates to compounds 1,5,12, 29,37,43,56, 61 and 62 represented in Table 1 above and to pharmaceutically acceptable salts and stereoisomers thereof.

[00024] Unless specifically indicated throughout the specification and the attached claims, a certain formula or chemical name must encompass tautomers and all stereo, optical and geometric isomers (for example, enantiomers, diastereoisomers , E/Z isomers, etc.) and racemates thereof as well as mixtures in different proportions of the separate enantiomers, mixtures of diastereoisomers or mixtures of any of the foregoing forms in which such isomers and enantiomers exist, as well as salts, including pharmaceutically acceptable salts thereof and solvates thereof such as, for example, hydrates including solvates of the free compounds or solvates of a salt of the compound.

[00025] Some of the compounds of formula (I) may exist in more than one tautomeric form. The invention includes methods of using all such tautomers.

[00026] The compounds of the invention also include their isotope-labeled forms. An isotope-labeled form of an active agent of a combination of the present invention is identical to said active agent except for the fact that one or more atoms of said active agent have been replaced by an atom or atoms having an atomic mass or an atomic number. different from the atomic mass or atomic number of said atom that is generally found in nature. Examples of isotopes that are readily commercially available and that can be incorporated into an active agent of a combination of the present invention in accordance with well-established procedures include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, e.g. , 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F and 36Cl, respectively. An active agent of a combination of the present invention, a prodrug thereof or a pharmaceutically acceptable salt of any containing one or more of the aforementioned isotopes and/or other isotopes of other atoms, is considered to be within the scope of the present invention. .

[00027] The invention includes pharmaceutically acceptable derivatives of compounds of formula (I). A "pharmaceutically acceptable derivative" refers to any pharmaceutically acceptable salt or ester or any other compound which, upon administration to a patient, is capable of providing (directly or indirectly) a compound useful for the invention or a pharmacologically active metabolite or a pharmacologically active residue thereof. A pharmacologically active metabolite should be understood as meaning any compound of the invention capable of being enzymatically or chemically metabolized. This includes, for example, hydroxylated or oxidized derivative of compounds of formula (I).

[00028] As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds in which the original compound is modified through the production of acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkaline or organic salts of acid residues such as carboxylic acids; and the like. For example, such salts include acetates, ascorbates, benzenesulfonates, benzoates, besylates, bicarbonates, bitartrates, bromides/hydrobromides, edetates, camsylates, carbonates, chlorides/hydrochlorides, citrates, edisylates, ethane disulfonates, stolates, esylates, fumarates, gluceptates , gluconates, glutamates, glycolates, glycolylarsnilates, hexylresorcinates, hydrabamines, hydroxymaleates, hydroxynaphthoates, iodides, isethionates, lactates, lactobionates, malates, maleates, mandelates, methanesulfonates, methylbromides, methylnitrates, methylsulfates, mucates, napsilates, nitrates, oxalates, pamolates , pantothenates, phenylacetates, phosphates/di-phosphates, polygalacturonates, propionates, salicylates, stearates, subacetates, succinates, sulfamides, sulfates, thanates, tartrates, theoclates, toluenesulfonates, triethiodides, ammonium, benzathines, chloroprocaines, cholines, diethanolamines, ethylenediamines , meglumines and procaines. Additional pharmaceutically acceptable salts can be formed with metal cations such as aluminum, calcium, lithium, magnesium, potassium, sodium, zinc and the like. (see also Pharmaceutical Salts, Birge, S.M. et al., J. Pharm. Sci., (1977), 66, 1-19).

[00029] The pharmaceutically acceptable salts of the present invention can be synthesized starting from the original compound that contains a basic or acidic group through conventional chemical methods. Generally, such salts can be prepared by reacting the acid or free base forms of these compounds with a sufficient amount of the appropriate base or acid in water or an organic diluent such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile or a mixture of the same.

[00030] Salts of acids other than those mentioned above which, for example, are useful for the purification or isolation of the compounds of the present invention (for example, trifluoroacetate salts) also comprise a part of the invention.

[00031] In addition, the use of prodrugs of compounds of formula (I) is within the scope of the invention. Prodrugs include those compounds that, after simple chemical transformation, are modified to produce compounds of the invention. Simple chemical transformations include hydrolysis, oxidation, and reduction. Specifically, when a prodrug is administered to a patient, the prodrug can be transformed into a compound disclosed previously herein, thereby imparting the desired pharmacological effect.

[00032] The compounds of the invention are only those that are considered to be 'chemically stable' as will be considered by those skilled in the art. For example, peroxides or a compound that would have a 'swing valence' or a 'carbanion' are not the compounds considered by the methods of the invention disclosed herein.

[00033] For all compounds previously disclosed herein in this patent application, in the event that the nomenclature conflicts with the structure, it should be understood that the compound is defined by the structure.

[00034] All terms that are used here in this specification, unless otherwise mentioned, must be understood in their common meaning that is known in the art. For example, "C1-4alkyl" is a monovalent saturated aliphatic hydrocarbon radical containing 1-4 carbons such as methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl or t-butyl; "C1-4 alkoxy" is a C1-4 alkyl with a terminal oxygen, such as methoxy, ethoxy, propoxy, butoxy. All alkyl, alkenyl and alkynyl groups are to be understood as being branched or unbranched, cyclized or uncyclized when structurally possible and unless otherwise specified. Other more specific definitions are as follows:

[00035] The term "C1-n-alkyl", where n is an integer from 2 to n, alone or in combination with another radical means an acyclic, saturated, branched or linear hydrocarbon radical with 1 to n C atoms For example, the term C1-5-alkyl includes the radicals H3C-, H3C-CH2-, H3C-CH2-CH2-, H3C-CH(CH3)-, H3C-CH2-CH2-CH2-, H3C-CH2- CH(CH3)-, H3C-CH(CH3)-CH2-, H3C-C(CH3)2-, H3C-CH2-CH2-CH2- CH2-, H3C-CH2-CH2-CH(CH3)-, H3C- CH2-CH(CH3)-CH2-, H3C-CH(CH3)- CH2-CH2-, H3C-CH2-C(CH3)2-, H3C-C(CH3)2-CH2-, H3C-CH(CH3) -CH(CH3)- and H3C-CH2-CH(CH2CH3)-.

[00036] The term "C1-n-alkylene" in which n is an integer from 1 to n, alone or in combination with another radical, means a divalent acidic, straight or branched chain radical containing from 1 to n carbon atoms. For example, the term C1-4-alkylene includes -(CH2)-, -(CH2-CH2)-, -(CH(CH3))-, -(CH2-CH2-CH2)-, -(C(CH3) 2)-, -(CH(CH2CH3))-, -(CH(CH3)-CH2)-, -(CH2-CH(CH3))-, -(CH2-CH2-CH2- CH2)-, -(CH2 -CH2-CH(CH3))-, -(CH(CH3)-CH2-CH2)-, -(CH2-CH(CH3)- CH2)-, -(CH2-C(CH3)2)-, -( C (CH3)2-CH2)-, -(CH(CH3)-CH(CH3))-, -(CH2- CH(CH2CH3))-, -(CH(CH2CH3)-CH2)-, -(CH( CH2CH2CH3))-,-(CHCH(CH3) 2)- and -C(CH3)(CH2CH3)-.

[00037] The term "C3-n-cycloalkyl", where n is an integer from 4 to n, alone or in combination with another radical means an unbranched saturated cyclic hydrocarbon radical with 3 to n C atoms. For example , the term C3-7-cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

[00038] The term "heteroatom" as used herein should be understood to mean non-carbon atoms such as O, N, S and P.

[00039] In all alkyl groups or carbon chains one or more carbon atoms can be optionally replaced by heteroatoms: O, S or N, it must be understood that if N is not replaced then it is NH, it must be understood that heteroatoms can replace terminal carbon atoms or internal carbon atoms within a branched or unbranched carbon chain. Such groups may be substituted as described above for groups such as oxo to result in definitions such as, but not limited to: alkoxycarbonyl, acyl, amido and thioxo.

[00040] The term "aryl" as used herein, alone or in combination with another radical, means a monocyclic aromatic carbocyclic group containing 6 carbon atoms that can be additionally fused to a second 5- or 6-membered carbocyclic group that can be aromatic, saturated or unsaturated. Aryl includes, but is not limited to, phenyl, indanyl, indenyl, naphthyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl and dihydronaphthyl.

[00041] The term "heteroaryl" means a monocyclic 5 to 6 membered aromatic heteroaryl ring or bicyclic heteroaryl 7 to 11 membered aromatic ring in which at least one of the rings is aromatic, in which the heteroaryl ring contains 1-4 heteroatoms such as N, O and S. Non-limiting examples of 5- to 6-membered monocyclic heteroaryl rings include furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, pyrazolyl, pyrrolyl, imidazolyl, tetrazolyl, triazolyl, thienyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl and purinyl. Non-limiting examples of 7- to 11-membered heteroaryl bicyclic heteroaryl rings include benzimidazolyl, quinolinyl, dihydro-2H-quinolinyl, tetrahydroquinolinyl, isoquinolinyl, quinazolinyl, indazolyl, thieno[2,3-d]pyrimidinyl, indolyl, isoindolyl , benzofuranyl, dihydrobenzofuranyl, benzopyranyl, benzodioxolyl, benzoxazolyl and benzothiazolyl.

[00042] The term "heterocyclyl" means a stable non-aromatic 4-8 membered monocyclic heterocyclic radical or a stable non-aromatic fused bicyclic, bridged bicyclic or spirocyclic 6 to 11 membered heterocyclic radical. The 5 to 11 member heterocycle consists of carbon atoms and one or more, preferably one to four heteroatoms chosen from nitrogen, oxygen and sulfur. The heterocycle can be saturated or partially unsaturated. Non-limiting examples of non-aromatic 4-8 membered monocyclic heterocyclic radicals include tetrahydrofuranyl, azetidinyl, pyrrolidinyl, pyranyl, tetrahydropyranyl, dioxanyl, thiomorpholinyl, 1,1-dioxo-1À6-thiomorpholinyl, morpholinyl, piperidinyl, piperazinyl and azepinil. Non-limiting examples of non-aromatic 6- to 11-membered fused bicyclic radicals include octahydroindolyl, octahydrobenzofuranyl and octahydrobenzothiophenyl. Non-limiting examples of non-aromatic 6- to 11-membered bicyclic bridged radicals include 2-azabicyclo[2.2.1]heptanyl, 3-azabicyclo[3.1.0]hexanyl, and 3-azabicyclo[3.2.1]octanyl. Non-limiting examples of non-aromatic 6- to 11-membered spirocyclic heterocyclic radicals include 7-azaespiro[3,3]heptanyl, 7-azaespiro[3,4]octanyl, and 7-azaespiro[3,4]octanyl. The term "heterocyclyl" is intended to include all possible isomeric forms.

[00043] The term "halogen" as used in the present patent application should be understood as meaning bromine, chlorine, fluorine or iodine. The definitions "halogenated", "partially or completely halogenated"; partially or completely fluorinated; "substituted by one or more halogen atoms", include for example mono-, di- or tri-halo derivatives on one or more carbon atoms. For alkyl, a non-limiting example would be -CH2CHF2, -CF3 etc.

[00044] Each alkyl, cycloalkyl, heterocycle, aryl or heteroaryl or analogues thereof described here should be understood as being optionally partially or completely halogenated.

[00045] As used herein, "nitrogen" or N and "sulfur" or S include any oxidized form of nitrogen and sulfur and the quaternized form of any basic nitrogen. For example, for an -S-C1-6 alkyl radical, unless otherwise specified, it should be understood as including -S(O)-C1-6 alkyl and -S(O)2-C1-6 alkyl, similarly, -S-Ra can be represented as phenyl-S(O)m- when Ra is phenyl and when m is 0, 1 or 2.

GENERAL SYNTHESIS METHODS

[00046] The compounds of the invention can be prepared using the methods and examples presented below and methods known to those of ordinary skill in the art. The methods that are described here are intended to be an illustration and enable the present invention without restricting the scope of its subject matter, the claimed compounds and the examples. Optimal reaction conditions and reaction times may vary depending on the particular reagents used. Unless otherwise specified, solvents, temperatures, pressures and other reaction conditions can be readily selected by one of ordinary skill in the art. Specific procedures are provided below. The intermediates used in the synthesis below are commercially available or are readily prepared by methods known to those skilled in the art. The progress of the reaction can be monitored using conventional methods such as thin layer chromatography (TLC) or high pressure liquid chromatography mass spectrometry (HPLC-MS). Intermediates and products can be purified by methods known in the art, including column chromatography, HPLC, preparatory TLC, supercritical fluid chromatography (SFC) and recrystallization.

[00047] The compounds of formula (I) can be prepared as illustrated in Scheme 1. Scheme 1

[00048] As illustrated in Scheme 1, a suitable heteroaromatic bromide can be converted to boronate II ester through the palladium-catalyzed coupling reaction with a diboronyl ester such as bis(pinacolato)diboron. The Suzuki Reaction with vinyl bromide III (Intermediate 1) gives IV. Aminolysis of ester IV gives amide V. Hydrogenation over palladium on carbon gives the desired compound of formula I (R1=CONH2).

[00049] The compounds of formula (I) can also be prepared as illustrated in Scheme 2. Scheme 2

[00050] As illustrated in Scheme 2, compounds of formula I can also be prepared through hydrogenation of compound IV followed by aminolysis to provide I.

[00051] The compounds of formula (I) can also be prepared as illustrated in Scheme 3. Scheme 3

[00052] As illustrated in Scheme 3, a suitable heteroaromatic bromide can be converted to a boronate II ester through the palladium-catalyzed coupling reaction with a diboroyl ester such as bis(pinacolato)diboron. The Suzuki reaction with vinyl bromide VII (Intermediate 2) gives VIII. Hydrogenation over palladium on carbon provides the desired compound of formula I (R1=CONH2).

[00053] Compounds of formula I R1= -CN can be prepared starting from compounds of formula 1 R1= -CONH2 by reacting with a suitable dehydration reagent such as trifluoroacetic anhydride in the presence of base as shown in the Scheme 4.Scheme 4 SYNTHESIS EXAMPLES Synthesis of Intermediates Intermediate 1: 2-bromo-benzo[1,4]dioxin-5-carboxylic acid methyl ester

[00054] Step A: To a suspension of 2,3-dihydro-benzo[1,4]dioxin-5-carboxylic acid (49.7 g, 275.6 mmoles) in 1000 mL of MeOH, chloride is added of acetyl (40.0 mL, 560.5 mmoles) in a drip form. After complete addition, the reaction is stirred at room temperature for 18 hours. The reaction mixture is then concentrated in vacuo and the residue is dissolved in EtOAc and washed with sat. The organic layer is separated and extracted with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated to provide 50.7 g of 2,3-dihydro-benzo[1,4]dioxin-5-carboxylic acid methyl ester.

[00055] Step B: A mixture of 2,3-dihydro-benzo[1,4]dioxin-5-carboxylic acid methyl ester (50.7 g, 261.1 mmoles) in carbon tetrachloride (300 mL) 2,2'-azobis (isobutyronitrile) (125 mg, 0.7 mmol) and N-bromosuccinimide (90.0 g, 505.7 mmol) are added. The reaction mixture is refluxed using a 60W lamp (covered with aluminum foil) for 24 hours. After this time, another 100.0 g (561.8 mmol) of N-bromosuccinimide, 175 mg (1.1 mmol) of 2,2'-azobis (isobutyronitrile) and 100 mL of carbon tetrachloride are added. The reaction mixture is stirred under the same conditions for a further 24 hours. After this time, another 40.0 g (224.7 mmol) of N-bromosuccinimide and 100 mg (0.6 mmol) of 2,2'-azobis (isobutyronitrile) are added. The reaction mixture is stirred under the same conditions for a further 72 hours after which period of time the reaction appears to be complete. To a reaction mixture, 1 L of ether is added. The resulting solid is filtered off and washed with ether. The combined organic phases are concentrated and the crude solid is dissolved in 20% EtOAc/heptane and purified through a block of silica gel (500 g), eluting with 20% EtOAc/heptane. The product fractions are collected and concentrated to provide 86.5 g of 2,3-dibromo-2,3-dihydro-benzo[1,4]dioxin-5-carboxylic acid methyl ester.

[00056] Step C: A suspension of 2,3-dibromo-2,3-dihydro-benzo[1,4]dioxin-5-carboxylic acid methyl ester (22.7 g, 64.5 mmoles) in 200 mL of MeOH is heated to 50 oC and treated with 500 mL of sodium methoxide (0.5 M in methanol, 250 mmol). The reaction mixture is heated to 65°C and stirred for 2 hours. The reaction mixture is treated with silica gel and concentrated. The dry residue is purified by flash silica gel column chromatography eluting with 0-15% EtOAc/heptane to provide 2.6 g of the title compound. Intermediate 2: 2-bromo-benzo[acid] amide 1,4]dioxin-5-carboxylic acid

[00057] A 20 mL reaction vessel is charged with 2-bromo-benzo[1,4]dioxin-5-carboxylic acid methyl ester (1.2 g, 4.4 mmoles) and 7 N ammonia solution in methanol (13.0 mL, 88.5 mmol). The container is covered and heated at 75°C for 18 hours. After cooling to room temperature, the mixture is concentrated to dryness. The remainder of the solid is diluted with MeOH (10 mL) and subjected to ultrasound. Filtration yields 1.00 g of 2-bromo-benzo[1,4]dioxin-5-carboxylic acid amide. Intermediate 3: 2-bromo-benzo[1,4]dioxin-5-carboxylic acid methylamide

[00058] The title compound is prepared in a similar way to Intermediate 2 by replacing ammonia with methylamine. Intermediate 4: 3-bromo-5-fluoro-4-methyl-pyridine

[00059] A solution of diisopropylamine (1.9 mL, 13.7 mmoles) in 20 mL of THF is cooled to 0°C and treated with n-butyllithium (6.7 mL, 13.6 mmoles). The mixture is stirred at 0°C for 15 minutes and then cooled to -78°C. 3-Bromo-5-fluoropyridine (2.0 g, 11.4 mmol) is added dropwise as a solution in 20 mL of THF. This mixture is stirred at -78°C for 45 minutes. A separate solution of iodomethane (2.1 mL, 34.1 mmol) in 20 mL of THF is cooled to -78°C. The anion solution is then introduced via cannula into the iodomethane solution. Once transfer is complete, the mixture is stirred at -78°C for 30 minutes. The cooling bath is removed and the mixture is stirred for 30 minutes and then quenched with saturated NH4Cl solution. The mixture is diluted with EtOAc and water. The organic layer is washed with brine, dried over MgSO4, filtered and concentrated. The residue is purified by flash silica gel column chromatography eluting with 0-10% EtO-Ac/heptane to provide 1.4 g of the title compound. Intermediate 5: 3-bromo-5-difluoromethyl-pyridine

[00060] A solution of 5-bromo-3-formylpyridine (1.5 g, 8.1 mmol) in 15.00 mL of DCM is cooled to -78°C and then treated with diethylaminosulfur trifluoride (5. 3 mL, 40.3 mmol) in drops. The solution is allowed to cool to room temperature overnight. The reaction mixture is added dropwise to a cooled stirred solution of dilute NH4OH and is diluted with more DCM. The organic layer is separated and the organic layer is extracted again with DCM. The organic layers are combined and washed with brine, dried over MgSO4, filtered and concentrated. The residue is purified by flash silica gel column chromatography eluting with 0-30% EtOAc/heptane to provide 1.1 g of the title compound. Intermediate 6: 3-[(5-bromo-3-pyridyl )methyl]oxazolidin-2-one

[00061] Step A: A solution of (5-bromo-3-pyridyl)methanol (7.0 g, 37.2 mmol) in 10 mL of DCM is cooled to 0°C. Triphenylphosphine (9.8g, 37.2 mmoles) is added followed by the slow addition of carbon tetrabromide (18.5 g, 55.8 mmoles) as the reaction is exothermic. The mixture is stirred at 0°C for 3 hours. After the reaction is complete, the reaction mixture is absorbed with silica gel and purified by fast silica gel column chromatography to provide 7.5 g of 3-bromo-5-(bromomethyl)pyridine.

[00062] Step B: 2-Oxazolidone (0.6 g, 7.2 mmoles) is dissolved in 20 mL of DMF and cooled to 0°C. 60% sodium hydride (0.29 g, 7.2 mmoles) is added. Bubble formation is observed. The mixture is stirred for 5 minutes. 3-Bromo-5-(bromomethyl)pyridine (1.2 g, 4.8 mmol) as a solution in 15 mL of DMF is added slowly. The reaction mixture is allowed to warm to room temperature for 16 hours. The reaction is quenched with 10 mL of water. The mixture is filtered through diatomaceous earth and washed with EtOAc (50 mL). The EtOAc layer is concentrated. The crude product is obtained by flash silica gel column chromatography eluting with 0-10% MeOH in DCM to give 0.9 g of the title compound.

[00063] The following intermediates are synthesized according to the procedure for Intermediate 6, replacing appropriate commercially available reagents. Intermediate 10: 4-(5-bromo-pyridin-3-yl)-benzenesulfonamide

[00064] 3,5-Dibromopyridine (1.0 g, 4.2 mmoles), (4-aminosulfonyl)benzeneboronic acid (0.8 g, 4.2 mmoles), 1,1'-bis complex ( diphenylphosphine)ferrocenedichloropalladium(II) DCM (172 mg, 0.211 mmol), 20 mL of 1,4-dioxane and 2.0 M sodium carbonate solution (4.2 mL, 8.4 mmol) are combined in a container depression. The container is discharged with argon, sealed and stirred at 120°C for 2 hours. The reaction mixture is diluted with EtOAc/water. The mixture is filtered through diatomaceous earth and the layers are separated. The organic layer is washed with brine, dried over MgSO4, filtered and concentrated. The residue is purified by flash silica gel column chromatography eluting with 50-100% EtOAc/Heptane to provide 0.6 g of the title compound. Intermediate 11: 1-[(S)-3-(5-bromo -pyridin-3-yloxy)-pyrrolidin-1-yl]-ethanone

[00065] To a stirred solution of triphenylphosphine (28.9 g, 110 mmoles) in 100 mL of THF cooled to 0°C is added diisopropyl azodicarboxylate (20.9 g, 103 mmoles) and 5-bromo-pyridine -3-ol (12.0 g, 69 mmol) as a solution in 50 mL of THF. 1-((R)-3-Hydroxycyclopentyl)-ethanone (8.8 g, 69 mmol) as a solution in 50 mL of THF is added slowly. The reaction is stirred at room temperature for 3 hours. The reaction is quenched with water and extracted with EtOAc (2 X 200 mL). The combined organic layers are concentrated under reduced pressure. The crude product is purified by flash chromatography on silica gel and washed with diethyl ether to provide 6.5 g of the title compound.

[00066] The following intermediates are synthesized according to the procedure for Intermediate 10, replacing appropriate commercially available reagents. Intermediate 15: 3-bromo-5-methanesulfonylmethyl-pyridine

[00067] Step A: To a cooled solution (0 °C) of (5-bromo-pyridin-3-yl)-methanol (5.0 g, 26.6 mmol) and triphenylphosphine (8.4 g, 31. 9 mmol) in 130 ml of DCM carbon tetrabromide (13.2 g, 39.9 mmol) is added. The resulting mixture is stirred at 0°C for 10 minutes. The mixture is concentrated and purified by flash chromatography on silica gel eluting with 0-40% EtOAc in heptane to provide 6.1 g of 3-bromo-5-bromomethyl-pyridine.

[00068] Step B: 3-Bromo-5-bromomethyl-pyridine (100 mg, 0.4 mmol), sodium methanesulfinate (122 mg, 1.2 mmol) and 1 mL of DMF are combined in a reaction vial. The vial is sealed and the reaction is stirred at 65°C on a heating block for 1 hour. The mixture is cooled to room temperature, diluted with EtOAc (30 mL), washed with water (3 x 15 mL) and brine, dried over sodium sulfate, filtered and concentrated. The crude product is purified by flash chromatography on silica gel eluting with 0-100% EtOAc in heptane to provide 70 mg of the title compound. Intermediate 16: 1-[(R)-3-(5-bromo-pyridin- 3-yloxy)-piperidin-1-yl]-ethanone

[00069] Step A: To a cooled solution (0°C) of PPh3 (1.2 g, 4.5 mmol) in 50 mL of THF is added diisopropyl azodicarboxylate (0.81 mL, 4.1 mmol ), in drops. After stirring at 0°C for 15 minutes, 5-bromo-pyridin-3-ol (441 mg, 2.5 mmol) and (S)-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (500 mg, 2.5 mmol) are added and the mixture is heated and stirred at room temperature for 16 hours. The mixture is concentrated and purified by flash silica gel column chromatography to provide 596 mg of (R)-3-(5-bromo-pyridin-3-yloxy)-piperidine-1-carboxylic acid tert-butyl ester.

[00070] Step B: A solution of (R)-3-(5-bromo-pyridin-3-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (596 mg, 1.7 mmol) in 5 mL of MeOH and 4N HCl solution in 1,4-dioxane (1.5 mL) is stirred at room temperature for 16 hours. The mixture is concentrated to provide 525 mg of 3-bromo-5-((R)-piperidin-3-yloxy)-pyridine in the form of the hydrochloride salt.

[00071] Step C: To a solution of 3-bromo-5-((R)-piperidin-3-yloxy)-pyridine hydrochloride salt (525 mg, 1.8 mmol) in 10 mL of DMF is added chloride of acetyl (0.19 mL, 2.7 mmol) and N,N-diisopropylethylamine (1.4 mL, 8.0 mmol). The mixture is stirred at room temperature for 16 hours. The reaction is fractionated between H2O and EtOAc and the layers are separated. The organic layer is extracted with EtOAc. The organic layers are combined, dried and concentrated. The crude product is purified by flash silica gel column chromatography to provide 271 mg of the title compound. Intermediate 17: methanesulfonic acid 5-(tetrahydro-pyran-4-yl)-pyridin-3-yl ester

[00072] Step A: 5-Bromo-pyridin-3-ol (15 g, 86.2 mmoles), 4- (4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl )-3,6-dihydro-2H-pyran (27 g, 129.3 mmol), potassium acetate (12.7 g, 129.3 mmol) and Bis(diphenylphosphine)ferrocene]dichloropalladium(II) (1 .3 g, 1.7 mmol) are combined in 150 mL of dioxane and 30 mL of water. The reaction is refluxed for 16 hours. The reaction is concentrated to dryness. The residue is partitioned between H2O and EtOAc and the layers are separated. The organic layer is extracted with EtOAc and the combined organic layers are dried and concentrated. The crude product is purified by flash silica gel column chromatography to provide 10.5 grams of 5-(3,6-dihydro-2H-pyran-4-yl)-pyridin-3-ol.

[00073] Step B: To the solution of 5-(3,6-dihydro-2H-pyran-4-yl)-pyridin-3-ol (9.0 g, 50.8 mmol) in one liter of MeOH 10% Pd-C is added. The suspension is degassed under vacuum and purged with hydrogen. The mixture is stirred in (50 psi) hydrogen at 50°C for 5 hours. At the end of the reaction, the mixture is filtered and washed with MeOH. The filtrate is concentrated and purified by flash silica gel column chromatography to provide 9 grams of 5-(tetrahydro-pyran-4-yl)-pyridin-3-ol.

[00074] Step C: To a solution of 5-(tetrahydro-pyran-4-yl)-pyridin-3-ol (500 mg, 2.8 mmol), DMAP (13 mg, 0.1 mmol) and triethylamine (0.78 mL, 5.6 mmol) in 20 mL of DCM is added triflic anhydride (0.47 mL, 2.8 mmol) dropwise. The reaction is allowed to stir at room temperature overnight. The reaction is diluted with 1 N NaOH. The layers are separated and the DCM layer is concentrated to dryness. The residue is purified by flash silica gel column chromatography eluting with 5-50% EtOAc in heptanes to provide 415 mg of the title compound. Intermediate 18: 1-(5-bromo-pyridin-3-yl) -cyclohexanol

[00075] To 3,5-dibromopyridine (1.5 g, 6.3 mmol) in 6 mL of THF at -20°C is added the 1.3M i-PrMgCl_LiCl solution (4.7 mL, 6. 1 mmoles) in one part. The mixture is allowed to be stirred for 30 minutes, heating to -10°C. The mixture is cooled to -20°C and cyclohexanone (0.79 mL, 7.6 mmol) is added. The reaction is quenched with 50 mL of saturated aqueous NH4Cl and diluted with 200 mL of EtOAc. The organic phase is washed with 2 x 100 ml of H2O and 1 x 100 ml of brine. The organic phase is dried with MgSO4, filtered and concentrated. The residue is purified by flash silica gel column chromatography eluting with 0-10% MeOH/CH2Cl2 to provide 560 mg of the title compound.

[00076] The following intermediates are synthesized according to the procedure for Intermediate 18, replacing commercially available reagents or appropriate intermediates described previously. Intermediate 21: 5-(5-bromo-pyridin-3-yl)-1-methyl-pyrrolidin-2-one

[00077] Step A: 3-Bromo-5-(pyrrolidin-2-yl)pyridine (400 mg, 1.8 mmol), 4 mL of glacial acetic acid and 1 mL of water are added to a reaction flask. Bromine (0.8 mL) is added dropwise. The flask is sealed and the reaction is heated to 90°C in an oil bath and stirring is continued at this temperature for 3 hours. The mixture is cooled to room temperature. Water (15 mL) is added to the cooled reaction mixture and the mixture is saturated with solid potassium carbonate. The mixture is extracted with EtOAc (3x30 mL). The combined organic phases are dried over sodium sulfate, filtered and concentrated. The residue is purified by flash silica gel column chromatography eluting with 0-6% MeOH in DCM to provide 0.65 g of 3,3-dibromo-5-(5-bromo-pyridin-3-yl)- pyrrolidin-2-one.

[00078] Step B: Sodium borohydride (0.74 g, 19.6 mmoles) is suspended in 17 mL of ethanol and tellurium metal powder (1.25 g, 9.8 mmoles) is added in portions. The mixture is heated at reflux for 15 minutes and the mixture turns light purple. The mixture is cooled to room temperature. 3,3-Dibromo-5-(5-bromo-pyridin-3-yl)-pyrrolidin-2-one (0.65 g, 1.6 mmol) dissolved in 5 mL of ethanol is added slowly. The mixture is stirred at room temperature for 72 hours. The mixture is filtered through diatomaceous earth and washed with MeOH. The filtrate is concentrated. The resulting crude product is purified by flash silica gel column chromatography eluting with 0-6% MeOH in DCM to provide 290 mg of 5-(5-bromo-pyridin-3-yl)-pyrrolidin-2-one.

[00079] Step C: To a solution of 5-(5-bromo-pyridin-3-yl)-pyrrolidin-2-one (202 mg, 0.84 mmol) in 5 mL of THF is added 60% NaH ( 50 mg, 1.3 mmol). The mixture is stirred at room temperature for 5 minutes and methyl iodide (0.078 mL, 1.3 mmol) is then added dropwise. The mixture is stirred at room temperature for 16 hours. The mixture is then concentrated and purified by flash silica gel column chromatography to provide 157 mg of the title compound. The enantiomers are separated using Chiral SFC (Chiralpak AD-H, 30% (1:1 Isopropanol+0.5% TFA: Hexanes):CO2, 70 mL/min, 140 bar, 25°C). Intermediate 22 : 1-(5-Bromo-4-methyl-pyridin-3-yl)-ethanol

[00080] A solution of 3,5-dibromo-4-methyl-pyridine (2.0 g, 8.0 mmol) in 100 mL of THF cooled in a liquid N2/ethanol bath below -100°C is A 2.5 M solution of n-butyllithium in hexanes (3.2 mL, 8.0 mmol) was added. This is stirred for 5 minutes, then pure acetaldehyde (4.5 mL, 8.0 mmol) is added all at once. The reaction is allowed to heat to -78°C over 30 minutes. The temperature is maintained at -78°C by adding dry ice to the bath. The reaction is maintained at -78°C for 1 hour. The reaction is quenched with sat NH4Cl at -78°C. The reaction is allowed to warm to room temperature. The reaction is diluted with EtOAc and water. The organic layer is concentrated to dryness. The residue is purified by flash silica gel column chromatography eluting with 20-100% EtOAc in heptanes to provide 0.88 g of the title compound. Chiral SFC (LUX Cellulose-4, 12%(1:1:1 MeOH:EtOH:IPA):CO2, 70 mL/min, 120 bar, 40°C) of 2.5 g of 1-(5- bromo-4-methyl-pyridin-3-yl)-ethanol provides 0.98 g of enantiomer A and 0.98 g of enantiomer B. Intermediate 23: 3-bromo-5-methanesulfonylmethoxy-pyridine

[00081] Step A: To a solution of 5-bromo-pyridin-3-ol (500 mg, 2.9 mmol) in 5 mL of DMF is added 60% dispersion of sodium hydride in mineral oil (230 mg, 5.8 mmoles). The reaction is stirred for 15 minutes when chloromethyl methyl sulfide (0.24 mL, 2.9 mmol) is added. The reaction is stirred for 1 hour, then diluted with EtOAc and water. The organic layer is concentrated to dryness to provide 330 mg of 3-bromo-5-methylsulfanylmethoxy-pyridine.

[00082] Step B: To a solution of 3-bromo-5-methylsulfanylmethoxypyridine (330 mg, 1.4 mmol) in 10 mL of DCM is added 77% 3-chloroperbenzoic acid (608 mg, 3.5 mmol ). The reaction is allowed to stir overnight. The mixture is quenched with 1 N NaOH. The layers are separated and the organic layer is concentrated to dryness. Fast silica gel column chromatography eluting with EtOAc in heptanes gives 175 mg of the title compound. Intermediate 24: 2-[(5-bromo-3-pyridyl)methoxy]-N,N-dimethyl-acetamide

[00083] (5-Bromo-pyridin-3-yl)-methanol (2.0 g, 11 mmoles) is added to a 0°C solution of 60% NaH (0.51 g, 12.8 mmoles) in 150 mL of THF. The mixture is stirred at room temperature for 1 hour and then cooled to 0°C. 2-Chloro-N,N-dimethylacetamide (1.42 g, 12 mmol) is added to the mixture. The cooling bath is removed and the mixture is stirred at room temperature for 16 hours. The reaction is quenched with brine (0.5 mL) and filtered through a block of diatomaceous earth. The filtrate is concentrated, diluted with DCM, treated with MgSO4 and filtered again through diatomaceous earth. The filtrate is concentrated and the crude product is purified by flash column chromatography with silica gel eluting with 0-6% MeOH/DCM to yield 1.95 g of the title compound. Intermediate 25: 2-(5-bromo- 3-pyridyl)-1-morpholino-ethanone

[00084] To the solution of 5-bromo-3-pyridineacetic acid (500 mg, 2.3 mmoles) in 3 mL of DMF is added TBTU (1.1g, 3.4 mmoles). Morpholine (0.61 mL, 6.9 mmol) is added dropwise. The resulting reaction mixture is stirred at room temperature for 16 hours. The mixture is diluted with 50 mL of EtOAc, washed with water (3x5 mL) and brine, dried over sodium sulfate, filtered and concentrated. The resulting crude product is purified by flash silica gel column chromatography eluting with 0-4.5% MeOH/DCM to provide 381 mg of the title compound.

[00085] The following intermediates are synthesized according to the procedure for Intermediate 25, replacing commercially available reagents or appropriate intermediates described previously. Intermediate 29:1-(5-bromo-pyridin-3-yl)-cyclopropanecarbonitrile

[00086] To a suspension of (5-bromo-pyridin-3-yl)-acetonitrile (1.0 g, 5.1 mmol) in 50% NaOH (20 mL) is added 1-bromo-2-chloro- ethane (764 mg, 5.3 mmol) and benzyl triethylammonium chloride (15 mg, 0.1 mmol). The resulting mixture is heated at 60°C for 2 hours. After cooling to room temperature, EtOAc is added. The layers are separated and the organic layer is extracted with fresh EtOAc. The organic layers are combined, washed with brine, dried over Na2SO4, filtered and concentrated. The product is purified by flash silica gel column chromatography to provide 626 mg of the title compound. Intermediate 30: (5-bromo-pyridin-3-ylmethyl)-cyclopropanecarboxylic acid amide

[00087] To a stirred solution of cyclopropanecarboxylic acid (0.58 g, 6.7 mmoles) in 50 mL of DMF is added HATU (3.1 g, 8.0 mmoles) followed by (5-bromo-pyridin-3yl )-methylamine (1.3 g, 6.7 mmol) and N,N-diisopropylethylamine (7.5 ml, 42.8 mmol). The resulting mixture is stirred at room temperature for 16 hours and after this period of time it is concentrated to low volume, poured into 150 ml of water and extracted with EtOAc (3x). The combined organic phases are dried over MgSO4, filtered and concentrated. The remainder of the residue is purified by flash silica gel column chromatography eluting with 0-8% MeOH/DCM to provide 1.10 g of the title compound.

[00088] The following intermediate is synthesized according to the procedure for Intermediate 30, replacing the appropriate commercially available reagent. Intermediate 32: 3-bromo-5-(4-fluoro-tetrahydro-pyran-4-yl)-pyridine

[00089] A solution of (diethylamino) sulfur trifluoride (0.63 g, 3.9 mmol) in 6.0 mL of DCM is cooled to -78 ° C and treated with a solution of 4-(5-bromo- pyridin-3-yl)-tetrahydro-pyran-4-ol (1.0 g, 3.9 mmol) in 15 mL of DCM. The reaction is stirred at -78°C for 2 hours and then warmed to room temperature and poured onto ice. The mixture is stirred until all the ice has melted, at which point the layers are separated. The aqueous phase is extracted once again with DCM and the combined organic phases are washed with water, brine and then dried (MgSO4). The organic phase is filtered and concentrated to provide 0.90 g of the title compound. Intermediate 33: 1 -(5-bromo-pyridin-3-yl)-2,2,2-trifluoroethanol

[00090] To a cooled solution (0 oC) of 5-bromo-pyridine-3-carboxaldehyde (2.0 g, 10.8 mmol) in 25 mL of THF is added trimethyl(trifluoromethyl)silane (2.8 mL, 18.8 mmol) and 1.0 M TBAF in THF solution (10.8 mL, 10.8 mmol). The mixture is heated at room temperature for 3 hours. The solvent is evaporated to provide the crude product. Purification by flash column chromatography with silica gel yields 1.9 g of the title compound. Intermediate 34: 4-Bromo-6,7-dihydro-5H-[2]pyrindin-7-ol

[00091] Step A: A solution of diisopropylamine (3.37 mL, 23.9 mmol) in 100 mL of THF is cooled to 0°C and then treated with n-butyl lithium (11.95 mL, 23.9 mmol) 9 mmoles). The mixture is stirred at 0°C for 15 minutes and then cooled to -78°C. Methyl 5-bomonicotinate (4.70 g, 21.7 mmol) is added as a solution in 20 mL of THF drops. The mixture is stirred at -78°C for 30 minutes and then treated with methyl acrylate (4.89 mL, 54.3 mmol) in 20 mL of THF drops. The mixture is stirred at -78°C for 1.5 hours and then quenched with 50 ml of 10% acetic acid. The reaction mixture is evaporated to dryness. The crude solid is treated with 54 ml of 6N HCl and stirred at 100°C for 1 hour. The reaction mixture is cooled on ice, basified to pH 7-8 with 5N NaOH and extracted twice with EtOAc. The combined organic layer is washed with brine, dried over MgSO4, filtered and concentrated. Purification by flash column chromatography with silica gel eluting with 20-50% EtO-Ac/heptane provides 817 mg of 4-bromo-5,6-dihydro-[2]pyrindin-7-one.

[00092] Step B: The mixture of 4-bromo-5,6-dihydro-[2]pyrindin-7-one (1.96 g, 9.2 mmol) in 100 mL of ethanol is cooled to 0° C and then treated with sodium borohydride (454.58 mg, 12.0 mmoles). The reaction is stirred at room temperature for 1 hour and the solvent is evaporated. The raw solid is collected in EtOAc/water and the layers are separated. The organic layer is washed with brine, dried over MgSO4, filtered and concentrated. Purification by flash silica gel column chromatography eluting with 50-100% EtOAc/heptane provides 1.5 g of the title compound.

Synthesis of final compounds

[00093] The conditions for Chiral SFC for resolving enantiomers are presented in Table 2. When absolute stoichiometry is not established, by definition, the enantiomer that is eluted first is referred to as enantiomer A and the enantiomer that is eluted second place is referred to as enantiomer B. When a compound contains two stereocenters, the diastereomers are named AA, AB, BA, and BB, with the first letter referring to the first resolved stereocenter and the second letter referring to the second resolved stereocenter at a certain point. synthetic sequence, with the designations of A and B for elution order as mentioned above. LCMS data is measured using the methods presented in Table 3. LCMS data for the compounds in Table 1 are shown in Table 4. Compounds that have been separated into their enantiomers are shown by separate entries in Tables 4 and 5 for the enantiomer A and the enantiomer B. Similarly, compounds that have been separated into their diastereomers are shown by separate entries for the diastereomers AA, AB, BA, and BB. Example 1: 2-[5-(4-hydroxy-tetra acid amide -hydro-pyran-4-yl)-pyridin-3-yl]-2,3-dihydro-benzo[1,4]dioxin-5-carboxylic acid. (Compound 1, Table 1)

[00094] Step A: 4-(5-Bromo-pyridin-3-yl)-tetrahydro-pyran-4-ol (516 mg, 2.0 mmol), bis(pinacolato)diboron (760 mg, 3.0 mmol), 0 mmoles), potassium acetate (785 mg, 8.0 mmoles) and Bis(diphenylphosphine)ferrocene]dichloropaladium(II) (146 mg, 0.2 mmol) are combined in one vial. Dioxane (5 mL) is added and Ar is bubbled through the mixture for 5 minutes. The vial is capped and heated at 80°C for 4 hours to provide 4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl ]-tetrahydro-pyran-4-ol. This is used in situ for the subsequent Suzuki coupling.

[00095] Step B: To the above mixture of 4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-tetrahydro -pyran-4-ol is added 2-bromo-benzo[1,4]dioxin-5-carboxylic acid methyl ester (540 mg, 2.0 mmol), [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium (II) (146 mg, 0.2 mmol) and 2 M aqueous sodium carbonate solution (2.0 mL, 4.0 mmol). Air is bubbled through the mixture for 5 minutes. The flask is covered and heated at 80°C for 16 hours. The reaction is cooled to room temperature and poured into water. This is extracted three times with EtOAc. The combined organic extracts are washed with brine, dried (Na2SO4), filtered and concentrated to dryness. The crude product is purified by flash chromatography on silica gel eluting with 1-5% MeOH in DCM to provide 290 mg of 2-[5-(4-hydroxy-tetrahydro-pyran-4-yl acid methyl ester) )-pyridin-3-yl]-benzo[1,4]dioxin-5-carboxylic acid.

[00096] Step C: The mixture of 2-[5-(4-hydroxy-tetrahydro-pyran-4-yl)-pyridin-3-yl]-benzo[1,4]dioxin-5 acid methyl ester -carboxylic acid (100 mg, 0.3 mmol) and 10% palladium on carbon, type Degussa (50 mg) in 1 mL of acetic acid is degassed and placed under a hydrogen flask. The reaction is stirred at room temperature for 4 hours. The catalyst is extracted by filtration and washed with methanol. The filtrate is concentrated to dryness. The residue is diluted with EtOAc and washed with 1N NaOH and brine. The EtOAc layer is dried (Na2SO4), filtered and concentrated to dryness. The crude product is purified by flash silica gel column chromatography eluting with 1-5% MeOH in DCM to provide 60 mg of 2-[5-(4-hydroxy-tetrahydro-acid) methyl ester. pyran-4-yl)-pyridin-3-yl]-2,3-dihydro-benzo[1,4]dioxin-5-carboxylic acid.

[00097] Step D: The mixture of 2-[5-(4-hydroxy-tetrahydro-pyran-4-yl)-pyridin-3-yl]-2,3-dihydro-benzo acid methyl ester [1,4]dioxin-5-carboxylic acid (400 mg, 1.1 mmol) and 7 N ammonia in methanol solution (3 mL, 20 mmol) is heated in a sealed tube at 70 ° C for 7 days. The reaction is concentrated to dryness. The residue is purified by flash chromatography on a Biotage KP-NH column (1-5% MeOH in DCM) to provide 300 mg of the title compound. Stereoisomers are separated using Chiral SFC.

[00098] Compound 2 in Table 1 is synthesized according to the procedure described in Example 1, substituting commercially available reagents or appropriate intermediates described previously. Example 2: 2-[5-(1) acid amide ,1-dioxo-1À6,-[1,2]thiazinan-2-ylmethyl)-pyridin-3-yl]-2,3-dihydro-benzo[1,4]dioxin-5-carboxylic acid (Compound 3, Table 1)

[00099] Step A: 2-(5-Bromo-pyridin-3-ylmethyl)-[1,2] thiazinane 1,1-dioxide (1.5 g, 5.0 mmol), bis(pinacolato)diboron ( 1.90 g, 7.5 mmoles), potassium acetate (1.96 g, 20.0 mmoles), [1,1'-bis(diphenylphosphine)ferrocene)dichloropalladium(II) (365.86 mg, 0. 5 mmol) and 16 mL of 1,4-dioxane are combined in a reaction vessel. The container receives argon discharge and is sealed. The mixture is stirred at 120°C for 2 hours and cooled to room temperature.

[000100] Step B: 2-Bromo-benzo[1,4]dioxin-5-carboxylic acid methyl ester (1.00 g, 3.7 mmoles) is added to a reaction mixture from step A, followed by 5.0 mL of 1,4-dioxane and 2 M aqueous sodium carbonate (3.7 mL, 7.4 mmol). The container is discharged with argon and sealed. The mixture is stirred at 100°C for 16 hours. The reaction mixture is diluted with EtOAc and water and filtered through diatomaceous earth. The layers are separated and the organic layer is washed with brine, dried over MgSO4, filtered and concentrated. The crude product is purified by flash column chromatography with silica gel eluting with EtOAc to provide 1.1 g of dioxo-1À6,-[1,2]thiazinan-2-ylmethyl)-pyridin-3-yl acid methyl ester ]-benzo[1,4]dioxin-5-carboxylic acid.

[000101] Step C: 2-[5-(1,1-dioxo-1À6,-[1,2] thiazinan-2-ylmethyl)-pyridin-3-yl]-benzo[1,4] acid methyl ester Dioxin-5-carboxylic acid (1.1 g, 2.6 mmol) and 7 N ammonia solution in MeOH (18.6 mL, 130.3 mmol) are combined in a pressure vessel. The container is sealed and stirred at 85°C for 16 hours. The resulting gray solid is filtered to provide 656 mg of 2-[5-(1,1-dioxo-1À6,-[1,2]thiazinan-2-ylmethyl)-pyridin-3-yl]-benzo[ acid amide 1,4]dioxin-5-carboxylic acid.

[000102] Step D: 2-[5-(1,1-dioxo-1À6,-[1,2]thiazinan-2-ylmethyl)-pyridin-3-yl]-benzo[1,4]dioxin acid amide -5-carboxylic acid (630 mg, 1.6 mmol), 50 mL of acetic acid and 10% palladium on carbon (167 mg, 0.16 mmol) are combined. The mixture is stirred in a hydrogen atmosphere for 3 hours at room temperature and the reaction mixture is filtered through diatomaceous earth. The filtrate is concentrated and the crude solid is purified by flash silica gel column chromatography eluting with 50-100% EtOAc/10% MeOH/EtOAc to provide 375 mg of the title compound. Stereoisomers are separated by Chiral SFC.

[000103] Compounds 4 to 27 and compounds 51 and 59 in Table 1 are synthesized according to the procedure for Example 2, substituting commercially available reagents or appropriate intermediates described previously.

[000104] Compound 28 in Table 1 is synthesized according to the procedure for Example 2, substituting the appropriate commercially available reagent and 33% Methylamine in ethanol for ammonia in methanol in Step C. Example 3: 2-[ 5-[2-(Dimethylamino)-2-oxo-ethyl]-3-pyridyl]-2,3-dihydro-1,4-benzodioxin-5-carboxamide (Compound 29, Table 1)

[000105] Step A: 2-(5-Bromo-3-pyridyl)-N,N-dimethyl-acetamide (0.8 g, 3.3 mmol), bis(pinacolato)diboron (1.0 g, 4, 1 mmoles), potassium acetate (1.3g, 13.2 mmoles), [1,1'-bis(diphenylphosphine)ferrocene) dichloropaladium(II) (0.24 g, 0.3 mmoles) and 37 mL of 1,4-dioxane are combined in a pressure vessel. The container is discharged with argon and sealed. The mixture is stirred at 120°C for 45 minutes and cooled to room temperature.

[000106] Step B: 2-Bromo-1,4-benzodioxin-5-carboxamide (0.9 g, 3.6 mmoles), [1,1'-bis(diphenylphosphine)ferrocene)dichloropalladium(II) (0. 12 g, 0.17 mmol) and 2 M aqueous sodium carbonate (3.3 mL, 6.6 mmol) are added to a reaction mixture from step A. The container is flushed with argon and sealed. The mixture is stirred at 100°C for 2 hours. The mixture is filtered through diatomaceous earth and washed with 10% MeOH in DCM (150 mL). The filtrate is concentrated. The resulting crude product is purified by flash silica gel column chromatography eluting with 0-6% MeOH in DCM as the gradient to provide 0.39 g of 2-[5-[2-(dimethylamino)-2-oxo -ethyl]-3-pyridyl]-1,4-benzodioxin-5-carboxamide.

[000107] Step C: To a pre-degassed solution of 2-[5-[2-(dimethylamino)-2-oxo-ethyl]-3-pyridyl]-1,4-benzodioxin-5-carboxamide (0.62 g, 1.8 mmol) in 49 ml of acetic acid are added 124 mg of 10% by weight palladium on carbon. The resulting mixture is evacuated and filled again with H2 (repeated twice). The mixture is then hydrogenated for 2 hours. The mixture is filtered through diatomaceous earth and washed with EtOAc. The filtrate is concentrated. The resulting residue is redissolved in EtOAc. Saturated NaHCO3 solution (20 mL) and water (10 mL) are added. The two layers are separated. The organic layer is extracted with EtOAc (4x50 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated. The resulting crude product is purified by flash silica gel column chromatography eluting with 0.10% MeOH in DCM to provide 0.43 g of 2-[5-[2-(dimethylamino)-2-oxo-ethyl]-3 -pyridyl]-2,3-dihydro-1,4-benzodioxin-5-carboxamide. Stereoisomers are separated by Chiral SFC.

[000108] Compounds 30 to 32 in Table 1 are synthesized according to the procedure for Example 3, substituting commercially available reagents or appropriate intermediates described previously.

[000109] Compound 33 in Table 1 is synthesized according to the procedure for Example 3, replacing 2-bromo-benzo[1,4]dioxin-5-carboxylic acid methylamide with 2-bromo-1,4-benzodioxin -5-carboxamide in Step B.Example 4: 2-[5-(2-Oxo-oxazolidin-3-ylmethyl)-pyridin-3-yl]-2,3-dihydro-benzo[1,4]dioxin -5-carbonitrile (Compound 34, Table 1)

[000110] To an amide solution of the acid 2-[5-(2-oxo-oxazolidin-3-ylmethyl)-pyridin-3-yl]-2,3-dihydro-benzo[1,4]dioxin- 5-carboxylic acid, compound 31, enantiomer A (35 mg, 0.10 mmol) into 2.0 mL of 1,4-dioxane is added pyridine (0.16 mL, 1.97 mmol) followed by trifluoroacetic anhydride ( 0.14 mL, 0.98 mmol). After 5 minutes, the reaction is poured into 7.5 mL of water and 7.5 mL of saturated NaHCO3 solution. The product is extracted into EtOAc (2x) and the combined organic phases are washed once with water and then dried (MgSO4). The organic phase is filtered and concentrated to provide the crude product which is purified by flash column chromatography on a Biotage KP-NH column eluting with methanol in DCM to provide 25 mg of the title compound.

[000111] Compounds 35 to 43 in Table 1 are synthesized according to the procedure for Example 4, substituting the appropriate compounds described previously. Chiral SFC is used to resolve enantiomers for the examples synthesized from racemic starting materials and conditions that can be found in Table 2. All other examples are prepared from enantiomerically pure starting materials.

[000112] Compound 44 in Table 1 is synthesized according to the procedures in Example 2 and Example 4, substituting the appropriate intermediate described previously. Example 5: 2-(5-ethoxy-pyridin-3-) acid amide il)-2,3-dihydro-benzo [1,4]dioxin-5-carboxylic acid (Compound 45, Table 1)

[000113] Step A: 2-(5-Benzyloxy-pyridin-3-yl)-benzo[1,4]dioxin-5-carboxylic acid methyl ester is synthesized from 3-benzyloxy-5-bromo-pyridine and 2-bromo-benzo[1,4]dioxin-5-carboxylic acid methyl ester according to the method of Example 2, steps A and B.

[000114] Step B: 2-(5-Benzyloxy-pyridin-3-yl)-benzo[1,4]dioxin-5-carboxylic acid methyl ester (500 mg, 1.3 mmol) is dissolved in 10 mL of DCM and 10 mL of methanol. Then 5% Pd on carbon (280 mg, 0.13 mmol) is added. A hydrogen balloon is attached to the reaction flask and the mixture is stirred in a hydrogen atmosphere for 1.5 hours. Then the mixture is filtered and the filtrate is concentrated to provide 375 mg of 2-(5-hydroxy-pyridin-3-yl)-2,3-dihydro-benzo[1,4]dioxin-5 acid methyl ester -carboxylic.

[000115] Step C: Ethanol (0.041 mL, 0.70 mmol), 2-(5-hydroxy-pyridin-3-yl)-2,3-dihydro-benzo[1,4]dioxin acid methyl ester -5-carboxylic acid (100 mg, 0.35 mmol) and triphenylphosphine (180 mg, 0.70 mmol) are dissolved in 3.0 mL of THF and diisopropyl azodicarboxylate (0.14 mL, 0.70 mmol) is added. The mixture is stirred for 5 hours and the solvent is removed. The residue is purified by flash column chromatography on silica gel to provide 79 mg of 2-(5-ethoxy-pyridin-3-yl)-2,3-dihydro-benzo[1,4] acid methyl ester 5-carboxylic dioxin.

[000116] Step D: Lithium hydroxide monohydrate (21 mg, 0.50 mmol) is dissolved in 1.0 mL of water and this solution is added to the 2-(5-ethoxy-pyridin-3) acid methyl ester solution -yl)-2,3-dihydro-benzo[1,4]dioxin-5-carboxylic acid (79 mg, 0.25 mmol) in 2.0 mL of 1,4-dioxane. The mixture is stirred for 64 hours and 0.3 ml of acetic acid is added. Then all solvents are removed and 25 mL of water is added. A solid is formed and is filtered, washed with more water and dried to provide 71 mg of 2-(5-ethoxy-pyridin-3-yl)-2,3-dihydro-benzo[1,4]dioxin-acid. 5-carboxylic.

[000117] Step E: 2-(5-ethoxy-pyridin-3-yl)-2,3-dihydro-benzo[1,4]dioxin-5-carboxylic acid (71 mg, 0.24 mmol) is dissolved in 2.0 mL of DMF and 1,1'-carbonyldiimidazole (77 mg, 0.48 mmol) is added. The mixture is heated to 60°C for 1 hour and is then cooled to room temperature. Then 28% aqueous ammonium hydroxide solution (0.33 mL, 2.4 mmol) is added and the mixture is stirred for another hour. Then 25 mL of water is added and a solid is formed. The solid is filtered, washed with more water and dried to provide 53 mg of the title product. The enantiomers of the title compound are separated using Chiral SFC.

[000118] Compounds 46 and 47 in Table 1 are synthesized according to the procedure for Example 5, replacing ethanol in Step C with appropriate commercially available alcohols. Example 6: 2-[5-(1-isobutyryl- piperidin-4-yloxy)-pyridin-3-yl]-2,3-dihydro-benzo[1,4]dioxin-5-carboxylic acid (Compound 48, Table 1)

[000119] Step A: 4-[5-(5-methoxycarbonyl-2,3-dihydro-benzo[1,4]dioxin-2-yl)-pyridin-3-yloxy]- acid tert-butyl ester Piperidine-1-carboxylic acid is synthesized according to Example 5, Step A through Step C, replacing the ethanol in Step C with commercially available 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester.

[000120] Step B: 4-[5-(5-methoxycarbonyl-2,3-dihydro-benzo[1,4]dioxin-2-yl)-pyridin-3-yloxy]- acid tert-butyl ester piperidine-1-carboxylic acid (380 mg, 0.80 mmol) is dissolved in 5.0 mL of DCM and 1.0 mL of trifluoroacetic acid is added. The mixture is stirred for 2 hours and all solvent is removed. EtOAc (30 mL) is added along with 10 mL of saturated aqueous NaHCO3 solution. The mixture is stirred for 10 min and the organic layer is separated and extracted with EtOAc. The organic layers are combined and concentrated to provide 300 mg of 2-[5-(piperidin-4-yloxy)-pyridin-3-yl]-2,3-dihydro-benzo[1,4] acid methyl ester 5-carboxylic dioxin.

[000121] Step C: 2-[5-(piperidin-4-yloxy)-pyridin-3-yl]-2,3-dihydro-benzo[1,4]dioxin-5-carboxylic acid methyl ester ( 300 mg, 0.80 mmol) is dissolved in 5.0 mL of DCM. Then isobutyryl chloride (0.16 mL, 1.52 mmol) and triethyl amine (0.28 mL, 2.04 mmol) are added. After the mixture is stirred for 16 hours, 5 mL of saturated aqueous NaHCO3 solution (5 mL) is added along with 15 mL of water and 15 mL of DCM. The mixture is stirred for 10 minutes and the organic layer is separated and extracted with DCM. The organic layers are combined and concentrated to provide the crude product. Purification by rapid column chromatography on silica gel yields 160 mg of 2-[5-(1-isobutyryl-piperidin-4-yloxy)-pyridin-3-yl]-2,3-dihydro acid methyl ester -benzo[1,4]dioxin-5-carboxylic acid.

[000122] Step D: Lithium hydroxide monohydrate (30 mg, 0.73 mmol) is dissolved in 1.0 mL of water and this solution is added to the 2-[5-(1-isobutyryl- piperidin-4-yloxy)-pyridin-3-yl]-2,3-dihydro-benzo[1,4]dioxin-5-carboxylic acid (160 mg, 0.36 mmol) in 2.0 mL of 1, 4-dioxane. The mixture is stirred for 64 hours and 3 mL of acetic acid is added along with 20 mL of EtO-Ac and 20 mL of water. The organic layer is separated and extracted with EtOAc. All organic layers are combined and concentrated to provide 110 mg of 2-[5-(1-isobutyryl-piperidin-4-yloxy)-pyridin-3-yl]-2,3-dihydro-benzo[1] acid. 4]dioxin-5-carboxylic acid.

[000123] Step E: 2-[5-(1-isobutyryl-piperidin-4-yloxy)-pyridin-3-yl]-2,3-dihydro-benzo[1,4]dioxin-5-carboxylic acid (110 mg, 0.26 mmol) is dissolved in 2.0 mL of DMF and 1,1'-carbonyldiimidazole (84 mg, 0.52 mmol) is added. The mixture is heated to 60°C for 1 hour and is then cooled to room temperature. Then 28% aqueous ammonium hydroxide solution (0.36 mL, 2.6 mmol) is added and the mixture is stirred for another hour. Then 25 mL of water are added and a solid is formed. The solid is filtered, washed with more water and dried to provide 75 mg of the title product. The enantiomers of the title compound are separated using Chiral SFC. Example 7: 2-[5-(2,2,2-Trifluoro-1-hydroxy-ethyl)-pyridin-3-yl]-2 acid amide, 3-dihydro-benzo[1,4]dioxin-5-carboxylic acid (Compound 49, Table 1)

[000124] Step A: 2-[5-(2,2,2-trifluoro-1-hydroxy-ethyl)-pyridin-3-yl]-benzo[1,4]dioxin-5-carboxylic acid amide is prepared starting from 1-(5-bromo-pyridin-3-yl)-2,2,2-trifluoro-ethanol and 2-bromo-benzo[1,4]dioxin-5-carboxylic acid methyl ester according to Example 2, Step A through Step C. The enantiomers are separated using Chiral SFC (LUX Cellulose-2, 30%(1:1:1 MeOH:EtOH:i-PrOH+0.1% DEA):CO2, 70 mL /min, 120 bar, 35°C).

[000125] Step B: 2-[5-(2,2,2-trifluoro-1-hydroxy-ethyl)-pyridin-3-yl]-benzo[1,4]dioxin-5-carboxylic acid amide, enantiomer A (125 mg, 0.36 mmol) is hydrogenated according to Example 2, Step D to provide 90 mg of product. The Chiral SFC of this material provides 14 mg of 49AA and 14 mg of 49AB.

[000126] Step C: 2-[5-(2,2,2-trifluoro-1-hydroxy-ethyl)-pyridin-3-yl]-benzo[1,4]dioxin-5-carboxylic acid amide, enantiomer B (120 mg, 0.34 mmol) is hydrogenated according to Example 2, Step D to provide 90 mg of product. The Chiral SFC of this material provides 13 mg of 49BA and 15 mg of 49BB.Example 8: 2-[5-(4-Hydroxy-tetrahydro-pyran-4-yl)-pyridin-3-yl]-2,3 -dihydro-benzo[1,4]dioxin-5-carbonitrile, (Compound 50, Table 1)

[000127] A mixture of 2-[5-(4-hydroxy-tetrahydro-pyran-4-yl)-pyridin-3-yl]-2,3-dihydro-benzo[1,4] acid ]dioxin-5-carboxylic acid, enantiomer B (40 mg, 0.1 mmol) and Palladium(II) chloride (20 mg, 0.1 mmol) in 1 mL of 1:1 ACN:Water is heated in a sealed flask at 50°C for 16 hours. The mixture is allowed to cool and water is added. The resulting precipitate is filtered off and dried. The solid is dissolved in 10% water in DMSO and purified by prep HPLC. The fractions are concentrated to dryness to provide 8 mg of the title compound.Example 9: 2-(7-Hydroxy-6,7-dihydro-5H-[2]pyrindin-4-yl)-2 acid amide ,3-dihydro-benzo[1,4]dioxin-5-carboxylic acid (Compound 52, Table 1)

[000128] Step A: 2-(7-hydroxy-6,7-dihydro-5H-[2]pyrindin-4-yl)-benzo[1,4]dioxin-5-carboxylic acid methyl ester is synthesized starting from 4-bromo-6,7-dihydro-5H-[2]pyrindin-7-ol and 2-bromo-benzo[1,4]dioxin-5-carboxylic acid methyl ester according to Example 2 , Steps A and B. The enantiomers are separated using SFC (LUX Cellulose-1, 45%(MeOH)CO2, 125 mL/min, 120 bar, 40°C).

[000129] Step B: 2-(7-hydroxy-6,7-dihydro-5H-[2]pyrindin-4-yl)-benzo[1,4]dioxin-5-carboxylic acid methyl ester, enantiomer A is converted to the title compound according to Example 2, Steps C and D. Chiral SFC provides 52AA and 52AB.

[000130] Step C: 2-(7-hydroxy-6,7-dihydro-5H-[2]pyrindin-4-yl)-benzo[1,4]dioxin-5-carboxylic acid methyl ester, enantiomer B is converted to the title compound according to Example 2, Steps C and D. Chiral separation using SFC yields 52BA and 52BB.Example 10: N-[5-(5-Cyano-2,3-dihydro -benzo[1,4]dioxin-2-yl)-pyridin-3-ylmethyl]-2,2,2-trifluoroacetamide (Compound 53, Table 1) and [5-(5-cyano-2,3- ethanesulfonic acid dihydro-benzo[1,4]dioxin-2-yl)-pyridin-3-ylmethyl]-amide (54, Table 1)

[000131] Step A: 2-Bromo-benzo[1,4]dioxin-5-carboxylic acid methyl ester and (5-bromo-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester are converted into [5-(5-Carbamoyl-2,3-dihydro-benzo[1,4]dioxin-2-yl)-pyridin-3-ylmethyl]-carbamic acid tert-butyl ester according to Example 2, Step A to Step D.

[000132] Step B: [5-(5-Carbamoyl-2,3-dihydro-benzo[1,4]dioxin-2-yl)-pyridin-3-ylmethyl]-carbamic acid tert-butyl ester is converted to [5-(5-cyano-2,3-dihydro-benzo[1,4]dioxin-2-yl)-pyridin-3-ylmethyl]-carbamic acid tert-butyl ester according to Example 4.

[000133] Step C: [5-(5-cyano-2,3-dihydro-benzo[1,4]dioxin-2-yl)-pyridin-3-ylmethyl]-carbamic acid tert-butyl ester ( 140 mg, 0.4 mmol) is dissolved in 5 mL of DCM. Trifluoroacetic acid (0.5 mL) is added and the reaction mixture is stirred at room temperature for 2 hours. The solvent is removed to provide 100 mg of 2-(5-aminomethyl-pyridin-3-yl)-2,3-dihydro-benzo[1,4]dioxin-5-carbonitrile. Crude 2-(5-Aminomethyl-pyridin-3-yl)-2,3-dihydro-benzo[1,4]dioxin-5-carbonitrile (100 mg, 0.4 mmol) containing residual trifluoroacetic acid is dissolved in 5 mL of THF. N,N-Diisopropylethylamine (0.12 mL, 0.8 mmol) and ethanesulfonyl chloride (75 μL, 0.8 mmol) are added. The reaction mixture is stirred at room temperature for two hours. It is then concentrated to dryness and is purified by flash chromatography on a Biotage KP-NH column eluting with EtAOc in heptanes to give 26 mg of 53 and 40 mg of [5-(5-cyano-2,3-di- hydro-benzo[1,4]dioxin-2-yl)-pyridin-3-ylmethyl]-ethanesulfonic acid amide (54). The enantiomers of 54 are separated using Chiral SFC.Example 11: 2-{5-[2-((R)-3-Hydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-pyridin-3-yl} - 2,3-dihydro-benzo[1,4]dioxin-5-carbonitrile (Compound 55, Table 1)

[000134] Step A: Ester (R)-3-{2-[5-(5-cyano-2,3-dihydro-benzo[1,4] dioxin-2-yl)-pyridin-3-yl ]-acetyl}-cyclopentyl trifluoromethanesulfonic acid is prepared from 2-(5-bromo-pyridin-3-yl)-1-((R)-3-hydroxy-pyrrolidin-1-yl)-ethanone and 2-bromo-benzo[1,4]dioxin-5-carboxylic acid methyl ester according to Example 2, Step A to Step D and Example 4.

[000135] Step B: To the ester (R)-3-{2-[5-(5-cyano-2,3-dihydro-benzo [1,4]dioxin-2-yl)-pyridin-3- yl]-acetyl}-cyclopentyl trifluoromethanesulfonic acid (140 mg, 0.30 mmol) in 5 mL of 1:1 THF:water lithium hydroxide (72 mg, 3.0 mmol) is added. The reaction is stirred at room temperature for 16 hours. The reaction is concentrated to dryness and the residue is partitioned between EtOAc and water. The EtOAc layer is concentrated to dryness and the residue is purified by silica gel chromatography to provide 90 mg of the title racemic compound. The enantiomers of 55 are separated using Chiral SFC.Example 12: 2-[5-Fluoro-4-((S)-1-hydroxy-ethyl)-pyridin-3-yl]-2,3-di-acid amide hydro-benzo[1,4]dioxin-5-carboxylic acid (Compound 56, Table 1)

[000136] Step A: 3-Bromo-5-fluoro-pyridine (13 g, 74 mmol) is dissolved in 140 mL of dry THF and cooled to -78°C. LDA solution (44 mL, 2.0 M in THF, 88 mmol) is added and the mixture is stirred for 2 hours at -78°C. Then acetaldehyde solution (30 mL, 5.0 M in THF, 150 mmol) is added at -78°C and the reaction is continued for a further 30 minutes. Then saturated aqueous NH4Cl solution (200 mL) is added and the mixture is warmed to room temperature. EtOAc (100 mL) is added along with 75 mL of water. The organic layer is separated and extracted with EtOAc (2x75 mL). The organic layers are combined and concentrated to provide the crude product. Purification by rapid column chromatography yields 14 g of racemic product. Chiral separation of the racemic product using Chiral SFC yields 6.5 g of (R)-1-(3-bromo-5-fluoro-pyridin-4-yl)-ethanol and 6.4 g of (S)-1- (3-bromo-5-fluoro-pyridin-4-yl)-ethanol.

[000137] Step B: A solution of (S)-1-(3-bromo-5-fluoro-pyridin-4-yl)-ethanol (1.62 g, 7.4 mmol) in 25 mL of THF is cooled at 0°C and 60% sodium hydride (736.23 mg, 18.4 mmol) is then added. The mixture is stirred at 0°C for 1 hour and then cooled to -78°C. n-Butyl lithium at 1.08 M in hexanes (10.23 mL, 11.0 mmoles) is added, followed by triisopropyl borate (2.55 mL, 11.0 mmoles). The cooling bath is removed and the mixture is stirred at room temperature for 16 hours. The reaction mixture is cooled to 0°C and then quenched with 5.0 mL of 1:1 conc. H2SO4:water solution. The mixture is stirred at room temperature for 1 hour. The organic solvent is evaporated and the organic layer is then neutralized to pH 6-7. The organic layer is extracted with EtOAc (3X) and the combined organic layers are washed with brine, dried over MgSO4, filtered and concentrated to provide (S)-4-fluoro-3-methyl-2-oxa-6-aza-1 -bora- crude indan-1-ol.

[000138] Step C: 2-Bromo-benzo[1,4]dioxin-5-carboxylic acid methyl ester (1.0 g, 3.7 mmoles), (S)-4-fluoro-3-methyl -2-oxa-6-aza- crude 1-bora-indan-1-ol (924 mg, 5.5 mmol), [1,1'-bis(diphenylphosphine)ferrocene)dichloropalladium(II) DCM complex (150 .63 mg, 0.18 mmol), 1,4-dioxane (15.00 mL) and 2.0 M Na2CO3 aqueous solution (3.69 mL, 7.4 mmol) are added to a pressure vessel. The container is discharged with argon, sealed and shaken at 100°C for 2 hours. The reaction mixture is cooled to room temperature, diluted with EtOAc and 25 mL of water and the mixture is filtered through diatomaceous earth. The filtrate layers are separated and the organic layer is washed with brine, dried over MgSO4, filtered and concentrated. Purification by rapid column chromatography with silica gel eluting with 50-100% EtOAc/heptane) provides 659 mg of 2-[5-fluoro-4-((S)-1-hydroxy-acid methyl ester ethyl)-pyridin-3-yl]-benzo[1,4]dioxin-5-carboxylic acid.

[000139] Step D: 2-[5-Fluoro-4-((S)-1-hydroxyethyl)-pyridin-3-yl]-benzo[1,4]dioxin-5-carboxylic acid methyl ester is converted to the title compound according to Example 2, Steps C and D. The benzodiozane enantiomers are separated by Chiral SFC.

[000140] Compound 57 in Table 1 is synthesized according to the procedure for Example 12, replacing (R)-1-(3-bromo-5-fluoro-pyridin-4-yl)-ethanol in Step B. Example 13: 2-[5-Fluoro-4-(1-hydroxy-1-methyl-ethyl)-pyridin-3-yl]-2,3-dihydro-benzo[1,4]dioxin-acid amide 5-carboxylic (Compound 58, Table 1)

[000141] Step A: To an amide solution of 2-[5-fluoro-4-(1-hydroxy-ethyl)-pyridin-3-yl]-2,3-dihydro-benzo[1,4] acid ]dioxin-5-carboxylic acid (compound 57) (632.00 mg, 2.0 mmol), and Dess-Martin periodinane (1.01 g, 2.4 mmol) in 35 mL of acetonitrile trifluoroacetic acid is added (0.15 mL, 2.0 mmol). The heterogeneous mixture is stirred at room temperature for 2 days. The reaction mixture is diluted with 150 mL of 15% MeOH/DCM. 1N NaOH and 2M Na2S2O3 are added and the mixture is filtered. The layers are separated and the organic layer is concentrated. Purification by flash column chromatography with silica gel eluting with 50-100% EtOAc/heptane provides 550 mg of 2-(4-acetyl-5-fluoro-pyridin-3-yl)-2,3- acid amide dihydro-benzo[1,4]dioxin-5-carboxylic acid.

[000142] Step B: An amide solution of 2-(4-acetyl-5-fluoro-pyridin-3-yl)-2,3-dihydro-benzo[1,4]dioxin-5-carboxylic acid ( 440.00 mg, 1.4 mmol) in 44 mL of THF is cooled to 0 ° C and then treated with 2.0 M methylmagnesium bromide solution in THF (2.3 mL, 6.6 mmol). The mixture is stirred at 0°C for 30 minutes. The reaction mixture is quenched with saturated aqueous NH4Cl solution and diluted with EtOAc/water. The organic layer is separated and extracted again with EtOAc. The combined organic layers are washed with brine, dried over MgSO4, filtered and concentrated. Purification by column chromatography on a Biotage KP-NH column eluting with 50-100% EtOAc provides 125 mg of the title compound. The enantiomers are separated using Chiral SFC.Example 14: 2-[5-(Cyclopropyl-ethanesulfonylamino-methyl)-pyridin-3-yl]-benzo[1,4]dioxin-5-carboxylic acid amide (Compound 60, Table 1)

[000143] Step A: To a mixture of 5-bromonicotinaldehyde (0.50 g, 2.69 mmoles) and ethanesulfonamide (0.37 g, 3.36 mmoles) in 9.0 mL of toluene is added titanium isopropoxide( IV) (1.59 mL, 5.4 mmol). The reaction mixture is stirred at 120°C for 3 hours thereafter and is concentrated to dryness. The remainder of the residue is dissolved in 10 mL of THF and cooled to -40°C. Cyclopropylmagnesium bromide (16.13 mL, 8.1 mmoles) is added dropwise and the reaction mixture is allowed to gradually warm to room temperature. After 16 hours, the reaction mixture is diluted with EtOAc and washed with saturated aqueous NH4Cl solution and then brine. The organic layer is dried (MgSO4), filtered and concentrated. The remainder of the residue is purified by flash silica gel column chromatography eluting with 0-5% MeOH/DCM to provide 0.59 g of [(5-bromo-pyridin-3-yl)-cyclopropyl-methyl] -ethanesulfonic acid amide.

[000144] Step B: [(5-Bromo-pyridin-3-yl)-cyclopropyl-methyl]-ethanesulfonic acid amide and 2-bromo-benzo [1,4]dioxin-5-carboxylic acid methyl ester are converted in 2-[5-(cyclopropyl-ethanesulfonylamino-methyl)-pyridin-3-yl]-benzo[1,4]dioxin-5-carboxylic acid amide according to Example 2, Steps A-C. The enantiomers are separated using SFC (Regis (S,S) Whelk-O 1.40%(EtOH+1% Isopropylamine):CO2, 80 mL/min, 100 bar, 25°C).

[000145] Step C: 2-[5-(Cyclopropyl-ethanesulfonylamino-methyl)-pyridin-3-yl]-benzo[1,4]dioxin-5-carboxylic acid amide, enantiomer A is hydrogenated from according to Example 2, Step D. Chiral SFC produces 60AA and 60AB.

[000146] Step D: 2-[5-(Cyclopropyl-ethanesulfonylamino-methyl)-pyridin-3-yl]-benzo[1,4]dioxin-5-carboxylic acid amide, enantiomer B is hydrogenated from according to Example 2, Step D. Chiral SFC produces 60BA and 60BB. Example 15: 2-(5-Cyano-4-methyl-pyridin-3-yl)-2,3-dihydro acid amide - benzo[1,4]dioxin-5-carboxylic acid (Compound 61, Table 1)

[000147] Step A: To a stirred suspension of 5-bromo-4-methyl-nicotinic acid (1.75 g, 8.10 mmol) in 20 mL of DMF is added CDI (1.97 g, 12.2 mmol ). The mixture is heated to 65oC for 0.75 hour after which period of time it is cooled to room temperature and treated with ammonium hydroxide (10.1 mL, 81.0 mmol). After stirring for 2 hours the reaction is poured into water (150 mL) and the product is extracted into EtOAc (3x). The combined organic phases are dried (MgSO4), filtered and concentrated. The crude residue is purified by flash silica gel column chromatography eluting with 0-6% MeOH/DCM to provide 1.4 g of 5-bromo-4-methyl-nicotinamide.

[000148] Step B: 5-Bromo-4-methyl-nicotinamide and 2-bromo-benzo[1,4]dioxin-5-carboxylic acid methyl ester are converted into 2-(5-carbamoyl-4 acid methyl ester -methyl-pyridin-3-yl)-2,3-dihydro-benzo[1,4]dioxin-5-carboxylic acid according to Example 1, Steps A-C

[000149] Step C: To a stirred solution of 2-(5-carbamoyl-4-methyl-pyridin-3-yl)-2,3-dihydro-benzo[1,4]dioxin-5 acid methyl ester - carboxylic acid (180 mg, 0.55 mmol) in 10.0 mL of 1,4-dioxane and pyridine (0.89 mL, 10.9 mmol) trifluoroacetic anhydride (0.77 mL, 5.5 mmol) is added dripped over 10 minutes. After complete addition the reaction is stirred for 5 minutes after which it is poured into water and NaHCO3 (sat., 1:1, 150 mL). The mixture is diluted with EtOAc and the layers are separated. The organic layer is washed once with water and then dried (MgSO4). Filtration and concentration yielded 160 mg of 2-(5-cyano-4-methyl-pyridin-3-yl)-2,3-dihydro-benzo[1,4]dioxin-5-carboxylic acid methyl ester .

[000150] Step D: A suspension of 2-(5-cyano-4-methyl-pyridin-3-yl)-2,3-dihydro-benzo[1,4]dioxin-5-carboxylic acid methyl ester (160 mg, 0.52 mmol) in 7 N ammonia in methanol (5.0 mL, 35.0 mmol) is heated to 85oC. After 24 hours the reaction is cooled to room temperature and concentrated. The remainder of the crude compound is purified by flash column chromatography on a Biotage KP-NH column eluting with DCM to provide 70 mg of the title compound. The enantiomers were separated using SFC.Example 16: 2-(5-{[Imino(methyl)oxo-À6-sulfanyl]methyl}pyridin-3-yl)-2,3-dihydro-1,4-benzodioxin- 5-carbonitrile (Compound 62, Table 1)

[000151] Step A: (2-(5-hydroxymethyl-pyridin-3-yl)-2,3-dihydro-benzo[1,4]dioxin-5-carboxylic acid methyl ester is synthesized starting from (5 -bromo-pyridin-3-yl)-methanol and 2-bromo-benzo[1,4]dioxin-5-carboxylic acid methyl ester according to Example 1, steps A to C. The enantiomers are separated by Chiral SFC (Chiracel-OJ-H, 0.5% DEA in methanol, 100 mL/min, 100 bar, 25°C).

[000152] Step B: To a cooled solution (0°C) of acid methyl ester (2-(5-hydroxymethyl-pyridin-3-yl)-2,3-dihydro-benzo[1,4]dioxin -5-carboxylic acid, enantiomer B (1.80 g, 6.0 mmol) and triphenylphosphine (1.88 g, 7.2 mmol) in 50 mL of DCM is added carbon tetrabromide (2.38 g, 7.2 mmoles).The reaction is stirred for 30 minutes after which the mixture is concentrated in vacuo. The crude residue is purified by flash silica gel column chromatography eluting with 10-100% EtOAc/heptane to give 1.3 g of 2-(5-bromomethyl-pyridin-3-yl)-2,3-dihydro-benzo[1,4]dioxin-5-carboxylic acid methyl ester, enantiomer B.

[000153] Step C: A solution of 2-(5-bromomethyl-pyridin-3-yl)-2,3-dihydro-benzo[1,4]dioxin-5-carboxylic acid methyl ester, enantiomer B ( 1.3 g, 3.6 mmoles) in 35 mL of DMF is treated with sodium thiomethoxide (325 mg, 4.6 mmoles) and potassium carbonate (987 mg, 7.1 mmoles) and stirred at room temperature throughout at night. After this time, the reaction is filtered and the solids are washed with DCM. The combined filtrates are concentrated and the remainder of the residue is purified by flash silica gel column chromatography eluting with 0-8% MeOH in DCM to provide 1 g of 2-(5-methylsulfanylmethyl-pyridin-acid methyl ester). 3-yl)-2,3-dihydro-benzo[1,4]dioxin-5-carboxylic acid, enantiomer B.

[000154] Step D: To a stirred solution at 0°C of 2-(5-methylsulfanylmethyl-pyridin-3-yl)-2,3-dihydro-benzo[1,4]dioxin-5 acid methyl ester -carboxylic acid, enantiomer B (1.00 g, 3.0 mmol) in 45 mL of chloroform is added 3-chloroperoxybenzoic acid (593 mg, 2.4 mmol) in 4 additions over 20 minutes. The reaction is stirred for 15 minutes at 0°C and treated with triethylamine (1.5 ml) and concentrated. The remainder of the residue is purified by flash chromatography on a Biotage KP-NH column eluting with 10-100% EtOAc/heptane to provide 600 mg of 2-(5-methanesulfinylmethyl-pyridin-3-yl acid methyl ester )-2,3-dihydro-benzo[1,4]dioxin-5-carboxylic acid, mixture of BA and BB diastereoisomers.

[000155] Step E: To a solution of 2-(5-methanesulfinylmethyl-pyridin-3-yl)-2,3-dihydro-benzo[1,4]dioxin-5-carboxylic acid methyl ester, diastereoisomers BA and BB (600 mg, 1.7 mmol) in 30 mL of DCM are sequentially added 2,2,2-trifluroacetamide (390 mg, 3.5 mmol), magnesium oxide (278 mg, 6.9 mmoles), rhodium(II) actate dimer (53 mg, 0.1 mmol) and iodobenzene diacetate (835 mg, 2.6 mmoles). The reaction is allowed to stir at room temperature for 17 hours. After this time, the reaction is reloaded with the reactants using the original equivalents. After stirring overnight at room temperature the reaction is filtered and the solids are washed with DCM. The combined filtrates are concentrated and the remainder of the crude residue is purified by flash silica gel column chromatography eluting with 5-100% EtO-Ac/heptane to provide 160 mg of 2-(5-{[methyl (oxo)[(trifluoroacetyl)imino]-À6-sulfanyl]methyl}pyridin-3-yl)-2,3-dihydro-1,4-benzodioxin-5-methyl carboxylate, mixture of BA and BB diastereoisomers.

[000156] Step F: A 20 mL microwave reaction vessel is charged with 2-(5-{[methyl(oxo)[(trifluoroacetyl)imino]-À6-sulfanyl]methyl} pyridine-3-yl) Methyl -2,3-dihydro-1,4-benzodioxin-5-carboxylate, BA and BB diastereoisomers (160 mg, 0.4 mmol) and 7 N ammonia in methanol (8 mL). The container is covered and heated at 85°C for 2 days. After this time the reaction is cooled and concentrated. The crude compound is purified by HPLC (5-60% ACN/H2O, 20 minutes, TFA-modified solvents) and the product-containing fractions are concentrated to give 2-(5-{[imino(methyl)oxo- À6-sulfanyl]methyl} pyridin-3-yl)-2,3-dihydro-1,4-benzodioxin-5-carboxamide, mixture of BA and BB diastereoisomers.

[000157] Step G: A mixture of 2-(5-{[imino(methyl)oxo-À6-sulfanyl]methyl}pyridin-3-yl)-2,3-dihydro-1,4-benzodioxin- 5-carboxamide, diastereoisomers BA and BB (220 mg, 0.5 mmol) in 25 mL of dioxane are added pyridine (0.77 mL, 9.5 mmol) and trifluoroacetic anhydride (0.67 mL, 4 .8 mmoles) in drops. The reaction is stirred at room temperature for 15 minutes after which the reaction is concentrated to dryness. The remainder of the residue is treated with 7N MeOH in ammonia (50 mL) and the mixture is concentrated. The remainder of the residue is purified via HPLC (10-100% CH3CN/H2O over 20 minutes, 0.1% TFA) to provide 70 mg of 2-(5-{[imino(methyl)oxo-À6 -sulfanyl]methyl}pyridin-3-yl)-2,3-dihydro-1,4-benzodioxin-5-carbonitrile. The BA and BB diastereoisomers are resolved by Chiral SFC to produce 62BA and 62BB.

[000158] Step H: (2-(5-hydroxymethyl-pyridin-3-yl)-2,3-dihydro-benzo[1,4]dioxin-5-carboxylic acid methyl ester, enantiomer A is converted into 2-(5-{[imino(methyl)oxo-À6-sulfanyl]methyl}pyridin-3-yl)-2,3-dihydro-1,4-benzodioxin-5-carbonitrile, mixture of AA and AB diastereoisomers according to the previous procedure, Example 16, Steps B to G. Diastereomers AA and AB are resolved by Chiral SFC to produce 62AA and 62BB. Table 2: Chiral SFC Separation Conditions Table 3: LC/MS Methods Continuation Table 4: LC/MS Data

ASSESSMENT OF BIOLOGICAL ACTIVITY Preparation of cynomolgus monkey adrenal mitochondria

[000159] Aldosterone synthase and cortisol synthase inhibition assays employ cynomolgus monkey adrenal gland mitochondria as the source of aldosterone synthase (CYP11B2) and cortisol synthase (CYP11B1). Mitochondria are prepared from frozen cynomolgus monkey adrenal glands according to Method A described by J.D. McGarry et al. (Biochem. J., 1983, 214, 21-28), with a final resuspension in buffer AT described in R. Yamaguchi and others (Cell Death and Differentiation, 2007, 14, 616-624), frozen as aliquots in liquid nitrogen and stored at -80oC until use. The activity of CYP11B2 and CYP11B1 in these preparations is defined as the amount of enzyme that generates 1 pmol of product in one hour under the conditions described.

Aldosterone Synthase Inhibition

[000160] The compounds of the invention can be evaluated in relation to the inhibition of aldosterone synthase through the following assay:

[000161] The assays are carried out in a 96-well format in a final volume of 60 μL/well, containing 100 mM potassium phosphate, pH 7.4, 1% (v/v) DMSO and additionally, 2 μM of corticosterone and 50 units of CYP11B2 activity. Reactions are initiated by adding 1 mM NADPH and allowed to continue for 90 minutes at 37°C. Reactions are terminated by adding 60 μL of MeCN which contains an internal standard for mass spectrometry. One hundred microliters is then transferred to a glass filter plate and centrifuged at 570 x g for 5 minutes and the filtrate is collected. The aldosterone reaction product is quantified by mass spectrometry. To determine the assay blank value (0% activity), NADPH is omitted from some reactions.

[000162] Dose-dependent inhibition is quantified by including the compound at various concentrations. Maximum activity (100%) is defined by reactions that contain NADPH, but without the compound. The activities at each concentration are expressed as a percentage of the maximum activity (y axis) and are represented graphically against the compound concentration (x axis) and the concentration that corresponds to 50% of the activity (IC50) is determined using the program XLFit curve fitting model using a 4-parameter logistic model.

Inhibition of Cortisol Synthesis

[000163] The assays are performed as for aldosterone synthase except that 150 units of CYP11B1, 11-deoxycortisol are used as the substrate and cortisol is measured as the product.

[000164] Representative compounds of the present invention were tested for activity in previous assays. Preferred compounds have an IC50 < 1,000 nM and most preferred compounds have an IC50 < 100 nM in this assay. As examples, data for representative compounds from Table 1 are shown in Table 5. Data for individual enantiomers are indicated by separate entries for enantiomers A and B. Table 5: Biological Data

METHODS OF THERAPEUTIC USE

[000165] According to the invention, new methods of using the compounds of formula (I) are provided. The compounds disclosed herein efficiently inhibit aldosterone synthase. Inhibition of aldosterone synthase is an attractive means of preventing and treating a variety of diseases or health conditions that can be alleviated by reducing aldosterone levels. Thus, the compounds are useful for treating diseases and health conditions that are described in the Background section, including the following health states and diseases: Diabetic kidney disease including diabetic nephropathy; Non-diabetic kidney disease including glomerulosclerosis, glomerulonephritis, IGA nephropathy, nephritic syndrome and focal segmental glomerulosclerosis (FSGS); Cardiovascular diseases including hypertension, pulmonary arterial hypertension, Conn syndrome, systolic heart failure, diastolic heart failure, left ventricular dysfunction, left ventricular stiffness and fibrosis, left ventricular filling abnormalities, arterial stiffness, atherosclerosis, and cardiovascular morbidity associated with hyperaldosteronism primary or secondary; Adrenal hyperplasia and primary and secondary hyperaldosteronism.

[000166] These disorders have been well characterized in humans, but also exist with a similar etiology in other mammals and can be treated by pharmaceutical compositions of the present invention.

[000167] Consequently, a compound of formula I according to any of the embodiments described herein or a pharmaceutically acceptable salt thereof can be used for the preparation of a medicament for the treatment of a disease or a disorder mediated by aldosterone synthase , including diabetic nephropathy, glomerulosclerosis, glomerulonephritis, IGA nephropathy, nephritic syndrome focal segmental glomerulosclerosis (FSGS), hypertension, pulmonary arterial hypertension, Conn syndrome, systolic heart failure, diastolic heart failure, left ventricular dysfunction, ventricular stiffness and fibrosis left ventricle filling abnormalities, arterial stiffness, atherosclerosis and cardio-vascular morbidity associated with primary or secondary hyperaldosteronism, adrenal hyperplasia and primary and secondary hyperaldosteronism.

[000168] For therapeutic use, the compounds of the invention can be administered through a pharmaceutical composition in any conventional pharmaceutical dosage form in any conventional manner. Conventional dosage forms typically include a pharmaceutically acceptable carrier suitable for the particular dosage form selected. Routes of administration include, but are not limited to, intravenous, intramuscular, subcutaneous, intrasynovial, infusion, sublingual, transdermal, oral, topical or inhalation. The preferred modes of administration are oral and intravenous.

[000169] The compounds of this invention can be administered individually or in combination with adjuvants that increase the stability of the inhibitors, facilitate the administration of pharmaceutical compositions containing them in certain embodiments, provide greater dissolution or dispersion, increase the inhibition activity, provide adjunct therapy and the like, including other active ingredients. In one embodiment, for example, various compounds of the present invention can be administered. Advantageously, such combination therapies use lower dosages of conventional therapeutic agents, thus avoiding toxicity and possible adverse side effects caused when such agents are used in the form of monotherapies. The compounds of the invention can be physically combined with conventional therapeutic agents or other adjuvants in a single pharmaceutical composition. Advantageously, the compounds can then be administered together in a single dosage form. In some embodiments, pharmaceutical compositions comprising such combinations of compounds contain at least approximately 5%, but more preferably at least approximately 20%, of a compound of formula (I) (w/w) or a combination thereof. The optimum percentage (w/w) of a compound of the invention may vary and is within the competence of those skilled in the art. Alternatively, the compounds of the present invention and conventional therapeutic agents or other adjuvants may be administered separately (sequentially or in parallel). Separate dosing allows for greater flexibility in dosing regimen.

[000170] As mentioned previously, dosage forms of the compounds of this invention may include pharmaceutically acceptable carriers and adjuvants known to those of ordinary skill in the art and suitable for the dosage form. These carriers and adjuvants include, for example, ion exchangers, alumina, aluminum stearate, lecithin, whey proteins, buffering substances, water, salts or electrolytes and cellulose-based substances. Preferred dosage forms include tablet, capsule, pill, liquid, solution, emulsion, lozenge, syrup, reconstitutable powder, granule, suppository and transdermal patch. Methods for preparing such dosage forms are known (see, for example, H.C. Ansel and N.G. Popovish, Pharmaceutical Dosage Forms and Drug Delivery Systems, 5th ed., Lea and Febiger (1990)). Dosage levels and requirements for the compounds of the present invention can be selected by those of ordinary skill in the art from available methods and techniques suitable for a particular patient. In some embodiments, dosage levels range from approximately 1-1000 mg/dose for a 70 kg patient. Although one dose per day may be sufficient, up to 5 doses per day may be provided. For oral doses, up to 2000 mg/day may be required. As one skilled in the art will appreciate, lower or higher doses may be necessary depending on particular factors. For example, specific dosage and treatment regimens will depend on factors such as the patient's general health profile, the severity and course of the patient's disorder or disposition, and the judgment of the attending physician.

Claims (21)

1. Compound, characterized by the fact that it presents Formula I: in which: R1 is selected from -C(O)NH2, -C(O)NH(CH3) and -CN; R2 is -(X)-R4, where -(X)- is a bond, -CH2- or -O-; and R4 is selected from - H; C1-3alkyl, optionally substituted by one of up to four groups selected from -F, -OH, and -SO2Ci—3alkyl; halogen; - CN; - SO2C1-3alkyl; - C(O)N(C1-3alkyl)2, as long as -(X)- is not -O-; - NHC(O)R5 or -N(CH3)C(O)R5, provided that -(X)- is -CH2- and wherein R5 is selected from C3-6cycloalkyl and C1-3alkyl optionally substituted by one to three groups -F; - NHSO2C1-3alkyl; - CH(cyclopropyl)NHSO2C1-3alkyl; - OCH2C(O)N(C1-3alkyl)2, as long as -(X)- is -CH2-; - S(=O)(=NH)CH3, as long as -(X)- is -CH2-; heterocyclyl selected from tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, 1,1-dioxo[1,2]-thiazine, morpholinyl, oxazolidinyl, piperidinyl, azetidinyl, wherein said heterocyclyl is optionally substituted by one of up to three groups selected from - C(O)C1-3alkyl, halogen, -OH, oxo and C1-3alkyl; -C(O)-heterocyclyl, provided that -(X)- is -CH2, wherein said heterocyclyl is selected from morpholin-4-yl, pyrrolidin-1-yl and piperidin-1-yl, optionally substituted by one or two groups selected from -F and -OH; C3-6cycloalkyl optionally substituted by -CN or -OH; and phenyl, optionally substituted by -SO2NH2; and R3 is H or C1-3alkyl optionally substituted by -OH; or R2 and R3 together form an annealed five-membered cycloalkyl ring optionally substituted by -OH; or a salt or stereoisomer thereof. 2. Compound according to claim 1, characterized by the fact that: R1 is -C(O)NH2 or -CN; R2 is -(X)-R4, where - (X)- is a bond and R4 is selected from - CH3; - CF3; - CHF2; - CH2OH; - CH(OH)CH3; - CH(OH)CF3; - F; - CN; heterocyclyl selected from tetrahydropyranyl and pyrrolidinyl, wherein said heterocyclyl is optionally substituted by one to three groups selected from C1-3alkyl, halogen, -OH and oxo; C3-6cycloalkyl optionally substituted by -CN or -OH; and phenyl, optionally substituted by -SO2NH2; or - (X)- is O and R4 is selected from C1-3alkyl; - CH2SO2C1-3alkyl; and heterocyclyl selected from tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl and azetidinyl, wherein said heterocyclyl is optionally substituted by one to three groups selected from -C(O)C1-3alkyl, halogen, -OH, oxo and C1-3alkyl; or X is (-CH2-) and R4 is selected from -SO2C1-3alkyl; - C(O)N(C1-3alkyl)2; - NHC(O)R5 or -N(CH3)C(O)R5, where R5 is selected from cyclopropyl and C1-3alkyl optionally substituted by one to three -F groups; - OCH2C(O)N(C1-3alkyl)2; - NHSO2C1-3alkyl; - S(=O)(=NH)CH3; heterocyclyl selected from pyrrolidinyl, 1,1-dioxo[1,2]-thiazine, morpholinyl and oxazolidinyl, wherein said heterocyclyl is optionally substituted by one to three groups selected from - C(O)C1-3alkyl, halogen, -OH , oxo and C1-3alkyl; and - C(O)-heterocyclyl, wherein the heterocyclyl is selected from morpholin-4-yl, pyrrolidin-1-yl and piperidin-1-yl, optionally substituted by one or two groups selected from -F and -OH; and R3 is H or C1-3alkyl optionally substituted by -OH; or a salt or stereoisomer thereof. 3. Compound according to claim 1 or 2, characterized by the fact that: R2 is -(X)-R4, wherein - (X)- is a bond and R4 is selected from - CF3; - CHF2; - CH2OH; - CH(OH)CH3; - CH(OH)CF3; - F; - CN; heterocyclyl selected from tetrahydropyranyl and pyrrolidinyl, wherein said heterocyclyl is replaced by one to three groups selected from C1-3alkyl, -F, -OH and oxo; C3-6cycloalkyl, substituted by -CN or -OH; and phenyl, optionally substituted by -SO2NH2; and R3 is H or C1-3alkyl optionally substituted by -OH; or a salt or stereoisomer thereof. 4. Compound according to any one of claims 1 to 3, characterized by the fact that: R2 is -(X)-R4, where -(X)- is O and R4 is selected from C1-3alkyl; -CH2SO2C1-3alkyl; and heterocyclyl selected from tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl and azetidinyl, wherein said heterocyclyl is optionally substituted by -C(O)C1-3alkyl; and R3 is H or C1-3alkyl optionally substituted by -OH; or a salt or stereoisomer thereof. 5. Compound according to any one of claims 1 to 4, characterized by the fact that: R2 is -(X)-R4, where X is (-CH2-) and R4 is selected from - SO2C1-3alkyl; - C(O)N(C1-3alkyl)2; - NHC(O)R5 or -N(CH3)C(O)R5, where R5 is selected from cyclopropyl and C1-3alkyl optionally substituted by one to three -F groups; - OCH2C(O)N(C1-3alkyl)2; - NHSO2C1-3alkyl; - S(=O)(=NH)CH3; heterocyclyl selected from pyrrolidinyl, 1,1-dioxo[1,2]-thiazine, morpholinyl and oxazolidinyl, wherein said heterocyclyl is optionally substituted by one to two groups selected from oxo and C1-3alkyl; and -C(O)-heterocyclyl, wherein the heterocyclyl is selected from morpholin-4-yl, pyrrolidin-1-yl and piperidin-1-yl, optionally substituted by one or two groups selected from -F and -OH; and R3 is H or C1-3alkyl optionally substituted by -OH; or a salt or stereoisomer thereof. 6. Compound according to any one of claims 1 to 5, characterized by the fact that: R1 is -C(O)NH2; or a salt or stereoisomer thereof. 7. Compound according to any one of claims 1 to 5, characterized by the fact that: R1 is -CN; or a salt or stereoisomer thereof. 8. Compound according to claim 1, characterized by the fact that it is selected from the group consisting of: or a pharmaceutically acceptable salt or stereoisomer thereof. 9. Compound according to claim 8, characterized by the fact that it is selected from the group consisting of: 10. Compound, according to claim 1, characterized by the fact that it is: 11. Compound, as characterized by the fact that it is: claim 1, characterized by the fact that it is: 12. Compound, according to claim 1, characterized by the fact that it is: 13. Compound, according to claim 1, characterized by the fact that it is: 14. Compound, according to claim 1, characterized by the fact that it is: 15. Compound, according to claim 1, characterized by the fact that it is: 16. Pharmaceutically acceptable salt, characterized by the fact that it is a salt of the compounds, as defined in any one of claims 1 to 15. 17. Pharmaceutical composition, characterized by the fact that it comprises a compound, as defined in any one of claims 1 to 15, and a pharmaceutically acceptable excipient or carrier. 18. Use of a compound as defined in any one of claims 1 to 15, characterized in that it is for the manufacture of a composition or medicine for the treatment of a disease or a disorder that can be alleviated through inhibition of aldosterone synthase. 19. Use of a compound, as defined in any one of claims 1 to 15, characterized by the fact that it is for the manufacture of a medicine or pharmaceutical composition for the patient who needs it for the treatment of a disease or a disorder, which can be relieved by inhibiting aldosterone synthase selected from diabetic nephropathy, glomerulosclerosis, glomerulonephritis, IGA nephropathy, nephritic syndrome, focal segmental glomerulosclerosis (FSGS), hypertension, pulmonary arterial hypertension, Conn syndrome, systolic heart failure, diastolic heart failure, left ventricular dysfunction, left ventricular stiffness and fibrosis, left ventricular filling abnormalities, arterial stiffness, atherosclerosis, and cardiovascular morbidity associated with primary or secondary hyperaldosteronism, adrenal hyperplasia, and primary and secondary hyperaldosteronism. 20. Use according to claim 19, characterized in that the disease or disorder is selected from diabetic nephropathy, glomerulosclerosis, glomerulonephritis, IGA nephropathy, nephritic syndrome and focal segmental glomerulosclerosis (FSGS). 21. Use according to claim 19, characterized by the fact that the disease is diabetic nephropathy.