APJ agonists

Abstract

The invention provides compounds having the general formula (I) A B (I) wherein A, B, X, Y, R1, R2, R3, R4, m, and n are as described herein, compositions including the compounds, processes of manufacturing the compounds and methods of sing the compounds in the treatment or prevention of diseases that are associated with obesity. ***

Description

[0001] F. Hoffmann-La Roche AG, CH-4070 Basel, Switzerland

[0002] Case: P60020-WO-1

[0003] APJ AGONISTS

[0004] Field of the Invention

[0005] The present invention relates to organic compounds useful for therapy or prophylaxis in a mammal, and in particular to APJ agonists for the treatment or prevention of diseases or disorders associated with obesity.

[0006] Background of the Invention

[0007] Obesity is now considered a chronic metabolic disorder with a prevalence expected to reach 1 billion globally by 2030 and has associated co -morbidities such as type-2 diabetes and heart failure. Current therapeutic options include GLP-1R agonists that suppress appetite to reduce caloric intake leading to highly significant body weight loss. Although GLP-1R agonists primarily drive weight loss via fat mass loss, up to 40% of weight loss also comes from muscle mass loss (Neeland et al. 2024 Diabetes Obes Metab. Suppl 4:16). Preserving muscle mass has the potential to improve basal metabolic rate, enhance overall weight loss and facilitate the maintenance of weight loss.

[0008] Apelin is an adipokine that engages the class A G-protein coupled receptor (GPCR) apelin receptor (APJ) to activate the G protein (cAMP, AKT, ERK, AMPK, PKC) and β-arrestin pathways leading to the modulation of a wide array of biological functions involved in cardiovascular, metabolic and central nervous system diseases (Li et al. 2022 Front. Endocrinol.

[0009] 13:820002). As expected for such diverse biological effects, apelin and APJ are broadly expressed in the lung, heart, kidney, vasculature, central nervous system, pancreas, skeletal muscle and adipose tissue. Apelin exists as several peptide isomers generated from the proteolytic processing of a 77-amino acid pre-propeptide that include apelin-12, apelin-13, apelin-17 and apelin-36, with apelin-13 and -36 considered the most active and physiologically relevant. In terms of heart failure, intravenous administration of apelin-13 has been shown to improve cardiac function in rodent models of heart failure as well as in patients with heart failure (Japp et al. 2010 Circulation. 121: 1818; Boal et al. 2016 Br J Pharmacol. 173:1850). The apelin / APJ axis also plays an important role in multiple metabolic pathways by increasingintestinal glucose absorption, cellular glucose uptake, mitochondrial biogenesis, fatty acid oxidation and lipolysis leading to improved insulin sensitivity, muscle hypertrophy and reduced adiposity. In this regard, apelin KO mice are more susceptible to weight gain and developing insulin resistance when fed on a high fat diet whereas mice transgenically overexpressing apelin or treated with APJ agonists are more resistant (Yue et al. 2010 Am J Physiol Endocrinol Metab.

[0010] 298:E59; Yamamoto et al. 2011 Biochim Biophys Acta. 1810:853). Accordingly, acute systemic apelin-13 administration in lean or obese / insulin resistant mice improves insulin sensitivity (Dray et al. 2008 Cell Metab. 8: 437). More importantly from a clinical perspective, intravenous infusion of apelin-13 into overweight human males improved insulin sensitivity as measured using a hyperinsulinaemic-euglycaemic clamp (Gourdy et al. Diabetes Obes Metab. 2018 20:157). With respect to muscle hypertrophy, a small molecule APJ agonist azelaprag prevented atrophy of the thigh muscle vastus lateralis caused by extended bed rest in elderly patients. In a mouse model of diet-induced obesity, although azelaprag treatment alone had no significant effect on body weight, a combination with a GLP-1R agonist gave a synergistic increase in body weight loss without a further reduction in food intake, indicating that the synergistic MoA of APJ agonism was not through appetite suppression but most likely via increased energy expenditure.

[0011] In view of the above, there is a high unmet need for new APJ agonists.

[0012] Summary of the Invention

[0013] In a first aspect, the present invention provides compounds of formula (I)

[0014]

[0015] wherein A, B, X, Y, R1, R2, R3, R4, m, and n are as defined herein.

[0016] In further aspects, the invention provides compositions including the compounds of formula (I), processes of manufacturing the compounds of formula (I) and methods of using the compounds of formula (I).Detailed Description of the Invention

[0017] Definitions

[0018] Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein, unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and / or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and / or steps are mutually exclusive. The invention is not restricted to the details of any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.

[0019] The term “GLP-1R agonist” refers to a compound which is capable of binding to the glucagon-like peptide 1 receptor (GLP-1R) and capable of activating it. In one embodiment, the GLP-1 receptor agonist is selected from albiglutide, exenatide, liraglutide, lixisenatide, semaglutide, and tirzepatide. In a preferred embodiment, the GLP-1 receptor agonist is semaglutide. In one embodiment, the GLP-1 receptor agonist is a dual-acting GLP-1 receptor agonist, and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist or glucagon receptor agonist. In one embodiment, the dual-acting GLP-1 receptor agonist is tirzepatide. In one embodiment, the GLP-1 receptor agonist is a triple-acting GLP-1 receptor agonist, GIP receptor agonist, and glucagon receptor agonist. In one embodiment, the triple-acting GLP-1 receptor agonist is retatrutide. In one embodiment, the GLP-1 receptor agonist is selected from albenatide, albiglutide, avexitide, cafraglutide, cotadutide, danuglipron, dapiglutide, diabegone, dulaglutide, ecnoglutide, efpeglenatide, efinopegdutide, efocipegtrutide, exenatide, exenatide biobetter, exenatide SR, froniglutide, liraglutide, liraglutide biobetter, lixisenatide, CT-868, efocipegtrutide, LY-3502970, maridebart, mazdutide, NLY-001, orforglipron, pegapamodutide, pemvidutide, retatrutide (LY-3437943), semaglutide, semaglutide injection, survodutide, vurolenatide, dapagliflozin + semaglutide, (cagrilintide + semaglutide), (LAL287 + semaglutide), (semaglutide + GIP analogue), 4P-004, AMG-133, AP-026, AZD-9550, BGM-0504, BMS-686117, Zn / BMS-686117 adduct, CT-388, CT-868, CT-996, DD-01, DR-10624, DR-10627, ECC-5004, E-2HSA, GL-0034, GLP-06, GMA-105, GMA-106, GMA-102, GSBR-1290, GXG-6, GZR-18, HEC-88473,HR-17031, HRS-7535, HRS-9531, HS-20004, HS-20094, HB-1085, HDM-1002, HL-08, HZ-010, JY-09, KN-056, LY-3493269, MBX-1416, MDR-001, MWN-101, NLY-001, NN-9490, NNC0519-0130, NN-6177, NN-9847, NN-9904, NN-6535 (semaglutide), NN-9932 (semaglutide), PF-06954522, PF-07081532, PF-06882961, PB-1023, PB-119, PB-718, RGT-075, SAL-015, SAL-0112, SCO-094, TERN-601, TTP-273, Uni-E4, VK-2735, YH-25724, XW-004, XW-014, YH-25724, YN-012, YN-015, ZT-002, and pharmaceutically acceptable salts thereof. In one embodiment, the GLP-1 receptor agonist is selected from (dorzagliatin + GLP-1), (exenatide + insulin aspart), ACT-1003, Adogel Serna, AER-601, AGM-212, BEBT-808, BZ-043B, C-2816, DAJC-1, DD-02, DR-10625, DR-10628, DS-004, DS-005, DS-006, DS-012, E-6, efpeglenatide + HM-12470, exenatide 2, exenatide LA, exenatide SR, Extendin-Fc, G-49, GB-7001, Gene Encoding GLP-1, GLP-1 Incretin Triagonist, GLP-1 Oral Preparation, GLP-1R Antagonist for Hypoglycemia, glucagon, Glucagon-Like Peptide- 1 + insulin human, GPCR-targeted Project 012, GPCR-targeted Project 013, GT-01123, HM-15275, HPG-5119, HSP-001, HSP-004, HSP-005, HSP012-C, Hydrogel Exenatide, I2O-105S, I2O-110, KP-405, LA-EX, liraglutide biobetter, liraglutide LA, MK-1462, MLX-7000, MWN-105, MWN-109, NLY-12, NPM-115, OGB- 21502, OXM, P-1 1, PB-2301, PB-2309, RGT-028, RGT-274, RPC-8844, RT-104, SHX-022, SL-209, synthetic peptides to agonize GLP-1R and CCKBR for diabetes, TB-013, TB-222023, TB-592, TE-8105, THDBH-111, UDS-003, VTCG-15, XL-110, XL-310, XW-003 +XW-015, XW-003 +XW-017, Y-002, YGX-1, ZT-003, ZT-006, ZT-007, DA-1726, HDM-1005, (insulin degludec + liraglutide), DB-081, GW-002, HZCX-012, ID-110521156, THDB-0211, THDBH-110, THDBH-120, THDBH-121, UBT-251, ATBB-22, BEM-012, CIN-209, CIN-210, DD-03, exenatide + ND-017, exenatide + Synthetic Peptide 2, glucagon, Insulin-GLP1, MD-02, OGB-21501, P-01, PAT-201, PF-1807, PT-3, and pharmaceutically acceptable salts thereof.

[0020] The term “alkyl” refers to a mono- or multivalent, e.g., a mono- or bivalent, linear or branched saturated hydrocarbon group of 1 to 6 carbon atoms (“Ci-6-alkyl”), e.g., 1, 2, 3, 4, 5, or 6 carbon atoms. In some embodiments, the alkyl group contains 1 to 4 carbon atoms, e.g., 1, 2, 3, or 4 carbon atoms. In other embodiments, the alkoxy group contains 1 to 3 carbon atoms. Some nonlimiting examples of alkyl include methyl, ethyl, propyl, 2-propyl (isopropyl), n-butyl, iso-butyl, sec-butyl, tert-butyl, and 2,2-dimethylpropyl. Particularly preferred, yet non-limiting examples of alkyl are methyl, tert-butyl, and 2,2-dimethylpropyl.

[0021] The term “alkoxy” refers to an alkyl group, as previously defined, attached to the parent molecular moiety via an oxygen atom. Unless otherwise specified, the alkoxy group contains 1to 6 carbon atoms (“Ci-6-alkoxy”). In some embodiments, the alkoxy group contains 1 to 4 carbon atoms, e.g., 1, 2, 3, or 4 carbon atoms. In other embodiments, the alkoxy group contains 1 to 3 carbon atoms. Some non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy. A particularly preferred, yet nonlimiting example of alkoxy is methoxy.

[0022] The term “halogen” or “halo” refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).

[0023] Preferably, the term “halogen” or “halo” refers to fluoro (F), chloro (Cl) or bromo (Br).

[0024] Particularly preferred, yet non-limiting examples of “halogen” or “halo” are fluoro (F) and chloro (Cl).

[0025] The term “cycloalkyl” as used herein refers to a saturated monocyclic or bicyclic hydrocarbon group of 3 to 10 ring carbon atoms (“C3-10-cycloalkyl”). In some preferred embodiments, the cycloalkyl group is a monocyclic hydrocarbon group of 3 to 8 ring carbon atoms. “Bicyclic cycloalkyl” refers to cycloalkyl moieties consisting of two saturated carbocycles having two carbon atoms in common, i.e., the bridge separating the two rings is either a single bond or a chain of one or two ring atoms, and to spirocyclic moieties, i.e., the two rings are connected via one common ring atom. Preferably, the cycloalkyl group is a monocyclic hydrocarbon group of 3 to 6 ring carbon atoms, e.g., of 3, 4, 5 or 6 carbon atoms. Some non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1-bicyclo[l.l.l]pentanyl, bicyclo[3.1.0]hexanyl, norbornanyl, l-bicyclo[2.2.2]octanyl, and 4, 5,6,7-tetrahydro-l / 7-indenyl. Particularly preferred, yet non-limiting examples of cycloalkyl are cyclopropyl, bicyclo[l.l.l]pentanyl, bicyclo[3.1.0]hexanyl and cyclohexyl.

[0026] The term "aryl" refers to a monocyclic or bicyclic carbocyclic ring system having a total of 6 to 10 ring members (“Ce-Cio-aryl”), wherein at least one ring in the system is aromatic. Some nonlimiting examples of aryl include phenyl, 9H-fluorenyl (e.g. 9H-fluoren-9-yl), and 1 / 7-indenyl. A particularly preferred, yet non-limiting example of aryl is phenyl.

[0027] The term "heteroaryl" refers to a monocyclic or bicyclic ring system having a total of 5 to 10 ring members, preferably 5 to 9 ring members, more preferably 5 to 8 ring members, more preferably 5 to 7 ring members, more preferably 5 to 6 ring members, wherein at least one ring in the ring system is aromatic and contains one or more heteroatoms. Preferably, the heteroaryl comprises 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, the remaining ring atoms being carbon. Most preferably, the heteroaryl comprises 1 to 2 heteroatoms independently selectedfrom O, S and N, the remaining ring atoms being carbon. Some non-limiting examples of heteroaryl include thiazolyl (e.g. thiazol-2-yl); oxazolyl (e.g. oxazol-2-yl); oxadiazolyl; 1,2,4-oxadiazol-5-yl; pyridyl (e.g. 2-pyridyl); pyrimidinyl; thienyl; oxazolyl; pyrazolyl (e.g. pyrazol-1-yl); triazolyl; tetrazolyl; pyrazinyl; imidazolyl (e.g. imidazole- 1-yl), 177-indazolyl, indolyl, 1H-isoindolyl, 4,5,6,7-tetrahydro-l / f-indazolyl, and 4,5,6,7-tetrahydro-l / f-indolyl. Some preferred, yet non-limiting examples of heteroaryl include pyridyl, pyrimidinyl, thienyl, and oxazolyl.

[0028] The term “heterocyclyl” refers to a saturated or partly unsaturated monocyclic or bicyclic ring system having a total of 3 to 10 ring members, preferably 3 to 9 ring members, more preferably 3 to 8 ring members, more preferably 3 to 7 ring members, more preferably 3 to 6 ring members, more preferably 5 to 6 ring members, wherein one or more of said ring members are heteroatoms. Preferably, the heterocyclyl group comprises 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, the remaining ring atoms being carbon. Most preferably, the heterocyclyl group comprises 1 to 2 heteroatoms independently selected from O, S and N, the remaining ring atoms being carbon. Some non-limiting examples of heterocyclyl groups include azetidinyl, piperidyl, pyrrolidinyl, oxetanyl, piperidyl, 1,2-dihydropyridiynl, 1H-pyridine-2-one, piperidyl, pyrrolidinyl, tetrahydrothiophenyl, thietanyl, and 4,5,6,7-tetrahydro-177-isoindolyl. Some preferred, yet non-limiting examples of heterocyclyl groups include azetidinyl and oxetanyl.

[0029] The term “haloalkyl” refers to an alkyl group as defined herein, wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a halogen atom, preferably fluoro.

[0030] Preferably, “haloalkyl” refers to an alkyl group wherein 1, 2 or 3 hydrogen atoms of the alkyl group have been replaced by a halogen atom, most preferably fluoro. Particularly preferred, yet non-limiting examples of haloalkyl are trifluoromethyl, difluoromethyl, 1, 1 -difluoroethyl, 2,2-difluoroethyl, and 2,2,2-trifluoroethyl.

[0031] The term “haloalkoxy” refers to an alkoxy group as defined herein, wherein at least one of the hydrogen atoms of the alkoxy group has been replaced by a halogen atom, preferably fluoro. Preferably, “haloalkoxy” refers to an alkoxy group wherein 1, 2 or 3 hydrogen atoms of the alkoxy group have been replaced by a halogen atom, most preferably fluoro. Particularly preferred, yet non-limiting examples of haloalkoxy are trifluoromethoxy, difluoromethoxy, 1,1 -difluoroethoxy, 2,2-difluoroethoxy, and 2,2,2-trifluoroethoxy.The term “alkoxyalkyl” refers to an alkyl group as defined herein, wherein at least one of the hydrogen atoms of the alkyl group has been replaced by an alkoxy group, preferably methoxy. Preferably, “alkoxyalkyl” refers to an alkyl group wherein 1, 2 or 3 hydrogen atoms of the alkyl group have been replaced by an alkoxy group, most preferably methoxy. More preferably, “alkoxyalkyl” refers to an alkyl group wherein 1 hydrogen atom of the alkyl group has been replaced by an alkoxy group, most preferably methoxy. Particularly preferred, yet non-limiting examples of alkoxyalkyl are methoxymethyl and 2 -methoxy ethyl.

[0032] The term “hydroxyalkyl” refers to an alkyl group as defined herein, wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a hydroxy group. Preferably, “hydroxyalkyl” refers to an alkyl group wherein 1, 2 or 3 hydrogen atoms of the alkyl group have been replaced by a hydroxy group. Particularly preferred, yet non-limiting examples of alkoxyalkyl are hydroxymethyl and 2 -hydroxy ethyl.

[0033] The term “cyanoalkyl” refers to an alkyl group as defined herein, wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a cyano group. Preferably, “cyanoalkyl” refers to an alkyl group wherein 1, 2 or 3 hydrogen atoms of the alkyl group have been replaced by a cyano group. Particularly preferred, yet non-limiting examples of cyanoalkyl are cyanomethyl and 2-cyanoethyl.

[0034] The term “amino” refers to a group -NH2.

[0035] The term “cyano” refers to a group -CN (also known as nitrile group).

[0036] The term “hydroxy” refers to a group -OH.

[0037] The term “oxo” refer to an oxygen atom that is attached to the parent moiety via a double bond, i.e., oxo is a group =0.

[0038] The term "pharmaceutically acceptable salt" refers to those salts which retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable. The salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, in particular hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcy stein and the like. In addition these salts may beprepared by addition of an inorganic base or an organic base to the free acid. Salts derived from an inorganic base include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium salts and the like. Salts derived from organic bases include, but are not limited to salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimine resins and the like.

[0039] The compounds of formula (I) can contain several asymmetric centers and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereioisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.

[0040] The term “treatment” as used herein includes: (1) inhibiting the state, disorder or condition (e.g. arresting, reducing or delaying the development of the disease, or a relapse thereof in case of maintenance treatment, of at least one clinical or subclinical symptom thereof); and / or (2) relieving the condition (i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms). The benefit to a patient to be treated is either statistically significant or at least perceptible to the patient or to the physician. However, it will be appreciated that when a medicament is administered to a patient to treat a disease, the outcome may not always be effective treatment.

[0041] The term “prophylaxis” or “prevention” as used herein includes: preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a mammal and especially a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition.

[0042] The term “effective dose” refers to a quantity of a therapeutic substance that produces the desired therapeutic effect or beneficial outcome in a subject. This amount is sufficient to achieve the intended biological response without causing significant adverse effects or toxicity. The specific effective dose can vary based on factors such as the subject's age, weight, health condition, and the nature and severity of the disease or condition being treated.Compounds of the Invention

[0043] In a first aspect, the present invention provides a compound of formula (I)

[0044]

[0045] or a pharmaceutically acceptable salt thereof, wherein:

[0046] (i) X is C and Y is N; or

[0047] (ii) X is N and Y is C;

[0048] A is selected from the group consisting of C6-C10-aryl, 5- to 10-membered heteroaryl, C3-C10-cycloalkyl, and 3- to 10-membered heterocyclyl;

[0049] B is selected from the group consisting of C6-C10-aryl, 5- to 10-membered heteroaryl, C3-C10-cycloalkyl, and 3- to 10-membered heterocyclyl;

[0050] C is selected from the group consisting of C6-C10-aryl, 5- to 10-membered heteroaryl, C3-C10-cycloalkyl, and 3- to 10-membered heterocyclyl;

[0051] D is selected from the group consisting of C6-C10-aryl, 5- to 10-membered heteroaryl, C3-C10-cycloalkyl, and 3- to 10-membered heterocyclyl;

[0052] L1is selected from the group consisting of a covalent bond, -(CHRL1)r-,

[0053] *-NRL2(CHRL1)r-, and *-O(CHRL1)r-;

[0054] wherein an asterisk indicates the point of attachment of L1to ring C;

[0055] L2is selected from the group consisting of a covalent bond, -(CHRL3)S-, -(CHRL3)SCO-*, -(CHRL3)SO-*, -O(CHRL3)S-*, -NH(CHRL3)S-*, -NH(SO2)-* and -NHSO2CH2-*;

[0056] wherein an asterisk indicates the point of attachment of L2to ring D;

[0057] m is 1, 2, or 3;

[0058] n is 0, 1, 2, or 3;

[0059] p is 0, 1, 2, or 3;

[0060] q is 0, 1, 2, or 3;

[0061] r is 1 or 2;

[0062] s is 1 or 2;R1is selected from the group consisting of halogen, hydroxy, Ci-Ce-alkyl, halo-C1-C6- alkyl, Ci-Ce-alkoxy, halo-Ci-Ce-alkoxy, and Ci-Ce-alkoxy-Ci-Ce-alkyl;

[0063] R2is selected from the group consisting of halogen, oxo, Ci-Ce-alkyl, halo-Ci-Ce-alkyl, Ci-Ce-alkoxy, halo-Ci-Ce-alkoxy, and Ci-Ce-alkoxy-Ci-Ce-alkyl;

[0064] R3is selected from the group consisting of hydrogen, Ci-Ce-alkyl, hydroxy-Ci-Ce-alkyl, halo-Ci-Ce-alkyl, cyano-Ci-Ce-alkyl, Ci-Ce-alkoxy-Ci-Ce-alkyl, -(CHRL1)r-

[0065] COORL2, -(CHRL1)r-CON(RL2)2, and a group

[0066]

[0067] ; and

[0068] R4is selected from the group consisting of hydrogen, amino, hydroxy, halogen, C1-C6- alkyl, halo-Ci-Ce-alkyl, Ci-Ce-alkoxy, halo-Ci-Ce-alkoxy, Ci-Ce-alkoxy-Ci-Ce-alkyl, -(CHRL1)r-COORL2, C1-C6-alkyl-CONRL2-, Ci-C6-alkyl-NRL2-, halo-Ci-C6-alkyl- NRL2-, C1-C6-alkyl-SO2NRL2-, Ci-C6-alkoxy-C1-C6-alkyl-CONRL2-, a group

[0069]

[0070] R3and R4, taken together with the atoms to which they are attached, form a group

[0071]

[0072] R5is selected from the group consisting of halogen, Ci-Ce-alkyl, halo-Ci-Ce-alkyl, Ci- Ce-alkoxy, halo-Ci-Ce-alkoxy, Ci-Ce-alkoxy-Ci-Ce-alkyl, and 5- to 10-membered heteroaryl;

[0073] R6is selected from the group consisting of halogen, Ci-Ce-alkyl, halo-Ci-Ce-alkyl, Ci- Ce-alkoxy, halo-Ci-Ce-alkoxy, and Ci-Ce-alkoxy-Ci-Ce-alkyl;

[0074] each RL1is independently selected from the group consisting of hydrogen, hydroxy, C1-C6- alkyl, and Ci-Ce-alkoxy;

[0075] each RL2is independently selected from the group consisting of hydrogen and Ci-Ce-alkyl;

[0076] andeach RL3is independently selected from the group consisting of hydrogen, Ci-Ce-alkyl, and Ci-Ce-alkoxy;

[0077] wherein each heterocyclyl and each heteroaryl comprises 1 to 4 heteroatoms independently selected from the group consisting of N, O, and S, the remaining ring atoms being carbon.

[0078] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (la) or (lb):

[0079]

[0080] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (la):

[0081]

[0082] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (lb):

[0083]

[0084] (Ib).

[0085] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0086] A is phenyl;

[0087] R1is Ci-Ce-alkoxy; and

[0088] m is 1 or 2.

[0089] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0090] A is phenyl;

[0091] R1is methoxy; and

[0092] m is 2.

[0093] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (Ic):

[0094]

[0095] wherein each Z is independently selected from the group consisting of N and CH, provided that at most 3 Z are N, and wherein the remaining variables are as defined herein.

[0096] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (Id):

[0097]

[0098] (Id)

[0099] wherein each Z is independently selected from the group consisting of N and CH, provided that at most 3 Z are N, Rlais selected from the group consisting of hydroxy, Ci-Ce-alkyl, halo-Ci-Ce-alkyl, Ci-Ce-alkoxy, halo-Ci-Ce-alkoxy, and Ci-Ce-alkoxy-Ci-Ce-alkyl, and the remaining variables are as defined herein.

[0100] In one embodiment, the present invention provides a compound of formula (Id) as described herein, or a pharmaceutically acceptable salt thereof, wherein Rlais selected from the group consisting of hydroxy and Ci-Ce-alkoxy.

[0101] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (le):

[0102]

[0103] wherein the variables are as defined herein.

[0104] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (If):

[0105]

[0106] wherein the variables are as defined herein.

[0107] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R1is Ci-Ce-alkoxy.

[0108] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R1is methoxy.

[0109] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (Ig):

[0110]

[0111] wherein the variables are as defined herein.

[0112] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is selected from the group consisting of 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl.

[0113] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is selected from the group consisting of 6-membered heteroaryl and 6-membered heterocyclyl.In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is selected from the group consisting of 1,2-dihydropyridyl and pyridyl.

[0114] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is a 6 -membered heteroaryl

[0115] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is pyridyl.

[0116] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0117] R2is selected from the group consisting of oxo and Ci-Ce-alkoxy; and

[0118] n is 1.

[0119] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0120] R2is selected from the group consisting of oxo and ethoxy; and

[0121] n is 1.

[0122] In a preferred embodiment, the present invention provides a compound of formula (I) as

[0123]

[0124] described herein, or a pharmaceutically acceptable salt thereof, wherein the group

[0125] is selected from the group consisting

[0126]

[0127] of

[0128] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the group

[0129]

[0130] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0131] R3is selected from the group consisting of hydrogen, Ci-Ce-alkyl, and a group

[0132]

[0133] R5is selected from the group consisting of halogen, Ci-Ce-alkyl, Ci-Ce-alkoxy, and 5- to 6-membered heteroaryl;

[0134] C is selected from the group consisting of Ce-Cio-aryl and 5- to 6-membered heteroaryl;

[0135] L1is selected from the group consisting of -(CHR, l)r- and *-O(CHR, l)r-;

[0136] wherein an asterisk indicates the point of attachment of L1to ring C;

[0137] RL1is selected from the group consisting of hydrogen and Ci-Ce-alkyl;

[0138] p is 0, 1, or 2; and

[0139] r is 1 or 2.

[0140] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0141] R3is selected from the group consisting of hydrogen, methyl, and a group

[0142]

[0143] R5is selected from the group consisting of chloro, methyl, methoxy, and thienyl; C is selected from the group consisting of phenyl, pyridyl, pyrimidinyl, and oxazolyl; L1is selected from the group consisting of -(CHR, l)r- and *-O(CHR, l)r-;

[0144] wherein an asterisk indicates the point of attachment of L1to ring C;

[0145] RL1is selected from the group consisting of hydrogen and methyl;

[0146] p is 0, 1, or 2; and

[0147] r is 1 or 2.

[0148] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0149] R3is selected from the group consisting of hydrogen, Ci-Ce-alkyl, and a group

[0150]

[0151] C is 5- to 6-membered heteroaryl;

[0152] L1is -(CHR" ),- RL1is hydrogen;

[0153] p is 0; and

[0154] r is 1.

[0155] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0156] R3is selected from the group consisting of hydrogen, methyl, and a group

[0157]

[0158] C is pyridyl;

[0159] L1is -(CHR" ),- RL1is hydrogen;

[0160] p is 0; and

[0161] r is 1.

[0162] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0163] R3is a group

[0164]

[0165] C is 5- to 6-membered heteroaryl;

[0166] L1is -(CHR" ),- RL1is hydrogen;

[0167] p is 0; and

[0168] r is 1.

[0169] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0170] is a group

[0171] is pyridyl;

[0172]

[0173] is -(CHRL1)r-;

[0174] RLI is hydrogen; andp is 0; and

[0175] r is 1.

[0176] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0177] R4is selected from the group consisting of hydrogen, amino, hydroxy, Ci-Ce-alkyl, - (CHRL1)r-COORL2, C1-C6-alkyl-CONRL2-, halo-C1-C6-alkyl-NRL2-, Ci-C6-alkyl-

[0178] SO2NRL2-, Ci-C6-alkoxy-C1-C6-alkyl-CONRL2- a group

[0179]

[0180] group

[0181]

[0182] ' — s;

[0183] L2is selected from the group consisting of -(CHRL3)S-, -NH(CHRL3)S-*, -NH(SO2)-* and -NHSO2CH2-*;

[0184] wherein an asterisk indicates the point of attachment of L2to ring D;

[0185] D is a 5- to 6-membered heteroaryl;

[0186] R6is halogen;

[0187] q is 0 or 1;

[0188] r is 1 or 2;

[0189] s is 1;

[0190] RL1is selected from the group consisting of hydrogen and Ci-Ce-alkyl;

[0191] RL2is selected from the group consisting of hydrogen and Ci-Ce-alkyl; and

[0192] RL3is hydrogen.

[0193] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0194] R4is selected from the group consisting of hydrogen, amino, hydroxy, methyl, -(CHRL1)r-COORL2, CH3CONRL2-, CF3CH2NRL2-, CH3SO2NRL2-,

[0195] (R6)q

[0196]

[0197] CH3OCH2CONRL2-, a group and a group

[0198]

[0199] L2is selected from the group consisting of -(CHRL3)S-, -NH(CHRL3)S-*, -NH(SO2)-* and -NHSO2CH2-*;

[0200] wherein an asterisk indicates the point of attachment of L2to ring D; D is a pyridyl, pyrimidinyl;

[0201] R6is chloro;

[0202] q is 0 or 1;

[0203] r is 1 or 2;

[0204] s is 1;

[0205] RL1is selected from the group consisting of hydrogen and methyl;

[0206] RL2is selected from the group consisting of hydrogen and methyl; and

[0207] RL3is hydrogen.

[0208] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R4is amino.

[0209] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0210] R3and R4, taken together with the atoms to which they are attached, form a group

[0211]

[0212] R3ais a group

[0213]

[0214] L1is a covalent bond;

[0215] C is a 5- to 6-membered heteroaryl,

[0216] P is 1;

[0217] R5is halogen.

[0218] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:R3and R4, taken together with the atoms to which they are attached, form a group

[0219]

[0220] R3ais a group

[0221]

[0222] L1is a covalent bond;

[0223] C is pyridyl,

[0224] P is 1;

[0225] R5is chloro.

[0226] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0227] (i) X is C and Y is N; or

[0228] (ii) X is N and Y is C;

[0229] A is phenyl;

[0230] B is selected from the group consisting of 6-membered heteroaryl and 6-membered heterocyclyl;

[0231] C is selected from the group consisting of Ce-Cio-aryl and 5- to 6-membered heteroaryl;

[0232] D is a 5- to 6-membered heteroaryl;

[0233] m 2;

[0234] n 1;

[0235] p is 0, 1, or 2;

[0236] q is 0 or 1;

[0237] r is 1 or 2;

[0238] s is 1;

[0239] L1is selected from the group consisting of a covalent bond, -(CHRL1)r- and *- O(CHRL1)r-;

[0240] wherein an asterisk indicates the point of attachment of L1to ring C;

[0241] L2is selected from the group consisting of -(CHRL3)S-, -NH(CHRL3)S-*, -NH(SO2)-* and -NHSO2CH2-*;wherein an asterisk indicates the point of attachment of L2to ring D;

[0242] R1is Ci-Ce-alkoxy;

[0243] R2is selected from the group consisting of oxo and Ci-Ce-alkoxy;

[0244] R3is selected from the group consisting of hydrogen, Ci-Ce-alkyl, and a group

[0245]

[0246] ; and

[0247] R4is selected from the group consisting of hydrogen, amino, hydroxy, Ci-Ce-alkyl, - (CHRL1)r-COORL2, C1-C6-alkyl-CONRL2-, halo-C1-C6-alkyl-NRL2-, Ci-C6-alkyl-

[0248] SO2NRL2-, Ci-C6-alkoxy-C1-C6-alkyl-CONRL2-, a group

[0249]

[0250] C^D

[0251] group

[0252]

[0253] ; or

[0254] R3and R4, taken together with the atoms to which they are attached, form a group

[0255] N

[0256] N.

[0257]

[0258] R3ais a group

[0259]

[0260] R5is selected from the group consisting of halogen, Ci-Ce-alkyl, Ci-Ce-alkoxy, and 5- to 6-membered heteroaryl;

[0261] R6is halogen;

[0262] each RL1is independently selected from the group consisting of hydrogen and Ci-Ce-alkyl; RL2is selected from the group consisting of hydrogen and Ci-Ce-alkyl; and

[0263] RL3is hydrogen.

[0264] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0265] (i) X is C and Y is N; or

[0266] (ii) X is N and Y is C;A is phenyl;

[0267] B is selected from the group consisting of 6-membered heteroaryl and 6-membered heterocyclyl;

[0268] C is 6-membered heteroaryl;

[0269] L1is –(CHRL1)r–;

[0270] m is 2;

[0271] n is 1;

[0272] p is 0;

[0273] r is 1;

[0274] R1is Ci-Ce-alkoxy;

[0275] R2is selected from the group consisting of oxo and Ci-Ce-alkoxy;

[0276] R3is selected from the group consisting of hydrogen, Ci-Ce-alkyl, and a group

[0277]

[0278] R4is amino; and

[0279] RL1is hydrogen.

[0280] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0281] (i) X is C and Y is N; or

[0282] (ii) X is N and Y is C;

[0283] A is phenyl;

[0284] B is selected from the group consisting of pyridyl and 1,2 -dihydropyridyl;

[0285] C is pyridyl;

[0286] L1is –(CHRL1)r–;

[0287] m is 2;

[0288] n is 1;

[0289] p is 0;

[0290] r is 1;

[0291] R1is methoxy;

[0292] R2is selected from the group consisting of oxo and methoxy;R3is selected from the group consisting of hydrogen, methyl, and a group

[0293]

[0294] R4is amino; and

[0295] RL1is hydrogen.

[0296] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0297] X is C and Y is N;

[0298] A is phenyl;

[0299] B is 6-membered heteroaryl;

[0300] C is 6-membered heteroaryl;

[0301] L1is –(CHRL1)r–; m is 2;

[0302] n is 1;

[0303] p is 0;

[0304] r is 1;

[0305] R1is Ci-Ce-alkoxy;

[0306] R2is Ci-Ce-alkoxy;

[0307]

[0308] R4is amino; and

[0309] RL1is hydrogen.

[0310] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0311] X is C and Y is N;

[0312] A is phenyl;

[0313] B is pyridyl;

[0314] C is pyridyl;

[0315] L1is –(CHRL1)r–; m is 2;

[0316] n is 1;

[0317] p is 0;r is 1;

[0318] R1is methoxy;

[0319] R2is ethoxy;

[0320]

[0321] R4is amino; and

[0322] RL1is hydrogen.

[0323] More particularly, in accordance with the present invention, each individual compound disclosed in the accompanying working exampled forms a separate embodiment. The individual compounds disclosed together with their EC 50 values in Table 1 herein are preferred. Especially preferred are those compounds of Table 1 with an EC 50 value below 20 nm; or below 15 nm; or below 10 nm; or below 5 nm; or below 2 nm; or below 1 nm; or below 0.5 nm; or which fall within the range of 0.08 to 0.4 nm. Those compounds can be easily identified through their corresponding Example No. (Ex.) in Table 1.

[0324] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from the group consisting of:

[0325] 2-amino-9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-l-(2-pyridylmethyl)purin-6-one; 2-amino-9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-l-methyl-purin-6-one;

[0326] 2-amino-9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-lH-purin-6-one;

[0327] 2-amino-9-(2,6-dimethoxyphenyl)-8-(6-keto-lH-pyridin-2-yl)hypoxanthine;

[0328] N-[9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-l-methyl-6-oxo-purin-2- yl]methanesulfonamide;

[0329] (7S)-7-(5-chloro-2-pyridyl)-3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-6-methyl-7,8- dihydropyrazino[l,2-a]purine-5, 10-dione;

[0330] N-[9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-6-oxo-l-(2-pyridylmethyl)purin-2- yl]methanesulfonamide;

[0331] 2-[9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-6-oxo-lH-purin-2-yl]propanoic acid;

[0332] 9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-2-hydroxy-l-[2-(4-methoxyphenyl)ethyl]purin- 6-one;

[0333] N-[l-benzyl-9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-6-oxo-purin-2- yl]methanesulfonamide;N-[9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-6-keto-lH-purin-2-yl]benzenesulfonamide; 2-amino-l-[(5-chloro-2-pyridyl)methyl]-9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)purin- 6-one;

[0334] N-[9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-6-keto-lH-purin-2-yl]-l -phenyl- methanesulfonamide;

[0335] 2-amino-9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-l-[2-(4-methoxyphenyl)ethyl]purin-6- one;

[0336] N-[9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-6-oxo-lH-purin-2-yl]acetamide;

[0337] 9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-2-(2,2,2-trifluoroethylamino)-lH-purin-6-one; 2-[(5-chloropyrimidin-2-yl)methyl]-9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-lH-purin- 6-one;

[0338] 2-[(5-chloro-2-pyridyl)methyl]-9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-lH-purin-6- one;

[0339] 9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-l-[[5-methyl-2-(2-thienyl)oxazol-4- yl]methyl]purin-6-one;

[0340] 9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-2-(2-pyridylmethylamino)-lH-purin-6-one; 2-amino-9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-l-(2-pyrimidin-2-yloxyethyl)purin-6- one;

[0341] 9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-l,2-dimethyl-purin-6-one;

[0342] 9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-2-hydroxy-l-(2-pyridylmethyl)purin-6-one; N-[9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-6-oxo-lH-purin-2-yl]-2-methoxy- acetamide;

[0343] 9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-lH-purin-6-one;

[0344] N-[9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-6-oxo-lH-purin-2-yl]methanesulfonamide; 2-[9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-l-methyl-6-oxo-purin-2-yl]acetic acid; 9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-2-methyl-lH-purin-6-one;

[0345] 2-amino-9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-l-[(5-methylpyrimidin-2- yl)methyl]purin-6-one;

[0346] 2-amino-l-[(6-chloro-2-pyridyl)methyl]-9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)purin- 6-one;

[0347] 2-amino-l-[(4-chloro-2-pyridyl)methyl]-9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)purin- 6-one;

[0348] 2-[9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-l-methyl-6-oxo-purin-2-yl]propanoic acid;9-(2,6-dimethoxyphenyl)-2-[(N, S-dimethylsulfonimidoyl)amino]-8-(6-ethoxy-2-pyridyl)-lH- purin-6-one;

[0349] 9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-3H-purine-2, 6-dione;

[0350] 9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-2-(2-pyridylmethyl)-lH-purin-6-one; and 5-amino-3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-6H-pyrazolo[4,3-d]pyrimidin-7-one; or from the group consisting of

[0351] 8-(4-chloro-6-ethoxy-2-pyridyl)-9-(2,6-dimethoxyphenyl)-2-hydroxy-l-[(6-methyl-2-pyridyl)methyl]purin-6-one;

[0352] 8-(6-eth oxy -2-pyridyl)-2-hydroxy-9-(5 -meth oxyindan-4-yl)- l-[(6-methy 1-2- pyridyl)methyl]purin-6-one;

[0353] 8-(6-ethoxy-2-pyridyl)-2-hydroxy-9-(2-isobutyl-6-methoxy-phenyl)-l-[(6-methyl-2- pyridyl)methyl]purin-6-one;

[0354] 9-(2,6-dimethoxyphenyl)-8-(2-ethoxypyrimidin-4-yl)-2-hydroxy-l-[(6-methyl-2- pyridyl)methyl]purin-6-one;

[0355] 9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-4-methyl-2-pyridyl)-2-hydroxy-l-[(6-methyl-2- pyridyl)methyl]purin-6-one;

[0356] 9-(2-ethoxy-6-methoxy-phenyl)-8-(6-ethoxy-2-pyridyl)-2-hydroxy-l-[(6-methyl-2- pyridyl)methyl]purin-6-one; and

[0357] 9-(2-ethoxy-4-methoxy-3-pyridyl)-8-(6-ethoxy-2-pyridyl)-2-hydroxy-l-[(6-methyl-2- pyridyl)methyl]purin-6-one.

[0358] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from the group consisting of:

[0359] 2-amino-9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-l-(2-pyridylmethyl)purin-6-one; 2-amino-9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-l-methyl-purin-6-one;

[0360] 2-amino-9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-lH-purin-6-one; and

[0361] 2-amino-9-(2,6-dimethoxyphenyl)-8-(6-keto-lH-pyridin-2-yl)hypoxanthine.

[0362] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is 2-amino-9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-l-(2-pyridylmethyl)purin-6-one.In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is 2-amino-9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-l-methyl-purin-6-one.

[0363] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is 2-amino-9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-lH-purin-6-one.

[0364] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is 2-amino-9-(2,6-dimethoxyphenyl)-8-(6-keto-lH-pyridin-2-yl)hypoxanthine.

[0365] In a particular embodiment, the present invention provides pharmaceutically acceptable salts of the compounds according to formula (I) as described herein. In a further particular embodiment, the present invention provides compounds according to formula (I) as described herein as free bases or acids.

[0366] In some embodiments, the compounds of formula (I) are isotopically -labeled by having one or more atoms therein replaced by an atom having a different atomic mass or mass number. Such isotopically-labeled (i.e., radiolabeled) compounds of formula (I) are considered to be within the scope of this disclosure. Examples of isotopes that can be incorporated into the compounds of formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine, and iodine, such as, but not limited to,2H,3H,11C,13C,14C,13N,15N,15O,17O,18O,31P,32P,35S,18F,36C1,123I, and125I, respectively. Certain isotopically-labeled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, i.e.3H, and carbon-14, i.e.,14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. For example, a compound of formula (I) can be enriched with 1, 2, 5, 10, 25, 50, 75, 90, 95, or 99 percent of a given isotope.

[0367] Substitution with heavier isotopes, such as deuterium, i.e.2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements. Therefore, deuterated versions of the compounds disclosed herein are to be understood to be within the scope of the present invention. In some embodiments, 1 -6 hydrogen atoms, for example 1, 2, 3, 4, 5, or 6 hydrogen atoms of the compounds of the invention are replaced by deuterium atoms.Substitution with positron emitting isotopes, such as11C,18F,15O and13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

[0368] Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples as set out below using an appropriate isotopically-labeled reagent in place of the nonlabeled reagent previously employed.

[0369] Processes of Manufacturing

[0370] The preparation of compounds of formula (I) of the present invention may be carried out in sequential or convergent synthetic routes. Syntheses of the invention are shown in the following general schemes. The skills required for carrying out the reaction and purification of the resulting products are known to those persons skilled in the art. The substituents and indices used in the following description of the processes have the significance given herein, unless indicated to the contrary.

[0371] If one of the starting materials, intermediates or compounds of formula (I) contain one or more functional groups which are not stable or are reactive under the reaction conditions of one or more reaction steps, appropriate protective groups (as described e.g., in “Protective Groups in Organic Chemistry” by T. W. Greene and P. G. M. Wutts, 5th Ed., 2014, John Wiley & Sons, N. Y.) can be introduced before the critical step applying methods well known in the art. Such protective groups can be removed at a later stage of the synthesis using standard methods described in the literature.

[0372] If starting materials or intermediates contain stereogenic centers, compounds of formula (I) can be obtained as mixtures of diastereomers or enantiomers, which can be separated by methods well known in the art e.g., chiral HPLC, chiral SFC or chiral crystallization. Racemic compounds can e.g., be separated into their antipodes via diastereomeric salts by crystallization with optically pure acids or by separation of the antipodes by specific chromatographic methods using either a chiral adsorbent or a chiral eluent. It is equally possible to separate starting materials and intermediates containing stereogenic centers to afford diastereomerically / enantiomerically enriched starting materials and intermediates. Using such diastereomerically / enantiomerically enriched starting materials and intermediates in the synthesis of compounds of formula (I) will typically lead to the respective diastereomerically / enantiomerically enriched compounds of formula (I).A person skilled in the art will acknowledge that in the synthesis of compounds of formula (I) -insofar not desired otherwise - an “orthogonal protection group strategy” will be applied, allowing the cleavage of several protective groups one at a time each without affecting other protective groups in the molecule. The principle of orthogonal protection is well known in the art and has also been described in literature (e.g. Barany and R. B. Merrifield, J. Am. Chem. Soc.

[0373] 1977, 99, 7363; H. Waldmann et al., Angew. Chem. Int. Ed. Engl. 1996, 35, 2056).

[0374] A person skilled in the art will acknowledge that the sequence of reactions may be varied depending on reactivity and nature of the intermediates.

[0375] In more detail, the compounds of formula (I) can be manufactured by the methods given below, by the methods given in the examples or by analogous methods. Appropriate reaction conditions for the individual reaction steps are known to a person skilled in the art. Also, for reaction conditions described in literature affecting the described reactions see for example:

[0376] Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock. John Wiley & Sons, New York, NY. 1999). It was found convenient to carry out the reactions in the presence or absence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve the reagents, at least to some extent. The described reactions can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. It is convenient to carry out the described reactions in a temperature range between -78 °C to reflux. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a period of from 0.5 hours to several days will usually suffice to yield the described intermediates and compounds. The reaction sequence is not limited to the one displayed in the schemes, however, depending on the starting materials and their respective reactivity, the sequence of reaction steps can be freely altered.

[0377] If starting materials or intermediates are not commercially available or their synthesis not described in literature, they can be prepared in analogy to existing procedures for close analogues or as outlined in the experimental section.

[0378] The following abbreviations are used in the present text:

[0379] dba = dibenzylideneacetone, HPLC = high-performance liquid chromatography, DMF = N, N-dimethylformamide, MS = mass spectrometry, ESI = electrospray ionization, xantphos = (9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane), Me = methyl, Ms = mesyl, FA = formic acid, NMP = N-methyl-2-pyrrolidone, DMSO = dimethylsulfoxide, DPPH = O-diphenylphosphinyl hydroxylamine, tBuXPhos = 2-Di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl, G3 = generation 3, DCM = dichloromethane, Et = ethyl, Ac =acetyl, EtOAc = ethylacetate, aq = aqueous, eq = equivalence, DIEA = diisopropylethylamine, rt = room temperature, Ar = argon, sat. = saturated, h = hours, tert. = tertiary, TFA = trifluoroacetic acid, TEA = Triethylamine, DIEA = Diisopropylethylamine, X-phos Pd G2 = Chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II).

[0380] The present compounds of formula la may be prepared by the route depicted in Scheme 1. A suitable amine 3 is reacted with 2,4,6-trichloro-5-nitropyrimidine 2 in an S\Ar reaction in the presence of a base (e.g. Et3N or DIPEA) to generate 4. A further S\Ar reaction with an alcohol group (PG-OH, where PG = e.g. Bn or allyl) in the presence of a suitable base (e.g. NaH) yields 5. Reduction (e.g. using Fe / NH4Cl) generates diamine 6, which could be condensed with an aldehyde 7 to give imidazopyrimidine 8 (e.g. in aqueous methanol at elevated temperatures, or in AcOH in presence of Cu(OAc)2). The R4group can be installed via S\Ar reaction (e.g. using an amine or an alkoxy group in the presence of a base such as LiHMDS or NaH; or using a carbon anion, for example generated by deprotonating a 2 -methylpyridine derivative with a base such as n-BuLi) or via a metal-catalyzed cross coupling (e.g. using Suzuki conditions and a suitable boronate derivative R4-B(OH)2, or Buchwald-type conditions with palladium catalysis and an (optionally protected) amine or alcohol). Deprotection of intermediate 9 to pyrimidone 10 (e.g. using Pd / C and H2 for Bn, or using palladium catalysis for allyl) could be followed by installation of the R3group by alkylation (e.g. using R4-W where W = Br, I, Cl in the presence of a base such as NaH, and LiBr to enhance regioselectivity; or under Mitsunobu-type conditions with an alcohol R4-W where W = OH).e.g3. Fe / NH 4. CI

[0381] reduction

[0382] installation of R4e.g. metal-catalyzed cross coupling, SNAr displacement

[0383] deprotection

[0384]

[0385] 10 (la) Scheme 1

[0386] Alternatively, compounds of formula la may be generated by the route depicted in Scheme 2._A suitable amine 3 is reacted with 4,6-dichloro-2-(methylthio)-5-nitropyrimidine (11) in an SNAr reaction in the presence of a base (e.g. K2CO3) to generate 12. A further S\ Ar reaction with an alcohol group (PG-OH, where PG = e.g. allyl) in the presence of a suitable base (e.g. NaH) yielded 13. Reduction (e.g. using Fe / NPUCl) generated diamine 14. Acylation with a suitable carboxylic acid derivative 15 (e.g. with an acid chloride, where X = Cl, in the presence of a base such as Et3N; or with an acid, where X = OH, in the presence of a coupling agent such as HATU and a base) yields an amide which can be further condensed in the presence of a dehydrating agent such as POCI3 to give to give imidazopyrimidine 16. The thioether group can be converted to a sulfone (e.g. using an oxidant such as mCPBA), which can then be reacted to install the (optionally protected) R4group, (e.g. via an S\Ar displacement in the presence of nucleophile and a suitable base, or a Pd-catalyzed cross-coupling). If not occurring concurrently to the installation of the R4group, deprotection of intermediate 17 to pyrimidone 18 (e.g under palladium catalysis for allyl) could be followed by installation of the R3group by alkylation (e.g. using R3-W where W = Br, I, Cl in the presence of a base such as NaH, and LiBr to enhanceregioselectivity, or alternatively LiHMDS). If required, the R4group could be further modified (e.g. removal of a protecting group) under standard conditions.

[0387] e.g3. Fe / NH 4. CI

[0388] reduction 1112

[0389] O

[0390] 1. oxidation, e.g.mCPBA 2. POCI32. installation of R4e.g. SNAr displacement or metal-catalyzed 16 cross coupling

[0391] deprotection

[0392]

[0393] 18 Scheme 2

[0394] Alternatively, compounds of formula la may be generated by the route depicted in Scheme 3. A suitable amine 3 is reacted with 2,4,6-trichloro-5-nitropyrimidine (2) in an S\Ar reaction in the presence of a base (e.g. Et3N) to generate 4. A further S\Ar reaction with an alcohol group (PG-OH, where PG = e.g. benzyl, allyl) in the presence of a suitable base (e.g. NaH) yielded 5.

[0395] Reduction (e.g. using Fe / NEUCl) generated diamine 6. Acylation with a suitable carboxylic acid derivative 15 (e.g. with an acid chloride, where X = Cl, in the presence of a base such as Et3N; or with an acid, where X = OH, in the presence of a coupling agent such as HATU and a base) yields an amide which can be further condensed in the presence of a dehydrating agent such as POCI3 to give to give imidazopyrimidine 8. The R4group can be installed via S\Ar reaction (e.g. using an amine or an alkoxy group in the presence of a base such as LiHMDS or NaH; or using a carbon anion, for example generated by deprotonating a 2 -methylpyridine derivative with a base such as n-BuLi) or via a metal-catalyzed cross coupling (e.g. using Suzuki conditions anda suitable boronate derivative R4-B(OH)2, or Buchwald-type conditions with palladium catalysis and an (optionally protected) amine or alcohol). Deprotection of intermediate 9 to pyrimidone 10 (e.g. using Pd / C and H2 for Bn, or using palladium catalysis for allyl) could optionally be followed by installation of a R3group by alkylation (e.g. using R3-W where W = Br, I, Cl in the presence of a base such as NaH, and LiBr to enhance regioselectivity; or under Mitsunobu-type conditions with an alcohol R4-W where W = OH).

[0396] e.g3. Fe / NH 4. CI

[0397] reduction

[0398] installation of R42. POCI3e.g. metal-catalyzed cross coupling, SNAr displacement

[0399] deprotection

[0400]

[0401] Scheme 3

[0402] Alternatively, compounds of formula la may be generated by the route depicted in Scheme 4. Deprotection of imidazopyrimidine 16 (e.g. using Pd / C and H2 for Bn, or using palladium catalysis for allyl) yields pyrimidone intermediate 19, which can be alkylated_(e.g. using R3-W where W = Br, I, Cl in the presence of a base such as NaH, and LiBr to enhance regioselectivity) to yield 20. Oxidation of the thioether to a sulfone 21 (e.g. using an oxidant such as mCPBA) can be followed by installation of the R4group, (e.g. via an S\Ar displacement in the presence of nucleophile and a suitable base, or a Pd-catalyzed cross-coupling). If required, the R4group could be further modified (e.g. removal of a protecting group) under standard conditions.deprotection R-W oxidation e g alkylation e g mCPBA

[0403] (R )m installataion of R4e g SNAr displacement MR3 or metal-catalyzed cross-coupling (R2O

[0404]

[0405] (la) Scheme 4

[0406] Alternatively, compounds of formula 26, where R4=H may be generated by the route depicted in Scheme 5. A suitable amine 3 is reacted with 5-amino-4,6-dichloropyrimidine (22) in an SNAr reaction in the presence of a base (e.g. DIPEA) to generate 23. Condensation with a suitable aldehyde 7 gave imidazopyrimidine 24 which could be hydrolyzed to 25 (e.g. by heating in the presence of water and NaOH). Optionally an R3group could be installed by alkylation (e.g. using R3-W where W = Br, I, Cl in the presence of a base such as K2CO3.

[0407] 24

[0408] 2223

[0409] R-W

[0410] e g alkylation,

[0411] Mitsunobu

[0412]

[0413] Scheme 5

[0414] Alternatively, compounds of formula la may be generated by the route depicted in Scheme 6. A suitable amine 3 is reacted with 4,6-dimethoxy-5-nitroso-pyrimidin-2-amine (28) in an S\Ar reaction to generate 29. Reduction (e.g. using H2 with a Pd / C catalyst) generated diamine 29. Condensation with a suitable aldehyde 7 (e.g. by heating in MeOH) gave imidazopyrimidine 30.

[0415] Sandmeyer reaction (e.g. using isopentyl nitrite, CH2I2, Cui) converted the amine into iodidederivative 31. This can then be used to install the (optionally protected) R4group, (e.g. via an S\Ar displacement in the presence of nucleophile and a suitable base, or a Pd-catalyzed crosscoupling). Deprotection of the methoxy group under standard conditions (e.g. TMSI, Nal) to yield 33 could optionally be followed by installation of the R3group by alkylation (e.g. using R3-W where W = Br, I, Cl in the presence of a base such as NaH, and LiBr to enhance regioselectivity).

[0416] isopentyl nitrite NH2e g Pd / C, H2> nitrosation reduction OMe

[0417] Sandmeyer reaction installation of R4e g isopentyl nitrite, e g metal-catalyzed 30 CH2I2, Cui cross coupling, SNAr 31

[0418] displacement

[0419] deprotection of methoxy group e g TMSI, Nal

[0420]

[0421] (la)

[0422] Scheme 6

[0423] Alternatively, compounds of formula lb may be generated by the route depicted in Scheme 7.

[0424] Alkylation of an alkyl 4-nitro-lH-pyrazole-3 -carboxylate (34) with a suitable alkylating agent (35), for example using K2CO3 in DMF, yields 36. Reduction of the nitro group to yield amine 37 (e.g. using H2 in the presence of Pd / C catalyst) can be followed by iodination, for example using N-iodosuccinamide (NIS) in the presence of AcOH, to yield iodide 38. Hydrolysis of the alkyl-ester to the carboxylic acid 39 (e.g. using LiOH in water) can be followed by an amide coupling with a suitable amine (40) (e.g. using HATU, DIPEA) to yield 41. Reaction with triphosgene yields a 5-hydroxy-6H-pyrazolo[4,3-d]pyrimidin-7-one intermediate (42, R4= OH), which if required can be converted into further R4derivatives (e.g. via triflation or conversion to a leaving group, followed by further functionalization via metal-catalyzed cross-coupling orSNAF displacement). Installation of the A-ring could finally be carried out via metal-catalyzed cross coupling (e.g. Suzuki conditions with a suitable boronic acid derivative 43).

[0425] e g Pd / C, H2reduction

[0426] H2N-R340 e g LiOH, H2O e g HATU, DIPEA e g NIS, AcOH amide formation iodination hydrolysis

[0427] B(OHh

[0428] 1 triphosgene 2 further functionalization Suzuki cross coupling to convert -OH into R4 if needed

[0429]

[0430] (lb)

[0431] Scheme 7

[0432] In one aspect, the present invention provides a process of manufacturing a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein the process is as described in Scheme 1.

[0433] In one aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, when manufactured according to any one of the processes described herein.

[0434] APJ Agonistic Activity

[0435] Compounds of the present invention are APJ agonists. Thus, in one aspect, the present invention provides the use of compounds of formula (I) as described herein for activating human APJ in a subject in need thereof.

[0436] In a further aspect, the present invention provides compounds of formula (I) as described herein for use in a method of activating human APJ in a subject in need thereof.In a further aspect, the present invention provides the use of compounds of formula (I) as described herein for the preparation of a medicament for activating human APJ in a subject in need thereof.

[0437] In a further aspect, the present invention provides a method for activating human APJ in a subject in need thereof, which method comprises administering an effective amount of a compound of formula (I) as described herein to the subject.

[0438] cAMP Hunter CH0-K1 AGTRL1 Gi Cell Line (95-0147C2), stably expressing vector containing untagged human AGTRL1 were purchased from Eurofins and cultured at 37°C - 5% C02 in DMEM (Dulbecco's Modified Eagle Medium): F-12 (1:1) supplemented with 10% fetal bovine serum.

[0439] Changes in intracellular cyclic adenosine monophosphate (cAMP) levels were quantified using the Nano-TRF Detection Assay kit (Roche Diagnostics, Cat. No. 05214386001). This assay allows for direct cAMP quantification in a homogeneous solution. cAMP is detected based on time-resolved fluorescence energy transfer (TR-FRET) and competitive binding of ruthenylated cAMP and endogenous cAMP to an anti-cAMP monoclonal antibody labeled with AlexaFluor-700. The Ruthenium complex serves as the FRET donor and transfers energy to AlexaFluor-700. The FRET signal is inversely proportional to the cAMP concentration.

[0440] cAMP Hunter CHO-K1 AGTRL1 Gi cells were detached with Accutase and resuspended in assay buffer consisting of Hank's Balanced Salt Solution (HBSS), 10 mMHEPES (4-(2-hydroxyethyl) piperazine- 1 -ethanesulfonic acid solution), IBDX 0.5mM and 0.1% bovine serum albumin (pH 7.2). Test agonist compounds were serially diluted in dimethyl sulfoxide (DMSO) and spotted in black 384-well plates (Corning). Frozen cells were thawed and immediately seeded in the 384-well plates where the compounds were pre-spotted, at a density of 20000 cells / 20pl assay buffer. Forskolin (15pM final concentration) was added and the cells were incubated at 37°C for 30 minutes. The assay was stopped by adding lOuL of cAMP detection mix (containing detergents for cell lysis) for 60 minutes at room temperature. Cellular cAMP was measured using a Paradigm reader (Molecular Devices).

[0441] The raw data was used to calculate the FRET signal based on the assay’s P -factor as per cAMP kit instructions. The data was normalized to the maximal activity of a reference antagonist and dose response curves were fitted to the percent activity of the test compounds using a sigmoidal dose response model (Genedata Screener).APJ agonistic potencies of the compounds of formula (I) according to the invention as measured in the assay described above are presented in Table 1.

[0442] Table 1

[0443] APJ ECso APJ ECso Ex. Ex.

[0444] (nM) (nM)

[0445] 1 18.6 45 0.11

[0446] 2 864.3 46 1.13

[0447] 3 10.3 47 0.25

[0448] 4 0.4 48 1.60

[0449] 5 0.4 49 0.14

[0450] 6 0.4 50 18.33

[0451] 8 2.1 51 5.09

[0452] 9 17.9 52 1.50

[0453] 26 0.13 53 0.08

[0454] 36 23.04 54 0.31

[0455] 37 0.39 55 0.32

[0456] 38 17.89 56 3.82

[0457] 39 18.26 57 11010.87

[0458] 40 0.10 58 163.6

[0459] 41 0.14 59 160.0

[0460] 42 0.20 60 231.1

[0461] 43 0.12 61 452.6

[0462] 44 0.15 62 147.3

[0463]

[0464]

[0465] APJ ECso APJ ECso

[0466] Ex. Ex.

[0467] (nM) (nM)

[0468] 63 95.0 64 328.1

[0469]

[0470]

[0471] Using the Compounds of the Invention

[0472] In one aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, as described herein for use as a therapeutically active substance.

[0473] The compounds of the invention may be used as standalone treatments, i.e. as monotherapies, or as combination treatments together with other therapeutic agents.

[0474] Monotherapies

[0475] In one aspect, the present invention provides a method of treating or preventing a disease or condition which benefits from increased activity of APJ in a subject in need thereof, the method comprising administering to the subject an effective dose of a compound of formula (I) described herein, or of a pharmaceutically acceptable salt thereof, or of a pharmaceutical composition described herein.

[0476] In a further aspect, the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for use in a method of treating or preventing a disease or condition which benefits from increased activity of APJ in a subject in need thereof.

[0477] In a further aspect, the present invention provides the use of a compound of formula (I) described herein, or of a pharmaceutically acceptable salt thereof, or of a pharmaceutical composition described herein, in a method of treating or preventing a disease or condition which benefits from increased activity of APJ in a subject in need thereof.

[0478] In a further aspect, the present invention provides the use of a compound of formula (I) described herein, or of a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating or preventing a disease or condition which benefits from increased activity of APJ in a subject in need thereof.In one embodiment, said disease or condition which benefits from increased activity of APJ is one or more selected from the group consisting of muscle atrophy, obesity, diabetes mellitus, insulin insensitivity, cardiovascular disease, heart failure, atherosclerosis, cardiorenal disease, myocardial infarction, aortic aneurysm, pulmonary arterial hypertension, neurologic disease, ischemic stroke, traumatic brain injury, Alzheimer's disease, Parkinson's disease, obesity -linked gallbladder disease, obesity-induced sleep apnea, hyperinsulinemia, nighttime hypoglycemia, excessive appetite, hyponatremia, metabolic dysfunction-associated fatty liver disease, metabolic dysfunction-associated steatohepatitis, dyslipidemia, metabolic syndrome, acute kidney injury, chronic kidney disease, preeclampsia and insufficient satiety.

[0479] In one embodiment, said disease or condition which benefits from increased activity of APJ is one or more selected from the group consisting of cardiovascular disease, heart failure, atherosclerosis, cardiorenal disease, myocardial infarction, aortic aneurysm, pulmonary arterial hypertension, acute kidney injury, chronic kidney disease, preeclampsia.

[0480] In a preferred embodiment, said disease or condition which benefits from increased activity of APJ is one or more selected from the group consisting of heart failure, neuromuscular diseases, and kidney diseases.

[0481] In a particularly preferred embodiment, said disease or condition which benefits from increased activity of APJ is heart failure.

[0482] In a particularly preferred embodiment, said disease or condition which benefits from increased activity of APJ is a neuromuscular disease.

[0483] In a particularly preferred embodiment, said disease or condition which benefits from increased activity of APJ is a chronic kidney disease.

[0484] In a particularly preferred embodiment, said disease or condition which benefits from increased activity of APJ is a cardiovascular disease.

[0485] In a particularly preferred embodiment, said disease or condition which benefits from increased activity of APJ is atherosclerosis.

[0486] In a particularly preferred embodiment, said disease or condition which benefits from increased activity of APJ is cardiorenal disease.In a particularly preferred embodiment, said disease or condition which benefits from increased activity of APJ is a myocardial infarction.

[0487] In a particularly preferred embodiment, said disease or condition which benefits from increased activity of APJ is an aortic aneurysm.

[0488] In a particularly preferred embodiment, said disease or condition which benefits from increased activity of APJ is pulmonary arterial hypertension.

[0489] In a particularly preferred embodiment, said disease or condition which benefits from increased activity of APJ is an acute kidney injury.

[0490] In a particularly preferred embodiment, said disease or condition which benefits from increased activity of APJ is preeclampsia.

[0491] The APJ agonists of the invention may lead to preservation of muscle mass or muscle strength (muscle atrophy) in subjects at risk of muscle atrophy. Thus, in a particularly preferred embodiment, said disease or condition which benefits from increased activity of APJ is muscle atrophy.

[0492] In one embodiment, the muscle atrophy is due to a therapy, for example therapy with a GLP-1R agonist.

[0493] In one embodiment, the muscle atrophy is due to a disease or condition.

[0494] In one embodiment, the subject at risk of muscle atrophy is at bed rest.

[0495] In one embodiment, the subject at risk of muscle atrophy is an elderly subject (>65 years old).

[0496] In one embodiment, the subject at risk of muscle atrophy is an elderly subject (>65 years old) at bed rest.

[0497] Combination Treatments

[0498] As outlined above, the compounds of the invention may be used as combination treatments together with other therapeutic agents, in particular as combination treatments with GLP-1R agonists.

[0499] In one aspect, the present invention provides a method of inducing weight loss with maintenance of lean muscle mass in a subject in need of weight loss, comprising:co-administering to a subject in need thereof:

[0500] an effective dose of a compound according of formula (I) described herein, or a pharmaceutically acceptable salt thereof; and

[0501] an effective dose of a GLP-1R agonist,

[0502] to maintain lean muscle mass while inducing fat and weight loss in the subject.

[0503] In one aspect, the present invention provides a method of increasing total weight loss caused by administration of a pre-determined amount of a GLP-1R agonist to a subject in need thereof, the method comprising:

[0504] co-administering to a subject in need thereof:

[0505] an effective dose of a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof; and

[0506] an effective dose of a GLP-1R agonist,

[0507] to increase total weight loss in the subject relative to weight loss caused by administration of a pre-determined amount of a GLP-1 receptor agonist alone.

[0508] In one aspect, the present invention provides a method of treating or preventing further muscle mass decrease caused by administration of a GLP-1R agonist to a subject in need thereof, the method comprising:

[0509] adding an effective dose of a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, to the GLP-1 receptor agonist treatment regimen of a subject in need thereof,

[0510] to treat or prevent further lean muscle mass decrease in the subject.

[0511] In one embodiment, the co-administering stimulates muscle mass preservation, or stimulates an increase in muscle mass in the subject relative to a baseline level.

[0512] In one embodiment, the subject exhibits after the co-administration:

[0513] loss of fat but not lean muscle;

[0514] increased lean mass percentage;

[0515] increased lean / fat mass ratio; and / or

[0516] reduced or normal fed glucose level,

[0517] relative to a baseline level immediately before administration.

[0518] In one embodiment, the subject is overweight or obese.In one embodiment, the subject has a disease or condition associated with weight gain.

[0519] In one embodiment, the disease or condition associated with weight gain is selected from obesity, obesity-linked gallbladder disease, obesity-induced sleep apnea, diabetes, excessive appetite, fatty liver disease, non-alcoholic fatty liver disease (NASH), dyslipidemia, metabolic syndrome, insufficient satiety, hyperinsulinemia, and nighttime hypoglycemia.

[0520] In one embodiment, the subject has a metabolic disorder.

[0521] In one embodiment, the subject has diabetic obesity.

[0522] In one embodiment, the subject has type 1 diabetes, type 2 diabetes, or gestational diabetes.

[0523] In one embodiment, the subject has one or more of hypertension, dyslipidemia, obstructive sleep apnea, and cardiovascular disease.

[0524] In a further aspect, the present invention provides a method of treating or preventing a disease or disorder selected from the group consisting of muscle atrophy, obesity, diabetes mellitus, insulin insensitivity, cardiovascular disease, heart failure, atherosclerosis, cardiorenal disease, myocardial infarction, aortic aneurysm, pulmonary arterial hypertension, neurologic disease, ischemic stroke, traumatic brain injury, Alzheimer's disease, Parkinson's disease, obesity -linked gallbladder disease, obesity-induced sleep apnea, hyperinsulinemia, nighttime hypoglycemia, excessive appetite, hyponatremia, metabolic dysfunction-associated fatty liver disease, metabolic dysfunction-associated steatohepatitis, dyslipidemia, metabolic syndrome, acute kidney injury, chronic kidney disease, preeclampsia and insufficient satiety in a subject in need thereof, the method comprising:

[0525] co-administering to a subject in need thereof:

[0526] an effective dose of a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof; and

[0527] an effective dose of a GLP-1R agonist.

[0528] In a further aspect, the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, for use in any of the therapeutic methods described herein.In a further aspect, the present invention provides the use of a compound of formula (I) described herein, or of a pharmaceutically acceptable salt thereof, in any of the therapeutic methods described herein.

[0529] In a further aspect, the present invention provides the use of a compound of formula (I) described herein, or of a pharmaceutically acceptable salt thereof, in the preparation of a medicament for use in any of the therapeutic methods described herein.

[0530] Pharmaceutical Compositions and Administration

[0531] In one aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as described herein and a therapeutically inert carrier.

[0532] In one embodiment, there is provided a pharmaceutical composition according to Example 37 or 38.

[0533] The compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicaments (e.g. in the form of pharmaceutical preparations). The pharmaceutical preparations can be administered internally, such as orally (e.g. in the form of tablets, coated tablets, dragées, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasally (e.g. in the form of nasal sprays) or rectally (e.g. in the form of suppositories). However, the administration can also be effected parentally, such as intramuscularly or intravenously (e.g. in the form of injection solutions).

[0534] The compounds of formula (I) and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic adjuvants for the production of tablets, coated tablets, dragées and hard gelatin capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc. can be used, for example, as such adjuvants for tablets, dragées and hard gelatin capsules.

[0535] Suitable adjuvants for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid substances and liquid polyols, etc.

[0536] Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose, etc.

[0537] Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols, etc.

[0538] Moreover, the pharmaceutical preparations can contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.

[0539] The dosage can vary in wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, in the case of oral administration a daily dosage of about 0.1 mg to 20 mg per kg body weight, preferably about 0.5 mg to 4 mg per kg body weight (e.g. about 300 mg per person), divided into preferably 1-3 individual doses, which can consist, for example, of the same amounts, should be appropriate. It will, however, be clear that the upper limit given herein can be exceeded when this is shown to be indicated.

[0540] Numbered Clauses

[0541] The invention is further described in the following numbered clauses:

[0542] 1. A compound of formula (I)

[0543]

[0544]

[0545] or a pharmaceutically acceptable salt thereof, wherein:

[0546] (i) X is C and Y is N; or

[0547] (ii) X is N and Y is C;

[0548] A is selected from the group consisting of Ce-Cio-aryl, 5- to 10-membered heteroaryl, Cs-Cio-cycloalkyl, and 3- to 10-membered heterocyclyl;

[0549] B is selected from the group consisting of Ce-Cio-aryl, 5- to 10-membered heteroaryl, Cs-Cio-cycloalkyl, and 3- to 10-membered heterocyclyl;

[0550] C is selected from the group consisting of Ce-Cio-aryl, 5- to 10-membered heteroaryl, Cs-Cio-cycloalkyl, and 3- to 10-membered heterocyclyl;D is selected from the group consisting of Ce-Cio-aryl, 5- to 10-membered heteroaryl, Cs-Cio-cycloalkyl, and 3- to 10-membered heterocyclyl;

[0551] L1is selected from the group consisting of a covalent bond, -(CHRL1)r-,

[0552] *-NRL2(CHRL1)r-, and *-O(CHRL1)r-;

[0553] wherein an asterisk indicates the point of attachment of L1to ring C;

[0554] L2is selected from the group consisting of a covalent bond, -(CHRL3)S-, -(CHRL3)SCO-*, -(CHRL3)SO-*, -O(CHRL3)S-*, -NH(CHRL3)S-*,

[0555] -NH(SO2)-* and -NHSO2CH2-*;

[0556] wherein an asterisk indicates the point of attachment of L2to ring D;

[0557] m is 1, 2, or 3;

[0558] n is 0, 1, 2, or 3;

[0559] p is 0, 1, 2, or 3;

[0560] q is 0, 1, 2, or 3;

[0561] r is 1 or 2;

[0562] s is 1 or 2;

[0563] R1is selected from the group consisting of halogen, hydroxy, Ci-Ce-alkyl, halo-C1-C6- alkyl, Ci-Ce-alkoxy, halo-Ci-Ce-alkoxy, and Ci-Ce-alkoxy-Ci-Ce-alkyl;

[0564] R2is selected from the group consisting of halogen, oxo, Ci-Ce-alkyl, halo-Ci-Ce-alkyl, Ci-Ce-alkoxy, halo-Ci-Ce-alkoxy, and Ci-Ce-alkoxy-Ci-Ce-alkyl;

[0565] R3is selected from the group consisting of hydrogen, Ci-Ce-alkyl, hydroxy-Ci-Ce-alkyl, halo-Ci-Ce-alkyl, cyano-Ci-Ce-alkyl, Ci-Ce-alkoxy-Ci-Ce-alkyl, -(CHRL1)r-. >1\<^<(R5)P

[0566] COORL2, -(CHRL1)r-CON(RL2)2, and a group

[0567]

[0568] ; and

[0569] R4is selected from the group consisting of hydrogen, amino, hydroxy, halogen, C1-C6- alkyl, halo-Ci-Ce-alkyl, Ci-Ce-alkoxy, halo-Ci-Ce-alkoxy, Ci-Ce-alkoxy-Ci-Ce-alkyl, -(CHRL1)r-COORL2, C1-C6-alkyl-CONRL2-, Ci-C6-alkyl-NRL2-, halo-Ci-C6-alkyl- NRL2-, C1-C6-alkyl-SO2NRL2-, Ci-C6-alkoxy-C1-C6-alkyl-CONRL2-, a group

[0570] -'Xx(R6)q

[0571] D J

[0572]

[0573] and a group; orR3and R4, taken together with the atoms to which they are attached, form a group

[0574]

[0575] v >1\£~><(r5)p

[0576] Vc)

[0577] R3ais a group

[0578]

[0579] ;

[0580] R5is selected from the group consisting of halogen, Ci-Ce-alkyl, halo-Ci-Ce-alkyl, Ci- Ce-alkoxy, halo-Ci-Ce-alkoxy, Ci-Ce-alkoxy-Ci-Ce-alkyl, and 5- to 10-membered heteroaryl;

[0581] R6is selected from the group consisting of halogen, Ci-Ce-alkyl, halo-Ci-Ce-alkyl, Ci- Ce-alkoxy, halo-Ci-Ce-alkoxy, and Ci-Ce-alkoxy-Ci-Ce-alkyl;

[0582] each RL1is independently selected from the group consisting of hydrogen, hydroxy, C1-C6- alkyl, and Ci-Ce-alkoxy;

[0583] each RL2is independently selected from the group consisting of hydrogen and Ci-Ce-alkyl;

[0584] and

[0585] each RL3is independently selected from the group consisting of hydrogen, Ci-Ce-alkyl, and Ci-Ce-alkoxy;

[0586] wherein each heterocyclyl and each heteroaryl comprises 1 to 4 heteroatoms independently selected from the group consisting of N, O, and S, the remaining ring atoms being carbon.

[0587] The compound of formula (I) according to clause 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (la) or (lb):

[0588]

[0589] The compound of formula (I) according to clause 1 or 2, or a pharmaceutically acceptable salt thereof, wherein:A is phenyl;

[0590] R1is Ci-Ce-alkoxy; and

[0591] m is 1 or 2.

[0592] The compound of formula (I) according to clause 1 or 2, or a pharmaceutically acceptable salt thereof, wherein:

[0593] A is phenyl;

[0594] R1is methoxy; and

[0595] m is 2.

[0596] The compound of formula (I) according to clause 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (Ic):

[0597]

[0598] wherein each Z is independently selected from the group consisting of N and CH, provided that at most 3 Z are N, and wherein the remaining variables are as defined in clause 1.

[0599] The compound of formula (I) according to clause 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (Id):

[0600] O

[0601]

[0602] (Id) wherein each Z is independently selected from the group consisting of N and CH, provided that at most 3 Z are N, Rlais selected from the group consisting of hydroxy, Ci-Ce-alkyl, halo-Ci-Ce-alkyl, Ci-Ce-alkoxy, halo-Ci-Ce-alkoxy, and Ci-Ce-alkoxy-Ci-Ce-alkyl, and the remaining variables are as defined in clause 1.The compound of formula (Id) according to clause 6, or a pharmaceutically acceptable salt thereof, wherein Rlais selected from the group consisting of hydroxy and Ci-Ce-alkoxy.

[0603] The compound of formula (I) according to clause 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (le):

[0604]

[0605] (le) wherein the variables are as defined in clause 1.

[0606] The compound of formula (I) according to clause 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (If):

[0607]

[0608] wherein the variables are as defined in clause 1.

[0609] The compound of formula (I) according to clause 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (Ig):

[0610]

[0611] wherein the variables are as defined in clause 1.11. The compound of formula (I) according to any one of clauses 1 to 10, or a pharmaceutically acceptable salt thereof, wherein B is selected from the group consisting of 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl.

[0612] 12. The compound of formula (I) according to any one of clauses 1 to 10, or a pharmaceutically acceptable salt thereof, wherein B is selected from the group consisting of 6-membered heteroaryl and 6-membered heterocyclyl.

[0613] 13. The compound of formula (I) according to any one of clauses 1 to 10, or a pharmaceutically acceptable salt thereof, wherein B is selected from the group consisting of 1,2-dihydropyridyl and pyridyl.

[0614] 14. The compound of formula (I) according to any one of clauses 1 to 10, or a pharmaceutically acceptable salt thereof, wherein B is a 6 -membered heteroaryl.

[0615] 15. The compound of formula (I) according to any one of clauses 1 to 10, or a pharmaceutically acceptable salt thereof, wherein B is pyridyl.

[0616] 16. The compound of formula (I) according to any one of clauses 1 to 15, or a pharmaceutically acceptable salt thereof, wherein:

[0617] R2is selected from the group consisting of oxo and Ci-Ce-alkoxy; and

[0618] n is 1.

[0619] 17. The compound of formula (I) according to any one of clauses 1 to 15, or a pharmaceutically acceptable salt thereof, wherein:

[0620] R2is selected from the group consisting of oxo and ethoxy; and

[0621] n is 1.

[0622] 18. The compound of formula (I) according to any one of clauses 1 to 10, or a

[0623]

[0624] pharmaceutically acceptable salt thereof, wherein the group is selected from

[0625]

[0626] o

[0627] the group consisting of andThe compound of formula (I) according to any one of clauses 1 to 10, or a

[0628] pharmaceutically acceptable salt thereof, wherein the group

[0629]

[0630]

[0631] The compound of formula (I) according to any one of clauses 1 to 19, or a pharmaceutically acceptable salt thereof, wherein:

[0632] R3is selected from the group consisting of hydrogen, Ci-Ce-alkyl, and a group

[0633]

[0634] R5is selected from the group consisting of halogen, Ci-Ce-alkyl, Ci-Ce-alkoxy, and 5- to 6-membered heteroaryl;

[0635] C is selected from the group consisting of Ce-Cio-aryl and 5- to 6-membered heteroaryl;

[0636] L1is selected from the group consisting of -(CHR, l)r- and *-O(CHR, l)r-;

[0637] wherein an asterisk indicates the point of attachment of L1to ring C;

[0638] RL1is selected from the group consisting of hydrogen and Ci-Ce-alkyl;

[0639] p is 0, 1, or 2; and

[0640] r is 1 or 2.

[0641] The compound of formula (I) according to any one of clauses 1 to 19, or a pharmaceutically acceptable salt thereof, wherein:

[0642] R3is selected from the group consisting of hydrogen, methyl, and a group

[0643]

[0644] R5is selected from the group consisting of chloro, methyl, methoxy, and thienyl; C is selected from the group consisting of phenyl, pyridyl, pyrimidinyl, and oxazolyl; L1is selected from the group consisting of -(CHR, l)r- and *-O(CHR, l)r-;

[0645] wherein an asterisk indicates the point of attachment of L1to ring C;RL1is selected from the group consisting of hydrogen and methyl;

[0646] p is 0, 1, or 2; and

[0647] r is 1 or 2.

[0648] The compound of formula (I) according to any one of clauses 1 to 19, or a pharmaceutically acceptable salt thereof, wherein:

[0649] R3is selected from the group consisting of hydrogen, Ci-Ce-alkyl, and a group

[0650]

[0651] C is 5- to 6-membered heteroaryl;

[0652] L1is –(CHRL1)r–;

[0653] RL1is hydrogen;

[0654] p is 0; and

[0655] r is 1.

[0656] The compound of formula (I) according to any one of clauses 1 to 19, or a pharmaceutically acceptable salt thereof, wherein:

[0657] R3is selected from the group consisting of hydrogen, methyl, and a group

[0658]

[0659] C is pyridyl;

[0660] L1is -(CHR" ),-;

[0661] RL1is hydrogen;

[0662] p is 0; and

[0663] r is 1.

[0664] The compound of formula (I) according to any one of clauses 1 to 19, or a pharmaceutically acceptable salt thereof, wherein:

[0665] R3is a group

[0666]

[0667] C is 5- to 6-membered heteroaryl;

[0668] L1is -(CHR" ),-;

[0669] RL1is hydrogen;p is 0; and

[0670] r is 1.

[0671] The compound of formula (I) according to any one of clauses 1 to 19, or a pharmaceutically acceptable salt thereof, wherein:

[0672] R3is a group

[0673] C is pyridyl;

[0674] L

[0675]

[0676] 1is -(CHR"

[0677] RL1is hydrogen; and

[0678] p is 0; and

[0679] r is 1.

[0680] The compound of formula (I) according to any one of clauses 1 to 25, or a pharmaceutically acceptable salt thereof, wherein:

[0681] R4is selected from the group consisting of hydrogen, amino, hydroxy, Ci-Ce-alkyl, - (CHRL1)r-COORL2, C1-C6-alkyl-CONRL2-, halo-C1-C6-alkyl-NRL2-, Ci-C6-alkyl-

[0682]

[0683] SO2NRL2-, Ci-C6-alkoxy-C1-C6-alkyl-CONRL2-, a group and a

[0684] group

[0685]

[0686] L2is selected from the group consisting of -(CHRL3)S-, -NH(CHRL3)S-*, -NH(SO2)-* and -NHSO2CH2-*;

[0687] wherein an asterisk indicates the point of attachment of L2to ring D;

[0688] D is a 5- to 6-membered heteroaryl;

[0689] R6is halogen;

[0690] q is 0 or 1;

[0691] r is 1 or 2;

[0692] s is 1;

[0693] RL1is selected from the group consisting of hydrogen and Ci-Ce-alkyl;

[0694] RL2is selected from the group consisting of hydrogen and Ci-Ce-alkyl; andRL3is hydrogen.

[0695] 27. The compound of formula (I) according to any one of clauses 1 to 25, or a pharmaceutically acceptable salt thereof, wherein:

[0696] R4is selected from the group consisting of hydrogen, amino, hydroxy, methyl, -(CHRL1)r-COORL2, CH3CONRL2-, CF3CH2NRL2-, CH3SO2NRL2-

[0697] Lt / -

[0698]

[0699] CH3OCH2CONRL2-, a group and a group

[0700]

[0701] L2is selected from the group consisting of -(CHRL3)S-, -NH(CHRL3)S-*, -NH(SO2)-* and -NHSO2CH2-*;

[0702] wherein an asterisk indicates the point of attachment of L2to ring D;

[0703] D is a pyridyl, pyrimidinyl;

[0704] R6is chloro;

[0705] q is 0 or 1;

[0706] r is 1 or 2;

[0707] s is 1;

[0708] RL1is selected from the group consisting of hydrogen and methyl;

[0709] RL2is selected from the group consisting of hydrogen and methyl; and

[0710] RL3is hydrogen.

[0711] 28. The compound of formula (I) according to any one of clauses 1 to 25, or a pharmaceutically acceptable salt thereof, wherein R4is amino.

[0712] 29. The compound of formula (I) according to any one of clauses 1 to 19, or a pharmaceutically acceptable salt thereof, wherein:

[0713] R3and R4, taken together with the atoms to which they are attached, form a group

[0714] N

[0715] N.

[0716]

[0717] R3ais a group

[0718]

[0719] V— ';

[0720] L1is a covalent bond;

[0721] C is a 5- to 6-membered heteroaryl,

[0722] P is 1;

[0723] R5is halogen.

[0724] 30. The compound of formula (I) according to any one of clauses 1 to 19, or a pharmaceutically acceptable salt thereof, wherein:

[0725] R3and R4, taken together with the atoms to which they are attached, form a group

[0726] N

[0727] N..3a

[0728]

[0729] R3ais a group

[0730]

[0731] L1is a covalent bond;

[0732] C is pyridyl,

[0733] P is 1;

[0734] R5is chloro.

[0735] 31. The compound of formula (I) according to clause 1, or a pharmaceutically acceptable salt thereof, wherein:

[0736] (iii) X is C and Y is N; or

[0737] (iv) X is N and Y is C;

[0738] A is phenyl;

[0739] B is selected from the group consisting of 6-membered heteroaryl and 6-membered heterocyclyl;

[0740] C is selected from the group consisting of Ce-Cio-aryl and 5- to 6-membered heteroaryl;

[0741] D is a 5- to 6-membered heteroaryl;

[0742] m 2;n

[0743] p is 0, 1, or 2;

[0744] q is 0 or 1;

[0745] r is 1 or 2;

[0746] s is 1;

[0747] L1is selected from the group consisting of a covalent bond, -(CHR, l)r- and *- O(CHRL1)r-;

[0748] wherein an asterisk indicates the point of attachment of L1to ring C;

[0749] L2is selected from the group consisting of -(CHRL3)S-, -NH(CHRL3)S-*, -NH(SO2)-* and -NHSO2CH2-*;

[0750] wherein an asterisk indicates the point of attachment of L2to ring D;

[0751] R1is Ci-Ce-alkoxy;

[0752] R2is selected from the group consisting of oxo and Ci-Ce-alkoxy;

[0753] R3is selected from the group consisting of hydrogen, Ci-Ce-alkyl, and a group

[0754] . >1><^<(R5)P

[0755]

[0756] ; and

[0757] R4is selected from the group consisting of hydrogen, amino, hydroxy, Ci-Ce-alkyl, - (CHRL1)r-COORL2, C1-C6-alkyl-CONRL2-, halo-C1-C6-alkyl-NRL2-, Ci-C6-alkyl- RL21 L2 / Kr^o

[0758]

[0759] SO2NRL2-, Ci-C6-alkoxy-Ci-C6-alkyl-CONRL2-, a group and a

[0760] \D)

[0761] group

[0762]

[0763] ; or

[0764] R3and R4, taken together with the atoms to which they are attached, form a group

[0765]

[0766] R3ais a group

[0767]

[0768] R5is selected from the group consisting of halogen, Ci-Ce-alkyl, Ci-Ce-alkoxy, and 5- to 6-membered heteroaryl;

[0769] R6is halogen;

[0770] each RL1is independently selected from the group consisting of hydrogen and Ci-Ce-alkyl; RL2is selected from the group consisting of hydrogen and Ci-Ce-alkyl; and

[0771] RL3is hydrogen.

[0772] The compound of formula (I) according to clause 1, or a pharmaceutically acceptable salt thereof, wherein:

[0773] (iii) X is C and Y is N; or

[0774] (iv) X is N and Y is C;

[0775] A is phenyl;

[0776] B is selected from the group consisting of 6-membered heteroaryl and 6-membered heterocyclyl;

[0777] C is 6-membered heteroaryl;

[0778] L1is -(CHR" ),-;

[0779] m is 2;

[0780] n is 1;

[0781] p is 0;

[0782] r is 1;

[0783] R1is Ci-Ce-alkoxy;

[0784] R2is selected from the group consisting of oxo and Ci-Ce-alkoxy;

[0785] R3is selected from the group consisting of hydrogen, Ci-Ce-alkyl, and a group

[0786]

[0787] R4is amino; and

[0788] RL1is hydrogen.

[0789] The compound of formula (I) according to clause 1, or a pharmaceutically acceptable salt thereof, wherein:

[0790] (iii) X is C and Y is N; or

[0791] (iv) X is N and Y is C;

[0792] A is phenyl;

[0793] B is selected from the group consisting of pyridyl and 1,2 -dihydropyridyl;C is pyridyl;

[0794] L1is -(CHR" ),-;

[0795] m is 2;

[0796] n is 1;

[0797] p is 0;

[0798] r is 1;

[0799] R1is methoxy;

[0800] R2is selected from the group consisting of oxo and methoxy;

[0801] R3is selected from the group consisting of hydrogen, methyl, and a group

[0802]

[0803] R4is amino; and

[0804] RL1is hydrogen.

[0805] The compound of formula (I) according to clause 1, or a pharmaceutically acceptable salt thereof, wherein:

[0806] X is C and Y is N;

[0807] A is phenyl;

[0808] B is 6-membered heteroaryl;

[0809] C is 6-membered heteroaryl;

[0810] L1is -(CHR" ),-;

[0811] m is 2;

[0812] n is 1;

[0813] p is 0;

[0814] r is 1;

[0815] R1is Ci-Ce-alkoxy;

[0816] R2is Ci-Ce-alkoxy;

[0817]

[0818] is a group

[0819] R4is amino; and

[0820] is hydrogen.The compound of formula (I) according to clause 1, or a pharmaceutically acceptable salt thereof, wherein:

[0821] X is C and Y is N;

[0822] A is phenyl;

[0823] B is pyridyl;

[0824] C is pyridyl;

[0825] L1is -(CHR" ),-;

[0826] m is 2;

[0827] n is 1;

[0828] p is 0;

[0829] r is 1;

[0830] R1is methoxy;

[0831] R2is ethoxy;

[0832] R3is a group

[0833]

[0834] R4is amino; and

[0835] RL1is hydrogen.

[0836] The compound of formula (I) according to clause 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from the group consisting of: 2-amino-9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-l-(2-pyridylmethyl)purin-6-one; 2-amino-9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-l-methyl-purin-6-one;

[0837] 2-amino-9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-lH-purin-6-one;

[0838] 2-amino-9-(2,6-dimethoxyphenyl)-8-(6-keto-lH-pyridin-2-yl)hypoxanthine;

[0839] N-[9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-l-methyl-6-oxo-purin-2- yl]methanesulfonamide;

[0840] (7S)-7-(5-chloro-2-pyridyl)-3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-6-methyl- 7, 8-dihydropyrazino[l,2-a]purine-5, 10-dione;

[0841] N-[9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-6-oxo-l-(2-pyridylmethyl)purin-2- yl]methanesulfonamide;

[0842] 2-[9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-6-oxo-lH-purin-2-yl]propanoic acid; 9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-2-hydroxy-l-[2-(4- methoxyphenyl)ethyl]purin-6-one;N-[l-benzyl-9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-6-oxo-purin-2- yl]methanesulfonamide;

[0843] N-[9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-6-keto-lH-purin-2- yl]benzenesulfonamide;

[0844] 2-amino-l-[(5-chloro-2-pyridyl)methyl]-9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2- pyridyl)purin-6-one;

[0845] N-[9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-6-keto-lH-purin-2-yl]-l -phenyl- methanesulfonamide;

[0846] 2-amino-9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-l-[2-(4- methoxyphenyl)ethyl]purin-6-one;

[0847] N-[9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-6-oxo-lH-purin-2-yl]acetamide; 9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-2-(2,2,2-trifluoroethylamino)-lH-purin- 6-one;

[0848] 2-[(5-chloropyrimidin-2-yl)methyl]-9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-lH- purin-6-one;

[0849] 2-[(5-chloro-2-pyridyl)methyl]-9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-lH-purin- 6-one;

[0850] 9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-l-[[5-methyl-2-(2-thienyl)oxazol-4- yl]methyl]purin-6-one;

[0851] 9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-2-(2-pyridylmethylamino)-lH-purin-6- one;

[0852] 2-amino-9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-l-(2-pyrimidin-2- yloxyethyl)purin-6-one;

[0853] 9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-l,2-dimethyl-purin-6-one;

[0854] 9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-2-hydroxy-l-(2-pyridylmethyl)purin-6- one;

[0855] N-[9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-6-oxo-lH-purin-2-yl]-2-methoxy- acetamide;

[0856] 9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-lH-purin-6-one;

[0857] N-[9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-6-oxo-lH-purin-2- yl]methanesulfonamide;

[0858] 2-[9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-l-methyl-6-oxo-purin-2-yl]acetic acid; 9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-2-methyl-lH-purin-6-one;2-amino-9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-l-[(5-methylpyrimidin-2- yl)methyl]purin-6-one;

[0859] 2-amino-l-[(6-chloro-2-pyridyl)methyl]-9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2- pyridyl)purin-6-one;

[0860] 2-amino-l-[(4-chloro-2-pyridyl)methyl]-9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2- pyridyl)purin-6-one;

[0861] 2-[9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-l-methyl-6-oxo-purin-2-yl]propanoic acid;

[0862] 9-(2,6-dimethoxyphenyl)-2-[(N, S-dimethylsulfonimidoyl)amino]-8-(6-ethoxy-2-pyridyl)- lH-purin-6-one;

[0863] 9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-3H-purine-2, 6-dione;

[0864] 9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-2-(2-pyridylmethyl)-lH-purin-6-one; and 5-amino-3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-6H-pyrazolo[4,3-d]pyrimidin-7- one; or from the group consisting of

[0865] 8-(4-chloro-6-ethoxy-2-pyridyl)-9-(2,6-dimethoxyphenyl)-2-hydroxy-l-[(6-methyl-2- pyridyl)methyl]purin-6-one;

[0866] 8-(6-ethoxy-2-pyridyl)-2-hydroxy-9-(5-methoxyindan-4-yl)-l-[(6-methyl-2- pyridyl)methyl]purin-6-one;

[0867] 8-(6-ethoxy-2-pyridyl)-2-hydroxy-9-(2-isobutyl-6-methoxy-phenyl)-l-[(6-methyl-2- pyridyl)methyl]purin-6-one;

[0868] 9-(2,6-dimethoxyphenyl)-8-(2-ethoxypyrimidin-4-yl)-2-hydroxy-l-[(6-methyl-2- pyridyl)methyl]purin-6-one;

[0869] 9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-4-methyl-2-pyridyl)-2-hydroxy-l-[(6-methyl-2- pyridyl)methyl]purin-6-one;

[0870] 9-(2-ethoxy-6-methoxy-phenyl)-8-(6-ethoxy-2-pyridyl)-2-hydroxy-l-[(6-methyl-2- pyridyl)methyl]purin-6-one; and

[0871] 9-(2-ethoxy-4-methoxy-3-pyridyl)-8-(6-ethoxy-2-pyridyl)-2-hydroxy-l-[(6-methyl-2- pyridyl)methyl]purin-6-one.

[0872] The compound of formula (I) according to any one of clauses 1 to 36, or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

[0873] A pharmaceutical composition comprising a compound of formula (I) according to any one of clauses 1 to 36, or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.39. A pharmaceutical combination comprising a compound of formula (I) according to any one of clauses 1 to 36, or a pharmaceutically acceptable salt thereof, and a GLP-1R agonist.

[0874] 40. The pharmaceutical combination according to clause 39, for separate administration of the compound of formula (I) and the GLP-1R agonist.

[0875] 41. The pharmaceutical combination according to clause 39, wherein the combination is a fixed-dose combination.

[0876] 42. A method of treating or preventing a disease or condition which benefits from increased activity of APJ in a subject in need thereof, the method comprising administering to the subject an effective dose of a compound according to any one of clauses 1 to 36, or a pharmaceutically acceptable salt thereof.

[0877] 43. The method according to clause 42, wherein the disease or condition which benefits from increased activity of APJ is one or more selected from the group consisting of muscle atrophy, obesity, diabetes mellitus, insulin insensitivity, cardiovascular disease, heart failure, atherosclerosis, cardiorenal disease, myocardial infarction, aortic aneurysm, pulmonary arterial hypertension, neurologic disease, ischemic stroke, traumatic brain injury, Alzheimer's disease, Parkinson's disease, obesity -linked gallbladder disease, obesity-induced sleep apnea, hyperinsulinemia, nighttime hypoglycemia, excessive appetite, hyponatremia, metabolic dysfunction-associated fatty liver disease, metabolic dysfunction-associated steatohepatitis, dyslipidemia, metabolic syndrome, acute kidney injury, chronic kidney disease, preeclampsia and insufficient satiety.

[0878] 44. A method of inducing weight loss with maintenance of lean muscle mass in a subject in need of weight loss, comprising:

[0879] co-administering to a subject in need thereof:

[0880] an effective dose of a compound according of formula (I) to any one of clauses 1 to 36, or a pharmaceutically acceptable salt thereof; and

[0881] an effective dose of a GLP-1R agonist,

[0882] to maintain lean muscle mass while inducing fat and weight loss in the subject.

[0883] 45. A method of increasing total weight loss caused by administration of a pre -determined amount of a GLP-1R agonist to a subject in need thereof, the method comprising:

[0884] co-administering to a subject in need thereof:an effective dose of a compound of formula (I) according to any one of clauses 1 to 36, or a pharmaceutically acceptable salt thereof; and

[0885] an effective dose of a GLP-1R agonist,

[0886] to increase total weight loss in the subject relative to weight loss caused by administration of a pre-determined amount of a GLP-1 receptor agonist alone.

[0887] 46. A method of treating or preventing further muscle mass decrease caused by administration of a GLP-1 R agonist to a subject in need thereof, the method comprising:

[0888] adding an effective dose of a compound of formula (I) according to any one of clauses 1 to 36, or a pharmaceutically acceptable salt thereof, to the GLP-1 receptor agonist treatment regimen of a subject in need thereof,

[0889] to treat or prevent further lean muscle mass decrease in the subject.

[0890] 47. The method of any one of clauses 44 to 46, wherein the co -administering stimulates muscle mass preservation, or stimulates an increase in muscle mass in the subject relative to a baseline level.

[0891] 48. The method of any one of clauses 44 to 47, wherein the subject exhibits after the coadministration:

[0892] loss of fat but not lean muscle;

[0893] increased lean mass percentage;

[0894] increased lean / fat mass ratio; and / or

[0895] reduced or normal fed glucose level,

[0896] relative to a baseline level immediately before administration.

[0897] 49. The method of any one of Clauses 44 to 48, wherein the subject is overweight or obese.

[0898] 50. The method of any one of Clauses 44 to 49, wherein the subject has a disease or condition associated with weight gain.

[0899] 51. The method of clause 50, wherein the disease or condition associated with weight gain is selected from obesity, obesity -linked gallbladder disease, obesity-induced sleep apnea, diabetes, excessive appetite, fatty liver disease, non-alcoholic fatty liver disease (NASH), dyslipidemia, metabolic syndrome, insufficient satiety, hyperinsulinemia, and nighttime hypoglycemia.

[0900] 52. The method of any one of Clauses 44 to 51, wherein the subject has a metabolic disorder.53. The method of clause 52, wherein the subject has diabetic obesity.

[0901] 54. The method of clause 52 or 53, wherein the subject has type 1 diabetes, type 2 diabetes, or gestational diabetes.

[0902] 55. The method of any one of Clauses 44 to 54, wherein the subject has one or more of hypertension, dyslipidemia, obstructive sleep apnea, and cardiovascular disease.

[0903] 56. A method of treating or preventing a disease or disorder selected from the group consisting of obesity, diabetes mellitus, insulin insensitivity, cardiovascular disease, heart failure, atherosclerosis, cardiorenal disease, myocardial infarction, aortic aneurysm, pulmonary arterial hypertension, neurologic disease, ischemic stroke, traumatic brain injury, Alzheimer's disease, Parkinson's disease, obesity-linked gallbladder disease, obesity- induced sleep apnea, hyperinsulinemia, nighttime hypoglycemia, excessive appetite, hyponatremia, metabolic dysfunction-associated fatty liver disease, metabolic dysfunction- associated steatohepatitis, dyslipidemia, metabolic syndrome, acute kidney injury, chronic kidney disease, preeclampsia and insufficient satiety in a subject in need thereof, the method comprising:

[0904] co-administering to a subject in need thereof:

[0905] an effective dose of a compound of formula (I) according to any one of clauses 1 to 36, or a pharmaceutically acceptable salt thereof; and

[0906] an effective dose of a GLP-1R agonist.

[0907] 57. A compound of formula (I) according to any one of clauses 1 to 36, or a pharmaceutically acceptable salt thereof, for use in a method according to any one of clauses 42 to 56.

[0908] 58. Use of a compound of formula (I) according to any one of clauses 1 to 36, or of a pharmaceutically acceptable salt thereof, in a method according to any one of clauses clause 42 to 56.

[0909] 59. Use of a compound of formula (I) according to any one of clauses 1 to 36, or of a pharmaceutically acceptable salt thereof, in the preparation of a medicament for use in a method according to any one of clauses clause 42 to 56.Examples

[0910] The invention will be more fully understood by reference to the following examples. The claims should not, however, be construed as limited to the scope of the examples.

[0911] In case the preparative examples are obtained as a mixture of enantiomers, the pure enantiomers can be separated by methods described herein or by methods known to the man skilled in the art, such as e.g., chiral chromatography (e.g., chiral SFC) or crystallization.

[0912] The compounds of formula I can contain several asymmetric centers and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers or mixtures of diastereoisomers. According to the Cahn-Ingold-Prelog Convention the asymmetric carbon atom can be of the " R" or " S" configuration. For the compounds described in the patent the absolute stereochemistry was arbitrarily assigned.

[0913] All reaction examples and intermediates were prepared under an argon atmosphere if not specified otherwise.

[0914] The compounds disclosed and described herein have been named using the IUPAC naming function of Biovia Draw 22.1. If there is a discrepancy between a depicted structure and a name given to that structure, then the depicted structure controls.

[0915] Examples 1 and 2

[0916] 2-amino-9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-lH-purin-6-one and 2-amino-9-(2,6-dimethoxyphenyl)-8-(6-keto-lH-pyridin-2-yl)hypoxanthine

[0917]

[0918] Step a) 4,6-dimethoxy-5-nitroso-pyrimidin-2-amine

[0919] To a solution of 2-amino-4,6-dimethoxypyrimidine (10.0 g, 64.5 mmol) in DMSO (159 mL) was added isoamylnitrite (9.82 mL, 70.9 mmol) and the reaction was stirred at 23 °C for 72h. The deep blue mixture was poured into water (800 ml) and stirred at 23 °C for 2h and the resultingprecipitate was filtered and washed with 300 ml of water and dried in vacuo. The crude title compound (9.9 g, 79% yield) was used for the next step without further purification. MS (ESI): m / z = 185.0 [M+H]+

[0920] Step b) N4-(2, 6-dimethoxyphenyl)-6-methoxy-5-nitroso-pyrimidine-2, 4-diamine

[0921] (2,6-dimethoxyphenyl)amine (7.82 g, 51.1 mmol) and (4,6-dimethoxy-5-nitroso-pyrimidin-2-yl)amine (9.9 g, 51.07 mmol) were suspended in water (255 mL) and the mixture stirred at 90°C for 48h. The reaction was cooled to ambient temperature and the brown / red precipitate was filtered and washed with water affording the crude title compound (13,6g, 87% yield) as a dark brown / red solid. MS (ESI): m / z = 306.2 [M+H]+

[0922] Step c) N4-(2,6-dimethoxyphenyl)-6-methoxy-pyrimidine-2,4,5-triamine

[0923] To a black suspension of N4-(2,6-dimethoxyphenyl)-6-methoxy-5-nitroso-pyrimidine-2,4-diamine (2.3 g, 4.52 mmol) in isopropanol (40 mL) was added 10% palladium on charcoal (481 mg, 0.45 mmol) and the mixture was stirred at 50°C for 2h under hydrogen atmosphere (3.5 bar). The reaction was filtered over diatomaceous earth and the filtrate was concentrated. The crude product was purified by reversed phase-HPLC (0.1% FA) to afford the title compound (1.0g, 51% yield) as a black solid. MS (ESI): m / z = 292.2 [M+H]+

[0924] Step d) 9-(2, 6-dimethoxyphenyl)-8-( 6-ethoxy-2-pyridyl)-6-methoxy-purin-2-amine

[0925] To a solution of N4-(2,6-dimethoxyphenyl)-6-methoxy-pyrimidine-2,4,5-triamine (300 mg, 0.76 mmol) in methanol (6 mL) was added 6-ethoxypyridine-2-carbaldehyde (115 mg, 0.76 mmol) and the mixture heated to 50°C for 2h to give a brown suspension. The mixture was concentrated to dryness and purified by reversed phase-HPLC(0.1% FA) and lyophilized to afford the title compound (160.0 mg, 50% yield) as a yellow solid. MS (ESI): m / z = 423.2 [M+H]+

[0926] Step e) 2-amino-9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-lH-purin-6-one and 2-amino-9-(2,6-dimethoxyphenyl)-8-(6-keto-lH-pyridin-2-yl)hypoxanthine

[0927] To a solution of 9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-6-methoxy-purin-2-amine (330 mg, 625 mmol) in acetonitrile (3 mL) was added sodium iodide (468 mg, 3.1 mmol) and iodotrimethylsilane (425 mL, 3.12 mmol) and the reaction was stirred at 65 °C for 2h after which time the reaction was poured onto a mixture of water (10ml) and MeCN (10ml) at 0°C, the mixture was stirred for 30 min, filtered and the filter cake washed with 5ml MeCN and dried in vacuo. The solid was purified by reverse phase combiflash (0.01% TFA and acetonitrilegradient) to yield the title compounds 2-amino-9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)- lH-purin-6-one (50.0 mg, 15% yield); MS (ESI): m / z = 407.2 [M-H]' as a light brown powder and 2-amino-9-(2,6-dimethoxyphenyl)-8-(6-keto-lH-pyridin-2-yl)hypoxanthine (20.0 mg, 7% yield). MS (ESI): m / z = 379.2 [M-H]'

[0928] Example 3

[0929] 2-amino-9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-1-methyl-purin-6-one

[0930]

[0931] Step a) N-tert-butoxycarbonyl-N-[9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-6-keto-lH-purin-2-yl]carbamic acid tert-butyl ester

[0932] To a suspension of 2-amino-9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-lH-purin-6-one (130 mg, 0.29 mmol) and triethylamine (0.12 mL, 0.88 mmol) in DMF (2 mL) was added di-t-butyldicarbonate (192 mg, 0.88 mmol) and the mixture heated to 50°C for 16h. The reaction mixture was poured into water (10 mL), the aqueous phase was extracted repeatedly with EtOAc. The combined organic phase was washed with brine, dried (Na2SO4) and concentrated. The crude product was purified by preparative -TLC (PE: EtOAc) to afford the title compound (30 mg, 20% yield) as a yellow solid. MS (ESI): m / z = 609.2 [M+H]+

[0933] Step b) tert-butyl N-tert-butoxycarbonyl-N-[9-(2, 6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-l -methyl-6-oxo-purin-2-yl] carbamate

[0934] To a solution of N-tert-butoxycarbonyl-N-[9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-6-keto-lH-purin-2-yl]carbamic acid tert-butyl ester (30.0 mg, 0.05 mmol) in MeCN (1 mL) was added potassium carbonate (13.6 mg, 0.1 mmol) and iodomethane (50.0 pL, 0.05 mmol) at 15°C and the mixture warmed to 30°C and stirred for 2h. The reaction was filtered and the filtrate was concentrated in vacuo. Purification by preparative-TLC(PE: EtOAc=l:2) afforded the title compound (20.0 mg, 53% yield) as a white solid. MS (ESI): m / z = 623.3 [M+H]+

[0935] Step c) 2-amino-9-(2, 6-dimethoxyphenyl)-8-( 6-ethoxy-2-pyridyl)- 1 -methyl-purin-6-oneTo a solution of tert-butyl N-tert-butoxycarbonyl-N-[9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-l-methyl-6-oxo-purin-2-yl]carbamate (20.0 mg, 0.03 mmol) in DCM(l mL) was added trifluoroacetic acid (1.0 mL, 12.98 mmol) at 15 °C and the mixture was stirred at 30 °C for 1 h. The mixture was then concentrated to dryness and the residue purified by prep-HPLC(0.2% FA) and lyophilized to afford the title compound (4.2 mg, 37% yield) as a white solid. MS (ESI): m / z = 423.3 [M+H]+

[0936] Example 4

[0937] 2-amino-9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-l-(2-pyridylmethyl)purin-6-one

[0938]

[0939] Step a) N-tert-butoxycarbonyl-N-[9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-6-keto-l-(2-pyridylmethyl)purin-2-yl]carbamic acid tert-butyl ester

[0940] N-tert-butoxycarbonyl-N-[9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-6-keto-lH-purin-2-yl]carbamic acid tert-butyl ester, Example 3 -step a: (10 mg, 16.4 mmol) was dissolved in N, N-dimethylformamide (82 uL) and cesium carbonate (10.7 mg, 32.8 mmol) and 2-(bromomethyl)pyridine (HBr salt) (2.8 mg, 16.4 mmol) were added and the reaction was stirred at 80°C for 2h. The reaction was diluted with water, extracted with EtOAc, the combined organic dried (Na2SO4) and concentrated. It was used crude in the next step. MS (ESI): m / z = 700.3 [M+H]+

[0941] Step b) 2-amino-9-(2, 6-dimethoxyphenyl)-8-( 6-ethoxy-2-pyridyl)-l-(2-pyridylmethyl)purin-6-one

[0942] To a solution of N-tert-butoxycarbonyl-N-[9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-6-keto-l-(2-pyridylmethyl)purin-2-yl]carbamic acid tert-butyl ester (7 mg, 10.0 pmol ) in DCM (200 L) and trifluoroacetic acid (15 pL, 200 mmol) was added and the mixture stirred at ambient temperature for 1 h. Another batch of trifluoroacetic acid (15 pL, 200 pmol) was added and the mixture stirred for a further Ih. The reaction was then concentrated to dryness and theresidue purified by preparative Supercritical Fluid Chromatography to afford the title compound (2.8 mg, 48% yield) as a light yellow solid. MS (ESI): m / z = 500.2 [M+H]+

[0943] Example 5

[0944] N-[9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-6-keto-lH-purin-2-yl] benzenesulfonamide -trifluoroacetic acid salt

[0945] HNS °

[0946]

[0947] Step a) N-[9-(2, 6-dimethoxyphenyl)-8-( 6-ethoxy-2-pyridyl)-6-methoxy-purin-2-yl]benzenesulfonamide

[0948] To a solution of [9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-6-methoxy-purin-2-yl]amine (Example 1, step d, 30 mg, 67.5 pmol) in pyridine (340 pL) was added benzenesulfonyl chloride (10.4 pL, 81.0 pmol) and the reaction stirred for 16h at ambient temperature. The reaction was concentrated to dryness, the residue redissolved in EtOAc, washed with IM aqueous hydrochloric acid, dried (Na2SO4) and concentrated to yield the title compound (30.0 mg, 62% yield) as a light brown solid used crude in the next step. MS (ESI): m / z = 563.1 [M+H]+

[0949] Step b) N-[9-(2, 6-dimethoxyphenyl)-8-( 6-ethoxy-2-pyridyl)-6-keto-lH-purin-2-yl]benzenesulfonamide -trifluoroacetic acid salt

[0950] To a solution of N-[9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-6-methoxy-purin-2-yl]benzenesulfonamide (30.0 mg, 44.2 pmol) in acetonitrile (220 pL) was added iodotrimethylsilane (15.0 pL, 110.7 pmol) and sodium iodide (16.5 mg, 110.7 pmol) and the reaction was stirred at ambient temperature for Ih. The reaction was concentrated to dryness and the residue purified by reverse phase (0.01% TFA and acetonitrile gradient) to afford the title compound (20.0 mg, 68% yield) as a light brown solid. MS (ESI): m / z = 549.1 [M+H]+Example 6

[0951] N-[9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-6-keto-lH-purin-2-yl]-l-phenyl-methanesulfonamide

[0952]

[0953] The title compound, a light brown solid, was prepared in analogy to example 11 by using phenylmethanesulfonyl chloride instead of benzenesulfonyl chloride in step a. MS (ESI): m / z = 536.3 [M+H]+

[0954] Example 7

[0955] 9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-lH-purin-6-one

[0956]

[0957] Step a) 6-chloro-N4-(2, 6-dimethoxyphenyl)pyrimidine-4,5-diamine

[0958] To a solution of 5-amino-4,6-dichloropyrimidine (500.0 mg, 3.11 mmol) and 2,6-dimethoxyaniline (467.0 mg, 3.1 mmol) in NMP (5 mL) was added DIEA (1.51 mL, 9.2 mmol) and mixture was heated under microwave irradiation at 200°C for 2h after which time the reaction was poured onto water and extracted repeatedly with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated. The residue purified by reversed phase (0.1%FA) and lyophilized to afford the title compound (410.0 mg, 48% yield) as a brown solid. MS (ESI): m / z = 280.9 [M+H ]+

[0959] Step b) 6-chloro-9-(2, 6-dimethoxyphenyl)-8-( 6-ethoxy-2-pyridyl)purineTo a solution of 6-chloro-N4-(2,6-dimethoxyphenyl)pyrimidine-4,5-diamine (300.0 mg, 1.1 mmol) in methanol (3 mL) was added 6-ethoxypyridine-2-carbaldehyde (329.6 mg, 2.2 mmol,) and the reaction was stirred at 70°C for 12 h. The reaction was cooled to ambient temperature and MnO2(919.1 mg, 10.7 mmol) was added and the reaction heated to 30°C for 2h after which time it was filtered and concentrated. The residue purified by reversed phase (0.1% FA) and lyophilized to afford the title compound (90.0 mg, 20% yield), as a brown solid. MS (ESI): m / z = 412.2 [M+H]+

[0960] Step c) 9-(2, 6-dimethoxyphenyl)-8-( 6-ethoxy-2-pyridyl)-lH-purin-6-one

[0961] To a solution of 6-chloro-9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)purine (70.0 mg, 0.17 mmol) in THF (1 mL) and water (2 mL) was added NaOH (70.0 mg, 1.75 mmol) and the reaction was then heated to 50°C for 12h. The reaction mixture was poured onto water and extracted repeatedly with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by reversed phase (0.2% FA) and lyophilized to afford the title compound (7.3 mg, 11% yield) as a white solid. MS (ESI): m / z = 394.2 [M+H]+

[0962] Example 8

[0963] 9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-3-purine-2,6-dione

[0964]

[0965] To a solution of [9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-6-methoxy-purin-2-yl]amine (Example 1, step d, 20.0 mg, 47.3 μmol) in acetic acid (880 μL) was added a solution of sodium nitrite (32.7 mg, 473.4 pmol) in water (88 μL) and the reaction was stirred at 90°C for 16h. The reaction was concentrated to dryness and the residue purified by reversed phase (0.01% TFA) to afford the title compound (6.0 mg, 31% yield) as a light brown solid. MS (ESI): m / z = 410.1 [M+H]+Example 9

[0966] 5-amino-3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-6H-pyrazolo[4,3-d]pyrimidin-7-one

[0967]

[0968] Step a) methyl (2E)-4-(2,6-dimethoxyphenyl)-2-[(6-ethoxy-2-pyridyl)hydrazono]-3-nitroso-4-oxo-butanoate

[0969] To a solution of ethyl 4-(2,6-dimethoxyphenyl)-2,4-dioxo-butanoate [CAS: 839554-07-2] (3.7 g, 13.9 mmol) in acetic acid (40 mL) cooled to 10°C was added dropwise a concentrated aqueous solution of sodium nitrite (1.0 g, 14.6 mmol) maintaining the temperature at 10°C. After 30 minutes (6-ethoxy-2-pyridyl)hydrazine hydrochloride (3.2 g, 16.7 mmol) was added in portions and the mixture stirred for a further hour after which time it was concentrated_to dryness. The residue was purified by reversed phase (0.1%FA) and lyophilized to afford the title compound (1.4 g, 23% yield) as a yellow solid. MS (ESI): m / z = 431.2 [M+H]+

[0970] Step b) methyl 5-(2,6-dimethoxyphenyl)-l-(6-ethoxy-2-pyridyl)-4-nitroso-pyrazole-3-carboxylate

[0971] To a solution of methyl (2E)-4-(2,6-dimethoxyphenyl)-2-[(6-ethoxy-2-pyridyl)hydrazono]-3-nitroso-4-oxo-butanoate (1.4 g, 3.25 mmol) in isopropanol (20.0 mL) was added H2SO4(1.0 mL, 3.25 mmol) and the mixture was heated to 60°C for 3 h to give a yellow suspension. The reaction mixture was filtered and concentrated. The residue was purified by reversed phase (0.1%FA) and lyophilized to afford the title compound (280.0 mg, 21% yield) as a yellow solid. MS (ESI): m / z = 399.1 [M+H]+

[0972] Step c) methyl 4-amino-5-(2,6-dimethoxyphenyl)-l-(6-ethoxy-2-pyridyl)pyrazole-3-carboxylate

[0973] To a suspension of 10% Pd / C (23.0 mg, 0.22 mmol) in methanol (5 mL) was added a solution of methyl 5 -(2, 6-dimethoxyphenyl)-l-(6-ethoxy-2-pyridyl)-4-nitroso-pyrazole-3 -carboxy late (230.0 mg, 0.56 mmol) in methanol (5 mL) and the reaction heated to 30°C under hydrogen atmosphere(30Psi) for 0.5 h. The reaction was filtered and concentrated. The residue was purified by reversed phase HPLC (0.1% FA) and lyophilized to afford the title compound (50.0 mg, 23% yield), as a yellow solid. MS (ESI): m / z = 399.2 [M+H]+

[0974] Step d) 5-amino-3-(2, 6-dimethoxyphenyl)-2-( 6-ethoxy-2-pyridyl)-6H -pyrazolo[ 4, 3-d]pyrimidin-7-one

[0975] To a solution of methyl 4-amino-5 -(2, 6-dim ethoxyphenyl)- 1 -(6-ethoxy-2-pyri dyl)pyrazole-3-carboxylate (40.0 mg, 0.1 mmol) in 1,4-dioxane (0.5 mL) was added HC1 (0.5 mL, 4N in dioxane, 2.0 mmol,) followed by cyanamide (17.0 mg, 0.4 mmol) and the reaction heated to 100°C for 12h. The reaction was concentrated to dryness and the residue re -dissolved in aqueous 2M NaOH (8.0 mL), heated to 100 °C for 0.5h after which time it was allowed to cool to ambient temperature, the pH was adjusted to 4 with 1M aqueous HCl and the mixture concentrated. The residue purified by reversed phase (0.2% FA) and lyophilized to afford the title compound (4.5 mg, 10% yield), as a white solid. MS (ESI): m / z = 409.1 [M+H]+

[0976] The following examples may be prepared in analogy to examples 1 -9 described above, as well as based on the general synthetic procedures described herein.

[0977] Ex. No. Structure Systematic Name

[0978] N- [9 -(2,6 -dimethoxyphenyl) -8 -(6 -ethoxy -2 - O

[0979] 10 pyridyl)- 1 -methyl -6 -oxo -purin -2- yl]methanesulfonamide

[0980] (7S)-7-(5-chloro-2-pyridyl)-3-(2,6- n

[0981] dimethoxyphenyl) -2 -(6 -ethoxy -2 -py ri dyl ) -6 - 11

[0982] methyl-7,8-dihydropyrazino [ 1,2-a]purine-5,10- dione

[0983] N- [9 -(2,6 -dimethoxyphenyl) -8 -(6 -ethoxy -2 - 12 nJ A py ridyl ) - 6 -oxo - 1 -(2 -py ridylmethyljpurin -2 -ryl]methanesulfonamide

[0984]

[0985] Ex. No. Structure Systematic Name

[0986] 2 - [9 -(2,6 -dimethoxyphenyl) -8 -(6 -ethoxy -2 - 13

[0987] py ridyl)-6 -oxo - 1 H-purin -2 -yl]propanoic acid

[0988] 9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)- 14 Z 2-hydroxy- 1 -[2-(4-methoxyphenyl)ethyl]purin-6- Q one

[0989] N-[l-benzyl-9-(2,6-dimethoxyphenyl)-8-(6- C^ci /

[0990] 15 ethoxy-2-pyridyl)-6-oxo-purin-2- Qi.lXh

[0991] yl]methanesulfonamide

[0992] " 6

[0993] 2-amino-l-[(5-chloro-2-pyridyl)methyl]-9-(2,6- XjUx

[0994] 16 dimethoxyphenyl) -8 -(6 -ethoxy -2 -py ridyl)purin-6 - 0 ° one

[0995] jfZX-Y

[0996] 2 -amino -9 -(2.6 -dimethoxypheny l)-8 -(6 -ethoxy -2 - 17 QYXX pyridyl)- 1 -[2-(4-methoxyphenyl)ethyl]purin-6-one 1

[0997] N- [9 -(2,6 -dimethoxyphenyl) -8 -(6 -ethoxy -2 - 18

[0998] U Y py ridyl)-6 -oxo - 1 H-purin -2 -yl] acetamide^

[0999] C^-°ZF 9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)- 19

[1000] fY / TV1^

[1001] Z=r / 2-(2,2,2-trifluoroethylamino)-lH-purin-6-one / ~Q

[1002]

[1003] Ex. No. Structure Systematic Name

[1004] 2 - [(5 -chloropy rimidin -2 -yl)methyl] -9 -(2,6- 20 dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-lH- »AC,

[1005] r° / ° purin-6-one

[1006] Jpr

[1007] X °f 2 - [(5 -chloro -2 -pyridyl )methyl] -9 -(2,6 - © / \ /

[1008] 21 dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-lH- »AC,

[1009] r° ° purin-6-one

[1010] 9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-xSO

[1011] 22 1 - [ [5 -methyl -2 -(2 -thienyl)oxazol -4 - CHYI r>

[1012] r° 0 yl]methyl]purin-6-one

[1013] 9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)- 23

[1014] r\ N' j T v

[1015] N^p-NHn2 -(2 -pyridylmethyl amino) - 1 H-purin-6 -one

[1016] GY, Z

[1017] 2 -amino -9 -(2,6 -dimethoxypheny l)-8 -(6 -ethoxy -2 - 24 CniY

[1018] r° ° k pyridyl)- 1 -(2-pyrimidin-2-yloxyethyl)purin-6-one N^N

[1019] u

[1020] 9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)- 25

[1021] 1,2-dimethyl-purin-6-one

[1022] N- [9 -(2,6 -dimethoxyphenyl) -8 -(6 -ethoxy -2 - C^QZ

[1023] 27. - N. N. XXpy ridyl)-6 -oxo - 1 H-purin -2 -yl] -2 -methoxy- fXY Y Y Y^°

[1024] y-0 I) acetamide

[1025]

[1026] Ex. No. Structure Systematic Name

[1027] N- [9 -(2,6 -dimethoxyphenyl) -8 -(6 -ethoxy -2 - 28 pyridyl)-6-oxo-lH-purin-2- yl]methanesulfonamide

[1028] 2 - [9 -(2,6 -dimethoxyphenyl) -8 -(6 -ethoxy -2 - 29

[1029] pyridyl)- 1 -methyl-6-oxo-purin-2-yl]acetic acid

[1030] f

[1031] 9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)- 30

[1032] 2 -methyl - 1 H-purin -6 -one Gz z

[1033] 2 -amino -9 -(2.6 -dimethoxypheny l)-8 -(6 -ethoxy -2 - 31 pyridyl) - 1 - [(5 -methy Ipy rimidin-2 - Q G zG

[1034] yl)methyl]purin-6-one

[1035] X 2-amino-l-[(6-chloro-2-pyridyl)methyl]-9-(2,6- 32 dimethoxyphenyl) -8 -(6 -ethoxy -2 -py ridyl)purin-6 - O^X^N-^ANXC|

[1036] one

[1037] .. < G 2 -amino - 1 - [(4 -chloro -2 -py ridyl)methyl] -9 -(2,6 - 33 N^-N NH dimethoxyphenyl) -8 -(6 -ethoxy -2 -py ridyl)purin-6 - GHZQU)

[1038] ^ one

[1039] 2 - [9 -(2,6 -dimethoxyphenyl) -8 -(6 -ethoxy -2 - 34 pU pyridyl)- 1 -methyl -6 -oxo -purin -2 -yl]propanoic W N'V1- °

[1040] acid

[1041]

[1042] Ex. No. Structure Systematic Name

[1043] 9 -(2,6 -dimethoxyphenyl) -2 - [(N, S -0\ iHM 5

[1044] 35 dimethy lsulfonimidoyl)amino ] -8 -(6 -ethoxy -2 - pyridyl)- lH-purin-6-one

[1045] °) °

[1046]

[1047] Example 26

[1048] 9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-2-hydroxy-l-(2-pyridylmethyl)purin-6-one

[1049]

[1050] Step a) 6-chloro-2-(methylthio)-5-nitro-pyrimidin-4-yl]-(2, 6-dimethoxyphenyl)amine

[1051] 4,6-dichloro-2-(methylthio)-5-nitro-pyrimidine (CAS: 1979-96-0) (100 mg, 416 pmol) was dissolved in N, N-dimethylformamide, extra dry (1 mL) and cooled to 0 °C. K2CO3(173 mg, 1.25 mmol) was added, and the reaction was stirred for 10 min. (2,6-dimethoxyphenyl)amine (63.8 mg, 417 pmol) was added, and reaction was stirred for 10 min at 0 °C. The reaction was allowed to warm up to room temperature, was quenched with sat. aq. NH4CI, and was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo to yield the title compound as yellow solid (150 mg, 84%,) which was used directly in the next step without further purification. MS (ESI): m / z = 357.0 [M+H]+

[1052] Step_b)_J6-allyloxy-2-(methylthio)-5-nitro-pyrimidin-4-yl]-(2,6-dimethoxyphenyl)amine

[1053] Allyl alcohol (1.13 g, 1.32 mL, 19.45 mmol) was dissolved in tetrahydrofuran (15 mL) and the reaction mixture was cooled to 0 °C. NaH (60% dispersion in mineral oil) (2.33 g, 58.4 mmol) was added slowly, and the reaction was stirred at 0 °C for 30 min. [6-chloro-2-(methylthio)-5-nitro-pyrimidin-4-yl]-(2,6-dimethoxyphenyl)amine (6.94 g, 19.5 mmol) was dissolved in tetrahydrofuran (85 mL) and added dropwise to the reaction. The reaction was stirred for 30 minat 0 °C, then the ice bath was removed, and the reaction was stirred at room temperature for 1.5 h. Allyl alcohol (113mg, 132 pL, 1.95 mmol) was added, and the reaction stirred for 1 h. The reaction was cooled to 0 °C and quenched with 15 mL sat. aq. NH4CI solution. The reaction was stirred for 30 min at 0 °C, then extracted with EtOAc. The organic layer was washed with water and brine, dried over MgSC and concentrated in vacuo to yield the title compound as yellow solid (7616 mg, 99%, which was used directly in the next step without further purification. MS (ESI): m / z = 379.1 [M+H]+

[1054] Step c) [ 6-allvloxv-5-amino-2-(methylthio)pvrimidin-4-vl]-(2, 6-dimethoxyphenyl)amine

[1055] [6-allyloxy-2-(methylthio)-5-nitro-pyrimidin-4-yl]-(2,6-dimethoxyphenyl)amine (7616 mg, 19.3 mmol) was dissolved in ethanol (80 mL) and tetrahydrofuran (80 mL). Water (20 mL), ammonium chloride (10.3 g, 193 mmol) and iron (5.4 g, 96.6 mmol) were added and the reaction was stirred at 70 °C overnight. The reaction was allowed to cool down to room temperature, was filtered over Dicalite®, and the reaction mixture was extracted with EtOAc and washed with sat. aq. NaHCO3solution. The organic layer was washed with brine, dried over MgSO4and concentrated in vacuo, to yield the title compound as yellow solid (7400 mg, 99 %) which was used directly in the next step without further purification. MS (ESI): m / z = 349.1 [M+H]+

[1056] Step d) N-[4-allyloxy-6-(2, 6-dimethoxyanilino)-2-(methylthio)pyrimidin-5-yl]-6-ethoxy-picolinamide

[1057] To a solution of [6-allyloxy-5-amino-2-(methylthio)pyrimidin-4-yl]-(2,6-dimethoxyphenyl)amine (1.00 g, 2.87 mmol) with Et3N (1.16 g, 1.6 mL, 11.5

[1058] mmol) in dichloromethane (11.5 mL) was added under the surface a solution of 6-ethoxypyridine-2-carbonyl chloride (A.l) (CAS: 2415199-33-4) (0.2 M in CH₂Cl₂) (16.92 mL, 3.38 mmol). Excess of the carbonyl chloride was quenched by addition of MeOH. Isolute was added and the mixture was evaporated to dryness, then purified by flash chromatography (eluting with 0-40% EtOAc in heptane) to yield the title compound (1.31 g, 89%) as yellow solid. MS (ESI): m / z = 498.5 [M+H]+

[1059] Step e) 6-allyloxy-9-(2, 6-dimethoxyphenyl)-8-( 6-ethoxy-2-pyridyl)-2-(methylthio)purine

[1060] N-[4-allyloxy-6-(2,6-dimethoxyanilino)-2-(methylthio)pyrimidin-5-yl]-6-ethoxy-picolinamide (1.31 g, 2.63 mmol) was dissolved in acetonitrile (60 mL). DMAP (643 mg, 5.27 mmol) was added, followed by pyridine (2.08 g, 2.13 mL, 26.3 mmol), and the reaction was stirred for 15min. Phosphorus oxychloride (1.41 g, 859 pL, 9.21 mmol) was added dropwise, and the reaction was stirred for 1 h. Et3N (1.33 g, 1.83 mL, 13.2 mmol) was added and the reaction stirred at 50 °C for 16 h. The reaction was cooled to room temperature, poured into MeOH, Isolute was added, and the mixture evaporated to dryness. The crude product was purified by flash chromatography, eluting with CH₂Cl₂ to give the title compound (1.07 g, 83%) as light yellow solid. MS (ESI): m / z = 480.5 [M+H]+

[1061] Step f) 6-allyloxy-9-(2, 6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-2-mesyl-purine

[1062] 6-allyloxy-9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-2-(methylthio)purine (700 mg, 1.24 mmol) was dissolved in dichloromethane, extra dry (8 mL). 3 -chloroperoxybenzoic acid (>70% purity) (428 mg, 2.48 mmol ) was added, and the reaction was stirred at room temperature overnight. A further equivalent of 3 -chloroperoxybenzoic acid (>70% purity) (214 mg, 1.24 mmol ) was added, and the reaction stirred for 3 h. The reaction was quenched with 0.1 N Na2S2C>3 solution, and was extracted with EtOAc. The organic layer was washed with sat. aq. NaHCO3solution and brine, then dried over MgSC and concentrated in vacuo to yield the title compound as a light yellow solid (684 mg, 97%), which was used directly in the next step without further purification. MS (ESI): m / z = 512.2 [M+H]+

[1063] Step g) 9-(2, 6-dimethoxyphenyl)-8-( 6-ethoxy-2-pyridyl)-2-p-anisyloxy-hypoxanthine

[1064] 6-allyloxy-9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-2-mesyl-purine (440 mg, 834 pmol) was dissolved in tetrahydrofuran, extra dry (8 mL), and 4-methoxybenzyl alcohol (173 mg, 156 pL, 1.25 mmol), KOtBu (187 mg, 1.67 mmol) and [tBuXPhos Pd(allyl)]OTf (57.5 mg, 78.4 pmol) were added. The reaction was split evenly into two tubes, the tubes sealed and the reaction was stirred at 70 °C for 6 h. The reaction was cooled to room temperature, filtered over Dicalite® and extracted with EtOAc and water. The organic layer was washed with brine, dried over MgSO4, concentrated under reduced pressure and purified by flash chromatography (eluting with 0-20% MeOH in CH₂Cl₂) to yield the title compound (113 mg, 20%) as a light brown solid. MS (ESI): m / z = 530.2 [M+H]+

[1065] Step h) 9-(2, 6-dimethoxyphenyl)-8-( 6-ethoxy-2-pyridyl)-2-hydroxy-l-(2-pyridylmethyl)purin-6-one

[1066] In a vial, flushed with nitrogen, 9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-2-p-anisyloxy-hypoxanthine (17 mg, 26.3 pmol) was dissolved in N, N-dimethylformamide (132 pL) and NaH (60% dispersion in mineral oil) (1.11 mg, 27.6 pmol) was added at 0 °C, and the reaction wasstirred at 0 °C for 10 min. Lithium bromide (4.57 mg, 52.7 pmol) was added and the reaction was stirred at 23 °C for 10 min. 2-(bromomethyl)pyridine hydrobromide (CAS: 31106-82-8) (9.06 mg, 52.7 pmol) was added and the reaction was stirred at 65 °C for 3.5 h.

[1067] Additional lithium bromide (9.15 mg, 105 pmol) was added and the reaction was stirred for another 2 h at 65 °C. The reaction mixture was purified via prep-HPLC to yield the title compound (4.8 mg, 36%) as off-white powder. MS (ESI): m / z = 499.2 [M-H]'

[1068] The following Examples were generated in analogy to Example 26, using the indicated building blocks in place of 2-(bromomethyl)pyridine hydrobromide in step h):

[1069] Ex. Structure Systematic Name Building Block MS, ESI; m / z 37 9-(2,6-dimethoxyphenyl)-8-(6- 2,2,2- 492.3 ethoxy-2-pyridyl)-2-hydroxy- 1 - [M+H] i “■ trifluoroethyltriflu+\ / Ou_— (2,2,2-trifluoroethyl)purin-6-one oromethanesulfon

[1070] ate

[1071] °x

[1072] Z O / ^

[1073] 40z1 -[(5 -chloro-2-pyridyl)methyl] -9- 5-chloro-2- 533.2

[1074] (2,6-dimethoxyphenyl)-8-(6- (chloromethyl)pyr [M-H]’ N N^OH

[1075] ethoxy-2-pyridyl)-2-hydroxy- idine (CAS:

[1076] purin-6-one 70258-18-3)

[1077] o0

[1078] ) Q

[1079] Cl

[1080] 41 9-(2,6-dimethoxyphenyl)-8-(6- 2-(chloromethyl)- 515.2 ethoxy-2-pyridyl)-2-hydroxy- 1 - 5 -methylpyridine [M+H]+N^N^OH

[1081] [(5-methyl-2- hydrochloride pyridyl)methyl]purin-6-one (CAS: 71670-70- o0

[1082] 7)

[1083] ) y

[1084]

[1085] 9-(2,6-dimethoxyphenyl)-8-(6- 2-chloromethyl-4- 515.2 ethoxy-2-pyridyl)-2-hydroxy- 1 - methyl-pyridine- [M+H]+V°T ^ / / / ^ Z O z O / y z o< [(4-methyl-2- hydrochloride

[1086] kkpp z z-~ pyridyl)methyl]purin-6-one (CAS: 71670-71- kJn z

[1087] 8)

[1088] i^= O°OZ°fJ\

[1089] kf v / \ <) < o —

[1090] § yr \ / I — 9-(2,6-dimethoxyphenyl)-8-(6- 2-(chloromethyl)- 516.2 ethoxy-2-pyridyl)-2-hydroxy- 1 - 5- [M+H]+[(5-methylpyrimidin-2- methylpyrimidine yl)methyl]purin-6-one (CAS: 126504- 85-6)

[1091] 9-(2,6-dimethoxyphenyl)-8-(6- 2-methyl-6- 515.2 ethoxy-2-pyridyl)-2-hydroxy- 1 - chloromethylpyri [M+H]+[(6-methyl-2- dine

[1092] v^> o

[1093] pyridyl)methyl]purin-6-one hydrochloride

[1094] t> t> o °°° (CAS: 3099-30- Ytt C dv 7)

[1095] Zz O / O A^

[1096] 9-(2,6-dimethoxyphenyl)-8-(6- 2-chloromethyl 3- 513.3 G Voo- '- '

[1097] ethoxy-2-pyridyl)-2-hydroxy- 1 - methyl pyridine [M-H]- [(3-methyl-2- hydrochloride pyridyl)methyl]purin-6-one (CAS: 4370-22-3)

[1098] 9-(2,6-dimethoxyphenyl)-8-(6- 5- 502.2 ethoxy-2-pyridyl)-2-hydroxy- 1 - (chloromethyl)pyr [M+H]+(5-pyrimidylmethyl)purin-6-one imidine

[1099] hydrochloride

[1100] (CAS: 1337879- 54-5)

[1101]

[1102] 48 9-(2,6-dimethoxyphenyl)-8-(6- 2- 500.3 ethoxy-2-pyridyl)-2-hydroxy- 1 - (chloromethyl)pyr [M-H]- (2-pyrimidylmethyl)purin-6-one imidine (CAS:

[1103] 0

[1104] 54198-88-8)

[1105] 49 (' ' O 7 — 9-(2,6-dimethoxyphenyl)-8-(6- 2-(chloromethyl)- 516.2

[1106] \1=z

[1107] ethoxy-2-pyridyl)-2-hydroxy- 1 - 5 -methylpyrazine [M+H]+[(5-methylpyrazin-2- (CAS: 81831-68- yl)methyl]purin-6-one 7)

[1108]

[1109] Example 36

[1110] / \ XZ=

[1111] 9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-2-(2-pyridylmethyl)-lH-purin-6-one

[1112] z O A

[1113]

[1114] Step a) (2, 6-dichloro-5-nitro-pyrimidin-4-yl)-(2, 6-dimethoxyphenyl)amine

[1115] A solution of 2,4, 6-trichloro-5 -nitro-pyrimidine (CAS: 4359-87-9) (2.0 g, 8.76 mmol) in 10 mL THF (extra dry) was cooled to -78 °C. A solution of (2,6-dimethoxyphenyl)amine (1.34 g, 8.76 mmol) in 10 ml THF (extra dry) was added. Triethylamine (1.33 g, 1.83 mL, 13.1 mmol) was added dropwise and the reaction was stirred at -78 °C for 1 h. The cool reaction mixture was poured into water (300 mL) and then extracted with EtOAc. The combined organic layers were dried over Na2SO4, evaporated to dryness, redissolved in CH₂Cl₂, Isolute was added, and the mixture evaporated to dryness. The crude material was purified by flash chromatography (eluting with 0-100 % EtOAc in heptane) to yield the title compound (2050 mg, 68%) as yellow solid.MS (ESI): m / z = 345.0 [M+H]+; 'H NMR (300 MHz, CHLOROFORM-d) 8 = 7.32 - 7.28 (m, 1H), 6.64 (d, J = 8.5 Hz, 2H), 3.84 (s, 6H).

[1116] Step b) 6-benzyloxy-2-chloro-N-(2, 6-dimethoxyphenyl)-5-nitro-pyrimidin-4-amine

[1117] To a colorless solution of benzyl alcohol (2.35 g, 21.7 mmol) in THF (30 mL) was added NaH (1.04 g, 26.1 mmol) at 0 °C under N2, and the reaction mixture was stirred at 0 °C for 0.5 h. 2,6-dichloro-N-(2,6-dimethoxyphenyl)-5-nitro-pyrimidin-4-amine (7.5 g, 21.7 mmol) in THF (30 mL) was added slowly to the solution at -50 °C

[1118]

[1119] -40 °C under N2. The reaction mixture was stirred at 20 °C for 12 h. The reaction was quenched with water (300 mL) and extracted with EtOAc (3 x 300 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give a residue which was purified by reverse phase-HPLC (FA, 60% ACN) and concentrated under reduced pressure to give a crude product. EtOAc (10 mL) and petroleum ether (10 mL) were added, and the reaction stirred at room temperature for 0.5 h. The mixture was filtered and the filter cake was dried to give title compound (3.48 g, 8.35 mmol, 31% yield) as yellow solid. MS (ESI): m / z = 416.9 [M+H]+

[1120] Step c) 6-benzyloxy-2-chloro-N4-(2, 6-dimethoxyphenyl)pyrimidine-4, 5 -diamine

[1121] To a yellow suspension of 6-benzyloxy-2-chloro-N-(2,6-dimethoxyphenyl)-5-nitro-pyrimidin-4-amine (3.48 g, 8.35 mmol) in EtOH (50 mL) and water (10 mL) was added Fe (2.33 g, 41.7 mmol) and NH4CI (4.47 g, 83.5 mmol). The reaction mixture was stirred at 60 °C for 12 h. The reaction mixture was filtered and the filtrate was concentrated under vacuum to give a residue. The residue was dissolved in CH₂Cl₂ (100 mL), then filtered and the filter was concentrated under vacuum to give the title compound (3.04 g, 7.86 mmol, 84 % yield) as a brown gum, which was used directly for the next step without further purification. MS (ESI): m / z = 387.1 [M+H]+

[1122] Step d) N-[4-benzyloxy-2-chloro-6-(2,6-dimethoxyanilino)pyrimidin-5-yl]-6-ethoxy-pyridine-2-carboxamide

[1123] To a brown solution of 6-benzyloxy-2-chloro-N4-(2,6-dimethoxyphenyl)pyrimidine-4,5-diamine (2.5 g, 6.46 mmol) in DMF (30 mL) was added 6-ethoxypyridine-2-carboxylic acid (1.08 g, 6.46 mmol), DIPEA (1.67 g, 12.9 mmol) and HATU (3.69 g, 9.69 mmol) at 20 °C. The reaction mixture was stirred at 30 °C for 12 h. The reaction mixture was poured into water (200 mL) and extracted with EtOAc (3 x 200mL). The combined organic phase was washed with brine (2 x 100 mL), dried over Na2SO4, and concentrated under vacuum to give a residue, which waspurified by flash chromatography (petroleum ether: EtOAc=l:0 to 1:1) to yield a crude product.

[1124] 10 mL EtOAc was added and the mixture stirred at room temperature for 0.5 h. The mixture was filtered and the filter cake was dried to give the title compound (1.88 g, 3.51 mmol, 54% yield) as a yellow solid. MS (ESI): m / z = 536.1 [M+H]+

[1125] Step e) 6-benzyloxy-2-chloro-9-(2, 6-dimethoxyphenyl)-8-( 6-ethoxy-2-pyridyl)purine

[1126] A yellow solution of N-[4-benzyloxy-2-chloro-6-(2,6-dimethoxyanilino)pyrimidin-5-yl]-6-ethoxy-pyridine-2-carboxamide (800 mg, 1.49 mmol) in pyridine (10 mL). The air of the flask was replaced by N2 for three times, and the solution was cooled to 0 °C. POCI3 (3.15 mL, 14.9 mmol) was added drop wise under a nitrogen atmosphere at 0 °C. The mixture was stirred at 30 °C for 36 h, then was added drop wise into water (200 mL) at 20 °C, and then extracted with ethyl acetate (100 mL x 3). The combined organic phase was dried with Na₂SO₄, then concentrated under vacuum to give a residue, which was purified by reverse phase-HPLC (LA) to give the title compound (402 mg, 0.78 mmol, 43% yield) as light yellow solid. MS (ESI): m / z = 518.0 [M+H]+

[1127] Step f) 6-benzyloxy-9-(2, 6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-2-(2-pyridylmethyl)purine

[1128] A mixture of 6-benzyloxy-2-chloro-9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)purine (150 mg, 0.29 mmol), 2-[(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)methyl]pyridine (127 mg, 0.58 mmol), Ir[dF(CF₃)ppy]₂(dtbpy)(PF₆) (3.25 mg), NiCh.dtbbpy (5.76 mg, 0.01 mmol) and morpholine (37.8 mg, 0.43 mmol) in DMF (3 mL) was stirred at 25 °C for 16 h with irradiation with a 455nm blue LED. The reaction was purified by prep-HPLC (LA) and lyophilized to give 6-benzyloxy-9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-2-(2-pyridylmethyl)purine (10.0 mg, 0.02 mmol, 5% yield) as light yellow solid. MS (ESI): m / z = 575.3 [M+H]+

[1129] Step g) 9-(2, 6-dimethoxyphenyl)-8-( 6-ethoxy-2-pyridyl)-2-(2-pyridylmethyl)-lH-purin-6-one

[1130] A yellow mixture of 6-benzyloxy-9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-2-(2-pyridylmethyl)purine (9.0 mg, 0.02 mmol) in 4 M HCl in dioxane (1.0 mL, 2.0 mmol) was stirred at 50 °C for 2 h. The reaction mixture was concentrated to give a crude product, which was dissolved in MeOH (0.5 mL) and adjusted pH=7 with Na2CC>3. The crude product was purified by prep-HPLC(LA) and lyophilized to give the title compound (3.4 mg, 0.01 mmol, 44% yield) as light yellow solid. MS (ESI): m / z = 485.2 [M+H]+Example 38

[1131] 9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-2-morpholino-hypoxanthine

[1132]

[1133] Step a) ( 6-allvloxv-2-chloro-5-nitro-pyrimidin-4-vl)-(2, 6-dimethoxyphenyl)amine

[1134] (2,6-dichloro-5-nitro-pyrimidin-4-yl)-(2,6-dimethoxyphenyl)amine (Example 36, Step a) (5250 mg, 14.2 mmol) was dissolved in 50 ml of THF (extra dry) and cooled to -60 °C. In a separate flask, NaH (60% dispersion in mineral oil) (1.7 g, 21.2 mmol) was dissolved in 6 mL THF (extra dry) and allyl alcohol (822 mg, 962 pL, 14.2 mmol) was added dropwise at 0°C, and the mixture stirred for 10 min. The alkoxide solution was added dropwise to the solution of the nitroaryl at -60 °C, and the reaction was stirred at this temperature for 1 h, before warming to room temperature and stirring for 2 h. The reaction was carefully quenched with water and extracted with CH₂Cl₂. The organic layers were dried over Na₂SO₄ and concentrated to dryness, to yield a crude product which was used directly for the next step without further purification. MS (ESI): m / z = 367.1 [M+H]+

[1135] Step b) ( 6-allyloxy-5-amino-2-chloro-pyrimidin-4-yl)-(2, 6-dimethoxyphenyl)amine

[1136] (6-allyloxy-2-chloro-5-nitro-pyrimidin-4-yl)-(2,6-dimethoxyphenyl)amine (5950 mg, 9.41 mmol) was suspended in ethanol (82.2 mL) and water (16.4 mL). NH4CI (5.03 g, 94 mmol) and iron (2.63 g, 47.1 mmol) were added and the reaction was stirred at 90 °C for 2 h. The suspension was filtered over Dicalite® and rinsed with MeOH. The filtrate was concentrated, and the residue dissolved in CH₂Cl₂, loaded onto Isolute and purified by flash chromatography (eluting with 0-90% EtOAc in heptane) to give the title compound (2.1 g, 54% yield) as a yellow powder. MS (ESI): m / z = 337.1 [M+H]+

[1137] Step c) N- [4-allyloxy-2-chloro-6-(2,6-dimethoxyanilino)pyrimidin-5-yl] -6-ethoxy-picolinamide6-ethoxypicolinic acid (1.63 g, 9.74 mmol) was dissolved in 300 pl of DMF. HATU (4.44 g, 11.7 mmol) and DIEA (1.51 g, 2.04 mL, 11.7 mmol) were added and the reaction was stirred at 45 °C for 2 h. (6-allyloxy-5-amino-2-chloro-pyrimidin-4-yl)-(2,6-dimethoxyphenyl)amine (1600 mg, 3.9 mmol) was added and the reaction was stirred at 45 °C for 2 h. The reaction mixture was purified by flash chromatography (eluting with 0-30 % EtOAc in heptane), followed by further purification by reverse phase HPLC (5-100 % acetonitrile in water). The title compound (1400 mg, 69%) was isolated as light yellow solid. MS (ESI): m / z = 486.1 [M+H]+

[1138] Step d) 6-allyloxy-2-chloro-9-(2, 6-dimethoxyphenyl)-8-( 6-ethoxy-2-pyridyl)purine

[1139] A solution of N-[4-allyloxy-2-chloro-6-(2,6-dimethoxyanilino)pyrimidin-5-yl]-6-ethoxy-picolinamide (1400 mg, 2.68 mmol) in pyridine (18.6 mL) was cooled to 0 °C and phosphorus oxychloride (4.11 g, 2.5 mL, 26.8 mmol) was added dropwise. The ice bath was removed and the reaction was stirred at 70 °C for 7 h, and then at 60 °C for 16 h. The reaction mixture was cooled to room temperate, and added dropwise to water (400 mL), with temperature maintained below 60 °C. The reaction was cooled to room temperature, and extracted with EtOAc. The combined organic layers were dried over Na₂SO₄ and concentrated to give a residue which was loaded onto Isolute and purified by flash chromatography (eluting with 0-60% EtOAc in heptane) to give the title compound (560 mg, 40 %) as a light yellow powder. MS (ESI): m / z = 468.2 [M+H]+

[1140] Step e) 9-(2, 6-dimethoxyphenyl)-8-( 6-ethoxy-2-pyridyl)-2-morpholino-hypoxanthine

[1141] In a vial, flushed with argon, 6-allyloxy-2-chloro-9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)purine (50 mg, 96.2 pmol) was dissolved in 1,4-dioxane (extra dry) (481 pL), and methanesulfonamide (22.9 mg, 240 pmol) and cesium carbonate (94.0 mg, 289 pmol) were added. The reaction was degassed with nitrogen for 1-2 min and [tBuXPhos Pd(allyl)]OTf (3.53 mg, 4.81 pmol) was added, and the reaction was stirred at 100 °C for 3 h. A further addition of [tBuXPhos Pd(allyl)]OTf (7.05 mg, 9.62 pmol) was made and the reaction was stirred for 1 h at 100 °C. Morpholine (100 mg, 100 pL, 1.15 mmol) was added and the reaction was stirred at room temperature for 45 min, followed by 90 °C for 16 h. The reaction was cooled to room temperature, diluted with dioxane and filtered via syringe and concentrated under reduced pressure. The residue was dissolved in DMSO (2 mL) and purified by reversed phase HPLC (5-100 % acetonitrile in water). The title compound was isolated as a light brown solid (8 mg, 17 %). MS (ESI): m / z = 479.2 [M+H]+Note: N-[9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-6-keto-lH-purin-2-yl]methanesulfonamide was also isolated (11.5 mg, 15 %) as light brown solid. MS (ESI): m / z = 487.1 [M+H]+

[1142] The following Examples were generated in analogy to the sequence Example 36, Step a) / Example 38 Steps a-d), using the indicated building blocks in place of 2,4,6-trichloro-5-nitro-pyrimidine in Example 36 Step a)

[1143] Ex. Structure Systematic Name Building Block MS, ESI; m / z 39 9-(2,6-dimethoxyphenyl)-8-(6- 4,6-dichloro-2- 440.2 ethoxy-2-pyridyl)-2- (methylthio)-5- [M+H]+(methylthio)hypoxanthine nitropyrimidine

[1144] (CAS: 1979-96-0)

[1145]

[1146] QTZZ

[1147] Example 46 z O A

[1148] Go--7'-9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-2-(methylthio)-l-(2-pyridylmethyl)purin-6-one

[1149]

[1150] 9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-2-(methylthio)hypoxanthine (Example 39) (50 mg, 114 pmol) was dissolved in N, N-dim ethylformamide (877 pL), and the solution was cooled to 0 °C. NaH (60% dispersion in mineral oil) (11.4 mg, 284 pmol) and lithium bromide (29.6 mg, 341 pmol) were added, and the reaction stirred for 10 min at 0 °C. 2-(bromomethyl)pyridine hydrobromide (43.2 mg, 171 pmol) was added. The reaction was stirred for 10 min at 0 °C, after which the reaction was heated to 40 °C and stirred overnight. The reaction was quenched withsat. aq. NH4CI solution, and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4and concentrated under reduced pressure to yield the title compound as orange solid (62 mg, 92%). MS (ESI): m / z = 531.2 [M+H]+

[1151] Note: crude product could be used directly without further purification, or further purified by HPLC to yield a white solid.

[1152] Examples 50 and 51

[1153] 9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-2-hydroxy-l-methyl-purin-6-one and N-[9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-6-keto-l-methyl-purin-2-yl] benzenesulfonamide

[1154] and

[1155]

[1156] Step a) 9-(2, 6-dimethoxyphenyl)-8-( 6-ethoxy-2-pyridyl)-l-methyl-2-(methylthio)purin-6-one

[1157] 9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-2-(methylthio)hypoxanthine (Example 39) (50 mg, 111 pmol) was dissolved in N, N-dim ethylformamide (860 pL) and the solution was cooled to 0 °C. NaH (6.69 mg, 167 pmol) and lithium bromide (29.1 mg, 334 pmol) were added, and the reaction was stirred for 10 min at 0 °C. lodomethane (47.5 mg, 20.9 pL, 334 pmol) was added and the reaction was stirred at 0 °C for 30 min. The reaction was heated to 40 °C and stirred for 50 min. The reaction was cooled, quenched with sat. aq. Na₂S₂O₃ solution and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO₄, and concentrated in vacuo to yield the title compound as light brown solid (46 mg, 73%) which was used directly in the next step without further purification. MS (ESI): m / z = 454.3 [M+H]+

[1158] Step b) 9-(2, 6-dimethoxyphenyl)-8-( 6-ethoxy-2-pyridyl)-2-mesyl-l-methyl-purin-6-one

[1159] 9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-l -methyl-2-(methylthio)purin-6-one (46 mg, 0.081 mmol) was dissolved in dichloromethane (500 pL), 3 -chloroperoxybenzoic acid (>70% purity) (42.0 mg, 243 pmol) was added, and the reaction was stirred at room temperatureovernight. The reaction was quenched with sat. aq. Na₂S₂O₃ solution and extracted with CH₂Cl₂. The organics were washed with 1 N NaOH aq. solution, dried over MgSO₄, and concentrated in vacuo, to yield the title compound as light yellow solid (24 mg, 49%), which was used directly in the next step without further purification. MS (ESI): m / z = 486.5 [M+H]+

[1160] Step c) 9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-2-hydroxy-l-methyl-purin-6-one and A-[9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-6-keto-l-methyl-purin-2-yl]benzenesulfonamide

[1161] 9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-2-mesyl-l-methyl-purin-6-one (26 mg, 26.8 pmol) was dissolved in N, N-dimethylformamide, extra dry (300 pL), and benzenesulfonamide (12.6 mg, 80.3 pmol) and potassium carbonate (37.0 mg, 268 pmol) were added. The reaction was stirred at 65 °C overnight, cooled to room temperature, diluted with 1 H HC1 aq. solution, and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO₄, concentrated in vacuo and purified by reverse phase HPLC to yield the title compounds: 9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-2-hydroxy-l-methyl-purin-6-one (3.4 mg, 29%) as an off-white solid, MS (ESI): m / z = 424.2 [M+H]+; and N-[9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-6-keto-l-methyl-purin-2-yl]benzenesulfonamide (6 mg, 39%) as an off-white solid, MS (ESI): m / z = 563.2 [M+H]+.

[1162] Example 52

[1163] 3- [9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-6-oxo-purin-l-yl] propanoic acid

[1164]

[1165] Step a) 9-(2, 6-dimethoxyphenyl)-8-( 6-ethoxy-2-pyridyl)-l-methyl-2-(methylthio)purin-6-one

[1166] To a light yellow solution of 9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-lH-purin-6-one (Example 7) (50.0 mg, 0.13 mmol) in DMF (2 mL) was added ethyl 3 -bromopropionate (34.5 mg, 0.19 mmol), K2CO3 (52.7 mg, 0.38 mmol) in sequence at room temperature. The reaction mixture was stirred at 50 °C for 12 h. The reaction mixture was cooled to room temperature, poured into water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase waswashed with brine (8 mL), dried over Na₂SO₄, and concentrated in vacuum to give a residue which was purified by flash chromatography (eluting with petroleum ether / EtOAc =100 - 0%) to yield the title compound (30.0 mg, 0.06 mmol, 48% yield) as a light yellow solid, MS (ESI): m / z = 494.2 [M+H]+.

[1167] Step b) 3-[9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-6-oxo-purin-l-yl]propanoic acid

[1168] Ethyl 3-[9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-6-oxo-purin-l-yl]propanoate (30.0 mg, 0.06 mmol) was dissolved in THF (0.9 mL) and water (0.3 mL). Lithium hydroxide monohydrate (7.65 mg, 0.18 mmol) was added to the reaction mixture at room temperature, and reaction mixture was stirred at 0 °C for 0.5 h. The reaction mixture was adjusted pH to 3 with IM HC1 (aq.) (0.2 mL) and extracted with EtOAc (15 mL x 3). The organic phase was washed with brine (5 mL), dried over Na₂SO₄, and concentrated in vacuo to give a residue, which was purified by prep-HPLC (FA) to yield the title compound (11.0 mg, 0.02 mmol, 39%) as an off-white solid. MS (ESI): m / z = 466.1 [M+H]+.

[1169] Example 53

[1170] l-benzyl-9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-2-hydroxy-purin-6-one

[1171] O OH

[1172] yNN

[1173] O

[1174]

[1175] Step a) l-benzyl-9-(2, 6-dimethoxyphenyl)-8-( 6-ethoxy-2-pyridyl)-2-(methylthio)purin-6-one

[1176] 9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-2-(methylthio)hypoxanthine (Example 39) (65 mg, 145 pmol ) was dissolved in N, N-dim ethylformamide, extra dry (1.08 mL), and the reaction was cooled to 0 °C. NaH (60% dispersion in mineral oil) (14.5 mg, 362 pmol) and lithium bromide (37.8 mg, 435 pmol) were added, and the reaction was stirred for 10 min at 0 °C.

[1177] Benzyl bromide (37.2 mg, 25.9 pL, 217 pmol) was added and the reaction was stirred at 0 °C for 5 min. The reaction was heated to 40 °C for 1 h, and then at 65 °C overnight. The reaction mixture was quenched with sat. aq. NH4CI solution and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4and concentrated in vacuo to yield the title compounda yellow viscous oil (73 mg, 48%) which was used directly in the next step without further purification. MS (ESI): m / z = 430.2 [M+H]+.

[1178] Step b) l-benzyl-9-(2, 6-dimethoxyphenyl)-8-( 6-ethoxy-2-pyridyl)-2-mesyl-purin-6-one

[1179] 1 -benzyl-9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-2-(methylthio)purin-6-one (73 mg, 0.138 mmol) was dissolved in dichloromethane, extra dry (700 pL). 3 -chloroperoxybenzoic acid (77.2 mg, 345 pmol) was added and the reaction was stirred at room temperature overnight. The reaction was quenched with sat. aq. Na₂S₂O₃ solution and extracted with dichloromethane. The organic layer was washed with 1 N NaOH aq. solution, dried over MgSO4, and concentrated in vacuo to yield the title compound as off-white solid (67 mg, 69%) which was used directly in the next step without further purification. MS (ESI): m / z = 562.2 [M+H]+.

[1180] Step c) l-benzyl-9-(2, 6-dimethoxyphenyl)-8-( 6-ethoxy-2-pyridyl)-2-hydroxy-purin-6-one

[1181] l-benzyl-9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-2-mesyl-purin-6-one (67 mg, 0.119 mmol) was dissolved in 1,4-dioxane, extra dry (500 pL). 4 MNaOH aq. solution (298 pL, 1.19 mmol) was added, and the reaction was heated to 65 °C overnight. The reaction mixture was cooled, concentrated under vacuo and quenched with 1 N HC1 aq. solution. The resultant aqueous solution was extracted with EtOAc. The organic layer was washed with brine, dried Z O J^

[1182] over MgSO4, concentrated in vacuo, and the residue purified using HPLC to to yield the title compound as off-white solid (6.3 mg, 10%). MS (ESI): m / z = 500.3 [M+H]+.

[1183] The following Examples were generated in analogy to the sequence Example 53, using the indicated building blocks in place of benzyl bromide in Step a):

[1184] Ex. Structure Systematic Name Building Block MS, ESI; m / z 55 1 -(cyclopropylmethyl)-9-(2,6- (chloromethyl)cy 464.3 dimethoxyphenyl)-8-(6-ethoxy-2- clopropane (CAS: [M+H]+pyridyl)-2-hydroxy-purin-6-one 5911-08-0)

[1185]

[1186] Example 54

[1187] 9-(2,4-dimethoxy-3-pyridyl)-8-(6-ethoxy-2-pyridyl)-2-hydroxy-l-(2-pyridylmethyl)purin-6-one

[1188] \\ /

[1189] Z"'O

[1190] O N OH

[1191]

[1192] Step a) 6-allyloxy-9-(2,4-dimethoxy-3-pyridyl)-8-(6-ethoxy-2-pyridyl)-2-(methylthio)purine

[1193] Generated in analogy to Example 39 (Sequence of Example 36, Step a) / Example 38), using 4,6-dichloro-2-(methylthio)-5 -nitropyrimidine and (2,4-dimethoxy-3-pyridyl)amine (CAS: 217096-31-6) in the first step (equivalent of Example 36, Step a)).

[1194] Step b) 6-allyloxy-9-(2, 4-dimethoxy-3-pyridyl)-8-(6-ethoxy-2-pyridyl)-2-mesyl-purine

[1195] 6-allyloxy-9-(2,4-dimethoxy-3-pyridyl)-8-(6-ethoxy-2-pyridyl)-2-(methylthio)purine (240 mg, 499 pmol) was dissolved in dichloromethane (2.5 mL) and 3 -chloroperoxybenzoic acid (264 mg, 1.15 mmol) was added. The yellow suspension was stirred at 23 °C for 30 min. The reaction was quenched with 10% aq. Na₂S₂O₃ solution, diluted with sat. aq. NaHCO3 solution and extracted with dichloromethane. The organic layer was dried over Na₂SO₄, and concentrated to dryness. The title compound (225 mg, 86%) was isolated as a light yellow powder, and was used directly in the next step without further purification. MS (ESI): m / z = 513.2 [M+H]+.

[1196] Step c) 9-(2, 4-dimethoxy-3-pyridyl)-8-( 6-ethoxy-2-pyridyl)-2-p-anisyloxy-hypoxanthine

[1197] In a vial 6-allyloxy-9-(2,4-dimethoxy-3-pyridyl)-8-(6-ethoxy-2-pyridyl)-2-mesyl-purine (225 mg, 430 pmol) was dissolved in tetrahydrofuran, extra dry (2.15 mL). KOtBu (98.5 mg, 860 pmol) and 4-methoxybenzyl alcohol (89.2 mg, 80.3 pL, 645 pmol) were added. The reaction was degassed before the addition of [tBuXPhos Pd(allyl)]OTf (30.3 mg, 40.4 pmol), the vial sealed and stirred at 70°C for 16 h. The reaction was diluted with THF and filtered via syringe.The filter cake was washed with dichloromethane and MeOH, and the filtrate was concentrated to dryness to yield the title compound (125 mg, 53 %) as an off-white powder, which was used directly in the next step without further purification. MS (ESI): m / z = 531.2 [M+H]+.

[1198] Step d) 9-(2, 4-dimethoxy-3-pyridyl)-8-( 6-ethoxy-2-pyridyl)-2-hydroxy-l-(2-pyridylmethyl)purin-6-one

[1199] In a vial, flushed with nitrogen, 9-(2,4-dimethoxy-3-pyridyl)-8-(6-ethoxy-2-pyridyl)-2-p-anisyloxy-hypoxanthine (40 mg, 72.4 pmol) was dissolved in N, N-dim ethylformamide (659 pL) and cooled to 0 °C. NaH (60% dispersion in mineral oil) (4.34 mg, 109 pmol) was added at 0 °C, and the reaction was stirred for 10 min. Lithium bromide (25.1 mg, 290 pmol) was added and the reaction was stirred at room temperature for 10 min. 2-(bromomethyl)pyridine hydrobromide (CAS: 31106-82-8) (24.9 mg, 145 pmol) was added, and the suspension was stirred at 65 °C for 3.5 h. The reaction was cooled, quenched with water (300 pL) and purified by prep HPLC. The title compound (11 mg, 30%) was isolated as white powder. MS (ESI): m / z = 500.3 [M-H];

[1200] Example 56

[1201] 9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-2-[(N-methyl-S-phenyl-sulfonimidoyl)amino]-lH-purin-6-one

[1202]

[1203] Step a) 4,6-dimethoxy-5-nitroso-pyrimidin-2-amine

[1204] To a colorless solution of 2-amino-4,6-dimethoxypyrimidine (CAS: 36315-01-2) (10.0 g, 64.5 mmol) in DMSO (160 mL) was added isopentyl nitrite (8.31 g, 70.9 mmol), the resulting mixture was stirred at 25 °C for 96 h. The deep blue solution was poured into water (800 mL) and stirred for 1 h at room temperature. The resulting precipitate was filtered and washed with water (300 mL). The title compound (10.8 g, 58.7 mmol, 82% yield) was obtained as a blue solid, which was used directly in the next step without further purification. MS (ESI): m / z = 185.0 [M+H]+.

[1205] Step b) N4-(2, 6-dimethoxyphenyl)-6-methoxy-5-nitroso-pyrimidine-2, 4-diamineTo a blue suspension of 4,6-dimethoxy-5-nitroso-pyrimidin-2-amine (5.0 g, 26.9 mmol) in water (500 mL) was added 2,6-dimethoxyaniline (3.29 g, 21.5 mmol) at room temperature, and the mixture was stirred at 80 °C for 16 h. The reaction mixture was cooled to room temperature, filtered and the filter cake was washed with 50 mL of water, and lyophilized. The title compound (2.6 g, 8.52 mmol, 19% yield) was obtained as a black solid, which was used directly in the next step without further purification. MS (ESI): m / z = 306.2 [M+H]+.

[1206] Step c) N4-(2,6-dimethoxyphenyl)-6-methoxy-pyrimidine-2,4,5-triamine

[1207] To a black suspension of N4-(2,6-dimethoxyphenyl)-6-methoxy-5-nitroso-pyrimidine-2,4-diamine (2.3 g, 4.52 mmol) in isopropylalcohol (40 mL) was added Pd / C (481 mg, 0.45 mmol) at room temperature under argon atmosphere. The reaction was then placed under a hydrogen atmosphere (2586 mmHg) and stirred at 50 °C for 2 h. The reaction mixture was filtered by diatomaceous earth under a nitrogen atmosphere, and the filtrate was concentrated to give a crude product, which was purified by reversed phase-HPLC (0.1% FA) to yield the title compound (300 mg, 1.03 mmol, 17%) as a yellow solid. MS (ESI): m / z = 292.2 [M+H]+.

[1208] Step d) 9-(2, 6-dimethoxyphenyl)-8-( 6-ethoxy-2-pyridyl)-6-methoxy-purin-2-amine

[1209] To a black solution of N4-(2,6-dimethoxyphenyl)-6-methoxy-pyrimidine-2,4,5-triamine (600 mg, 1.75 mmol) in methanol (6 mL) was added 6-ethoxypyridine-2-carbaldehyde (CAS: 85259-47-8) (265 mg, 1.75 mmol) at room temperature. The mixture was stirred at 60 °C for 12 h, then cooled to room temperature, and concentrated in vacuo. The residue was purified by prep-HPLC (0.1% FA) and lyophilized to give the title compound (410 mg, 47%) as light brown solid. MS (ESI): m / z = 423.1 [M+H]+.

[1210] Step e) 9-(2, 6-dimethoxyphenyl)-8-( 6-ethoxy-2-pyridyl)-2-iodo-6-methoxy-purine

[1211] To a suspension of 9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-6-methoxy-purin-2-amine (160 mg, 0.38 mmol) in THF (2 mL) was added CH2I2 (507 mg, 1.89 mmol) and Cui (72.1 mg, 0.38 mmol) at room temperature. The reaction mixture was degassed by N2 for three times and cooled to 0 °C. Isopentyl nitrite (133 mg, 1.14 mmol) was added, and reaction mixture was stirred at 70 °C for 1 h under N2. The reaction mixture was cooled to room temperature, poured into water (20 mL) and extracted with EtOAc (3 x 15 mL). The organic phase was washed with brine (10 mL), dried over Na2SO4, and concentrated in vacuo to give a residue which was purified by reverse phase HPLC and lyophilized to yield the title compound (110 mg, 0.21 mmol, 55%) as white solid. MS (ESI): m / z = 534.0 [M+H]+.Step f) 9-(2, 6-dimethoxyphenyl)-8-( 6-ethoxy-2-pyridyl)-6-methoxy-N-(N-methyl-S-phenyl-sulfonimidoyl)purin-2 -amine

[1212] To a suspension of 9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-2-iodo-6-methoxy-purine (80.0 mg, 0.15 mmol) in 1,4-dioxane (2 mL) was added (S-amino-N-methyl-sulfonimidoyl)benzene (A.2) (76.6 mg, 0.45 mmol), CS2CO3 (146 mg, 0.45 mmol), (R, R)-1,2-bis(N-methylamino)cyclohexane (42.6 mg, 0.3 mmol) and Cui (14.3 mg, 0.08 mmol) in sequence at room temperature. The reaction mixture was degassed by N2 three times and then stirred at 80 °C for 16 h. The reaction mixture was cooled to room temperature, poured into water (20 mL) and extracted with ethyl acetate (15 mL x 3). The organic phase was washed with brine (10 mL) dried over Na₂SO₄ and concentrated in vacuo to give a residue which was purified by preparative TLC (eluting with EtOAc) to give the title compound (25.0 mg, 0.04 mmol, 29%) as light yellow gum. MS (ESI): m / z = 576.2 [M+H]+.

[1213] Step g) 9-(2, 6-dimethoxyphenyl)-8-( 6-ethoxy-2-pyridyl)-2-[ (N-methyl-S-phenyl-sulfonimidoyl)amino]-lH-purin-6-one

[1214] To a reaction mixture of 9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-6-methoxy-N-(N-methyl-S-phenyl-sulfonimidoyl)purin-2-amine (25.0 mg, 0.04 mmol) in MeCN (1 mL) was added sodium iodide (32.6 mg, 0.22 mmol) at room temperature. Trimethylsilyl iodide (43.5 mg, 0.22 mmol) was added to mixture at 0 °C under N2. The reaction mixture was stirred at 20 °C for 1 h, poured into water (20 mL) and extracted with EtOAc (15 mL x 3). The organic phase was washed with brine (10 mL), dried over Na2SO4, and concentrated in vacuo to give a residue which was purified by prep-HPLC(FA) and lyophilized to yield the title compound (14.6 mg, 0.03 mmol, 60% yield) as yellow solid. MS (ESI): m / z = 562.2 [M+H]+.

[1215] Example 57

[1216] 2-cyclopentyl-3-(2,6-dimethoxyphenyl)-5-hydroxy-6-(2-pyridylmethyl)pyrazolo[4,3-d]pyrimidin-7-one

[1217] N

[1218] N

[1219]

[1220] Step a) methyl l-cyclopentyl-4-nitro-pyrazole-3-carboxylate

[1221] To a yellow solution of methyl 4-nitro-lH-pyrazole-3-carboxylate (CAS: 138786-86-4) (10.0 g, 58.4 mmol) in DMF (100 mL) was added potassium carbonate (16.2 g, 117 mmol) at 0 °C under N2. The reaction was stirred at 0°C for 0.5 h, then cyclopentyl bromide (10.5 g, 70.1 mmol) was added. The mixture was allowed to warm to room temperature and was stirred at 25 °C for 12 h. The reaction mixture was quenched by water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic phase was washed with brine (30 mL), dried over Na₂SO₄ and concentrated under vacuum to give a residue which was purified by flash chromatography (eluting with 50-55% EtOAc in petroleum ether). The title compound (8.6 g, 36.0 mmol, 61 %) was obtained as yellow oil. MS (ESI): m / z = 240.2 [M+H]+.

[1222] Step b) methyl 4-amino-l-cyclopentyl-pyrazole-3-carboxylate

[1223] To a solution of methyl l-cyclopentyl-4-nitro-pyrazole-3 -carboxylate (7.6 g, 31.8 mmol) in EtOH (80 mL) and water (8 mL) was added Fe (8.87 g, 159 mmol) and NH4CI (17.0 g, 318 mmol), and the mixture was stirred at 70 °C for 12 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue which was purified by flash chromatography (60-70% EtOAc in petroleum ether) to give the title compound (5.4 g, 25.8 mmol, 81%) as brown oil. MS (ESI): m / z = 210.2 [M+H]+.

[1224] Step c) methyl 4-amino-l-cyclopentyl-5-iodo-pyrazole-3-carboxylate

[1225] To a colorless solution of methyl 4-amino-l-cyclopentyl-pyrazole-3 -carboxylate (5.0 g, 23.9 mmol) in AcOH (50 mL) was added NIS (5.38 g, 23.9 mmol) at 25 °C. The mixture was stirred at 60 °C for 2 h, poured into sat. aq. NaHCOs solution (200 mL) (Caution: gas release!), and the pH adjusted to pH 8. The aqueous phase was extracted with EtOAc (100 mL x 3), then the combined organic phase was washed with brine (100 mL x 3), dried over Na2SO4, filtered and concentrated under vacuum to give a residue which was purified by flash chromatography (45-50% EtOAc in petroleum ether) to give the title compound (6.6 g, 19.7 mmol, 73% yield) as yellow solid. MS (ESI): m / z = 336.1 [M+H]+.

[1226] Step d) 4-amino-l-cyclopentyl-5-iodo-pyrazole-3-carboxylic acid

[1227] Lithium hydroxide monohydrate (2.48 g, 59.1 mmol) was added to a suspension of methyl 4-amino-l-cyclopentyl-5-iodo-pyrazole-3 -carboxylate (6.6 g, 19.7 mmol) in MeOH (25 mL), tetrahydro furan (25 mL) and water (25 mL) at 20 °C, and stirred at this temperature for 12h. The mixture was adjusted pH to 5 by addition of 1 N HC1 (aq.). The mixture was poured into water (50 mL) and extracted EtOAc (100 mL x 3). The combined organic phase was washed with brine (100 mL x 3), dried over Na2SO4, filtered and concentrated under vacuum to give a the title compound (4.6 g, 14.3 mmol, 73% yield) as yellow solid, which was used directly in the next step without further purification. MS (ESI): m / z = 322.1 [M+H]+.

[1228] Step e) 4-amino-l-cyclopentyl-5-iodo-N-(2-pyridylmethyl)pyrazole-3-carboxamide

[1229] To a solution of 4-amino-l-cyclopentyl-5-iodo-pyrazole-3-carboxylic acid (1.0 g, 3.11 mmol) and 2-(aminomethyl)pyridine (0.34 g, 3.11 mmol) in DCM (10 mL) was added HATU (1.1 g, 4.67 mmol) and N, N-diisopropylethylamine (1.63 mL, 9.34 mmol). The mixture was stirred at 30 °C for 12 h, then concentrated to give a residue which was purified by flash chromatography (eluting with 58-60% EtOAc in petroleum ether) to give the title compound (1.2 g, 2.92 mmol, 94% yield) as brown oil. MS (ESI): m / z = 412.2 [M+H]+.

[1230] Step f) 2-cyclopentyl-5-hydroxy-3-iodo-6-(2-pyridylmethyl)pyrazolo[4,3-d]pyrimidin-7-one

[1231] A solution of 4-amino-l-cyclopentyl-5-iodo-N-(2-pyridylmethyl)pyrazole-3-carboxamide (1.1 g, 2.67 mmol) and triethylamine (1.86 mL, 13.4 mmol) in dichloromethane (15 mL) was cooled to 0°C, and bis(trichloromethyl) carbonate (0.63 g, 2.14 mmol) was added slowly. The mixture was allowed to warm to 25 °C and stirred for 1 h, then quenched by slow addition of sat. aq. NaHCO3 solution (100 mL), and the reaction mixture was stirred for 30 min. The mixture was extracted with EtOAc (30 mL x 3). The combined organic phase was washed with brine (30 mL x 3), dried over Na2SO4, filtered and concentrated under vacuum to give a residue which was purified by reverse phase HPLC (water (0.1%FA)-acetonitrile) and lyophilized to give the title compound (300 mg, 0.69 mmol, 23% yield) as yellow solid. MS (ESI): m / z = 438.2 [M+H]+.

[1232] Step g) 2-cyclopentyl-3-(2, 6-dimethoxyphenyl)-5-hydroxy-6-(2-pyridylmethyl)pyrazolo[ 4,3-d ] pyrim idin -7 -on e

[1233] To a solution of 2,6-dimethoxyphenylboronic acid (175 mg, 0.96 mmol) in THE (3 mL) were added 2-cyclopentyl-5-hydroxy-3-iodo-6-(2-pyridylmethyl)pyrazolo[4,3-d]pyrimidin-7-one (280 mg, 0.64 mmol), K3PO4 (408 mg, 1.92 mmol) and Sphos-Pd-G3 (50 mg, 0.06 mmol). The flask was placed under nitrogen and the reaction was stirred at 80 °C for 12 h. The reaction was cooled to room temperature, filtered and the filtrate was concentrated in vacuo. The residue was purified by prep-HPLC (LA) and lyophilized to give the title compound (43.7 mg, 0.1 mmol, 15 % yield) as a light yellow solid. MS (ESI): m / z = 448.2 [M+H]+.Example 58

[1234] 8-(4-chloro-6-ethoxy-2-pyridyl)-9-(2,6-dimethoxyphenyl)-2-hydroxy-l-[(6-methyl-2-pyridyl)methyl] purin-6-one

[1235]

[1236] Step a) N- [4-allyloxy-6-(2,6-dimethoxyanilino)-2-(methylthio)pyrimidin-5-yl] -4-chloro-6-ethoxy-picolinamide

[1237] Et3N (131 mg, 180 pL, 1.29 mmol) was added to a solution of [6-allyloxy-5-amino-2-(methylthio)pyrimidin-4-yl]-(2,6-dimethoxyphenyl)amine (Example 26, Step c) (450 mg, 1.29 mmol) in dichloromethane (5 mL) at 0 °C. A solution of 4-chloro-6-ethoxy-pyridine-2-carbonyl chloride (A.10) (426 mg, 1.94 mmol) in dichloromethane (1 mL) was added dropwise, and the reaction was stirred for 5 min at 0 °C, then 10 min at room temperature. The reaction was quenched with MeOH and purified by flash chromatography (eluting with 0% - 40% EtOAc in heptane). A further purification by flash chromatography (eluting with 15% EtOAc in heptane) yielded the title compound (183 mg) as a yellow solid; MS (ESI): m / z = 532.5 [M+H]+.

[1238] Step b) 6-allyloxy-8-(4-chloro-6-ethoxy-2-pyridyl)-9-(2, 6-dimethoxyphenyl)-2- (methylthio)purine

[1239] N-[4-allyloxy-6-(2,6-dimethoxyanilino)-2-(methylthio)pyrimidin-5-yl]-4-chloro-6-ethoxy-picolinamide (183 mg, 334 pmol) was suspended in acetonitrile (3 mL) and DMAP (84.1 mg, 688 pmol) followed by pyridine (272 mg, 278 pL, 3.44 mmol) were added, and the reaction stirred for 15 min. Phosphorus oxychloride (185 mg, 112 pL, 1.2 mmol) was added dropwise and the suspension stirred atRT for 1 h. Et3N (169 mg, 233 pL, 1.67 mmol) was added and stirred for 1 hour at RT, then heated to 50 °C for 16 hours. The reaction was poured into MeOH, the material loaded onto Isolute, evaporated to dryness, and purified by flash chromatography (eluting with 0-15% EtOAc in heptane) to give the title compound (150 mg, 87 %) as white solid; MS (ESI): m / z = 514.5 [M+H]+.Step c) 8-(4-chloro-6-ethoxy-2-pyridyl)-9-(2, 6-dimethoxyphenyl)-2-(methylthio)hypoxanthine

[1240] 6-allyloxy-8-(4-chloro-6-ethoxy-2-pyridyl)-9-(2,6-dimethoxyphenyl)-2-(methylthio)purine (150 mg, 292 pmol) was dissolved in dichloromethane (1.26 mL) and morpholine (254 mg, 254 pL, 2.92 mmol) and tetrakis(triphenylphosphine)palladium(0) (6.74 mg, 5.84 pmol) were added and the reaction was stirred for 5 min at RT. The material was loaded onto Isolute, evaporated to dryness and purified by flash chromatography (eluting with 0-40% EtOAc in dichloromethane) to give the title compound (100 mg, 72%) as white solid; MS (ESI): m / z = 474.2 [M+H]+.

[1241] Step d) 8-(4-chloro-6-ethoxy-2-pyridyl)-9-(2,6-dimethoxyphenyl)-l-[(6-methyl-2-pyridyl)methyl]-2-(methylthio)purin-6-one

[1242] LiHMDS (1 M in THF) (528 pL, 528 pmol) was added to a suspension of 8-(4-chloro-6-ethoxy-2-pyridyl)-9-(2,6-dimethoxyphenyl)-2-(methylthio)hypoxanthine (100 mg, 211 pmol) in tetrahydrofuran (2 mL), and the reaction stirred for 10 min. 2-(bromomethyl)-6-methyl-pyridine (86.4 mg, 464 pmol) was added and the mixture stirred at 60 °C for 1 h. A further addition of 2-(bromomethyl)-6-methyl-pyridine (87.9 mg, 473 pmol) was made and the mixture stirred for 16 h at 60 °C. The material was loaded onto Isolute, evaporated to dryness and purified by flash chromatography (eluting with 0-70% EtOAc in heptane) to give the title compound (123 mg, 100 %) as white foam; MS (ESI): m / z = 579.5 [M+H]+.

[1243] Step e) 8-(4-chloro-6-ethoxy-2-pyridyl)-9-(2,6-dimethoxyphenyl)-2-hydroxy-l-[(6-methyl-2-pyridyl)m e thy I Jpurin -6-one

[1244] To a solution of 8-(4-chloro-6-ethoxy-2-pyridyl)-9-(2,6-dimethoxyphenyl)-l-[(6-methyl-2-pyridyl)methyl]-2-(methylthio)purin-6-one (123 mg, 0.212 mmol) in 1,4-dioxane (4 mL) was added 1 M aq. NaOH solution (4 mL, 4 mmol), and the mixture was stirred for 16 hours at 60 °C. The reaction mixture was poured onto water and twice with extracted with EtOAc, and the combined organics washed with water. The combined aqueous layers were acidified with formic acid to pH 5, extracted twice with EtOAc, and the combined organics were dried over Na2SO4, filtered, evaporated onto Isolute and purified by flash chromatography (eluting with 0-2% MeOH in dichloromethane) to give the title compound (74 mg, 63%) as off-white solid; MS (ESI): m / z = 549.5 [M+H]+.

[1245] The following Examples were generated in analogy to the sequence Example 58, using the indicated building blocks in Step a):Ex. Structure Systematic Name Building Block MS, ESI; m / z 59 8-(6-ethoxy-2-pyridyl)-2- 6-ethoxypyridine- 525.5 rW

[1246] . —. 'NN^ OH hydroxy-9-(5-methoxyindan-4- 2-carbonyl [M+H]+CHXA yl)-l -[(6-methyl-2- chloride; [6- pyridyl)methyl]purin-6-one allyloxy-5-amino- 2- (methylthio)pyri midin-4-yl]-(5- methoxyindan-4- yl)amine (A.3)

[1247] 60 8-(6-ethoxy-2-pyridyl)-2- 6-ethoxypyridine- 539.6 N N OH hydroxy-9-(2-isobutyl-6- 2-carbonyl [M-H]- O VN^NNK yX > methoxy -phenyl)- 1 - [(6-methy 1-2- chloride; [6- o pyridyl)methyl]purin-6-one allyloxy-5-amino- °) u

[1248] Q°°x2- (methylthio)pyri midin-4-yl]-(2- isobutyl-6- methoxy- phenyl)amine

[1249] (A.4)

[1250] 61 9-(2,6-dimethoxyphenyl)-8-(2- 2- 514.5 ethoxypyrimidin-4-yl)-2- ethoxypyrimidine [M-H]’ hydroxy- 1 - [(6-methyl-2- -4-carbonyl pyridyl)methyl]purin-6-one chloride (A.9);

[1251] [6-allyloxy-5- amino-2- (methylthio)pyri midin-4-yl]-(2,6- dimethoxyphenyl)

[1252]

[1253] amine (Example

[1254] 26, Step c)

[1255] / y o_

[1256] J' / J ' / «^ z O^ Z o 9-(2,6-dimethoxyphenyl)-8-(6- 6-ethoxy-4- 527.6 ethoxy-4-methyl-2-pyridyl)-2- methyl-pyridine- [M-H]- ^p o

[1257] hydroxy- 1 - [(6-methyl-2- 2-carbonyl

[1258] Q ° ° =

[1259] ° xxr y 8r § y pyridyl)methyl]purin-6-one chloride (A.7);

[1260] [6-allyloxy-5- amino-2- (methylthio)pyri midin-4-yl]-(2,6- dimethoxyphenyl) amine (Example

[1261] 26, Step c)

[1262] 9-(2-ethoxy-6-methoxy-phenyl)- 6-ethoxypyridine- 527.6..o£>o- 8-(6-ethoxy-2-pyridyl)-2- 2-carbonyl [M-H]’ N^ZNX / OH

[1263] C hydroxy- 1 - [(6-methyl-2- chloride; [6- \=NHNX yX >

[1264] pyridyl)methyl]purin-6-one allyloxy-5-amino- °> ° 4 2- (methylthio)pyri midin-4-yl]-(2- ethoxy-6- methoxy- phenyl)amine

[1265] (A.8)

[1266] 9-(2-ethoxy-4-methoxy-3- 6-ethoxypyridine- 528.6 pyridyl)-8-(6-ethoxy-2-pyridyl)- 2-carbonyl [M-H]’ 2-hydroxy- 1 - [(6-methyl-2- chloride; [6- pyridyl)methyl]purin-6-one allyloxy-5-amino- 2- (methylthio)pyri midin-4-yl]-(2- ethoxy-4-

[1267]

[1268] methoxy -3- pyridyl)amine

[1269] (A.5)

[1270]

[1271] Synthesis of non-commercial building blocks:

[1272] Example A.1

[1273] 6-ethoxypyridine-2-carbonyl chloride

[1274] To a solution of 6-ethoxypicolinic acid (CAS: 42955-22-6) (2.5 g, 15.0 mmol) in dichloromethane (75 mL) and N, N-dimethylformamide (10 pL) was dropwise added oxalyl chloride (2.09 g, 1.44 mL, 16.5 mmol). (Note: strong gas evolution). The reaction was stirred for 90 min at room temperature, and the product was used directly in the next step without further purification. LCMS was non-informative.

[1275] Example A.2

[1276] (S-amino-N-methyl-sulfonimidoyl)benzene

[1277] Step a) N-methylbenzenesulfinamide

[1278] To benzenesulfinyloxysodium (CAS: 873-55-2) (2.0 g, 12.2 mmol) in dichloromethane (12 mL) was added DMF (44.53 mg, 0.61 mmol) at room temperature. The reaction mixture was degassed with N2 and cooled to 0°C. Oxalyl dichloride (1.04 mL, 12.2 mmol) was added at 0 °C under N2, and the reaction was stirred at 0 °C for 2 h. The mixture was concentrated under vacuum, keeping temperature below 30 °C. The residue was dissolved in dichloromethane (2 mL).

[1279] In a separate flask, Et₃N (2.47 g, 24.4 mmol) and methylamine hydrochloride (987 mg, 14.6 mmol) in dichloromethane (10 mL) were stirred at room temperature for 10 min. The dichloromethane solution of the initially generated residue was added to the mixture at 0°C under N2. The reaction was slowly warmed to 20°C, and stirred at 20 °C for 16 h. The reaction mixture was poured into water (50 mL) and extracted with dichloromethane (40 mL x 3). The organic phase was washed with brine (30 mL), dried over Na₂SO₄, and concentrated in vacuo to give a residue which purified by flash chromatography (petroleum ether / EtOAc=l / 0 to 1 / 1) and concentrated under reduced pressure to give the title compound (420 mg, 2.71 mmol, 22%) aslight yellow oil. 'H NMR (400 MHz, DMSO-d6) 8 = 7.81 - 7.73 (m, 2H), 7.67 - 7.59 (m, 3H), 7.45 (br d, J = 4.4 Hz, 1H), 2.40 (d, J = 5.0 Hz, 3H)

[1280] Step b) chloro-methylimino-oxo-phenyl-X6-sulfane

[1281] N-methylbenzenesulfinamide (100 mg, 0.64 mmol) was dissolved in acetonitrile (2 mL) and the reaction mixture was degassed with N2 and cooled to 0 °C. Tert-butyl hypochlorite (140 mg, 1.29 mmol) was added to mixture at 0 °C under N2 and the reaction was stirred at 0 °C for 1 h. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (8 mL x 3). The organic phase was washed with brine (3 mL) and dried over Na₂SO₄, filtered, and concentrated in vacuum to give a residue. The residue was purified by silica gel column chromatography(SiO2, Petroleum ether / Ethyl acetate=1 / 0 to 3 / 1) to give the title compound (45.0 mg, 0.24 mmol, 37% yield) as a light yellow oil. 'H NMR (400 MHz, DMSO-d6) 8 = 7.81 - 7.74 (m, 2H), 7.69 - 7.56 (m, 3H), 2.40 (s, 3H)

[1282] Step c) (S-amino-N-methyl-sulfonimidoyl)benzene

[1283] A solution of chloro-methylimino-oxo-phenyl-X6-sulfane (35.0 mg, 0.18 mmol) in 28% ammonium hydroxide aq. solution (2.0 mL, 0.18 mmol) was stirred at 20 °C for 12 h, then concentrated under reduced pressure. The residue was purified by prep. TLC (petroleum ether: EtOAc=3:l) to give the title compound (17.0 mg, 0.1 mmol, 52%) as light yellow oil. 'H NMR (400 MHz, DMSO-d6) 8 = 7.84 - 7.70 (m, 2H), 7.69 - 7.56 (m, 3H), 2.40 (d, J = 5.0 Hz, 3H); GCMS: 171.1 [M+H]+ESI pos

[1284] Example A.3

[1285] [6-allyloxy-5-amino-2-(methylthio)pyrimidin-4-yl]-(5-methoxyindan-4-yl) amine

[1286] Made in analogy to of [6-allyloxy-5-amino-2-(methylthio)pyrimidin-4-yl]-(2,6-dimethoxyphenyl)amine (Example 26, Step c), using 5-methoxy-2,3-dihydro-lH-inden-4-amine (CAS: 1781690-28-5) in place of (2,6-dimethoxyphenyl)amine in Step a) to give the title compound (1.04 g, 89 %) as light yellow solid; MS (ESI): m / z = 359.4 [M+H]+.

[1287] Example A.4

[1288] [6-allyloxy-5-amino-2-(methylthio)pyrimidin-4-yl]-(2-isobutyl-6-methoxy-phenyl)amine Made in analogy to of [6-allyloxy-5-amino-2-(methylthio)pyrimidin-4-yl]-(2,6-dimethoxyphenyl)amine (Example 26, Step c), using 2-methoxy-6-(2-methylpropyl)aniline(CAS: 1784466-06-3) in place of (2,6-dimethoxyphenyl)amine in Step a) to give the title compound (1.01 g, 84 %) as light brown oil; MS (ESI): m / z = 375.4 [M+H]+.

[1289] Example A.5

[1290] [6-allyloxy-5-amino-2-(methylthio)pyrimidin-4-yl]-(2-ethoxy-4-methoxy-3-pyridyl)amine Made in analogy to of [6-allyloxy-5-amino-2-(methylthio)pyrimidin-4-yl]-(2,6-dimethoxyphenyl)amine (Example 26, Step c), using 2-ethoxy-4-methoxypyridin-3-amine (A.6) in place of (2,6-dimethoxyphenyl)amine in Step a) to give the title compound (107 mg, 72 %) as light brown solid; MS (ESI): m / z = 364.4 [M+H]+.

[1291] Example A.6

[1292] 2-ethoxy-4-methoxypyridin-3-amine

[1293] Step a) 2-ethoxy-4-methoxy-3-nitro-pyridine

[1294] 2-chloro-4-methoxypyridin-3-amine (100 mg, 514 pmol) was dissolved in THF (2.57 mL). The reaction was cooled to 0 °C and sodium ethoxide (167 mg, 192 pL, 514 pmol) was added. The reaction was stirred at 0 °C for 45 min. The reaction was quenched with water and extracted with EtOAc, dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by reverse phase HPLC (5-100% acetonitrile in water) to yield the title compound (62 mg, 51%) as colorless viscous oil MS (ESI): m / z = 199.1 [M+H]+.

[1295] Step b) 2-ethoxy-4-methoxypyridin-3-amine

[1296] 2-ethoxy-4-methoxy-3 -nitro-pyridine (3.5 g, 17.3 mmol) was dissolved in acetic acid (6 mL) and ammonium chloride (9.26 g, 173 mmol) and iron (4.83 g, 86.5 mmol) were added at room temperature. The mixture was stirred at 50 °C for 18.5 h, and a further addition of ammonium chloride (926 mg, 17.3 mmol) and iron (967 mg, 17.3 mmol) with acetic acid (5 mL) was made, and the reaction was stirred for 2.5 h at 60 °C. The reaction was quenched with water, diluted with sat. aq. NaHCO3 solution and IMNaOH (aq.) and extracted multiple times with EtOAc. The organic layers were combined, washed with water, dried over Na₂SO₄ and concentrated to obtain a residue which purified by flash chromatography (eluting with 0-60 % EtOAc in heptane) to yield the title compound (2.5 g, 72 %) as yellow oil; MS (ESI): m / z = 169.2 [M+H]+.

[1297] Example A.7

[1298] 6-ethoxy-4-methyl-pyridine-2-carbonyl chloride6-ethoxy-4-methylpyridinecarboxylic acid (CAS: 2281482-29-7) (860 mg, 4.65 mmol) was dissolved in dichloromethane (12.7 mL) and DMF (254 pL) was added. The reaction was cooled down to 0 °C, and oxalyl chloride (663 mg, 442 pL, 5.12 mmol) was added dropwise. The ice bath was removed, and the mixture was stirred at 23 °C for 1 h. The reaction was concentrated (volatile, only rotation no heating during concentration process). The crude material was used for the next step without further purification. The title compound (928 mg, 100 %) was obtained as light yellow viscous oil; MS (ESI): m / z = 196.1 [M+H]+.

[1299] Example A.8

[1300] [6-allyloxy-5-amino-2-(methylthio)pyrimidin-4-yl]-(2-ethoxy-6-methoxy-phenyl)amine Made in analogy to of [6-allyloxy-5-amino-2-(methylthio)pyrimidin-4-yl]-(2,6-dimethoxyphenyl)amine (Example 26, Step c), using 2-ethoxy-6-methoxyaniline (CAS: 344296-52-2) in place of (2,6-dimethoxyphenyl)amine in Step a) to give the title compound (113 mg, 64 %) as light brown viscous oil; MS (ESI): m / z = 363.4 [M+H]+.

[1301] Example A.9

[1302] 2-ethoxypyrimidine-4-carbonyl chloride

[1303] 2-ethoxypyrimidine-4-carboxylic acid (CAS: 1312556-74-3) (640 mg, 3.81 mmol) was dissolved in dichloromethane and DMF (0.1 mL), and (COC1)2 (531 mg, 367 pL, 4.19 mmol) was added dropwise. The reaction was stirred at room temperature for 10 min, and concentrated under vacuum to give the crude title compound, which was carried directly into the next step without further purification. LCMS no result; quenching with MeOH gave LCMS of the corresponding methyl ester.

[1304] Example A.10

[1305] 4-chloro- 6-ethoxy-pyridine-2-carbonyl chloride

[1306] Step a) 4,6-dichloropicolinic acid ethyl ester

[1307] 4,6-dichloropicolinic acid (CAS: 88912-25-8) (100 mg, 522 pmol) was dissolved in ethanol (1 mL). Acetyl chloride (110 mg, 100 pL, 1.4 mmol) was added dropwise, and the reaction was stirred at room temperature for 3 days. The reaction was concentrated under vacuum, diluted with sat. aq. NaHCO3 solution and extracted with EtOAc. The organic layer was washed with brine and dried over MgSO₄, to give the title compound as light brown liquid (80 mg, 70% yield) which was carried directly into the next step without further purification. MS (ESI): m / z = 220.0 [M+H]+.Step b) 4-chloro-6-ethoxy-picolinic acid

[1308] 4,6-dichloropicolinic acid ethyl ester (700 mg, 3.18 mmol) was dissolved in THF extra dry (15 mL). Sodium ethoxide (216.47 mg, 3.18 mmol) was added and the reaction was stirred at room temperature for 3 days. A further addition of sodium ethoxide (216 mg, 3.18 mmol) was made and reaction was stirred at room temperature until completion. Standard aqueous workup, extraction and purification conditions gave the title compound. MS (ESI): m / z = 230.1 [M+H]+.

[1309] Step c) 4-chloro-6-ethoxy-pyridine-2-carbonyl chloride

[1310] 4-chloro-6-ethoxy-picolinic acid (410 mg, 1.83 mmol) was dissolved in dichloromethane (5 mL) and DMF (0.1 mL). Oxalyl chloride (256 mg, 170 pL, 2.01 mmol) was added dropwise. The reaction was stirred for 10 min, and concentrated under vacuum, to give the crude title compound, which was carried directly into the next step without further purification. LCMS no result; quenching with MeOH gave LCMS of the corresponding methyl ester.

[1311] Example 65

[1312] A compound of formula (I) can be used in a manner known per se as the active ingredient for the production of tablets of the following composition:

[1313] Per tablet

[1314] Active ingredient 200 mg

[1315] Microcrystalline cellulose 155 mg

[1316] Corn starch 25 mg

[1317] Talc 25 mg

[1318] Hydroxypropylmethylcellulose 20 mg

[1319] 425 mg

[1320] Example 66

[1321] A compound of formula (I) can be used in a manner known per se as the active ingredient for the production of capsules of the following composition:

[1322] Per capsule

[1323] Active ingredient 100.0 mg

[1324] Corn starch 20.0 mg

[1325] Lactose 95.0 mg

[1326] Talc 4.5 mg

[1327] Magnesium stearate 0.5 mg

[1328] 220.0 mg

Claims

Claims1. A compound of formula (I)or a pharmaceutically acceptable salt thereof, wherein:(i) X is C and Y is N; or(ii) X is N and Y is C;A is selected from the group consisting of Ce-Cio-aryl, 5- to 10-membered heteroaryl, Cs-Cio-cycloalkyl, and 3- to 10-membered heterocyclyl; B is selected from the group consisting of Ce-Cio-aryl, 5- to 10-membered heteroaryl, Cs-Cio-cycloalkyl, and 3- to 10-membered heterocyclyl; C is selected from the group consisting of Ce-Cio-aryl, 5- to 10-membered heteroaryl, Cs-Cio-cycloalkyl, and 3- to 10-membered heterocyclyl; D is selected from the group consisting of Ce-Cio-aryl, 5- to 10-membered heteroaryl, Cs-Cio-cycloalkyl, and 3- to 10-membered heterocyclyl; L1is selected from the group consisting of a covalent bond, –(CHRL1)r–, *–NRL2(CHRL1)r–, and *–O(CHRL1)r–;wherein an asterisk indicates the point of attachment of L1to ring C; L2is selected from the group consisting of a covalent bond, –(CHRL3)s–, –(CHRL3)sCO–*, –(CHRL3)sO–*, –O(CHRL3)s–*, –NH(CHRL3)s–*, –NH(SO2)–* and –NHSO2CH2–*;wherein an asterisk indicates the point of attachment of L2to ring D; m is 1, 2, or 3;n is 0, 1, 2, or 3;p is 0, 1, 2, or 3;q is 0, 1, 2, or 3;r is 1 or 2;s is 1 or 2;R1is selected from the group consisting of halogen, hydroxy, Ci-Ce-alkyl, halo- Ci-Ce-alkyl, Ci-Ce-alkoxy, halo-Ci-Ce-alkoxy, and Ci-Ce-alkoxy-Ci-Ce-alkyl; R2is selected from the group consisting of halogen, oxo, Ci-Ce-alkyl, halo-C1-C6- alkyl, Ci-Ce-alkoxy, halo-Ci-Ce-alkoxy, and Ci-Ce-alkoxy-Ci-Ce-alkyl;R3is selected from the group consisting of hydrogen, Ci-Ce-alkyl, hydroxy-Ci- Ce-alkyl, halo-Ci-Ce-alkyl, cyano-Ci-Ce-alkyl, Ci-Ce-alkoxy-Ci-Ce-alkyl, -(CHRL1)r-COORL2, -(CHRL1)r-CON(RL2)2, and a groupandR4is selected from the group consisting of hydrogen, amino, hydroxy, halogen, Ci-Ce-alkyl, halo-Ci-Ce-alkyl, Ci-Ce-alkoxy, halo-Ci-Ce-alkoxy, Ci-Ce- alkoxy-Ci-Ce-alkyl, -(CHRL1)r-COORL2, C1-C6-alkyl-CONRL2-, Ci-C6-alkyl- NRL2-, halo-C1-C6-alkyl-NRL2-, Ci-Ce-alkyl-SO2NRL2-, Ci-C6-alkoxy-Ci-C6-Lt z- (^D alkyl-CONRL2-, a grouporR3and R4, taken together with the atoms to which they are attached, form a group pRN.R3ais a groupR5is selected from the group consisting of halogen, Ci-Ce-alkyl, halo-C1-C6- alkyl, Ci-Ce-alkoxy, halo-Ci-Ce-alkoxy, Ci-Ce-alkoxy-Ci-Ce-alkyl, and 5- to 10-membered heteroaryl;R6is selected from the group consisting of halogen, Ci-Ce-alkyl, halo-C1-C6- alkyl, Ci-Ce-alkoxy, halo-Ci-Ce-alkoxy, and Ci-Ce-alkoxy-Ci-Ce-alkyl;each RL1is independently selected from the group consisting of hydrogen, hydroxy, Ci-Ce-alkyl, and Ci-Ce-alkoxy;each RL2is independently selected from the group consisting of hydrogen and C1-C6- alkyl; andeach RL3is independently selected from the group consisting of hydrogen, C1-C6- alkyl, and Ci-Ce-alkoxy;wherein each heterocyclyl and each heteroaryl comprises 1 to 4 heteroatoms independently selected from the group consisting of N, O, and S, the remaining ring atoms being carbon.

2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein X is C and Y is N.

3. The compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (Id):wherein each Z is independently selected from the group consisting of N and CH, provided that at most 3 Z are N, Rlais selected from the group consisting of hydroxy, Ci-Ce-alkyl, halo-Ci-Ce-alkyl, Ci-Ce-alkoxy, halo-Ci-Ce-alkoxy, and Ci- Ce-alkoxy-Ci-Ce-alkyl, and the remaining variables are as defined in claim 1.

4. The compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein B is selected from the group consisting of 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl.

5. The compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein B is selected from the group consisting of 1,2-dihydropyridyl and pyridyl.

6. The compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein:R2is selected from the group consisting of oxo and Ci-Ce-alkoxy; andn is 1.

7. The compound of formula (I) according to any one of claims 1 to 5, or apharmaceutically acceptable salt thereof, wherein the group is selectedfrom the group consisting of8. The compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein:R3is selected from the group consisting of hydrogen, Ci-Ce-alkyl, and a groupR5is selected from the group consisting of halogen, Ci-Ce-alkyl, Ci-Ce-alkoxy, and 5- to 6-membered heteroaryl;C is selected from the group consisting of Ce-Cio-aryl and 5- to 6-membered heteroaryl;L1is selected from the group consisting of –(CHRL1)r– and *–O(CHRL1)r–;wherein an asterisk indicates the point of attachment of L1to ring C; RL1is selected from the group consisting of hydrogen and Ci-Ce-alkyl;p is 0, 1, or 2; andr is 1 or 2.

9. The compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein:R3is selected from the group consisting of hydrogen, Ci-Ce-alkyl, and a group- Ill - C is 5- to 6-membered heteroaryl;L1is –(CHRL1)r–;RL1is hydrogen;p is 0; andr is 1.

10. The compound of formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein:R4is selected from the group consisting of hydrogen, amino, hydroxy, C1-C6- alkyl, -(CHRL1)r-COORL2, C1-C6-alkyl-CONRL2-, halo-C1-C6-alkyl-NRL2-, C1-C6-alkyl-SO2NRL2-, Ci-C6-alkoxy-C1-C6-alkyl-CONRL2-, a groupL2is selected from the group consisting of -(CHRL3)S-, -NH(CHRL3)S-*, -NH(SO2)-* and -NHSO2CH2-*;wherein an asterisk indicates the point of attachment of L2to ring D;D is a 5- to 6-membered heteroaryl;R6is halogen;q is 0 or 1;r is 1 or 2;s is 1;RL1is selected from the group consisting of hydrogen and C1-C6-alkyl;RL2is selected from the group consisting of hydrogen and C1-C6-alkyl; and RL3is hydrogen.

11. The compound of formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R4is amino.

12. The compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein:R3and R4, taken together with the atoms to which they are attached, form a group>1><^X(R5)PR3ais a group';L1is a covalent bond;C is a 5- to 6-membered heteroaryl,P is 1;R5is halogen.

13. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from the group consisting of:2-amino-9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-l-(2-pyridylmethyl)purin- 6-one;2-amino-9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-l-methyl-purin-6-one; 2-amino-9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-lH-purin-6-one;2-amino-9-(2,6-dimethoxyphenyl)-8-(6-keto-lH-pyridin-2-yl)hypoxanthine;N-[9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-l-methyl-6-oxo-purin-2- yl] methanesulfonamide;(7S)-7-(5-chloro-2-pyridyl)-3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-6- methyl-7,8-dihydropyrazino[l,2-a]purine-5, 10-dione;N-[9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-6-oxo-l-(2- pyridylmethyl)purin-2-yl]methanesulfonamide;2-[9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-6-oxo-lH-purin-2-yl]propanoic acid;9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-2-hydroxy-l-[2-(4- methoxyphenyl)ethyl]purin-6-one;N-[l-benzyl-9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-6-oxo-purin-2- yl] methanesulfonamide;N-[9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-6-keto-lH-purin-2- yl]benzenesulfonamide;2-amino-l-[(5-chloro-2-pyridyl)methyl]-9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2- pyridyl)purin-6-one;N-[9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-6-keto-lH-purin-2-yl]-l- phenyl-methanesulfonamide;2-amino-9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-l-[2-(4- methoxyphenyl)ethyl]purin-6-one;N-[9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-6-oxo-lH-purin-2- yl]acetamide;9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-2-(2,2,2-trifluoroethylamino)-lH- purin-6-one;2-[(5-chloropyrimidin-2-yl)methyl]-9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2- pyridyl)- 1 H-purin-6-one;2-[(5-chloro-2-pyridyl)methyl]-9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-lH- purin-6-one;9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-l-[[5-methyl-2-(2-thienyl)oxazol- 4-yl]methyl]purin-6-one;9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-2-(2-pyridylmethylamino)-lH- purin-6-one;2-amino-9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-l-(2-pyrimidin-2- yloxyethyl)purin-6-one;9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-l,2-dimethyl-purin-6-one;9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-2-hydroxy-l-(2- pyridylmethyl)purin-6-one;N-[9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-6-oxo-lH-purin-2-yl]-2- methoxy -acetamide;9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-lH-purin-6-one;N-[9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-6-oxo-lH-purin-2- yl] methanesulfonamide;2-[9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-l-methyl-6-oxo-purin-2- yl]acetic acid;9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-2-methyl-lH-purin-6-one;2-amino-9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-l-[(5-methylpyrimidin-2- yl)methyl]purin-6-one;2-amino-l-[(6-chloro-2-pyridyl)methyl]-9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2- pyridyl)purin-6-one;2-amino-l-[(4-chloro-2-pyridyl)methyl]-9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2- pyridyl)purin-6-one;2-[9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-l-methyl-6-oxo-purin-2- yl]propanoic acid;9-(2,6-dimethoxyphenyl)-2-[(N, S-dimethylsulfonimidoyl)amino]-8-(6-ethoxy-2- pyridyl)- 1 H-purin-6-one;9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-3H-purine-2, 6-dione;9-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-2-(2-pyridylmethyl)-lH-purin-6- one; and5-amino-3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-6H-pyrazolo[4,3- d]pyrimidin-7 -one.

14. The compound of formula (I) according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

15. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

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