APJ agonists

Abstract

The invention provides compounds having the general formula (I) [Formula should be inserted here] wherein X, Y, Z, U, V, R1, R2, R3, and R4 are as described herein, compositions including the compounds, processes of manufacturing the compounds and methods of using 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: P39929-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 etal. 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 X, Y, Z, U, V, R1, R2, R3, and R4are 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 glucosedependent 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-11, 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-C10-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 (“C6-C10-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 (e.g. pyrimidin-2-yl); pyrazolyl (e.g. pyrazol-l-yl); triazolyl; tetrazolyl; pyrazinyl; imidazolyl (e.g. imidazole- 1-yl), 177-indazolyl, indolyl, 177-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 and pyrazolyl.

[0028] The term “heterocyclyl” refers to a saturated or partly unsaturated 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 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 nonlimiting examples of heterocyclyl groups include azetidinyl, piperidyl, pyrrolidinyl, oxetanyl, piperidyl, 1,2-dihydropyridiynl, piperidyl, pyrrolidinyl, tetrahydrothiophenyl, thietanyl, and 4,5,6,7-tetrahydro-l / f-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. 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.

[0030] 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.

[0031] 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. 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 "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 be prepared 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 asisopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimine resins and the like.

[0038] 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.

[0039] The compounds of formula (I) may exist in multiple tautomeric forms due to the occurrence of tautomerism. Tautomers are isomers of a compound which can be interconverted by the transfer of a chemical group, typically a hydrogen atom, accompanied by a change in the position of a double bond. Such tautomerization can occur readily under certain conditions, such as changes in pH or solvent, leading to the equilibrium between different tautomeric forms. The present invention encompasses all possible tautomeric forms of the compounds of formula (I). As an example, the compound of Example 25

[0040]

[0041] is understood to also encompass the following tautomers thereof (including, but not limited to):

[0042]

[0043] 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.

[0044] 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.

[0045] 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.

[0046] Compounds of the Invention

[0047] In a first aspect, the present invention provides a compound of formula (I)

[0048]

[0049] or a pharmaceutically acceptable salt or a tautomer thereof, wherein:

[0050] (i) X, Z, and U are C, Y is N, and V is N or CH; or

[0051] (ii) X, Y, and Z are C, U is N, and V is CH; or

[0052] (iii) Y, Z, and U are C, X is N, and V is N or CH; or

[0053] (iv) X, Y, and U are C, Z is N, and V is CH;

[0054] 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;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;

[0055] 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;

[0056] D is selected from the group consisting of C6-C10-aryl, 5- to 10-membered heteroaryl, C3-Cio-cycloalkyl, and 3- to 10-membered heterocyclyl;

[0057] L1is a covalent bond or -CHRL1-;

[0058] L2is selected from the group consisting of a covalent bond, -O-, -NRL2-, -SO2-, - CHRL1-, -CHRL1CO-*, -CHRL1O-*, -OCHRL1-*, -CHRL1ONRL2-*, and -ONRL2CRL1-*;

[0059] wherein an asterisk indicates the point of attachment of L2to ring C;

[0060] L3is a covalent bond or -(CHRL3)r-;

[0061] m is 0, 1, 2, or 3;

[0062] n is 0, 1, 2, or 3;

[0063] p is 0, 1, 2, or 3;

[0064] q is 0, 1, 2, or 3;

[0065] r is 1, 2, or 3;

[0066] . L<1X-X / (R5)m

[0067] R1is C1-C6-alkyl or a group

[0068]

[0069] R2is selected from the group consisting of C1-C6-alkyl, C1-C6-alkoxy, and a group

[0070] B

[0071]

[0072] R3is selected from the group consisting of hydrogen, hydroxy, halogen, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, and a

[0073] group

[0074]

[0075] R4is selected from the group consisting of hydrogen, amino, C1-C6-alkyl, hydroxy-Ci- Ce-alkyl, halo-C1-C6-alkyl, cyano-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, - (CHRL3)r-COORL2, -(CHRL3)r-CON(RL2)2, Ci-C6-alkyl-SO2-, Ci-C6-alkyl-SO2NRL2-

[0076] D

[0077] , and a group

[0078]

[0079] R5is selected from the group consisting of halogen, C1-C6-alkyl, halo-C1-C6-alkyl, Ci- Ce-alkoxy, halo-C1-C6-alkoxy, and C1-C6-alkoxy-C1-C6-alkyl;

[0080] R6is selected from the group consisting of halogen, C1-C6-alkyl, halo-C1-C6-alkyl, Ci- Ce-alkoxy, halo-C1-C6-alkoxy, and C1-C6-alkoxy-C1-C6-alkyl; and

[0081] R7is selected from the group consisting of halogen, C1-C6-alkyl, halo-C1-C6-alkyl, Ci- Ce-alkoxy, halo-C1-C6-alkoxy, and C1-C6-alkoxy-C1-C6-alkyl;

[0082] R8is selected from the group consisting of halogen, C1-C6-alkyl, halo-C1-C6-alkyl, Ci- Ce-alkoxy, halo-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, and 5- to 10-membered heteroaryl;

[0083] each RL1is independently selected from the group consisting of hydrogen, C1-C6-alkyl, and C1-C6-alkoxy;

[0084] each RL2is independently selected from the group consisting of hydrogen and C1-C6-alkyl;

[0085] and

[0086] each RL3is independently selected from the group consisting of hydrogen, hydroxy, Ci-Ce- alkyl, and C1-C6-alkoxy;

[0087] 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.

[0088] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:

[0089] 1. X, Z, and U are C, Y is N, and V is N or CH; or

[0090] 2. X, Y, and Z are C, U is N, and V is CH; or

[0091] 3. Y, Z, and U are C, X is N, and V is N or CH; or

[0092] 4. X, Y, and U are C, Z is N, and V is CH;

[0093] 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;

[0094] 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;

[0095] C is selected from the group consisting of C6-C10-aryl, 5- to 10-membered heteroaryl, C3-Cio-cycloalkyl, and 3- to 10-membered heterocyclyl;

[0096] 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;

[0097] L1is a covalent bond or -CHRL1-;L2is selected from the group consisting of a covalent bond, -O-, -NRL2-, -SO2-, - CHRL1- -CHRL1CO-*, -CHRL1O-*, -OCHRL1-*, -CHRL1ONRL2-*, and -ONRL2CRL1-*;

[0098] wherein an asterisk indicates the point of attachment of L2to ring C;

[0099] L3is a covalent bond or -(CHRL3)r-;

[0100] m is 0, 1, 2, or 3;

[0101] n is 0, 1, 2, or 3;

[0102] p is 0, 1, 2, or 3;

[0103] q is 0, 1, 2, or 3;

[0104] r is 1, 2, or 3;

[0105] R1is C1-C6-alkyl or a group

[0106]

[0107] ;

[0108] R2is selected from the group consisting of C1-C6-alkyl, C1-C6-alkoxy, and a group

[0109]

[0110] R3is selected from the group consisting of hydrogen, hydroxy, halogen, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, and a

[0111]

[0112] R4is selected from the group consisting of hydrogen, amino, C1-C6-alkyl, hydroxy-Ci- Ce-alkyl, halo-C1-C6-alkyl, cyano-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, - (CHRL3)r-COORL2, -(CHRL3)r-CON(RL2)2, Ci-C6-alkyl-SO2-, Ci-C6-alkyl-SO2NRL2-

[0113]

[0114] R5is selected from the group consisting of halogen, C1-C6-alkyl, halo-C1-C6-alkyl, Ci- Ce-alkoxy, halo-C1-C6-alkoxy, and C1-C6-alkoxy-C1-C6-alkyl;

[0115] R6is selected from the group consisting of halogen, C1-C6-alkyl, halo-C1-C6-alkyl, Ci- Ce-alkoxy, halo-C1-C6-alkoxy, and C1-C6-alkoxy-C1-C6-alkyl; and

[0116] R7is selected from the group consisting of halogen, C1-C6-alkyl, halo-C1-C6-alkyl, Ci- Ce-alkoxy, halo-C1-C6-alkoxy, and C1-C6-alkoxy-C1-C6-alkyl;R8is selected from the group consisting of halogen, C1-C6-alkyl, halo-C1-C6-alkyl, Ci- Ce-alkoxy, halo-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, and 5- to 10-membered heteroaryl;

[0117] each RL1is independently selected from the group consisting of hydrogen, C1-C6-alkyl, and C1-C6-alkoxy;

[0118] each RL2is independently selected from the group consisting of hydrogen and C1-C6-alkyl;

[0119] and

[0120] each RL3is independently selected from the group consisting of hydrogen, hydroxy, Ci-Ce- alkyl, and C1-C6-alkoxy;

[0121] 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.

[0122] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a tautomer thereof, wherein the compound of formula (I) is a compound of formula (la), (lb), or (Ic):

[0123]

[0124] wherein V is N or CH; and R1, R2, R3, and R4are as defined herein (e.g. in claim 1).

[0125] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a tautomer thereof, wherein the compound of formula (I) is a compound of formula (Ia):

[0126] 1 o

[0127]

[0128] (la)

[0129] wherein V, R1, R2, R3, and R4are as defined herein (e.g. in claim 1).

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

[0131] .< X-X / (R5)m

[0132] (^A

[0133] R1is a group

[0134]

[0135] A is selected from the group consisting of C6-C10-aryl and C3-C10-cycloalkyl;

[0136] L1is a covalent bond;

[0137] m is 0, 1, or 2; and

[0138] R5is selected from the group consisting of C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, and halo-C1-C6-alkyl.

[0139] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:

[0140] <L\< Z~_'X^(R5)rn

[0141] R1is a group

[0142]

[0143] A is selected from the group consisting of phenyl and cyclopropyl;

[0144] L1is a covalent bond;

[0145] m is 0, 1, or 2; and

[0146] R5is selected from the group consisting of methoxy, methoxymethyl, and trifluoromethyl.

[0147] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:

[0148] . L<1X-X / (R5)m

[0149] C^A

[0150] R1is a group

[0151]

[0152] A is C6-C10-aryl;

[0153] L1is a covalent bond;

[0154] m is 0, 1, or 2; and

[0155] R5is C1-C6-alkoxy.

[0156] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:

[0157]

[0158] is a group

[0159] A is phenyl;

[0160] L1is a covalent bond;

[0161] m is 0, 1, or 2; and

[0162] R5is methoxy.

[0163] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:

[0164]

[0165] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:

[0166] R1is a group

[0167]

[0168] A is C6-C10-aryl;

[0169] L1is a covalent bond;

[0170] m is 2; and

[0171] R5is C1-C6-alkoxy.

[0172] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:

[0173] R1is a group

[0174]

[0175] A is phenyl;

[0176] L1is a covalent bond;

[0177] m is 2; andR5is methoxy.

[0178] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:

[0179] .o.

[0180]

[0181] R1is a group

[0182] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:

[0183] B

[0184] R2is a group

[0185]

[0186] B is selected from the group consisting of C6-C10-aryl, 5- to 10-membered heteroaryl and C3-C10-cycloalkyl;

[0187] n is 0 or 1; and

[0188] R6is selected from the group consisting of C1-C6-alkyl and C1-C6-alkoxy.

[0189] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:

[0190] B

[0191] R2is a group

[0192]

[0193] B is selected from the group consisting of cyclopentyl, pyridyl, pyrazolyl, 1H- indazolyl, 4,5,6,7-tetrahydro-l / f-indazolyl, 1,2-benzoxazolyl, and 4, 5, 6, 7 -tetrahydro - 1,2-benzoxazolyl;

[0194] n is 0 or 1; and

[0195] R6is selected from the group consisting of C1-C6-alkyl and C1-C6-alkoxy.

[0196] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:

[0197] B

[0198] R2is a group

[0199]

[0200] B is selected from the group consisting of 5- to 10-membered heteroaryl and C3-C10- cycloalkyl;

[0201] n is 0 or 1; and

[0202] R6is selected from the group consisting of C1-C6-alkyl and C1-C6-alkoxy.

[0203] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:

[0204] A<~>r(R6)n

[0205] R2is a group

[0206]

[0207] kB7;

[0208] B is selected from the group consisting of cyclopentyl, pyridyl, and pyrazolyl; n is 0 or 1; and

[0209] R6is selected from the group consisting of methyl and methoxy.

[0210] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:

[0211] R2

[0212]

[0213] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:

[0214] B

[0215] R2is a group

[0216]

[0217] ;

[0218] B is 5- to 6-membered heteroaryl;

[0219] n is 1; and

[0220] R6is C1-C6-alkoxy.

[0221] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:(R )n

[0222] R2is a group

[0223]

[0224] ' - ';

[0225] B is pyridyl;

[0226] n is 1; and

[0227] R6is methoxy or ethoxy.

[0228] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:

[0229] B

[0230] R2is a group

[0231]

[0232] B is pyridyl;

[0233] n is 1; and

[0234] R6is ethoxy.

[0235] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:

[0236] B

[0237] R2is a group

[0238]

[0239] B is pyridyl;

[0240] n is 1; and

[0241] R6is methoxy.

[0242] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:

[0243]

[0244] is a group

[0245] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:R3is selected from the group consisting of hydrogen, hydroxy and a group

[0246]

[0247] C is 5- to 6-membered heteroaryl;

[0248] L2is -CHRL1-;

[0249] RL1is hydrogen; and

[0250] p is 0.

[0251] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:

[0252] R3is selected from the group consisting of hydrogen, hydroxy and a group

[0253] l C

[0254]

[0255] C is pyrimidine;

[0256] L2is -CHRL1-;

[0257] RL1is hydrogen; and

[0258] p is 0.

[0259] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a tautomer thereof, wherein R3is hydrogen.

[0260] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:

[0261] R4is selected from the group consisting of hydrogen, amino, C1-C6-alkyl, hydroxy-Ci- Ce-alkyl, halo-C1-C6-alkyl, cyano-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, - (CHRL3)r-COORL2, -(CHRL3)r-CON(RL2)2, Ci-C6-alkyl-SO2-, Ci-C6-alkyl-SO2NRL2- i.! / -, and a group

[0262]

[0263] ;

[0264] D is selected from the group consisting of C6-C10-aryl and 3- to 10-membered heterocyclyl;

[0265] L3is a covalent bond or -(CHRL3)r-;

[0266] q is 0 or 1;r is 1;

[0267] R8is C1-C6-alkoxy;

[0268] each RL2is independently selected from the group consisting of hydrogen and C1-C6-alkyl;

[0269] and

[0270] each RL3is hydrogen.

[0271] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:

[0272] R4is selected from the group consisting of hydrogen, amino, methyl, 2-hydroxyethyl, 2,2,2-trifluoroethyl, cyanomethyl, 2-methoxyethyl, -(CHRL3)r-COORL2, -(CHRL3)r-

[0273] CON(RL2)2, methyl-SO2-, methyl-SO2NRL2-, and a group

[0274]

[0275] D is selected from the group consisting of phenyl and azetidinyl;

[0276] L3is a covalent bond or -(CHRL3)r-;

[0277] q is 0 or 1;

[0278] r is 1;

[0279] R8is methoxy;

[0280] each RL2is independently selected from the group consisting of hydrogen and methyl; and each RL3is hydrogen.

[0281] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a tautomer thereof, wherein R4is selected from the group consisting of hydrogen, amino, methyl, 2-hydroxyethyl, 2,2,2-trifluoroethyl, cyanomethyl, 2-methoxyethyl, -CH2-COOH, -CH2-CONHCH3, -CH2-CON(CH3)2, methyl- 802-

[0282]

[0283] , methyl-SO2NH-, a group

[0284]

[0285] , and a group

[0286] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:

[0287] R4is selected from the group consisting of hydrogen, –CH2-COOH, and a group

[0288]

[0289] D is C6-C10-aryl;

[0290] L3is -(CHRL3)r-;

[0291] q is 1;

[0292] r is 1;

[0293] R8is C1-C6-alkoxy; and

[0294] RL3is hydrogen.

[0295] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:

[0296] R4is selected from the group consisting of hydrogen, –CH2-COOH, and a group

[0297]

[0298] D is phenyl;

[0299] L3is -(CHRL3)r-;

[0300] q is 1;

[0301] r is 1;

[0302] R8is methoxy; and

[0303] RL3is hydrogen.

[0304] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a tautomer thereof, wherein R4is selected from the group consisting of hydrogen, –CH2-COOH, and a group

[0305]

[0306] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:

[0307] V is N or CH;

[0308] A is C6-C10-aryl;

[0309] B is selected from the group consisting of 5- to 10-membered heteroaryl and C3-C10- cycloalkyl;

[0310] D is selected from the group consisting of C6-C10-aryl and 3- to 10-membered

[0311] heterocyclyl;L1is a covalent bond;

[0312] L3is a covalent bond or -(CHRL3)r-;

[0313] n is 0 or 1;

[0314] m is 0, 1, or 2;

[0315] q is 0 or 1;

[0316] r is 1;

[0317]

[0318] R3is hydrogen;

[0319] R4is selected from the group consisting of hydrogen, amino, C1-C6-alkyl, hydroxy-Ci- Ce-alkyl, halo-C1-C6-alkyl, cyano-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, - (CHRL3)r-COORL2, -(CHRL3)r-CON(RL2)2, Ci-C6-alkyl-SO2-, Ci-C6-alkyl-SO2NRL2-

[0320] , and a group

[0321]

[0322] ;

[0323] R5is C1-C6-alkoxy;

[0324] R6is selected from the group consisting of C1-C6-alkyl and C1-C6-alkoxy;

[0325] R8is C1-C6-alkoxy;

[0326] each RL2is independently selected from the group consisting of hydrogen and C1-C6-alkyl;

[0327] and

[0328] each RL3is hydrogen.

[0329] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:

[0330] V is N or CH;

[0331] A is phenyl;

[0332] B is selected from the group consisting of cyclopentyl, pyridyl, and pyrazolyl;

[0333] D is selected from the group consisting of phenyl and azetidinyl;

[0334] L1is a covalent bond;

[0335] L3is a covalent bond or -(CHRL3)r-:

[0336] n is 0 or 1;m is 0, 1, or 2;

[0337] q is 0 or 1;

[0338] r is 1;

[0339]

[0340] R3is hydrogen;

[0341] R4is selected from the group consisting of hydrogen, amino, methyl, 2 -hydroxy ethyl, 2,2,2-trifluoroethyl, cyanomethyl, 2-methoxyethyl, -(CHRL3)r-COORL2, -(CHRL3)r-

[0342] CON(RL2)2, methyl-SO2-, methyl-SO2NRL2-, and a group

[0343]

[0344] R5is methoxy;

[0345] R6is selected from the group consisting of methyl and methoxy;

[0346] R8is methoxy;

[0347] each RL2is independently selected from the group consisting of hydrogen and methyl; and each RL3is hydrogen.

[0348] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:

[0349] V is CH;

[0350] A is C6-C10-aryl;

[0351] B is 5- to 6-membered heteroaryl;

[0352] D is C6-C10-aryl;

[0353] L1is a covalent bond;

[0354] L3is -(CHRL3)r-;

[0355] n is 1;

[0356] m is 2;

[0357] q is 1;

[0358] r is 1;

[0359]

[0360] R3is hydrogen;

[0361] R4is selected from the group consisting of hydrogen, CH2-COOH, and a group

[0362]

[0363] R5is C1-C6-alkoxy;

[0364] R6is C1-C6-alkoxy;

[0365] R8is C1-C6-alkoxy; and

[0366] RL3is hydrogen.

[0367] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:

[0368] V is CH;

[0369] A is phenyl;

[0370] B is pyridyl;

[0371] D is phenyl;

[0372] L1is a covalent bond;

[0373] L3is -(CHRL3)r-;

[0374] n is 1;

[0375] m is 2;

[0376] q is 1;

[0377] r is 1;

[0378]

[0379] R3is hydrogen;R4is selected from the group consisting of hydrogen, CH2-COOH, and a group

[0380]

[0381] R5is methoxy;

[0382] R6is methoxy;

[0383] R8is methoxy; and

[0384] RL3is hydrogen.

[0385] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a tautomer thereof, wherein said compound of formula (I) is selected from:

[0386] 3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-5H-imidazo[4,5-c]pyridin-4-one;

[0387] 3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-5-[(4-methoxyphenyl)methyl]imidazo[4,5- c]pyridin-4-one;

[0388] 2-[3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-4-oxo-imidazo[4,5-c]pyridin-5-yl]acetic acid;

[0389] 3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-5-(2-hydroxyethyl)imidazo[4,5-c]pyridin-4- one;

[0390] 3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-5-(2-methoxyethyl)imidazo[4,5-c]pyridin-4- one;

[0391] 3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-5-methyl-imidazo[4,5-c]pyridin-4-one;

[0392] 3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-5-(2,2,2-trifluoroethyl)imidazo[4,5-c]pyridin- 4-one;

[0393] 2-[3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-4-oxo-imidazo[4,5-c]pyridin-5- yl]acetonitrile;

[0394] 2-[3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-4-oxo-imidazo[4,5-c]pyridin-5-yl]-N- methyl-acetamide;

[0395] 5-(azetidin-3-yl)-3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)imidazo[4,5-c]pyridin-4-one; 2-[3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-4-oxo-imidazo[4,5-c]pyridin-5-yl]-N, N- dimethyl-acetamide;

[0396] 5-amino-3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)imidazo[4,5-c]pyridin-4-one;

[0397] N-[3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-4-oxo-imidazo[4,5-c]pyridin-5- yl]methanesulfonamide;3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-5-methylsulfonyl-imidazo[4,5-c]pyridin-4-one; 2-(6-ethoxy-2-pyridyl)-3-(2-methoxyphenyl)-5H-imidazo[4,5-c]pyridin-4-one;

[0398] 3-(2,6-dimethoxyphenyl)-2-(1-methylpyrazol-3-yl)-5H-imidazo[4,5-c]pyridin-4-one;

[0399] 2-cyclopentyl-3-(2,6-dimethoxyphenyl)-5H-imidazo[4,5-c]pyridin-4-one;

[0400] 2-(6-ethoxy-2-pyridyl)-3-phenyl-5H-imidazo[4,5-c]pyridin-4-one;

[0401] 8-(6-ethoxy-2-pyridyl)-7-(2-methoxyphenyl)hypoxanthine;

[0402] 3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-5H-pyrazolo[3,4-d]pyrimidin-4-one;

[0403] 3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-5H-pyrazolo[4,3-c]pyridin-4-one;

[0404] 3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-5H-pyrazolo[l,5-a]pyrazin-4-one;

[0405] 3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-6H-imidazo[l,2-c]pyrimidin-5-one;

[0406] 7-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-2-(2-pyrimidylmethyl)hypoxanthine; and 7-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-2-hydroxy -hypoxanthine.

[0407] In another embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a tautomer thereof, wherein said compound of formula (I) is selected from:

[0408] 2-[(5-chloro-2-pyridyl)methyl]-7-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)hypoxanthine; (2S)-3-(cyclopropoxy)-2-[3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-4-oxo-imidazo[4,5- c]pyridin-5-yl]propanoic acid;formic acid;

[0409] (2R)-3-(cyclopropoxy)-2-[3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-4-oxo-imidazo[4,5- c]pyridin-5-yl]propanoic acid;

[0410] 7-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-2-(2-pyrimidyloxymethyl)hypoxanthine;

[0411] 2-[3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-4-oxo-imidazo[4,5-c]pyridin-5-yl]-3- phenoxy-propanoic acid;

[0412] 2-[3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-4-oxo-imidazo[4,5-c]pyridin-5-yl]-3- phenyl-propanoic acid;

[0413] 7-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-2-[(5-methylpyridazin-3- yl)oxymethyl]hypoxanthine;

[0414] 3-cyclopropyl-2-[3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-4-oxo-imidazo[4,5-c]pyridin- 5-yl]propanoic acid;

[0415] 2-[3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-4-oxo-imidazo[4,5-c]pyridin-5-yl]-2- phenyl-acetic acid;

[0416] 7-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)hypoxanthine;2-[7-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-6-oxo-purin-l-yl]-3 -methoxy -propanoic acid;

[0417] 2-[l-(5-chloro-2-pyridyl)ethyl]-7-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)hypoxanthine; 2-[2-[(5-chloro-2-pyridyl)methyl]-7-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-6-oxo-purin- l-yl]acetic acid;

[0418] 2-[3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-4-oxo-imidazo[4,5-c]pyridin-5-yl]-3- methoxy-propanoic acid;

[0419] 5-[(5-chloro-2-pyridyl)methyl]-3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)imidazo[4,5- c]pyridin-4-one;

[0420] 7-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-l-p-anisyl-purin-6-one;

[0421] 8-[6-(cyclopropoxy)-2-pyridyl]-7-(2,6-dimethoxyphenyl)-2-(pyrimidin-2-ylmethyl)-lH-purin-6- one;

[0422] 8-(6-ethoxy-2-pyridyl)-7-(2-methoxyphenyl)-2-(pyrimidin-2-ylmethyl)-lH-purin-6-one; and 5-[(5-chloropyrimidin-2-yl)methyl]-3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2- pyridyl)imidazo[4,5-c]pyridin-4-one.

[0423] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a tautomer thereof, wherein said compound of formula (I) is selected from:

[0424] 3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-5H-imidazo[4,5-c]pyridin-4-one;

[0425] 3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-5-[(4-methoxyphenyl)methyl]imidazo[4,5- c]pyridin-4-one; and

[0426] 2-[3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-4-oxo-imidazo[4,5-c]pyridin-5-yl]acetic acid.

[0427] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a tautomer thereof, wherein said compound of formula (I) is 3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-5H-imidazo[4,5-c]pyridin-4-one.

[0428] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a tautomer thereof, wherein said compound of formula (I) is 3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-5-[(4-methoxyphenyl)methyl]imidazo[4,5-c]pyridin-4-one.In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a tautomer thereof, wherein said compound of formula (I) is 2-[3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-4-oxo-imidazo[4,5-c]pyridin-5-yl]acetic acid.

[0429] 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.

[0430] 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,36Cl,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.

[0431] 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.

[0432] Substitution with positron emitting isotopes, such as11C,18F,15O and13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

[0433] 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 theExamples as set out below using an appropriate isotopically -labeled reagent in place of the nonlabeled reagent previously employed.

[0434] Processes

[0435]

[0436] 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.

[0437] 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.

[0438] 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).

[0439] 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 artand has also been described in literature (e.g. Barany and R. B. Merrifield, J. Am. Chem. Soc.

[0440] 1977, 99, 7363; H. Waldmann et al., Angew. Chem. Int. Ed. Engl. 1996, 35, 2056).

[0441] A person skilled in the art will acknowledge that the sequence of reactions may be varied depending on reactivity and nature of the intermediates.

[0442] 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:

[0443] 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.

[0444] 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.

[0445] The following abbreviations are used in the present text:

[0446] 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-dicy clohexylphosphino-2',4',6'-triisopropyl- 1, 1 '-biphenyl) [2-(2'-amino- 1,1'-biphenyl)] palladium(II).

[0447] The present compounds of formula I, where the heterocyclic core is of formula 1 or 8, may be prepared by the route depicted in Scheme 1. A suitable amine 2 is reacted with nitropyridine 3 (X = Cl) in an SNAr reaction in the presence of a base, such as LiHMDS, to generate 4.

[0448] Reduction (e.g. using Pd / C and H2, or Fe / NH₄Cl) generates diamine 6, which could be condensed with an aldehyde 5 to give imidazopyridine 7 (e.g. stirring in MeOH at RT in presence of oxygen or another suitable oxidant). Alternatively, the nitro derivative 4 could be reacted directly with aldehyde 5 under reductive conditions (e.g. heating with sodium dithionate in EtOH) to yield imidazopyridine 7. Heating with NaOAc in AcOH yielded pyridone 8, which could be further functionalized, e.g. by alkylation or acylation by reacting with a suitable alkylation or acylation agent R4-W (W = leaving group such as Cl, Br, I) in the presence of a base (e.g. NaH).

[0449]

[0450] Scheme 11. MeONa R1- NH22 R-^N - ►

[0451] 2H2N^N EtOH, heat e.g. K2CO3, TBAI 11

[0452] 14

[0453] O

[0454] R4— K2CO3, H2O2R3'^'OH W 16 9 O e.g. alkylation, acylation, Mitsunobu

[0455]

[0456] Scheme 2

[0457] Compounds where the heterocyclic core is of formula 10 or 17, may be prepared by the route shown in Scheme 2. A suitable cyanide 11 is reacted with MeONa to give an imidate intermediate which could then be reacted with cyanamide to give carboximidate intermediate 12. Reaction with a suitable amine R1-NH2(e.g. with heating in EtOH) yielded an N-cyanoamidine intermediate 13, which reacted with bromoacetonitrile or chloroacetonitrile in the presence of a base (e.g. K2CO3) to give imidazole intermediate 14. Hydrolysis of the nitrile group to the amide (e.g. using H2O2and K2CO3) gave intermediate 15, which could be condensed with a suitable acid (16) or orthoester (e.g. triethyl orthoformate) to give pyrimidone 17, which could be further functionalized, e.g. by alkylation or acylation by reacting with a suitable alkylation or acylation agent R4-W (W = leaving group such as Cl, Br, I) in the presence of a base (e.g. NaH). In case of R3being OH, intermediate 15 can be reacted with a suitable reagent such as for instance phosgene or triphosgene to give the corresponding compounds of formula 17.

[0458] In one aspect, the present invention provides a process of manufacturing a compound of formula (I) described herein, or a pharmaceutically acceptable salt or a tautomer thereof, wherein the process is as described in any one of schemes 1 or 2.

[0459] In one aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a tautomer thereof, when manufactured according to any one of the processes described herein.

[0460]

[0461] 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.

[0462] 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.

[0463] 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.

[0464] 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.

[0465] 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.

[0466] 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.

[0467] 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 incubatedat 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).

[0468] 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).

[0469] 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 (Ex. means Example No.).

[0470] Table 1

[0471] APJ EC50APJ EC50Ex. Ex. (nM) (nM)

[0472] 1 113 14 617

[0473] 2 4 15 1742

[0474] 3 18 16 7029

[0475] 4 22 17 14243

[0476] 5 39 18 14458

[0477] 6 48 19 1339

[0478] 7 79 20 2721

[0479] 8 95 21 3621

[0480] 9 172 22 3440

[0481] 10 183 23 359

[0482] 11 223 24 7

[0483] 12 246 25 22

[0484] 13 385 26 0.1

[0485]

[0486]

[0487] APJ EC50APJ EC50Ex. Ex. (nM) (nM)

[0488] 27 0.1 36 0.6

[0489] 28 3 37 0.6

[0490] 29 0.1 38 0.6

[0491] 30 0.1 39 1.2

[0492] 31 0.2 40 1.4

[0493] 32 0.3 41 2.1

[0494] 33 0.4 42 3.8

[0495] 34 0.4 43 600

[0496] 35 70 44 4.0

[0497]

[0498]

[0499] Using the Compounds of the Invention

[0500] In one aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or a tautomer thereof, as described herein for use as a therapeutically active substance.

[0501] The compounds of the invention may be used as standalone treatments, i.e. as monotherapies, or as combination treatments together with other therapeutic agents.

[0502] Monotherapies

[0503] 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.In a further aspect, the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt or a tautomer 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.

[0504] 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.

[0505] 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.

[0506] 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.

[0507] 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.

[0508] 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.

[0509] In a particularly preferred embodiment, said disease or condition which benefits from increased activity of APJ is heart failure.In a particularly preferred embodiment, said disease or condition which benefits from increased activity of APJ is a neuromuscular disease.

[0510] In a particularly preferred embodiment, said disease or condition which benefits from increased activity of APJ is a chronic kidney disease.

[0511] In a particularly preferred embodiment, said disease or condition which benefits from increased activity of APJ is a cardiovascular disease.

[0512] In a particularly preferred embodiment, said disease or condition which benefits from increased activity of APJ is atherosclerosis.

[0513] In a particularly preferred embodiment, said disease or condition which benefits from increased activity of APJ is cardiorenal disease.

[0514] In a particularly preferred embodiment, said disease or condition which benefits from increased activity of APJ is a myocardial infarction.

[0515] In a particularly preferred embodiment, said disease or condition which benefits from increased activity of APJ is an aortic aneurysm.

[0516] In a particularly preferred embodiment, said disease or condition which benefits from increased activity of APJ is pulmonary arterial hypertension.

[0517] In a particularly preferred embodiment, said disease or condition which benefits from increased activity of APJ is an acute kidney injury.

[0518] In a particularly preferred embodiment, said disease or condition which benefits from increased activity of APJ is preeclampsia.

[0519] 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.

[0520] In one embodiment, the muscle atrophy is due to a therapy, for example therapy with a GLP-1R agonist.

[0521] In one embodiment, the muscle atrophy is due to a disease or condition.In one embodiment, the subject at risk of muscle atrophy is at bed rest.

[0522] In one embodiment, the subject at risk of muscle atrophy is an elderly subject (>65 years old).

[0523] In one embodiment, the subject at risk of muscle atrophy is an elderly subject (>65 years old) at bed rest.

[0524] Combination Treatments

[0525] 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.

[0526] 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:

[0527] co-administering to a subject in need thereof:

[0528] an effective dose of a compound according of formula (I) described herein, or a pharmaceutically acceptable salt or a tautomer thereof; and

[0529] an effective dose of a GLP-1R agonist,

[0530] to maintain lean muscle mass while inducing fat and weight loss in the subject.

[0531] 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:

[0532] co-administering to a subject in need thereof:

[0533] an effective dose of a compound of formula (I) described herein, or a pharmaceutically acceptable salt or a tautomer thereof; and

[0534] an effective dose of a GLP-1R agonist,

[0535] 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.

[0536] 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:

[0537] adding an effective dose of a compound of formula (I) described herein, or a pharmaceutically acceptable salt or a tautomer thereof, to the GLP-1 receptor agonist treatment regimen of a subject in need thereof,to treat or prevent further lean muscle mass decrease in the subject.

[0538] 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.

[0539] In one embodiment, the subject exhibits after the co-administration:

[0540] loss of fat but not lean muscle;

[0541] increased lean mass percentage;

[0542] increased lean / fat mass ratio; and / or

[0543] reduced or normal fed glucose level,

[0544] relative to a baseline level immediately before administration.

[0545] In one embodiment, the subject is overweight or obese.

[0546] In one embodiment, the subject has a disease or condition associated with weight gain.

[0547] 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.

[0548] In one embodiment, the subject has a metabolic disorder.

[0549] In one embodiment, the subject has diabetic obesity.

[0550] In one embodiment, the subject has type 1 diabetes, type 2 diabetes, or gestational diabetes.

[0551] In one embodiment, the subject has one or more of hypertension, dyslipidemia, obstructive sleep apnea, and cardiovascular disease.

[0552] 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:

[0553] co-administering to a subject in need thereof:

[0554] an effective dose of a compound of formula (I) described herein, or a pharmaceutically acceptable salt or a tautomer thereof; and

[0555] an effective dose of a GLP-1R agonist.

[0556] In a further aspect, the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt or a tautomer thereof, for use in any of the therapeutic methods described herein.

[0557] 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.

[0558] 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.

[0559] Pharmaceutical Compositions and Administration

[0560] In one aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as described herein and a therapeutically inert carrier.

[0561] In one embodiment, there is provided a pharmaceutical composition according to Example 26 or 27.

[0562] 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, dragees, 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).

[0563] 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, dragees and hard gelatin capsules. Lactose, corn starch or derivatives thereof, talc, stearicacid or its salts etc. can be used, for example, as such adjuvants for tablets, dragees and hard gelatin capsules.

[0564] Suitable adjuvants for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid substances and liquid polyols, etc.

[0565] Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose, etc.

[0566] Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.

[0567] Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols, etc.

[0568] 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.

[0569] 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.

[0570] Numbered Clauses

[0571] The invention is further described in the following numbered clauses:

[0572] 1. A compound of formula (I)

[0573]

[0574] or a pharmaceutically acceptable salt or a tautomer thereof, wherein:

[0575] (i) X, Z, and U are C, Y is N, and V is N or CH; or(ii) X, Y, and Z are C, U is N, and V is CH; or

[0576] (iii) Y, Z, and U are C, X is N, and V is N or CH; or

[0577] (iv) X, Y, and U are C, Z is N, and V is CH;

[0578] 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;

[0579] 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;

[0580] C is selected from the group consisting of C6-C10-aryl, 5- to 10-membered heteroaryl, C3-Cio-cycloalkyl, and 3- to 10-membered heterocyclyl;

[0581] 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;

[0582] L1is a covalent bond or -CHRL1-;

[0583] L2is selected from the group consisting of a covalent bond, -O-, -NRL2-, -SO2-, - CHRL1-, -CHRL1CO-*, -CHRL10-*, -0CHRL1-*, -CHRL10NRL2-*, and -0NRL2CRL1-*;

[0584] wherein an asterisk indicates the point of attachment of L2to ring C;

[0585] L3is a covalent bond or -(CHRL3)r-;

[0586] m is 0, 1, 2, or 3;

[0587] n is 0, 1, 2, or 3;

[0588] p is 0, 1, 2, or 3;

[0589] q is 0, 1, 2, or 3;

[0590] r is 1, 2, or 3;

[0591] R1is C1-C6-alkyl or a group

[0592]

[0593] R2is selected from the group consisting of C1-C6-alkyl, C1-C6-alkoxy, and a group

[0594] B

[0595]

[0596] R3is selected from the group consisting of hydrogen, hydroxy, halogen, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, and a

[0597] group

[0598]

[0599] R4is selected from the group consisting of hydrogen, amino, C1-C6-alkyl, hydroxy-Ci- Ce-alkyl, halo-C1-C6-alkyl, cyano-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, - (CHRL3)r-COORL2, -(CHRL3)r-CON(RL2)2, Ci-C6-alkyl-SO2-, Ci-C6-alkyl-SO2NRL2-

[0600]

[0601] R5is selected from the group consisting of halogen, C1-C6-alkyl, halo-C1-C6-alkyl, Ci- Ce-alkoxy, halo-C1-C6-alkoxy, and C1-C6-alkoxy-C1-C6-alkyl;

[0602] R6is selected from the group consisting of halogen, C1-C6-alkyl, halo-C1-C6-alkyl, Ci- Ce-alkoxy, halo-C1-C6-alkoxy, and C1-C6-alkoxy-C1-C6-alkyl; and

[0603] R7is selected from the group consisting of halogen, C1-C6-alkyl, halo-C1-C6-alkyl, Ci- Ce-alkoxy, halo-C1-C6-alkoxy, and C1-C6-alkoxy-C1-C6-alkyl;

[0604] R8is selected from the group consisting of halogen, C1-C6-alkyl, halo-C1-C6-alkyl, Ci- Ce-alkoxy, halo-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, and 5- to 10-membered heteroaryl;

[0605] each RL1is independently selected from the group consisting of hydrogen, C1-C6-alkyl, and C1-C6-alkoxy;

[0606] each RL2is independently selected from the group consisting of hydrogen and C1-C6-alkyl;

[0607] and

[0608] each RL3is independently selected from the group consisting of hydrogen, hydroxy, Ci-Ce- alkyl, and C1-C6-alkoxy;

[0609] 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.

[0610] The compound of formula (I) according to clause 1, or a pharmaceutically acceptable salt or a tautomer thereof, wherein the compound of formula (I) is a compound of formula (la), (lb), or (Ic):

[0611]

[0612] (Ic)

[0613] wherein V is N or CH; and R1, R2, R3, and R4are as defined in clause 1.3. The compound of formula (I) according to clause 1, or a pharmaceutically acceptable salt or a tautomer thereof, wherein the compound of formula (I) is a compound of formula (Ia):

[0614] 1 o

[0615]

[0616] (la)

[0617] wherein V, R1, R2, R3, and R4are as defined in clause 1.

[0618] 4. The compound of formula (I) according to any one of clauses 1 to 3, or a pharmaceutically acceptable salt or a tautomer thereof, wherein V is CH.

[0619] 5. The compound of formula (I) according to any one of clauses 1 to 4, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:

[0620]

[0621] A is selected from the group consisting of C6-C10-aryl and C3-C10-cycloalkyl;

[0622] L1is a covalent bond;

[0623] m is 0, 1, or 2; and

[0624] R5is selected from the group consisting of C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, and halo-C1-C6-alkyl.

[0625] 6. The compound of formula (I) according to any one of clauses 1 to 4, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:

[0626]

[0627] A is selected from the group consisting of phenyl and cyclopropyl;

[0628] L1is a covalent bond;

[0629] m is 0, 1, or 2; and

[0630] R5is selected from the group consisting of methoxy, methoxymethyl, and trifluoromethyl.

[0631] 7. The compound of formula (I) according to any one of clauses 1 to 4, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:

[0632]

[0633] A is C6-C10-aryl;

[0634] L1is a covalent bond;

[0635] m is 0, 1, or 2; and

[0636] R5is C1-C6-alkoxy.

[0637] The compound of formula (I) according to any one of clauses 1 to 4, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:

[0638]

[0639] A is phenyl;

[0640] L1is a covalent bond;

[0641] m is 0, 1, or 2; and

[0642] R5is methoxy.

[0643] The compound of formula (I) according to any one of clauses 1 to 4, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:

[0644]

[0645] The compound of formula (I) according to any one of clauses 1 to 4, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:

[0646]

[0647] A is C6-C10-aryl;

[0648] L1is a covalent bond;

[0649] m is 2; andR5is C1-C6-alkoxy.

[0650] The compound of formula (I) according to any one of clauses 1 to 4, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:

[0651] <L\< Z~_'X^(R5)rn

[0652] R1is a group

[0653]

[0654] A is phenyl;

[0655] L1is a covalent bond;

[0656] m is 2; and

[0657] R5is methoxy.

[0658] The compound of formula (I) according to any one of clauses 1 to 4, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:

[0659] .o.

[0660]

[0661] is a group

[0662] The compound of formula (I) according to any one of clauses 1 to 12, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:

[0663] B

[0664] R2is a group

[0665]

[0666] B is selected from the group consisting of C6-C10-aryl, 5- to 10-membered heteroaryl and C3-C10-cycloalkyl;

[0667] n is 0 or 1; and

[0668] R6is selected from the group consisting of C1-C6-alkyl and C1-C6-alkoxy.

[0669] The compound of formula (I) according to any one of clauses 1 to 12, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:

[0670] B

[0671] R2is a group

[0672]

[0673] B is selected from the group consisting of cyclopentyl, pyridyl, pyrazolyl, 1H-indazolyl, 4,5,6,7-tetrahydro-1H-indazolyl, 1,2-benzoxazolyl, and 4, 5, 6, 7 -tetrahydro - 1,2-benzoxazolyl;

[0674] n is 0 or 1; and

[0675] R6is selected from the group consisting of C1-C6-alkyl and C1-C6-alkoxy.

[0676] The compound of formula (I) according to any one of clauses 1 to 12, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:

[0677] A<^v(R6)n

[0678] R2is a group

[0679]

[0680] kB7;

[0681] B is selected from the group consisting of 5- to 10-membered heteroaryl and C3-C10- cycloalkyl;

[0682] n is 0 or 1; and

[0683] R6is selected from the group consisting of C1-C6-alkyl and C1-C6-alkoxy.

[0684] The compound of formula (I) according to any one of clauses 1 to 12, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:

[0685] A y(R6)n

[0686] R2is a group \B7;

[0687] B is selected from the group consisting of cyclopentyl, pyridyl, and pyrazolyl;

[0688] n is 0 or 1; and

[0689] R6is selected from the group consisting of methyl and methoxy.

[0690] The compound of formula (I) according to any one of clauses 1 to 12, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:

[0691] R2is selected from the group consisting of:

[0692]

[0693] The compound of formula (I) according to any one of clauses 1 to 12, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:

[0694] \B7

[0695] R2is a group

[0696]

[0697] ';

[0698] B is 5- to 6-membered heteroaryl;

[0699] n is 1; and

[0700] R6is C1-C6-alkoxy.

[0701] The compound of formula (I) according to any one of clauses 1 to 12, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:

[0702]

[0703] B is pyridyl;

[0704] n is 1; and

[0705] R6is methoxy.

[0706] The compound of formula (I) according to any one of clauses 1 to 12, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:

[0707] R2

[0708]

[0709] B is pyridyl;

[0710] n is 1; and

[0711] R6is ethoxy.

[0712] The compound of formula (I) according to any one of clauses 1 to 12, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:

[0713]

[0714] The compound of formula (I) according to any one of clauses 1 to 21, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:R3is selected from the group consisting of hydrogen, hydroxy and a group

[0715]

[0716] C is 5- to 6-membered heteroaryl;

[0717] L2is -CHRL1-;

[0718] RL1is hydrogen; and

[0719] p is 0.

[0720] 23. The compound of formula (I) according to any one of clauses 1 to 21, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:

[0721] R3is selected from the group consisting of hydrogen, hydroxy and a group

[0722]

[0723] C is pyrimidine;

[0724] L2is -CHRL1-;

[0725] RL1is hydrogen; and

[0726] p is 0.

[0727] 24. The compound of formula (I) according to any one of clauses 1 to 21, or a pharmaceutically acceptable salt or a tautomer thereof, wherein R3is hydrogen.

[0728] 25. The compound of formula (I) according to any one of clauses 1 to 24, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:

[0729] R4is selected from the group consisting of hydrogen, amino, C1-C6-alkyl, hydroxy-Ci- Ce-alkyl, halo-C1-C6-alkyl, cyano-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, - (CHRL3)r-COORL2, -(CHRL3)r-CON(RL2)2, Ci-C6-alkyl-SO2-, Ci-C6-alkyl-SO2NRL2-

[0730] , and a group

[0731]

[0732] S;

[0733] D is selected from the group consisting of C6-C10-aryl and 3- to 10-membered heterocyclyl;

[0734] L3is a covalent bond or -(CHRL3)r-:

[0735] q is 0 or 1;

[0736] r is 1;R8is C1-C6-alkoxy;

[0737] each RL2is independently selected from the group consisting of hydrogen and C1-C6-alkyl;

[0738] and

[0739] each RL3is hydrogen.

[0740] 26. The compound of formula (I) according to any one of clauses 1 to 24, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:

[0741] R4is selected from the group consisting of hydrogen, amino, methyl, 2 -hydroxy ethyl, 2,2,2-trifluoroethyl, cyanomethyl, 2-methoxyethyl, -(CHRL3)r-COORL2, -(CHRL3)r-

[0742] kD / CON(RL2)2, methyl-SO2-, methyl-SO2NRL2-, and a group

[0743]

[0744] '; D is selected from the group consisting of phenyl and azetidinyl;

[0745] L3is a covalent bond or -(CHRL3)r-:

[0746] q is 0 or 1;

[0747] r is 1;

[0748] R8is methoxy;

[0749] each RL2is independently selected from the group consisting of hydrogen and methyl; and each RL3is hydrogen.

[0750] 27. The compound of formula (I) according to any one of clauses 1 to 24, or a pharmaceutically acceptable salt or a tautomer thereof, wherein R4is selected from the group consisting of hydrogen, amino, methyl, 2 -hydroxy ethyl, 2,2,2-trifluoroethyl, cyanomethyl, 2-methoxyethyl, -CH2-COOH, -CH2-CONHCH3, -CH2-CON(CH3)2,

[0751] methyl-SO2-, methyl-SChNH-, a group, and a group

[0752]

[0753] 28. The compound of formula (I) according to any one of clauses 1 to 24, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:R4is selected from the group consisting of hydrogen, –CH2-COOH, and a group

[0754]

[0755] D is C6-C10-aryl;

[0756] L3is -(CHRL3)r-;

[0757] q is 1;

[0758] r is 1;

[0759] R8is C1-C6-alkoxy; and

[0760] RL3is hydrogen.

[0761] The compound of formula (I) according to any one of clauses 1 to 24, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:

[0762] R4is selected from the group consisting of hydrogen, –CH2-COOH, and a group

[0763]

[0764] D is phenyl;

[0765] L3is -(CHRL3)r-;

[0766] q is 1;

[0767] r is 1;

[0768] R8is methoxy; and

[0769] RL3is hydrogen.

[0770] The compound of formula (I) according to any one of clauses 1 to 24, or a pharmaceutically acceptable salt or a tautomer thereof, wherein R4is selected from the

[0771]

[0772] group consisting of hydrogen, -CH2-COOH, and a group

[0773] The compound of formula (la), (lb), or (Ic) according to clause 2, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:

[0774] V is N or CH;

[0775] A is C6-C10-aryl;B is selected from the group consisting of 5- to 10-membered heteroaryl and C3-C10- cycloalkyl;

[0776] C is 5- to 6-membered heteroaryl;

[0777] D is selected from the group consisting of C6-C10-aryl and 3- to 10-membered heterocyclyl;

[0778] L1is a covalent bond;

[0779] L2is -CHRL1-;

[0780] L3is a covalent bond or -(CHRL3)r-;

[0781] n is 0 or 1;

[0782] m is 0, 1, or 2;

[0783] p is 0;

[0784] q is 0 or 1;

[0785] r is 1;

[0786]

[0787] R3is selected from the group consisting of hydrogen, hydroxy and a group

[0788]

[0789] R4is selected from the group consisting of hydrogen, amino, C1-C6-alkyl, hydroxy-Ci- Ce-alkyl, halo-C1-C6-alkyl, cyano-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, - (CHRL3)r-COORL2, -(CHRL3)r-CON(RL2)2, Ci-C6-alkyl-SO2-, Ci-C6-alkyl-SO2NRL2-

[0790] , and a group

[0791]

[0792] S;

[0793] R5is C1-C6-alkoxy;

[0794] R6is selected from the group consisting of C1-C6-alkyl and C1-C6-alkoxy;

[0795] R8is C1-C6-alkoxy;

[0796] RL1is hydrogen;

[0797] each RL2is independently selected from the group consisting of hydrogen and C1-C6-alkyl;

[0798] andeach RL3is hydrogen.

[0799] The compound of formula (la), (lb), or (Ic) according to clause 2, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:

[0800] V is N or CH;

[0801] A is phenyl;

[0802] B is selected from the group consisting of cyclopentyl, pyridyl, and pyrazolyl;

[0803] C is pyrimidine;

[0804] D is selected from the group consisting of phenyl and azetidinyl;

[0805] L1is a covalent bond;

[0806] L2is -CHRL1-;

[0807] L3is a covalent bond or -(CHRL3)r-:

[0808] n is 0 or 1;

[0809] m is 0, 1, or 2;

[0810] p is 0;

[0811] q is 0 or 1;

[0812] r is 1;

[0813] R1is a group

[0814]

[0815] >;

[0816] A<~>r(R6)n

[0817] kB7

[0818] R2is a group

[0819]

[0820] ';

[0821] R3is selected from the group consisting of hydrogen, hydroxy and a group

[0822]

[0823] R4is selected from the group consisting of hydrogen, amino, methyl, 2 -hydroxy ethyl, 2,2,2-trifluoroethyl, cyanomethyl, 2-methoxyethyl, -(CHRL3)r-COORL2, -(CHRL3)r-, > V^(R8)q\D1 CON(RL2)2, methyl-SO2-, methyl-SO2NRL2-, and a group

[0824]

[0825] '; R5is methoxy;

[0826] R6is selected from the group consisting of methyl and methoxy;

[0827] R8is methoxy;RL1is hydrogen;

[0828] each RL2is independently selected from the group consisting of hydrogen and methyl; and each RL3is hydrogen.

[0829] 33. The compound of formula (la) according to clause 3, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:

[0830] V is CH;

[0831] A is C6-C10-aryl;

[0832] B is 5- to 6-membered heteroaryl;

[0833] D is C6-C10-aryl;

[0834] L1is a covalent bond;

[0835] L3is -(CHRL3)r-;

[0836] n is 1;

[0837] m is 2;

[0838] q is 1;

[0839] r is 1;

[0840]

[0841] R3is hydrogen;

[0842] R4is selected from the group consisting of hydrogen, CH2-COOH, and a group

[0843]

[0844] R5is C1-C6-alkoxy;

[0845] R6is C1-C6-alkoxy;

[0846] R8is C1-C6-alkoxy; and

[0847] RL3is hydrogen.

[0848] 34. The compound of formula (la) according to clause 3, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:

[0849] V is CH;A is phenyl;

[0850] B is pyridyl;

[0851] D is phenyl;

[0852] L1is a covalent bond;

[0853] L3is -(CHRL3)r-;

[0854] n is 1;

[0855] m is 2;

[0856] q is 1;

[0857] r is 1;

[0858]

[0859] R3is hydrogen;

[0860] R4is selected from the group consisting of hydrogen, CH2-COOH, and a group

[0861]

[0862] R5is methoxy;

[0863] R6is methoxy;

[0864] R8is methoxy; and

[0865] RL3is hydrogen.

[0866] The compound of formula (I) according to clause 1, or a pharmaceutically acceptable salt or a tautomer thereof, wherein said compound of formula (I) is selected from:

[0867] 3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-5H-imidazo[4,5-c]pyridin-4-one;

[0868] 3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-5-[(4- methoxyphenyl)methyl]imidazo[4,5-c]pyridin-4-one;

[0869] 2-[3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-4-oxo-imidazo[4,5-c]pyridin-5- yl]acetic acid;

[0870] 3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-5-(2-hydroxyethyl)imidazo[4,5- c]pyridin-4-one;3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-5-(2-methoxyethyl)imidazo[4,5- c]pyridin-4-one;

[0871] 3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-5-methyl-imidazo[4,5-c]pyridin-4-one; 3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-5-(2,2,2-trifluoroethyl)imidazo[4,5- c]pyridin-4-one;

[0872] 2-[3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-4-oxo-imidazo[4,5-c]pyridin-5- yl]acetonitrile;

[0873] 2-[3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-4-oxo-imidazo[4,5-c]pyridin-5-yl]-N- methyl-acetamide;

[0874] 5-(azetidin-3-yl)-3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)imidazo[4,5-c]pyridin-4- one;

[0875] 2-[3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-4-oxo-imidazo[4,5-c]pyridin-5-yl]- N, N-dimethyl-acetamide;

[0876] 5-amino-3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)imidazo[4,5-c]pyridin-4-one; N-[3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-4-oxo-imidazo[4,5-c]pyridin-5- yl]methanesulfonamide;

[0877] 3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-5-methylsulfonyl-imidazo[4,5-c]pyridin- 4-one;

[0878] 2-(6-ethoxy-2-pyridyl)-3-(2-methoxyphenyl)-5H-imidazo[4,5-c]pyridin-4-one;

[0879] 3-(2,6-dimethoxyphenyl)-2-(1-methylpyrazol-3-yl)-5H-imidazo[4,5-c]pyridin-4-one; 2-cyclopentyl-3-(2,6-dimethoxyphenyl)-5H-imidazo[4,5-c]pyridin -4-one;

[0880] 2-(6-ethoxy-2-pyridyl)-3-phenyl-5H-imidazo[4,5-c]pyridin-4-one;

[0881] 8-(6-ethoxy-2-pyridyl)-7-(2-methoxyphenyl)hypoxanthine;

[0882] 3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-5H-pyrazolo[3,4-d]pyrimidin-4-one; 3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-5H-pyrazolo[4,3-c]pyridin-4-one;

[0883] 3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-5H-pyrazolo[l,5-a]pyrazin-4-one;

[0884] 3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-6H-imidazo[l,2-c]pyrimidin-5-one; 7-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-2-(2-pyrimidylmethyl)hypoxanthine; and 7-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-2-hydroxy -hypoxanthine.

[0885] 36. The compound of formula (I) according to clause 1, or a pharmaceutically acceptable salt or a tautomer thereof, wherein said compound of formula (I) is selected from:

[0886] 2-[(5-chloro-2-pyridyl)methyl]-7-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2- pyridyl)hypoxanthine;(2S)-3-(cyclopropoxy)-2-[3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-4-oxo-imidazo[4,5-c]pyridin-5-yl]propanoic acid;formic acid;

[0887] (2R)-3-(cyclopropoxy)-2-[3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-4-oxo-imidazo[4,5-c]pyridin-5-yl]propanoic acid;

[0888] 7-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-2-(2-pyrimidyloxymethyl)hypoxanthine;

[0889] 2-[3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-4-oxo-imidazo[4,5-c]pyridin-5-yl]-3-phenoxy-propanoic acid;

[0890] 2-[3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-4-oxo-imidazo[4,5-c]pyridin-5-yl]-3-phenyl-propanoic acid;

[0891] 7-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-2-[(5-methylpyridazin-3-yl)oxymethyl]hypoxanthine;

[0892] 3-cyclopropyl-2-[3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-4-oxo-imidazo[4,5-c]pyridin-5-yl]propanoic acid;

[0893] 2-[3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-4-oxo-imidazo[4,5-c]pyridin-5-yl]-2-phenyl-acetic acid;

[0894] 7-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)hypoxanthine;

[0895] 2-[7-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-6-oxo-purin-l-yl]-3 -methoxy-propanoic acid;

[0896] 2-[l-(5-chloro-2-pyridyl)ethyl]-7-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)hypoxanthine;

[0897] 2-[2-[(5-chloro-2-pyridyl)methyl]-7-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-6-oxo-purin-1 -yl]acetic acid;

[0898] 2-[3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-4-oxo-imidazo[4,5-c]pyridin-5-yl]-3-methoxy-propanoic acid;

[0899] 5-[(5-chloro-2-pyridyl)methyl]-3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)imidazo[4,5-c]pyridin-4-one;

[0900] 7-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-l-p-anisyl-purin-6-one;

[0901] 8-[6-(cyclopropoxy)-2-pyridyl]-7-(2,6-dimethoxyphenyl)-2-(pyrimidin-2-ylmethyl)-lH-purin-6-one;

[0902] 8-(6-ethoxy-2-pyridyl)-7-(2-methoxyphenyl)-2-(pyrimidin-2-ylmethyl)-lH-purin-6-one; and

[0903] 5-[(5-chloropyrimidin-2-yl)methyl]-3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)imidazo[4,5-c]pyridin-4-one.37. The compound of formula (I) according to any one of clauses 1 to 36, or a pharmaceutically acceptable salt or a tautomer thereof, for use as a therapeutically active substance.

[0904] 38. A pharmaceutical composition comprising a compound of formula (I) according to any one of clauses 1 to 36, or a pharmaceutically acceptable salt or a tautomer thereof, and a therapeutically inert carrier.

[0905] 39. A pharmaceutical combination comprising a compound of formula (I) according to any one of clauses 1 to 36, or a pharmaceutically acceptable salt or a tautomer thereof, and a GLP-1R agonist.

[0906] 40. The pharmaceutical combination according to clause 39, for separate administration of the compound of formula (I) and the GLP-1R agonist.

[0907] 41. The pharmaceutical combination according to clause 39, wherein the combination is a fixed-dose combination.

[0908] 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 or a tautomer thereof.

[0909] 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.

[0910] 44. A method of inducing weight loss with maintenance of lean muscle mass in a subject in need of weight loss, comprising:

[0911] co-administering to a subject in need thereof:an effective dose of a compound according of formula (I) to any one of clauses 1 to 36, or a pharmaceutically acceptable salt or a tautomer thereof; and

[0912] an effective dose of a GLP-1R agonist,

[0913] to maintain lean muscle mass while inducing fat and weight loss in the subject.

[0914] 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: co-administering to a subject in need thereof:

[0915] an effective dose of a compound of formula (I) according to any one of clauses 1 to 36, or a pharmaceutically acceptable salt or a tautomer thereof; and

[0916] an effective dose of a GLP-1R agonist,

[0917] 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.

[0918] 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: adding an effective dose of a compound of formula (I) according to any one of clauses 1 to 36, or a pharmaceutically acceptable salt or a tautomer thereof, to the GLP-1 receptor agonist treatment regimen of a subject in need thereof,

[0919] to treat or prevent further lean muscle mass decrease in the subject.

[0920] 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.

[0921] 48. The method of any one of Clauses 44 to 47, wherein the subject exhibits after the coadministration:

[0922] loss of fat but not lean muscle;

[0923] increased lean mass percentage;

[0924] increased lean / fat mass ratio; and / or

[0925] reduced or normal fed glucose level,

[0926] relative to a baseline level immediately before administration.

[0927] 49. The method of any one of Clauses 44 to 48, wherein the subject is overweight or obese.50. The method of any one of Clauses 44 to 49, wherein the subject has a disease or condition associated with weight gain.

[0928] 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.

[0929] 52. The method of any one of Clauses 44 to 51, wherein the subject has a metabolic disorder.

[0930] 53. The method of clause 52, wherein the subject has diabetic obesity.

[0931] 54. The method of clause 52 or 53, wherein the subject has type 1 diabetes, type 2 diabetes, or gestational diabetes.

[0932] 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.

[0933] 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:

[0934] co-administering to a subject in need thereof:

[0935] an effective dose of a compound of formula (I) according to any one of clauses 1 to 36, or a pharmaceutically acceptable salt or a tautomer thereof; and

[0936] an effective dose of a GLP-1R agonist.

[0937] 57. A compound of formula (I) according to any one of clauses 1 to 36, or a pharmaceutically acceptable salt or a tautomer thereof, for use in a method according to any one of clauses 42 to 56.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.

[0938] 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

[0939] 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.

[0940] 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.

[0941] 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.

[0942] All reaction examples and intermediates were prepared under an argon atmosphere if not specified otherwise.

[0943] 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.

[0944] Example 1

[0945] 3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-5H-imidazo[4,5-c]pyridin-4-one

[0946]

[0947] To a stirred solution of 4-chloro-3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)imidazo[4,5-c]pyridine (800 mg, 1.95 mmol) in acetic acid (3 mL) was added sodium acetate (1597 mg, 19.5 mmol), and the reaction mixture was stirred in a sealed tube at 140 °C for 12 h. The reaction mixture was quenched with sat. aq. NaHCO3solution and extracted with EtOAc. The combinedorganic layers were dried over Na2SC>4 and concentrated under reduced pressure to give a residue which was purified by combi-flash chromatography (eluting with 32% EtOAc in n-heptane). The title compound (360 mg, 0.92 mmol, 47% yield) was isolated as an off-white solid. MS (ESI): m / z = 393.0 [M+H]+

[0948] Step a) 2-chloro-N-(2, 6-dimethoxyphenyl)-4-nitro-pyridin-3-amine

[0949] To a stirred solution of 2,6-dimethoxyaniline (3.0 g, 19.6 mmol) in THF (40 mL) was added LiHMDS (1 M in THF) (39.2 mL, 39.2 mmol) under N2at -78 °C over 10 minutes, and the reaction mixture was stirred for 30 min at the same temperature. 2-chloro-3-fluoro-4-nitro-pyridine (3.8 g, 21.5 mmol) in THF (10 mL) was added at -78 °C, and the reaction mixture was stirred at this temperature for 2 h. The reaction was quenched with sat. aq. NH4CI solution (50 mL), and the aq. phase was extracted with EtOAc (4 x 30 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated under vacuum to obtain the crude title compound (5.0 g, 16.1 mmol, 51 % yield) as brown liquid, which was used in the next step without further purification. MS (ESI): m / z = 309.8 [M+H]+

[0950] Step b) 4-chloro-3-(2, 6-dimethoxyphenyl)-2-( 6-ethoxy-2-pyridyl)imidazo[ 4, 5-c ]pyridine

[0951] To a stirred solution of 2-chloro-N-(2,6-dimethoxyphenyl)-4-nitro-pyridin-3-amine (3.0 g, 9.69 mmol) and 6-ethoxypyridine-2-carbaldehyde (3.0 g, 19.9 mmol) in EtOH (50 mL), was added Na2S2O4 (33.7 g, 194 mmol) at RT and the resulting reaction mixture was heated under reflux for 24 h. The reaction mixture was concentrated under vacuum, diluted with ice cold water (30 mL) and the aq. phase was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum to obtain the crude product which was purified by flash column chromatography (eluting with 20-30% EtOAc in hexanes) to give the title compound (1.2 g, 2.92 mmol, 30 % yield) as a pale yellow solid. MS (ESI): m / z = 410.9 [M+H]+

[0952] The following Examples (Ex.) were generated in analogy to Example 1, using the indicated building blocks in place of 2,6-dimethoxyaniline (amine building block) and / or 6-ethoxypyridine-2-carbaldehyde (aldehyde building block).Ex. Structure Systematic Amine Aldehyde MS, ESI;

[0953] Name Building Building Block m / z ^O. Block

[0954] 15 I 2-(6-ethoxy-2- 2- 6- 363.3 pyridyl)-3-(2- methoxyan ethoxypyridine- [M+H]+methoxyphenyl)- iline 2-carbaldehyde

[0955] 5H-imidazo[4,5- c]pyridin-4-one

[0956] 16 3-(2,6- 2,6- 1 -methyl- 1H- 352.1 dimethoxyphenyl dimethoxy pyrazole-3- [M+H]+)-2-(l- aniline carbaldehyde methylpyrazol-3- yl)-5H- I

[0957] ^3.0 imidazo[4,5- / ( °=c]pyridin-4-one

[0958] 17 y T tr^ 2-cyclopentyl-3- 2,6- cyclopentanecar 340.1o\\ / ft r Q~% (2,6- dimethoxy baldehyde [M+H]+~-o 11

[0959] r — \ / ''ITNHdimethoxyphenyl aniline

[0960] u— / / — v IL J

[0961] )-5H- imidazo[4,5- c]pyridin-4-one

[0962] 18 2-(6-ethoxy-2- aniline 6- 333.0 pyridyl)-3- ethoxypyridine- [M+H]+phenyl-5H- 2-carbaldehyde imidazo[4,5- c]pyridin-4-one

[0963]

[0964] Example 2

[0965] 3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-5-[(4-methoxyphenyl)methyl] imidazo[4,5-c]pyridin-4-one

[0966]

[0967] To a stirred solution of 3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-5H-imidazo[4,5-c]pyridin-4-one (Example 1) (280 mg, 0.71 mmol) in THF (10 mL) was added potassium tert, butoxide (714 mg, 6.37 mmol), followed by 4 -methoxybenzylchloride (0.86 mL, 6.37 mmol), and sodium iodide (38.2 mg, 0.25 mmol). The reaction mixture was heated at 80 °C for 12 h. The reaction mixture was diluted with water (100 mL) and Ethyl acetate (200 mL). The organic layer was separated, dried over Na2SO4and concentrated under reduced pressure to get a residue which was purified by combi flash chromatography (eluting with 30-40% Ethyl Acetate in n-Heptane) to yield the title compound (120 mg, 0.23 mmol, 31% yield) as a light yellow solid. MS (ESI): m / z = 513.3 [M+H]+

[0968] The following Examples were generated in analogy to Example 2, using the indicated building blocks in place of 4-methoxybenzylchloride:

[0969] Ex. Structure Systematic Name Building MS,

[0970] Block ESI;

[0971] m / z

[0972] 40 5-[(5-chloro-2- 5-chloro-2- 518.3

[0973] pyridyl)methyl]-3-(2,6- (chloromethy [M+H]+

[0974] >=N dimethoxyphenyl)-2-(6- l)pyridine

[0975] O

[0976] ) ethoxy-2- pyridy l)imidazo [4, 5 - c]pyridin-4-one

[0977]

[0978] Example 3

[0979] 2-[3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-4-oxo-imidazo[4,5-c]pyridin-5-yl]acetic acid

[0980]

[0981] To a stirred solution of ethyl 2-[3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-4-oxo-imidazo[4,5-c]pyridin-5-yl]acetate (70 mg, 0.15 mmol) in THF (1 mL) and water (0.3 mL) was added lithium hydroxide monohydrate (12.3 mg, 0.29 mmol) at 0 °C. The reaction was stirred for 1 h, concentrated under reduced pressure and purified by reverse phase combiflash (0.05% formic acid and acetonitrile gradient) to yield the title compound (16.2 mg, 0.04 mmol, 20 % yield). MS (ESI): m / z = 450.9 [M-H]’

[0982] Step a) ethyl 2-[3-(2, 6-dimethoxyphenyl)-2-( 6-ethoxy-2-pyridyl)-4-oxo-imidazo[ 4, 5-c ]pyridin-5-yl]acetate

[0983] To a stirred solution of 3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-5H-imidazo[4,5-c]pyridin-4-one (Example 1) (50 mg, 0.13 mmol) in DMF (1 mL) was added sodium hydride (60% in mineral oil) (10.2 mg, 0.25 mmol) and the reaction mixture was stirred for 15 min. Ethyl bromoacetate (0.02 mL, 0.14 mmol) was added and the mixture stirred at 10 °C for 1 h. The reaction mixture was quenched with ice cool water (10 mL) to get a solid precipitate, which was filtered, washed with water (5 mL) and pentane (10 mL) and dried under vacuum to give the title compound (70.0 mg, 0.15 mmol, 75 % yield), which was carried directly to the next step without further purification. MS (ESI): m / z = 479.0 [M+H]+

[0984] Example 4

[0985] 3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-5-(2-hydroxyethyl)imidazo[4,5-c]pyridin- 4-one

[0986]

[0987] To a stirred solution of 5-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)imidazo[4,5-c]pyridin-4-one (50.0 mg, 0.09 mmol) in THF (2 mL) was added Tetrabutylammonium fluoride solution 1.0 M in THF (1.0 mL, 1.0 mmol). The resulting reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with sat. aq. NaHCO3solution (10 mL) and EtOAc (10 mL). The organic layer was separated and dried over Na2SC>4 and concentrated under reduced pressure to give a residue which was purified by reverse phase combiflash (40% acetonitrile in 0.025% FA in water) to yield the title compound (25.0 mg, 0.06 mmol, 62% yield) as an off white solid. MS (ESI): m / z = 437.1 [M+H]+

[0988] Step a) 5-[2-[ tert-butyl(dimethyl)silyl]oxyethyl] -3-(2, 6-dimethoxyphenyl)-2-( 6-ethoxy-2-pyridyl)imidazo[ 4, 5-c ]pyridin-4-one

[0989] To a stirred solution of 3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-5H-imidazo[4,5-c]pyridin-4-one (50.0 mg, 0.13 mmol) in DMF (1 mL) was added NaH (60% in mineral oil) (5.86 mg, 0.25 mmol) followed by (2-bromoethoxy)-tert-butyldimethylsilane (30.5 mg, 0.13 mmol). The resulting reaction mixture was stirred at 25 °C for 4 h. The reaction mixture was diluted with ice cold water (10 mL) and EtOAc (10 mL). The organic layer was separated, dried over Na2SO4and concentrated under reduced pressure to get a residue which was purified by combiflash chromatography (eluting with 40-60% EtOAc in n-Heptane) to give the title compound (50.0 mg, 0.09 mmol, 53% yield) as an yellow solid. MS (ESI): m / z = 551.0 [M+H]+Example 5

[0990] 3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-5-(2-methoxyethyl)imidazo[4,5-c]pyridin- 4-oneo

[0991]

[0992] To a stirred solution of 3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-5H-imidazo[4,5-c]pyridin-4-one (Example 1) (40.0 mg, 0.1 mmol) in DMF (1 mL) was added NaH (60% in mineral oil) (10.0 mg, 0.26 mmol), then 2-bromoethyl methyl ether (0.02 mL, 0.22 mmol) was added at 0°C. The resulting reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with ice cold water (10 mL) and EtOAc (10 mL). The organic layer was separated, dried over Na2SO4and concentrated under reduced pressure to get a residue which was purified by reverse combiflash (eluting with 50% acetonitrile in 0.025% FA in water) to give the title compound (30.0 mg, 0.07 mmol, 65 % yield) as an off-white solid. MS (ESI): m / z = 451.0 [M+H]+

[0993] The following Examples were generated in analogy to Example 5, using the indicated building / \= O

[0994] blocks in place of 2-bromoethyl methyl ether.

[0995] Ex. S ct Qructure Systematic Name Building

[0996] rx / \ ' MS,

[0997] Block ESI;

[0998] m / z

[0999] 6 3 -(2,6-dimethoxyphenyl)- methyl 407.1

[1000] 2-(6-ethoxy-2-pyridyl)-5- iodide [M+H]+-° \ o

[1001] methyl-imidazo[4,5- < )P=NMNNT-'V^I

[1002] c]pyridin-4-one

[1003] O

[1004] )

[1005] 7 3 -(2,6-dimethoxyphenyl)- 2,2,2- 475.1

[1006] 2-(6-ethoxy-2-pyridyl)-5- trifluoroethyl [M+H]+(2,2,2- trifluorometh trifluoroethyl)imidazo[4,5 anesulfonate

[1007] -c]pyridin-4-one

[1008]

[1009] 8 2-[3-(2,6- bromoaceton 432.3

[1010] dimethoxyphenyl)-2-(6- itrile [M+H]+ethoxy-2-pyridyl)-4-oxo- imidazo[4,5-c]pyridin-5- yl]acetonitrile

[1011] 9 ZI

[1012] / 2-[3-(2,6- 2-bromo-N- 464.1 dimethoxyphenyl)-2-(6- methylaceta [M+H]+ethoxy-2-pyridyl)-4-oxo- mide

[1013] imidazo[4,5-c]pyridin-5- yl]-N-methyl-acetamide

[1014] 11 2-[3-(2,6- 2-bromo- 478.4

[1015] dimethoxyphenyl)-2-(6- N, N- [M+H]+fynMN.'V- > N N^ 0 ethoxy-2-pyridyl)-4-oxo- dimethylacet

[1016] 0

[1017] imidazo[4,5-c]pyridin-5- ) amide

[1018] yl]-N, N-dimethyl- acetamide

[1019] i\= o

[1020] 44 5 -[(5 -chloropyrimidin-2- 5-chloro-2- 519.3

[1021] ^° \ H yl)methyl]-3-(2,6- (chloromethy [M+H]+

[1022] dimethoxyphenyl)-2-(6- l)pyrimidine

[1023] > NNX / <ci

[1024] 0 ethoxy-2- hydrochlorid

[1025] ) pyridy l)imidazo [4,5 - e (CAS:

[1026] c]pyridin-4-one 1427454-12- 3)

[1027]

[1028] Example 10

[1029] 5-(azetidin-3-yl)-3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)imidazo[4,5-c]pyridin-4-one

[1030]

[1031] To a stirred solution of tert-butyl 3-[3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-4-oxo-imidazo[4,5-c]pyridin-5-yl]azetidine-l -carboxylate (40.0 mg, 0.07 mmol) in DCM (1 mL) was added TFA (1.0 mL, 0.07 mmol) at 0 °C. The temperature was raised to 25°C and the reaction stirred at this temperature for 2 h. The reaction was concentrated under reduced pressure, and purified by reverse phase combiflash (40% acetonitrile in 0.025% FA in water) to give the title compound (14.0 mg, 0.03 mmol, 39 % yield) as an off white solid. MS (ESI): m / z = 448.1 [M+H]+

[1032] Step a) tert-butyl 3-[3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-4-oxo-imidazo[4,5-c]pyridin-5-yl]azetidine-l -carboxylate

[1033] To a stirred solution of 3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-5H-imidazo[4,5-c]pyridin-4-one (Example 1) (100 mg, 0.25 mmol) in DMSO (1 mL) was added cesium carbonate (300 mg, 0.92 mmol), followed by tert-butyl 3 -bromoazetidine- 1 -carboxylate (70.0 mg, 0.3 mmol). The reaction was heated to 80 °C and stirred at this temperature for 2 h. The reaction mixture was diluted with ice cold water (10 mL) and EtOAc (20 mL). The organic layer was separated, dried over Na2SC>4 and concentrated under reduced pressure to get a residue which was purified by combiflash chromatography (eluting with 20 - 30% EtOAc in n-heptane) to yield the title compound (52.0 mg, 0.09 mmol, 37% yield) as a yellow solid. MS (ESI): m / z = 548.1 [M+H]+

[1034] Note: Regioisomeric tert-butyl 3-[3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)imidazo[4,5-c]pyridin-4-yl]oxyazetidine-l -carboxylate (54.0 mg, 0.1 mmol, 36 % yield) was also isolated as a yellow solid. MS (ESI): m / z = 548.1 [M+H]+. The compound regiochemistry was confirmed via H NMR and NOE.

[1035] Example 12

[1036] 5-amino-3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)imidazo[4,5-c]pyridin-4-one

[1037]

[1038] To a stirred solution of 3-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-3,5-dihydro-4H-imidazo[4,5-c]pyridin-4-one (Example 1) (30.0 mg, 0.08 mmol) in DMF (1 mL) was added Cs2CO3(75 mg, 0.23 mmol) followed by DPPH (22 mg, 0.09 mmol) at rt, and the reaction mixture was stirred for 4 h at 100 °C. Upon completion, the reaction mixture was diluted with ice cold water (3 mL) and the aq. phase was extracted with EtOAc (3x 10 mL). The combined organic phase was dried over Na2SC>4, filtered, and concentrated under vacuum to obtain a residue which was purified by flash column chromatography (eluting with 60-70% EtOAc in hexanes) to give the title compound (15.0 mg, 0.04 mmol, 47 % yield) as a pale yellow solid. MS (ESI): m / z = 408.1 [M+H]+

[1039] Example 13

[1040] N-[3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-4-oxo-imidazo[4,5-c]pyridin-5-yl] methanesulfonamide; acetic acid salt

[1041]

[1042] To a stirred solution of N-(3-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-4-oxo-3,4-dihydro-5H-imidazo[4,5-c]pyridin-5-yl)-N-(methylsulfonyl)methanesulfonamide (30 mg, 0.05 mmol) in THF (20 mL) was added KOH (50 % in water, w / w) (9 mg, 0.08 mmol) and the resulting reaction mixture was stirred at rt for 4 h. Upon completion, the reaction mixture was acidified to pH = 4-5, with HCOOH, diluted with ice cold water (10 mL) and EtOAc (20 mL). The organic phase was separated, dried over Na2SO4and concentrated under vacuum to obtain a residue, which was purified by flash column chromatography (eluting with 50-55% acetonitrile)in water to afford the title compound (20.0 mg, 0.04 mmol, 77 % yield) as a white solid. MS (ESI): m / z = 486.1 [M+H]+

[1043] Step a) N-(3-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-4-oxo-3,4-dihydro-5H-imidazo[4,5-c]pyridin-5-yl)-N-(methylsulfonyl)methanesulfonamide

[1044] To a stirred solution of 5-amino-3-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-3,5-dihydro-4H-imidazo[4,5-c]pyridin-4-one (60 mg, 0.15 mmol) (Example 12) in DCM (5 mL), were added DIPEA (130 pL, 0.74 mmol) followed by MsCl (34 mg, 0.29 mmol) at 0 °C under N2. The reaction mixture was stirred for 4 h at 40 °C. The reaction was quenched with ice cold water (10 mL) and the aq. phase was extracted with EtOAc (2 x 10 mL). The combined organic phase was dried over Na2SO4, filtered and concentrated under vacuum to obtain the crude title compound, which was used in next step without further purification. MS (ESI): m / z = 564.0 [M+H]+

[1045] Example 14

[1046] 3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-5-methylsulfonyl-imidazo[4,5-c]pyridin-4-one

[1047]

[1048] To a stirred solution of 3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-5H-imidazo[4,5-c]pyridin-4-one (50.0 mg, 0.13 mmol) (Example 1) in DIPEA (0.83 mL, 4.69 mmol) was added methanesulfonyl chloride (0.33 mL, 4.31 mmol), and the reaction was stirred at 25 °C for 4 h. The reaction mixture was diluted with ice cold water (10 mL) and EtOAc (10 mL). The organic layer was separated, dried over Na2SO4and concentrated under reduced pressure to give a residue, which was purified by combiflash chromatography (eluting with 40-60% EtOAc in heptane) to give the title compound (5.0 mg, 0.01 mmol, 8 % yield) as a light brown solid. MS (ESI): m / z = 471.1 [M+H]+Example 19

[1049] 8-(6-ethoxy-2-pyridyl)-7-(2-methoxyphenyl)hypoxanthine

[1050]

[1051] Triethyl orthoformate (92.3 mg, 104 pL, 623 pmol) was added to a suspension of 5-amino-2-(6-ethoxy-2-pyridyl)-3-(2-methoxyphenyl)imidazole-4-carboxamide (55 mg, 156 pmol) in DMF (1 mL) at rt. The mixture was stirred for 2 h at 120 °C and then for 16 h at 140°C. The reaction mixture was diluted with sat. aq. NaHCO3solution and extracted two times with EtOAc. The organic layers were washed with water and brine, dried over Na2SO4and concentrated to dryness. The crude material was purified by flash chromatography on silica gel (eluting with heptane / EtOAc / EtOH). The title compound was isolated (15 mg, 25% yield) as a white solid. MS (ESI): m / z = 364.2 [M+H]+

[1052] Step a) methyl 6-ethoxypyridine-2-carboximidate

[1053] To a solution of 6-ethoxypyridine-2-carbonitrile (10.0 g, 67.5 mmol) in MeOH (100 mL) was added sodium methoxide (0.36 g, 6.75 mmol), and the solution was stirred at 30 °C for 12 h. The mixture was cooled to room temperature. The suspension was filtered and the filter cake was washed with methanol (20 mL). The filtrate was concentrated under reduced pressure affording the title compound as a yellow solid, which was used directly for the next step without further purification. MS (ESI): m / z = 181.0 [M+H]+

[1054] Step b) methyl (2E / Z)-N-cyano-6-ethoxy-pyridine-2-carboximidate

[1055] To a solution of cyanamide (12.6 g, 150 mmol), disodium hydrogen phosphate (10.6 g, 74.9 mmol) and sodium phosphate, monobasic, monohydrate (41.4 g, 300 mmol) in water (150 mL) was added methyl 6-ethoxypyridine-2-carboximidate (13.5 g, 74.9 mmol), the reaction mixture was stirred at 30 °C for 12 h. The reaction mixture was extracted with CH2Cl2(200 mL x 3). The combined organic phase was dried and concentrated under vacuum to give a residue, which waspurified by flash chromatography (15-20% EtOAc in petroleum ether) to give the title compound (2.8 g, 13.6 mmol, 18 % yield) as a white solid. MS (ESI): m / z = 205.9 [M+H]+

[1056] Step c) N'-cyano-6-ethoxy-N-(2-methoxyphenyl)pyridine-2-carboxamidine

[1057] To a solution of methyl (2E / Z)-N-cyano-6-ethoxy-pyridine-2-carboximidate (670 mg, 3.26 mmol) in EtOH (7 mL) was added O-anisidine (402 mg, 3.26 mmol), and the reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was cooled to 10 °C and filtered. The filter cake was washed with EtOH (5 mL) and dried under vacuum to give N'-cyano-6-ethoxy-N-(2-methoxyphenyl)pyridine-2-carboxamidine (130.0 mg, 0.44 mmol, 13% yield) as a yellow crystalline solid. MS (ESI): m / z = 297.1 [M+H]+

[1058] Step d) 5-amino-2-(6-ethoxy-2-pyridyl)-3-(2-methoxyphenyl)imidazole-4-carbonitrile

[1059] To a solution of N'-cyano-6-ethoxy-N-(2-methoxyphenyl)pyridine-2-carboxamidine (300 mg, 1.01 mmol), K2CO3(210 mg, 1.52 mmol), and tetrabutylammonium iodide (11.2 mg, 0.03 mmol) in DMF (8 mL) was added bromoacetonitrile (0.07 mL, 1.01 mmol) at 20 °C, The mixture was stirred at 20 °C for 1 h. The reaction was diluted with sat. aq. NaHCO3solution and extracted two times with EtOAc. The combined organic layers were washed with brine (20 mL x 3), dried over Na2SO4and concentrated under vacuum to give a residue. The residue was dissolved in MeOH (8 mL), sodium methoxide (30% in MeOH) (0.2 mL, 1.06 mmol) was added, and the mixture was stirred at 80 °C for 4 h. The reaction was cooled to room temperature, acetic acid (0.06 mL, 1.11 mmol) was added, and the mixture was concentrated under vacuum. The residue was diluted with sat. aq. NaHCO3solution and extracted two times EtOAc. The combined organic layers were washed with brine (20 mL x 3), dried over Na2SO4, and concentrated under vacuum to give a residue, which was purified by reversed phase (mobile phase: 30-42% acetonitrile in water(0.1%FA)) and lyophilized. The title compound (230 mg, 0.69 mmol, 68 % yield) was obtained as yellow solid. MS (ESI): m / z = 336.1 [M+H]+

[1060] Step e) 5-amino-2-(6-ethoxy-2-pyridyl)-3-(2-methoxyphenyl)imidazole-4-carboxamide

[1061] 5-amino-2-(6-ethoxy-2-pyridyl)-3-(2-methoxyphenyl)imidazole-4-carbonitrile (65 mg, 194 pmol) was suspended in DMSO and K2CO3(5.36 mg, 38.8 pmol) was added atRT. H2O2(75.3 mg, 67.9 pL, 775 pmol) was added dropwise at 0 °C. The mixture was stirred for 16 h at 20 °C. The reaction mixture was diluted with sat. aq. NaHCO3-solution and extracted two times with EtOAc. The organic layers were washed with water and brine, dried over Na2SO4and concentrated to dryness. The crude material was purified by flash chromatography on silica gel(EtOAc in Heptane), to give the title compound (45 mg, 62 % yield) as white solid. MS (ESI): m / z = 354.3 [M+H]+

[1062] Example 20

[1063] 3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-5H-pyrazolo[3,4-d]pyrimidin-4-one

[1064]

[1065] To a yellow solution of (4,6-dichloropyrimidin-5-yl)-(2,6-dimethoxyphenyl)methanone (1.0 g, 3.19 mmol) in DMF (15 mL) was added (6-ethoxy-2-pyridyl)hydrazine; hydrochloride (A.l) (727 mg, 3.83 mmol) and TEA (646 mg, 6.39 mmol) at 25 °C. The reaction mixture was stirred at 30 °C for 12 h. The reaction mixture was purified by prep-HPLC (mobile phase: 30-60% acetonitrile in water(0.225% FA)) and the purified solution was lyophilized to afford the title compound (10.1 mg, 0.03 mmol, 0.8% yield) as white solid, along with an additional quantity of the title compound (200 mg, 0.51 mmol, 12.% yield) as yellow solid with 75% purity. MS (ESI): m / z = 394.1 [M+H]+

[1066] Step a) (4, 6-dichloropyrimidin-5-yl)-(2, 6-dimethoxyphenyl)methanol

[1067] n-BuLi (2.5 M in THF) (19.0 mL, 47.5 mmol) was added dropwise to a solution of 2-bromo-l,3-dimethoxybenzene (8.59 g, 39.6 mmol) in THF (50 mL) and the resulting reaction mixture was stirred at -65 °C for 0.5 h. A solution of 4,6-dichloro-5-pyrimidinecarbaldehyde (CAS:

[1068] 5305-40-8) (7.0 g, 39.6 mmol) in THF (50 mL) was added dropwise to the preformed solution at -65 °C. The reaction mixture was stirred at -65 °C for another 1 h. The reaction mixture was warmed to 20 °C, quenched into sat. aq. NH4CI solution (200 mL), and then extracted with ethyl acetate (100 mL x 3). The combined organic phases were dried over anhydrous Na2SO4, then concentrated under vacuum to give a residue, which was purified on silica gel column chromatography (0 - 25% EtOAc in petroleum ether) and concentrated under reduced pressure to give the title compound (6.0 g, 19.0 mmol, 48% yield) as yellow solid. MS (ESI): m / z = 314.9 [M+H]+Step b) (4, 6-dichloropyrimidin-5-yl)-(2, 6-dimethoxyphenyl)methanone

[1069] To the colourless solution of (4,6-dichloropyrimidin-5-yl)-(2,6-dimethoxyphenyl)methanol (2.5 g, 7.93 mmol) in DCM (30 mL) was added MnO2(6.9 g, 79.3 mmol) at 25 °C to give a black suspension. The mixture was stirred at 30 °C for 24 h under N2atmosphere. The reaction mixture was purified by prep-HPLC (mobile phase: 35-55% acetonitrile in water(0.225%FA)) and the purified solution was lyophilized to afford the title compound (1.8 g, 5.75 mmol, 72% yield) as yellow solid. MS (ESI): m / z = 315.0 [M+H]+

[1070] Example 21

[1071] 3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-5H-pyrazolo[4,3-c]pyridin-4-one

[1072]

[1073] To a yellow solution of 4-chloro-3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)pyrazolo[4,3-c]pyridine (110 mg, 0.26 mmol) in 1,4-dioxane (2 mL) and water (0.200 mL) was added KOH (146 mg, 2.6 mmol) and t-BuXPhos Pd G3 (20.6 mg, 0.03 mmol) at room temperature. The reaction mixture was stirred at 100 °C for 12 h under N2atmosphere to give a black suspension. The reaction mixture was filtered and the filtrate was purified by prep-HPLC (mobile phase: 52-82% acetonitrile in H2O (0.225% FA)) and lyophilized to give the title compound (10.0 mg, 0.03 mmol, 10 % yield) as a white solid. MS (ESI): m / z = 393.2 [M+H]+

[1074] Step a) (2-chloro-4-fluoro-3-pyridyl)-(2, 6-dimethoxyphenyl)methanol

[1075] To a yellow solution of 2,2,6,6-tetramethylpiperidine (8.52 g, 60.3 mmol) in THF (120 mL) was added dropwise 2.5M n-BuLi in hexane (22.3 mL, 55.7 mmol) at -70 °C under N2atmosphere. The reaction mixture was stirred at -70 °C for 15 min, then 2-chloro-4-fluoropyridine (6.1 g, 46.4 mmol) was added at -70 °C and the mixture was stirred at this temperature for 1 h. 2,6-dimethoxybenzaldehyde (9.25 g, 55.7 mmol) was added dropwise at -70 °C and the mixture was stirred for 1 h at this temperature to give a brown suspension. The reaction mixture was poured into sat. aq. NH4CI solution (200 mL) and extracted with ethyl acetate (200 mL x 3). Thecombined organic phase was dried over Na2SC>4, then concentrated under reduced pressure to give a residue. The residue was purified by reversed phase chromatography (mobile phase 40-50% acetonitrile in water(0.1% FA)). Product containing fractions were evaporated under reduced pressure to give a solution, which was extracted with ethyl acetate (100 mL x 3). The combined organic phases were dried over Na2SO4and then concentrated under reduced pressure to give the title compound (5.59 g, 18.8 mmol, 32 % yield) as a yellow solid. MS (ESI): m / z = 297.9 [M+H]+

[1076] Step b) (2-chloro-4-fluoro-3-pyridyl)-(2, 6-dimethoxyphenyl)methanone

[1077] To a colorless solution of (COC1)2 (1.57 mL, 18.5 mmol) in DCM (30 mL) was added DMSO (1.31 mL, 18.5 mmol) dropwise at -70 °C under N2atmosphere and the reaction mixture was stirred at -70 °C for 15 min. (2-chloro-4-fluoro-3-pyridyl)-(2,6-dimethoxyphenyl)methanol (4.58 g, 12.3 mmol) in DCM (30 mL) was added dropwise at -70 °C, then the reaction mixture was stirred at -40 °C for 0.5 h. TEA (8.55 mL, 61.5 mmol) was added, and the mixture was stirred at 25 °C for 15 min under N2atmosphere to give a yellow suspension. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with brine (100 mL x 3) and dried over Na2SC>4, then concentrated in vacuum to give a residue. The residue was purified by reversed phase chromatography (mobile phase: 45-55% acetonitrile in water (0.1%FA)). Product containing fractions were concentrated under reduced pressure to give a solution, which was extracted with ethyl acetate (100 mL x 3). The combined organic phase was dried over Na2SC>4 and then concentrated under reduced pressure to give the title compound (3.22 g, 10.9 mmol, 66% yield) as a yellow solid. MS (ESI): m / z = 296.0 [M+H]+

[1078] Step c) 4-chloro-3-(2, 6-dimethoxyphenyl)-2-( 6-ethoxy-2-pyridyl)pyrazolo[ 4, 3-c]pyridine

[1079] To a yellow solution of (2-chloro-4-fluoro-3-pyridyl)-(2,6-dimethoxyphenyl)methanone (168 mg, 0.53 mmol) and (6-ethoxy-2-pyridyl)hydrazine; hydrochloride (A.l) (100 mg, 0.53 mmol) in DMSO (2 mL) was added DIEA (0.19 mL, 1.05 mmol) at room temperature. The reaction mixture was stirred at 120 °C for 1 h to give a brown solution. The reaction mixture was poured into water (15 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phase was washed with brine (15 mL x 3), dried over Na2SO4, and concentrated in vacuum to give a residue. The residue was purified by reversed phase chromatography (mobile phase (water(0.1%FA-acetonitrile) B% (55%-60%)). Product containing fractions were concentrated under reduced pressure to give a solution which was extracted with ethyl acetate (20 mL x 3).The combined organic phases were dried over Na2SO4, then concentrated under reduced pressure to give the title compound (110 mg, 0.27 mmol, 49% yield) as a yellow solid. MS (ESI): m / z = 411.0 [M+H]+

[1080] Example 22

[1081] 3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-5H-pyrazolo[l,5-a]pyrazin-4-one

[1082]

[1083] To a light yellow solution of 3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-7-hydroxy-6,7-dihydro-5H-pyrazolo[l,5-a]pyrazin-4-one (25.0 mg, 0.06 mmol) in toluene (0.500 mL) was added molecular sieves (4 A) (14.7 mg, 0.06 mmol), SOCI2 (14.5 mg, 0.12 mmol) and DMF (0.45 mg, 0.01 mmol) at 0 °C. The yellow solution was stirred at 80 °C for 1 h, then cooled to room temperature. The mixture was quenched by water (5 mL) and extracted EtOAc (5 mL x 3). The combined organic phase was washed with brine (5 mL x 3), dried over Na2SO4, filtered and concentrated under vacuum to give a residue. The residue was dissolved in MeOH and purified by prep-HPLC (FA) and the purified solution was lyophilized to give the title compound (4.6 mg, 0.01 mmol, 19 % yield) as a white solid. MS (ESI): m / z = 393.0 [M+H]+

[1084] Step a) of methyl 4-bromo-3-iodo-l-(2-trimethylsilylethoxymethyl)pyrazole-5-carboxylate

[1085] To a black solution of methyl 4-bromo-3-iodo-lH-pyrazole-5-carboxylate (CAS: 190263-22-0, Fluorochem) (6.6 g, 16.0 mmol) in DCM (60 mL) was added 2-(trimethylsilyl)ethoxymethyl chloride (4.24 mL, 23.9 mmol) and N,N-diisopropylethylamine (4.17 mL, 23.9 mmol) at 0 °C, the mixture was stirred at 25 °C for 3 h. The mixture was quenched by water (100 mL) and extracted DCM (100 mL x 3). The combined organic phases were washed with brine (50 mL x 3), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by flash chromatography (eluting with 16%-17% EtOAc in petroleum ether) and concentrated under vacuum. The title compound (5.2 g, 11.3 mmol, 59% yield) was obtained as a yellow solid. 1HNMR (400 MHz, CHLOROFORM-d) 8 = 5.81 (s, 2H), 3.97 (s, 3H), 3.62 - 3.55 (m, 2H), 0.92 -0.84 (m, 2H), 0.02 - -0.08 (m, 9H)

[1086] Note: Regioisomeric methyl 4-bromo-5-iodo-l-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate (3.3 g, 7.16 mmol, 40% yield) was also obtained as a yellow solid. 'H NMR (400 MHz, CHLOROFORM-d) 8 = 5.62 (s, 2H), 3.97 (s, 3H), 3.66 - 3.56 (m, 2H), 0.96 - 0.87 (m, 2H), 0.02 - -0.04 (m, 9H)

[1087] Step b) methyl 4-(2,6-dimethoxyphenyl)-5-(6-ethoxy-2-pyridyl)-2-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate

[1088] To a yellow solution of methyl 4-bromo-3-iodo-l-(2-trimethylsilylethoxymethyl)pyrazole-5-carboxylate (1.4 g, 3.04 mmol) in 1,4-dioxane (10 mL) was added cesium carbonate (1.98 g, 6.07 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (247 mg, 0.3 mmol), and (6-ethoxy-2-pyridyl)boronic acid (557 mg, 3.34 mmol). The resulting black suspension was stirred at 40 °C for 12 h under N2. The mixture was quenched by water (30 mL) and extracted EtOAc (30 mL x 3). The combined organic phase was washed with brine (30 mL x 3), dried over Na2SC>4, filtered and concentrated under vacuum. The mixture was purified by flash chromatography (eluting with 18%-19% EtOAc in petroleum ether) and concentrated under vacuum.

[1089] The title compound (560.0 mg, 1.23 mmol, 40% yield) was obtained as a colorless oil. MS (ESI): m / z = 458.1 [M+H]+

[1090] Step c) methyl 4-(2,6-dimethoxyphenyl)-5-(6-ethoxy-2-pyridyl)-2-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate

[1091] To a colorless solution of methyl 4-bromo-5-(6-ethoxy-2-pyridyl)-2-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate (1.2 g, 2.63 mmol) in DMF (10 mL) and water (1 mL) was added X-phos Pd G2 (207 mg, 0.26 mmol), sodium carbonate (836 mg, 7.89 mmol), 2,6-dimethoxyphenylboronic acid (957 mg, 5.26 mmol). The resulting black suspension was stirred at 110 °C for 12 h under N2. The reaction solution was cooled to room temperature, then the mixture was quenched by water (50 mL) and extracted 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. The residue was purified by flash chromatography (18-20% EtOAc in petroleum ether) and concentrated under vacuum. The title compound (420 mg, 0.82 mmol, 23 % yield) was obtained as a yellow oil. MS (ESI): m / z = 514.1 [M+H]+Step d) 4-(2,6-dimethoxyphenyl)-5-(6-ethoxy-2-pyridyl)-2-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylic acid

[1092] To a light yellow solution of methyl 4-(2,6-dimethoxyphenyl)-5-(6-ethoxy-2-pyridyl)-2-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate (120 mg, 0.16 mmol) in MeOH (1 mL), THF (1 mL) and water (0.500 mL) was added sodium hydroxide (13.1 mg, 0.33 mmol). The mixture was stirred at 50 °C for 6 h, then cooled to room temperature. The pH was adjusted to 3 with 1 M HC1, and the mixture was extracted with EtOAc (10 mL x 3). The combined organic phase was washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under vacuum.

[1093] Purification by reversed phase chromatography (water(0.1%FA)-acetonitrile) gave the title compound (55 mg, 0.11 mmol, 67% yield) as a white solid. MS (ESI): m / z = 500.3 [M+H]+

[1094] Step e) N-(2,2-diethoxyethyl)-4-(2,6-dimethoxyphenyl)-5-(6-ethoxy-2-pyridyl)-2-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxamide

[1095] To a yellow solution of 4-(2,6-dimethoxyphenyl)-5-(6-ethoxy-2-pyridyl)-2-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylic acid (100.0 mg, 0.2 mmol, 1.0 eq) in DMF (1 mL) was added N,N-diisopropylethylamine (0.1 mL, 0.6 mmol), aminoacetaldehyde diethylacetal (79.97 mg, 0.6 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (91.3 mg, 0.24 mmol) were added. The solution was stirred at 30 °C for 12 h, cooled to room temperature and concentrated in vacuum. The residue was purified by reversed phase chromatography (water(0.1%FA)-ACN) and the crude material was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with brine (30 mL), dried over Na2SO4, then concentrated in vacuum to give the title compound (95.0 mg, 0.15 mmol, 77 % yield) as a yellow oil. MS (ESI): m / z = 615.7 [M+H]+

[1096] Step f) 3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-7-hydroxy-6, 7 -dihydro-5 H-pyrazolo[l,5-a ]pyrazin-4-one

[1097] To a colorless solution of N-(2,2-diethoxyethyl)-4-(2,6-dimethoxyphenyl)-5-(6-ethoxy-2-pyridyl)-2-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxamide (80.0 mg, 0.13 mmol) in DCM (1 mL) was added trifluoroacetic acid (1.0 mL, 13.0 mmol), and the mixture was stirred at 30 °C for 0.5 h. The mixture was concentrated under vacuum, and purified by reversed phase chromatography ((0.1%FA)-acetonitrile) to give the title compound (25.0 mg, 0.06 mmol, 45.78% yield) as a white solid. MS (ESI): m / z = 411.1 [M+H]+Example 23

[1098] 3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-6H-imidazo[l,2-c]pyrimidin-5-one

[1099]

[1100] A light yellow solution of 3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-6-(2-trimethylsilylethoxymethyl)imidazo[l,2-c]pyrimidin-5-one (10 mg, 0.02 mmol, 1.0 eq) in DCM (0.5 mL) and trifluoroacetic acid (0.1 mL, 0.02 mmol, 1.0 eq) was stirred at 30 °C for 1 hour. After evaporation, the resulting residue was dissolved in MeOH (2mL) and the pH was adjusted to 8 by the addition of ammonium hydroxide. Preparative HPLC gave the title compound (2.6 mg, 0.01 mmol, 35% yield) as white solid. MS (ESI): m / z = 393.2 [M+H]+

[1101] Step a) 2-ethoxy-6-(l -ethoxyvinyl)pyridine

[1102] To a colorless solution of 2-bromo-6-ethoxypyridine (15.0 g, 68.3 mmol, 1.0 eq) and tributyl(l -ethoxy vinyl)tin (25.4 mL, 75.1 mmol, 1.1 eq) in 1,4-dioxane (150 mL) was added Pd(PPh3)2C12 (2.5 g, 3.4 mmol, 0.05 eq), and the reaction was stirred at 100 °C for 16 h under nitrogen. The reaction mixture was cooled to room temperature. The reaction mixture was quenched by the addition of sat. KF (200 mL) and the resulting mixture was extracted with ethyl acetate(150 mLx3). The combined organic phases were dried over anhydrous Na2SC>4 and concentrated under vacuum to give the crude title compound (20.0 g), which was used in the next step without further purification. MS (ESI): m / z = 194.1 [M+H]+

[1103] Step b) 2-bromo-l-(6-ethoxy-2-pyridyl)ethanone

[1104] To a yellow solution of 2-ethoxy-6-(l -ethoxyvinyl)pyridine (20 g, 56 mmol, 1.0 eq) in THE (100 mL) and water (40 mL) was added N-bromosuccinimide (9.95 g, 55.9 mmol, 1.0 eq) and the mixture was stirred at 25 °C for 1 h. The reaction mixture was poured into water (200 mL). Then the mixture was extracted with ethyl acetate (150 mL x 3). The combined organic phases were washed with brine (100 mL x 3), dried over anhydrous Na2SC>4 and concentrated under vacuumto give a residue. The residue was purified by flash chromatography (SiO2, petroleum ether / ethyl acetate=l / O to 20 / 1) and concentrated under reduced pressure to give the title compound (7.7 g, 31.6 mmol, 56% yield over two steps) as yellow oil. MS (ESI): m / z = 246.0 [M+H]+

[1105] Step c) 2-( 6-ethoxy-2-pyridyl)-6H-imidazo [ 1,2-c ]pyrimidin-5-one

[1106] To a light yellow solution of 2-bromo-l-(6-ethoxy-2-pyridyl)ethanone (7.7 g, 32 mmol, 1.0 eq) in DMF (70 mL) was added cytosine (CAS 71-30-7) (3.5 g, 31.55 mmol, 1.0 eq) at room temperature. The reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was cooled to room temperature, and was purified by reversed phase chromatography to give the title compound (1.4 g, 5.5 mmol, 17% yield) as light yellow solid. MS (ESI): m / z = 257.0 [M+H]+

[1107] Step d) 2-(6-ethoxy-2-pyridyl)-6-(2-trimethylsilylethoxymethyl)imidazo[l,2-c]pyrimidin-5-one

[1108] To a 100 mL three-neck flask equipped with a thermometer were added 2-(6-ethoxy-2-pyridyl)-6H-imidazo[l,2-c]pyrimidin-5-one (700 mg, 2.7 mmol, 1.0 eq) and t-BuOLi (240 mg, 3.0 mmol, 1.1 eq) in THF (7 mL) at room temperature. The reaction mixture was degassed by nitrogen gas three times and cooled to 0 °C. The reaction mixture stirred at 0 °C for 30 min and then 2-(trimethylsilyl)ethoxymethyl chloride (0.53 mL, 3.0 mmol, 1.1 eq) was added. The reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was added into sat. NH4CI (30mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with brine(20 mL x 3) and dried over Na2SC>4, then concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=l / O to 1 / 1) to give the title compound (550 mg, 1.42 mmol, 52% yield) as light yellow gum. MS (ESI): m / z = 287.2 [M+H]+

[1109] Step e) 2-(6-ethoxy-2-pyridyl)-3-iodo-6-(2-trimethylsilylethoxymethyl)imidazo[l,2-c]pyrimidin-5 -one

[1110] To a solution of 2-(6-ethoxy-2-pyridyl)-6-(2-trimethylsilylethoxymethyl)imidazo[l,2-c]pyrimidin-5-one (550 mg, 1.4 mmol, 1.0 eq) in MeCN (6 mL) was added N-iodosuccinimide (320 mg, 1.4 mmol, 1.0 eq) at room temperature. The mixture was stirred at 50 °C for 16 h. The reaction mixture was purified by silica gel column chromatography (SiO2, Petroleum ether / Ethyl acetate=l / O to 3 / 1) to give the title compound (550 mg, 1.1 mmol, 75 % yield) as a yellow solid. MS (ESI): m / z = 513.1 [M+H]+Step f) 3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-6-(2-trimethylsilylethoxymethyl)imidazo[l,2-c]pyrimidin-5-one

[1111] To a solution of 2-(6-ethoxy-2-pyridyl)-3-iodo-6-(2-trimethylsilylethoxymethyl)imidazo[l,2-c]pyrimidin-5-one (200 mg, 0.39 mmol, 1.0 eq) in DMF (2 mL) and water (0.2 mL) was added 2,6-dimethoxyphenylboronic acid (85 mg, 0.47 mmol, 1.2 eq), sodium carbonate (124 mg, 1.17 mmol, 3.0 eq) and X-Phos Pd G2 (31 mg, 0.04 mmol, 0.1 eq) and the mixture was stirred at 100 °C for 16 h under an atmosphere of nitrogen. The reaction mixture was cooled to room temperature and poured into water (20 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with brine (15 mL x 3), dried over Na2SC>4 and concentrated in vacuum to give a residue. The residue was purified by preparative TLC (petroleum ether: ethyl acetate=l:1) to give the title compound (10 mg, 0.02 mmol, 5% yield) as a light yellow gum. MS (ESI): m / z = 523.2 [M+H]+

[1112] Example 24

[1113] 7-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-2-(2-pyrimidylmethyl)hypoxanthine

[1114]

[1115] 3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-5-[[2-(2-pyrimidyl)acetyl]amino]imidazole-4-carboxamide (17 mg, 34 umol, 1.0 eq) was suspended in ethanol (300 uL) and water (300 uL) and IM NaOH (169 uL, 169 umol, 5.0 eq) was added at rt. The mixture was stirred for 3.5 h at 50 °C. The reaction mixture was diluted with sat. NaHCO3 and extracted two times with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na2SC>4 and concentrated to dryness. The crude material was purified by flash chromatography on silica gel eluting with heptane / (2% ethanol in ethyl acetate) 75:25 to yield the title compound (8 mg, 46% yield) as off-white foam. MS (ESI): m / z = 486.4 [M+H]+

[1116] Step a) N-(2,6-dimethoxyphenyl)-6-ethoxy-picolinamide6-Ethoxypicolinic acid (870 mg, 5.2 mmol, 1.2 eq) was dissolved in N,N-dimethylformamide (40 mL) and N,N-diisopropylethylamine (2.2 mL, 12.9 mmol, 3.0 eq) and (2,6-dimethoxyphenyl)amine (660 mg, 4.3 mmol, 1.0 eq) were added. HATU (CAS 148893-10-1) (2.5 g, 6.5 mmol, 1.5 eq) was added and the mixture was stirred for 1 h at rt. The reaction mixture was quenched with water and extracted three times with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na2SC>4 and concentrated to dryness. The crude material was purified by flash chromatography on silica gel (24 g, 5-50 % ethyl acetate in heptane) to yield the title compound (1.39 g, quantitative yield) as a light yellow solid. MS (ESI): m / z = 303.2 [M+H]+

[1117] Step b) N-(2,6-dimethoxyphenyl)-6-ethoxy-thiopicolinamide

[1118] N-(2,6-dimethoxyphenyl)-6-ethoxy-picolinamide (1.7 g, 5.6 mmol, 1.0 eq) was suspended in toluene (17 mL) and (2,4-bis(4-methoxyphenyl)-l,3-dithia-2,4-diphosphetane-2,4-disulfide) (Lawesson reagent) (1.43 g, 3.54 mmol, 0.63 eq) was added at rt. The mixture was stirred for 1.75 h at 110 °C under a nitrogen atmosphere. The reaction mixture was purified by flash chromatography on silica gel (40 g, 0-50 % ethyl acetate in heptane) to yield the title compound (750 mg, 29% yield, 69 % purity) as yellow solid. MS (ESI): m / z = 319.2 [M+H]+

[1119] Step c) N-(2,6-dimethoxyphenyl)-6-ethoxy-pyridine-2-carboximidothioic acid methyl ester

[1120] N-(2,6-dimethoxyphenyl)-6-ethoxy-thiopicolinamide (1.23 g, 3.86 mmol, 1.0 eq) was dissolved in acetonitrile (19 mL) and K2CO3(800 mg, 5.8 mmol, 1.5 eq) and iodomethane (0.48 mL, 7.7 mmol, 2.0 eq) were added at rt. The mixture was stirred for 5 h at 20 °C under an atmosphere of nitrogen. The reaction mixture was concentrated to dryness, dissolved in ethyl acetate and washed with water and brine. The organic phase was dried over Na2SO4and concentrated to dryness. The crude material was used in the next step without purification because of the instability of this intermediate on silica gel. MS (ESI): m / z = 333.2 [M+H]+

[1121] Step d) N'-cyano-N-(2, 6-dimethoxyphenyl)-6-ethoxy-picolinamidine

[1122] 7V-(2,6-dimethoxyphenyl)-6-ethoxy-pyridine-2-carboximidothioic acid methyl ester (1.14 g, 3.43 mmol, 1.0 eq) was dissolved in ethanol (11 mL) and EtsN (1.4 mL, 9.95 mmol, 2.9 eq) and cyanamide (CAS 420-04-2) (418 mg, 9.95 mmol, 2.9 eq) were added at rt. The mixture was stirred for 18 hr at 80 °C under an atmosphere of nitrogen. The reaction mixture was heated to 100 °C and was stirred for further 1.5 h. The reaction mixture was cooled to rt Et3N (1.4 mL, 9.95 mmol, 2.9 eq) and cyanamide (CAS 420-04-2) (418 mg, 9.95 mmol, 2.9 eq) were added tothe reaction mixture and it was stirred for another 1.5 h at 100 °C. The reaction mixture was cooled to room temperature diluted with water and extracted two times with ethyl acetate. The combined organic layers were washed with water and dried over Na2SC>4 and concentrated to dryness. The crude material was purified by flash chromatography on silica gel (40 g, 0-100 % ethyl acetate in heptane) to yield the title compound (420 mg, 38% yield over two steps) as yellow solid. MS (ESI): m / z = 327.2 [M+H]+

[1123] Step e) 5-amino-3-(2, 6-dimethoxyphenyl)-2-( 6-ethoxy-2-pyridyl)imidazole-4-carbonitrile

[1124] A'-cyano-7V-(2,6-dimethoxyphenyl)-6-ethoxy-picolinamidine (420 mg, 1.29 mmol, 1.0 eq), TBAI (CAS 311-28-4) (14 mg, 39 umol, 0.03 eq) and K2CO3(267 mg, 1.9 mmol, 1.5 eq) were suspended in N, A-dimethylformamide (4.4 mL) and bromoacetonitrile (112 uL, 1.6 mmol, 1.3 eq) was added at rt. The mixture was stirred for 1.25 h at 20°C. The reaction mixture was diluted with sat. NaHCO3 and extracted two times with ethyl acetate. The organic layers were washed with water and brine, dried over Na2SC>4 and concentrated to dryness. The crude material was dissolved MeOH (13 mL), sodium methoxide (73 mg, 1.35 mmol, 1.05 eq) was added and the mixture was stirred for 1.5 h at 80 °C. After cooling to room temperature, acetic acid (81 uL, 1.42 mmol, 1.1 eq) was added and the solvents evaporated. The residue was diluted with sat. NaHCO3and extracted two times with ethyl acetate. The organic layers were washed with water and brine, dried over Na2SC>4 and concentrated to dryness. The crude material was purified by flash chromatography on silica gel (12 g, 0-70 % ethyl acetate in heptane) to yield the title compound (170 mg, 36% yield) as light yellow solid. MS (ESI): m / z = 366.3 [M+H]+

[1125] Step f) 5-amino-3-(2, 6-dimethoxyphenyl)-2-( 6-ethoxy-2-pyridyl)imidazole-4-carboxamide

[1126] To 5-amino-3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)imidazole-4-carbonitrile (170 mg, 465 umol, 1.0 eq) was added H2SO4 (0.23 mL, 4.39 mmol, 9.4 eq) and trifluoro acetic acid (0.78 mL, 10 mmol, 22 eq) and the reaction mixture was stirred at 80 °C for 2 hr. The reaction mixture was poured slowly on ice with sat. Na2CO3 while stirring. The mixture was extracted two times with ethyl acetate and the combined organic layers were washed with brine, dried over Na2SC>4 and concentrated to dryness. The crude material was used as such in the next step without further purification. MS (ESI): m / z = 384.3 [M+H]+

[1127] Step g) 3-(2, 6-dimethoxyphenyl)-2-( 6-ethoxy-2-pyridyl)-5-[[2-(2-pyrimidyl)acetyl]amino]imidazole-4-carboxamide2-(2-pyrimidyl)acetic acid (CAS 103-82-2) (10.8 mg, 78.3 umol, 1.2 eq) was dissolved in dichloromethane (0.57 mL) and 1 -(3 -dimethylaminopropyl)-3 -ethylcarbodiimide hydrochloride (CAS 25952-53-8) (19 mg, 98 umol, 1.5 eq) and 1 -hydroxybenzotriazole hydrate (15 mg, 98 umol, 1.5 eq) were added. 5-amino-3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)imidazole-4-carboxamide (25 mg, 65 umol, 1.0 eq) was added. The mixture was stirred for 21 hr at 30 °C. N,N-dimethylformamide (0.58 mL) was added to the reaction mixture and was stirred for 2.5 h at 60 °C. The reaction mixture was cooled to rt was left stirring overnight. Diphenyl phosphoryl chloride (CAS 2524-64-3) (18 mg, 14 uL, 65 umol, 1.0 eq) was added to the reaction mixture at rt and the mixture was stirred for 22 hr at rt. The reaction mixture was quenched with water and was extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na2SC>4 and concentrated to dryness. The crude material was purified by flash chromatography on silica gel (12 g, 0-50 % ethyl acetate in heptane) to yield the title compound (4 mg, 12% yield) as yellow solid. MS (ESI): m / z = 504.3 [M+H]+

[1128] The following Examples were generated in analogy to Example 24, using the indicated building blocks in place of 2-(2-pyrimidyl)acetic acid in Step g).

[1129] Ex. Structure Systematic Name Building MS,

[1130] Block ESI;

[1131] m / z

[1132] 26 2-[(5-chloro-2- 2-(5-chloro- 519.3

[1133] pyridyl)methyl] -7 -(2,6- 2- [M+H]+dimethoxyphenyl)-8- pyridyl)aceti

[1134] >=N

[1135] / ^° (6-ethoxy-2-pyridyl)- c acid (CAS:

[1136] 1 ~ {H} -purin-6-one 1000522-43- 9)

[1137] 37 2-[l-(5-chloro-2- 2-(5- 533.2

[1138] Q-V

[1139] pyridyl)ethyl] -7 -(2,6- chloropyridin [M+H]+CW / rjV dimethoxyphenyl)-8- -2- r°T(6-ethoxy-2- yl)propanoic pyridyl)hypoxanthine acid (CAS:

[1140] 1537819-31- 0)

[1141]

[1142] The following Examples were generated in analogy to Example 24, using the indicated building blocks in place of 6-ethoxypicolinic acid in Step a).

[1143] Ex. Structure Systematic Name Building MS,

[1144] Block ESI;

[1145] m / z

[1146] 42 8-[6-(cyclopropoxy)-2- 6- 498.3

[1147] O-°z

[1148] pyridyl]-7-(2,6- (cyclopropox [M+H]+ft

[1149] dimethoxyphenyl)-2- y)pyridine-2- )=N (pyrimidin-2-ylmethyl)- carboxylic

[1150] lH-purin-6-one acid (CAS:

[1151] 2285278-30- 8)

[1152]

[1153] Example 25

[1154] 7-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-2-hydroxy-hypoxanthine

[1155]

[1156] 5-Amino-3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)imidazole-4-carboxamide (45 mg, 117 umol, 1.0 eq) was dissolved in 1,4-dioxane (0.9 mL) and triphosgene (CAS 32315-10-9) (35 mg, 0.12 mmol, 1.0 eq) was added at rt. The mixture was stirred at 80°C for 2 h. The reaction mixture was diluted with H2O and after stirring for 10 min at rt the mixture was extracted two times with ethyl acetate. The organic layers were washed with water and brine, dried over Na2SC>4 and concentrated to dryness. Flash chromatography on silica gel eluting heptane / (2%ethanol in ethyl acetate) 75:25 gave the title compound (18 mg, 36% yield) as light a yellow solid. MS (ESI): m / z = 410.3 [M+H]+

[1157] Examples 27 and 28

[1158] (25 -3-(cyclopropoxy)-2-[3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-4-oxo-imidazo[4,5-c]pyridin-5-yl] propanoic acid; formic acid salt (Example 27) and (2 / ?)-3-(cyclopropoxy)-2-[3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-4-oxo-imidazo[4,5-c]pyridin-5-yl] propanoic acid (Example 28)

[1159]

[1160] 3-(cyclopropoxy)-2-[3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-4-oxo-imidazo[4,5-c]pyridin-5-yl]propanoic acid (65.0 mg, 0.12 mmol) was purified by SFC to give two peaks. Peak 1 was concentrated under vacuum then purified by Prep-HPLC(FA) to give (2 )-3-(cyclopropoxy)-2-[3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-4-oxo-imidazo[4,5-c]pyridin-5-yl]propanoic acid; formic acid (13.0 mg, 0.02 mmol, 19.8% yield) as white solid; MS (ESI): m / z = 521.2 [M - HCOOH+H]+. Peak 2 was concentrated under vacuum then purified by Prep-HPLC(FA) to give (2A)-3-(cyclopropoxy)-2-[3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-4-oxo-imidazo[4,5-c]pyridin-5-yl]propanoic acid (11.0 mg, 0.02 mmol, 16.8% yield) as white solid; MS (ESI): m / z = 521.2 [M+H]+.

[1161] Step a) ethyl 2-[3-(2, 6-dimethoxyphenyl)-2-( 6-ethoxy-2-pyridyl)-4-oxo-imidazo[ 4, 5-c ]pyridin-5-yl]prop-2-enoate To a brown suspension of 3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-5H-imidazo[4,5-c]pyridin-4-one (Example 1) (1.0 g, 2.55 mmol) and ethyl propiolate (0.52 mL, 5.1 mmol) in DCM (10 mL) was added a solution of PPhs (1.34 g, 5.1 mmol) in DCM (5 mL) at 0 °C. The mixture was stirred at 20 °C for 2 h, then purified by silica gel chromatography (50 - 100% EtOAc in petroleum ether) to afford the title compound (1.0 g, 2.04 mmol, 80.0% yield) as orange solid; MS (ESI): m / z = 491.1 [M+H]+.

[1162] Step b) 3-(cyclopropoxy)-2-[3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-4-oxo-imidazo[4,5-c]pyridin-5-yl]propanoic acidNaH (60% dispersion in mineral oil) (97.9 mg, 2.45 mmol) was added to cyclopropanol (3.0 mL, 59.9 mmol) at 0 °C and stirred at this temperature for 30 min. Ethyl 2-[3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-4-oxo-imidazo[4,5-c]pyridin-5-yl]prop-2-enoate (200 mg, 0.41 mmol) was added and the mixture was stirred at 0 °C for 1 h. The reaction pH was adjusted to 7 with 1 M HC1 (aq.), with addition of acetonitrile to maintain a solution. The mixture was purified by Prep-HPLC(FA) to give the title compound (80.0 mg, 0.15 mmol, 37% yield) as white solid; MS (ESI): m / z = 521.2 [M+H]+.

[1163] Example 29

[1164] 7-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-2-(2-pyrimidyloxymethyl)hypoxanthine

[1165] o

[1166] o o

[1167] NH X O O N

[1168]

[1169] 7-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-2-methylol-hypoxanthine (20 mg, 0.047 mmol) was dissolved / suspended in DMF (1.5 mL) and NaH (60% dispersion in mineral oil) (4.72 mg, 118 pmol) was added at room temperature and stirred for 10 min. 2-chloropyrimidine (10.8 mg, 94.5 pmol) was added at room temperature and the mixture was stirred at 80 °C for 2 h. The reaction mixture was diluted with sat. aq. NaHCO3-solution and extracted two times with EtOAc. The organic layers were washed with water and brine, dried over Na2SO4and concentrated to dryness. The crude material was purified by flash chromatography on silica gel (eluting with 0-100% (EtOAc / EtOH 75:25) in heptane). The title compound (6 mg, 22.8%) was isolated as white solid. MS (ESI): m / z = 502.4 [M+H]+.

[1170] Step a) acetic acid [2-[[5-carbamoyl-l-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)imidazol-4-yl]amino]-2-keto-ethyl] ester

[1171] 2-acetoxyacetic acid (43.1 mg, 365 pmol) was dissolved in tetrahydrofuran (1.62 mL), DIEA (118 mg, 159 pL, 913 pmol) and T3P (50% in EtOAc) (290 mg, 269 pL, 456 pmol) were added, and the reaction stirred for 10 min. 5-amino-3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)imidazole-4-carboxamide (Example 24, Step f) (70 mg, 183 pmol) was added. The mixture was stirred for 1.5 h at 60 °C. Isolute was added to the reaction mixture, and it was concentrated to dryness. The crude material was purified by flash chromatography on silica gel(0-100 % ethyl acetate in heptane) to yield the title compound as colorless oil (45 mg, 48 %); MS (ESI): m / z = 484.4 [M+H]+.

[1172] Step b) 7 -(2, 6-dimethoxyphenyl)-8-( 6-ethoxy-2-pyridyl)-2-methylol-hypoxanthine

[1173] Acetic acid [2-[[5-carbamoyl-l -(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)imidazol-4-yl]amino]-2-keto-ethyl] ester (45 mg, 0.088 mmol) was suspended in ethanol (600 mL) and water (300 mL) and 1 MNaOH (aq.) (177 pL, 177 pmol) was added at room temperature. The mixture was stirred at 35 °C for 24 h. The reaction mixture was diluted with sat. aq. NaHCO3solution and extracted two times with EtOAc. The organic layers were washed with water and brine, dried over Na2SO4and concentrated to dryness. The crude material was purified by flash chromatography on silica gel (eluting with 0-100% (EtOAc / EtOH 75:25) in heptane). The title compound (20 mg, 45 %) was isolated as white solid; MS (ESI): m / z = 424.2 [M+H]+.

[1174] Example 30

[1175] 2-[3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-4-oxo-imidazo[4,5-c]pyridin-5-yl]-3-phenoxy-propanoic acid

[1176]

[1177] To a solution of 3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-5-[l-(hydroxymethyl)-2-phenoxy-ethyl]imidazo[4,5-c]pyridin-4-one (20.0 mg, 0.04 mmol) in acetonitrile (1 mL) and water (0.7 mL) was added TEMPO (1.16 mg, 0.01 mmol) and PIDA (26.1 mg, 0.08 mmol) in DCM (2 mL) at room temperature. The mixture was stirred at 30 °C for 1 h to give a yellow solution. The reaction was purified by Prep-HPLC(FA) to give the title compound (2.0 mg, 7.3% yield) as a white solid; MS (ESI): m / z = 557.3 [M+H]+.

[1178] Step a) 5-[l-(benzyloxymethyl)-2-phenoxy-ethyl]-3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)imidazo[ 4, 5-c ]pyridin-4-one

[1179] To a solution of 3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-5H-imidazo[4,5-c]pyridin-4-one (Example 1) (2.0 g, 5.1 mmol) and [l-(benzyloxymethyl)-2-phenoxy -ethyl]methanesulfonate (CAS: 246855-00-5) (2.57 g, 7.65 mmol) in DMF (50 mL) was added Cs2CO3(4.98 g, 15.3 mmol) and KI (0.85 g, 5.1 mmol) at room temperature. The mixture was stirred at 50 °C for 12 h, cooled to room temperature, poured into water (150 mL), and then extracted with ethyl acetate (150 mL x 3). The organic phase was washed with brine (150 mL x 3), dried over anhydrous Na2SC>4, and concentrated under vacuum to give a residue which was purified by Prep-HPLC(FA) to give the title compound (380 mg, 0.6 mmol, 12 % yield) as yellow oil; MS (ESI): m / z = 633.2 [M+H]+.

[1180] Step b) 3-(2, 6-dimethoxyphenyl)-2-( 6-ethoxy-2-pyridyl)-5-[ 1 -(hydroxymethyl)-2-phenoxy-ethyl]imidazo[ 4, 5-c ]pyridin-4-one

[1181] To a solution of 5-[l-(benzyloxymethyl)-2-phenoxy-ethyl]-3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)imidazo[4,5-c]pyridin-4-one (380 mg, 0.6 mmol) in Methanol (10 mL) was added Pd / C (64.0 mg, 0.06 mmol) at room temperature under N2. The reaction was placed under a H2 atmosphere and stirred under H2 (45 psi) at 40 °C for 16 h. The crude mixture was filtered through a pad of diatomaceous earth, and the filtrate was concentrated in vacuo to give a residue which was purified by silica gel chromatography (50-100% EtOAc in petroleum ether) to afford the title compound (120 mg, 0.22 mmol, 37 % yield) as white solid; MS (ESI): m / z = 543.3 [M+H]+.

[1182] Example 31

[1183] 2-[3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-4-oxo-imidazo[4,5-c]pyridin-5-yl]-3-phenyl-propanoic acid

[1184]

[1185] To a suspension of methyl 2-[3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-4-oxo-imidazo[4,5-c]pyridin-5-yl]-3-phenyl-propanoate (62.0 mg, 0.11 mmol) in MeOH (1 mL), THF (1 mL) and water (1 mL) was added NaOH (13.41 mg, 0.34 mmol) at room temperature. The mixture was stirred at 20 °C for 2 h, then the pH was adjusted to 7 with IM HCl,(aq.) and add acetonitrile to dissolve. Then purified by Prep-HPLC(FA) and lyophilized to give 2-[3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-4-oxo-imidazo[4,5-c]pyridin-5-yl]-3 -phenyl-propanoic acid (30.0 mg, 0.06 mmol, 50 % yield) as white solid; MS (ESI): m / z = 541.2 [M+H]+.

[1186] Step a) methyl 2-[3-(2, 6-dimethoxyphenyl)-2-( 6-ethoxy-2-pyridyl)-4-oxo-imidazo[ 4, 5-c ]pyridin-5-yl]-3-phenyl-propanoate

[1187] To a solution of 3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-5H-imidazo[4,5-c]pyridin-4-one (150.0 mg, 0.38 mmol) in DMF (3 mL) was added K2CO3(158 mg, 1.15 mmol), methyl 2-bromo-3-phenyl-propanoate (CAS: 3196-22-3) (139 mg, 0.57 mmol) and KI (63.5 mg, 0.38 mmol) at 20 °C in sequence. The reaction mixture was stirred at 100 °C for 12 h, cooled to room temperature and the reaction mixture was poured into water (50 mL), and then extracted with ethyl acetate (50 mL x 3). The organic phase was washed with brine (50 mL x 3), the organic phases were dried over anhydrous Na2SC>4, and concentrated under vacuum to give a residue X

[1188] which was purified by Prep-HPL °C(FA) to give the title compound (62.0 mg, 0.11 mmol, 29% yield) as white solid; MS (ESI 0 > \?= / O

[1189] )° -:=m / z = 555.2 [M+H]+

[1190] >( \ o= \

[1191] The following Examples were generated in analogy to Example 31, using the indicated building blocks in place of methyl 2-bromo-3-phenyl-propanoate in Step a).

[1192] ir (5

[1193] Z O r^zz

[1194] |t / r i / L

[1195] Ex. Structure Systematic Name Building MS,

[1196] Block ESI;

[1197] m / z

[1198] 33 3-cyclopropyl-2-[3- ethyl 2- 505.1

[1199] (2,6- bromo-3- [M+H]+dimethoxyphenyl)-2- cyclopropyl- (6-ethoxy-2-pyridyl)-4- propanoate

[1200] oxo-imidazo[4,5- (CAS:

[1201] c]pyridin-5- 2640365-80- yl]propanoic acid 4)

[1202] 34 2-[3-(2,6- a- 527.2

[1203] dimethoxyphenyl)-2- bromophenyl [M+H]+(6-ethoxy-2-pyridyl)-4- acetic acid

[1204] oxo-imidazo[4,5- methyl ester

[1205]

[1206] c]pyridin-5-yl]-2- (CAS:

[1207] phenyl-acetic acid 37167-62-7)

[1208] 39 2-[3-(2,6- methyl 2- 495.2

[1209] dimethoxyphenyl)-2- bromo-3- [M+H]+

[1210] (6-ethoxy-2-pyridyl)-4- methoxy- oxo-imidazo[4,5- propanoate

[1211] c]pyridin-5-yl]-3- (CAS:

[1212] methoxy -propanoic 27704-96-7)

[1213] acid

[1214]

[1215] Example 32

[1216] I

[1217] 7-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-2-[(5-methylpyridazin-3-yl)oxymethyl]hypoxanthine

[1218] To a mixture of 5-amino-3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)imidazole-4-carboxamide (Example 24, Step f) (80 mg, 209 pmol), 2-(5-methylpyridazin-3-yl)oxyacetic acid (CAS: 1695405-46-9) (42.9 mg, 230 pmol) and EDCI (80.0 mg, 417 pmol) in dichloromethane (0.5 mL) was added 1 -hydroxybenzo triazole hydrate (63.9 mg, 417 pmol). The mixture was stirred at 40 °C for 15 h. The reaction mixture was poured into EtOAc / THF 1: 1 and washed with water and brine. The organic layer was dried over Na2SO4and concentrated in vacuo. The crude material was dissolved in ethanol (0.5 mL), 2 M NaOH (aq.) (313 pL, 626 pmol) was added, and the reaction mixture stirred at 50 °C for 2 h. The reaction mixture was poured into EtOAc / THF 1: 1 and washed with water and brine. The organic layer was dried over Na2SC>4 and concentrated in vacuo, to give a residue which was purified by preparative HPLC to give the title compound (23 mg, 21%) as white solid; MS (ESI): m / z = 516.2 [M+H]+Example 35

[1219] 7-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)hypoxanthine

[1220]

[1221] 5-amino-3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)imidazole-4-carboxamide (Example 24, Step f) (91 mg, 237 pmol) was suspended in N, N-dim ethylformamide (1.52 mL) and triethyl orthoformate (141 mg, 158 pL, 949 pmol) was added at room temperature. The mixture was stirred for 18 h at 140 °C. The reaction mixture was diluted with sat. aq. NaHCO3solution and extracted twice with EtOAc. The organic layers were washed with water and brine, dried over Na2SC>4 and concentrated to dryness. The residue was purified by flash chromatography (0-100 % EtOAc / EtOH 3: 1 in heptane) to yield the title compound (30 mg, 32 %) as off-white solid; MS (ESI): m / z = 394.3 [M+H]+

[1222] Example 36

[1223] 2-[7-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-6-oxo-purin-l-yl]-3-methoxy-propanoic acid

[1224]

[1225] To a colorless solution of methyl 2-[7-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-6-oxo-purin-l-yl]-3-methoxy-propanoate (100 mg, 0.2 mmol, 1.0 eq) in THF (3 mL) and water (1 mL) was added NaOH (23.6 mg, 0.59 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 h. The pH was adjusted to 7 with IM HC1 (aq.), and the reaction was purified by Prep-HPLC to give the title compound (50 mg, 51 % yield) as white solid; MS (ESI): m / z = 496.2 [M+H]+Step a) methyl 2-[7-(2, 6-dimethoxyphenyl)-8-( 6-ethoxy-2-pyridyl)-6-oxo-purin- 1 -yl] -3-methoxy-propanoate

[1226] To a white suspension of 7-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)hypoxanthine (Example 35) (1.3 g, 3.3 mmol) in DMF (20 mL) was added K2CO3(0.91 g, 6.61 mmol) and methyl 2-bromo-3-methoxy-propanoate (CAS: 27704-96-7) (0.72 g, 3.63 mmol) at room temperature. The mixture was stirred at 30 °C for 2 h. The reaction mixture was poured into water (150 mL), and then extracted with ethyl acetate (150 mL x 3). The organic phase was washed with brine (150 mL x 3), the organic phases were dried over anhydrous Na2SO4, and concentrated under vacuum to give a residue which was purified by Prep-HPLC(FA) to give the title compound (1.0 g, 59 %) as brown solid; MS (ESI): m / z = 510.0 [M+H]+

[1227] Example 38

[1228] 2-[2-[(5-chloro-2-pyridyl)methyl]-7-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-6-oxo-purin- 1-yl] acetic acid

[1229]

[1230] To a mixture of methyl 2-[2-[(5-chloro-2-pyridyl)methyl]-7-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-6-oxo-purin-l-yl]acetate (20.0 mg, 0.03 mmol) in THF (1.5 mL) and water (0.5 mL) was added LiOH’FLO (4.26 mg, 0.1 mmol) at 20 °C, then the mixture was stirred at 30 °C for 1 h. The pH was adjusted to 7 with IM HC1, and the mixture was extracted with DCM (50 mL x 3). The combined organics were concentrated under vacuum to give a residue, which was dissolved in MeOH and purified by prep-HPLC. The purified solution was lyophilized to give the title compound (4.7 mg, 0.01 mmol, 24% yield) as white solid; MS (ESI): m / z = 577.2 [M+H]+

[1231] Step a) methyl 2-[2-[(5-chloro-2-pyridyl)methyl]-7-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-6-oxo-purin-l-yl] acetateTo a solution of 2-[(5-chloro-2-pyridyl)methyl]-7-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-lH-purin-6-one (260 mg, 0.5 mmol) and lithium bromide (43.5 mg, 0.5 mmol) in DMF (10 mL) was added NaH (60% dispersion in mineral oil) (40.1 mg, 1.0 mmol) at 0 °C for 30 min. Methyl 2-bromoacetate (CAS: 96-32-2) (115 mg, 0.75 mmol) was added to the mixture, and the reaction was stirred at 20 °C for 12 h. The reaction was quenched with sat.aq. NH4CI solution (30mL), extracted with EtOAc (20 mL x 3) and the mixture was filtered. The organic layer was concentrated in vacuo. The residue was purified by prep-HPLC and the eluent was lyophilized to give the title compound (25 mg, 8 % yield) as a light yellow solid; MS (ESI): m / z = 591.2 [M+H]+

[1232] Example 41

[1233] 7-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-l-p-anisyl-purin-6-one

[1234]

[1235] 7-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)hypoxanthine (Example 35) (25 mg, 63.6 pmol) was suspended in dimethyl sulfoxide (836 pL). KOtBu (20.8 mg, 186 pmol) and 4-methoxybenzyl chloride (29.1 mg, 25.3 pL, 186 pmol) were added and the reaction mixture was heated to 80 °C for 1.5 h. The reaction mixture was diluted with cold water and extracted two times with EtOAc. The organic layers were washed with water and brine, dried over Na2SO4and concentrated to dryness. The residue was purified by flash chromatography (0-80 % ethyl acetate in heptane) to yield the title compound as off-white solid (7 mg, 21%). MS (ESI): m / z = 514.3 [M+H]+

[1236] Example 43

[1237] 8-(6-ethoxy-2-pyridyl)-7-(2-methoxyphenyl)-2-(pyrimidin-2-ylmethyl)-lH-purin-6-one

[1238]

[1239] To a colorless solution of 2-(6-ethoxy-2-pyridyl)-3-(2-methoxyphenyl)-5-[(2-pyrimidin-2-ylacetyl)amino]imidazole-4-carboxamide (190 mg, 0.4 mmol) in ethanol (2 mL) and water (2 mL) was added NaOH (80.3 mg, 2.01 mmol), and the mixture was stirred at 30 °C for 12 h. The mixture was quenched by slow addition of water (10 mL). The resulting mixture was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure affording a residue, which was purified by prep-HPLC(EA) and lyophilized to give the title compound (27.5 mg, 15 % yield) as a white solid. MS (ESI): m / z = 456.0 [M+H]+

[1240] Step a) 2-( 6-ethoxy-2-pyridyl)-3-(2-methoxyphenyl)-5-[(2-pyrimidin-2-ylacetyl)amino]imidazole-4-carboxamide

[1241] To a colorless solution of 2-pyrimidin-2-ylacetic acid (109 mg, 0.79 mmol) in DCM (5 mL) was added EDCI (163 mg, 0.85 mmol) and HOBt (115 mg, 0.85 mmol). 5-amino-2-(6-ethoxy-2-pyridyl)-3-(2-methoxyphenyl)imidazole-4-carboxamide (Example 19, Step e) (200 mg, 0.57 mmol) was added, and the mixture was stirred at 30 °C for 12 h. The mixture was concentrated to give a residue, which was purified by flash chromatography (8%-10% MeOH in DCM) to give the title compound (190 mg, 71% yield) as white solid. MS (ESI): m / z = 474.2 [M+H]+

[1242] Synthesis of non-commercial building blocks:

[1243] Building block A.l

[1244] (6-ethoxy-2-pyridyl)hydrazine; hydrochloride

[1245] tert-butyl N-[(6-ethoxy-2-pyridyl)amino]carbamate (2.7 g, 10.7 mmol) was added to HC1 (4 M in MeOH) (20.0 mL, 80.0 mmol) at 20 °C, and the mixture was stirred at this temperature for 12 h. The reaction mixture was filtered, and the cake was washed with petroleum ether (10 mL) and dried under vacuum to give (6-ethoxy-2-pyridyl)hydrazine; hydrochloride (1.6 g, 8.44 mmol, 79 % yield) as a yellow solid. MS (ESI): m / z = 154.0 [M+H]+Step a) tert-butyl N- [(6-ethoxy-2-pyridyl)amino] carbamate

[1246] To a yellow solution of 2-chloro-6-ethoxypyridine (50.0 g, 317 mmol), tert-butyl carbazate (41.9 g, 317 mmol), and cesium carbonate (207 g, 635 mmol) in 1,4 -dioxane (600 mL) were added tris(dibenzylideneacetone)dipalladium (0) (14.5 g, 15.9 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (9.18 g, 15.9 mmol) at 25 °C under N2. The reaction was heated to 110 °C and stirred at this temperature for 16 h, to give a yellow suspension. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was poured into H2O (1 L) and then extracted with EtOAc (500 mL x 2). The combined organics were washed with brine (1 L), dried over Na2SC>4, and concentrated under vacuum to give a residue. The residue was purified by flash chromatography (eluting with 25 -75% EtOAc in petroleum ether) to afford the title compound (70.0 g, 276 mmol, 52 % yield) as a brown oil. MS (ESI): m / z = 154.1 [M-Boc+H]+

[1247] Example 26

[1248] 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:

[1249] Per tablet

[1250] Active ingredient 200 mg

[1251] Microcrystalline cellulose 155 mg

[1252] Corn starch 25 mg

[1253] Talc 25 mg

[1254] Hydroxypropylmethylcellulose 20 mg

[1255] 425 mg

[1256] Example 27

[1257] 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:

[1258] Per capsule

[1259] Active ingredient 100.0 mg

[1260] Corn starch 20.0 mg

[1261] Lactose 95.0 mg

[1262] Talc 4.5 mg

[1263] Magnesium stearate 0,5 mg

[1264] 220.0 mg

Claims

Claims1. A compound of formula (I)or a pharmaceutically acceptable salt or a tautomer thereof, wherein:(i) X, Z, and U are C, Y is N, and V is N or CH; or(ii) X, Y, and Z are C, U is N, and V is CH; or(iii) Y, Z, and U are C, X is N, and V is N or CH; or(iv) X, Y, and U are C, Z is N, and V is CH;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;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;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;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;L1is a covalent bond or -CHRL1-;L2is selected from the group consisting of a covalent bond, -O-, -NRL2-, -SO2-, - CHRL1-, -CHRL1CO-*, -CHRL1O-*, -OCHRL1-*, -CHRL1ONRL2-*, and -ONRL2CRL1-*;wherein an asterisk indicates the point of attachment of L2to ring C; L3is a covalent bond or -(CHRL3)r-;m is 0, 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, 2, or 3;is C1-C6-alkyl or a groupR2is selected from the group consisting of C1-C6-alkyl, C1-C6-alkoxy, and a group A<^v(R6)n\B7R3is selected from the group consisting of hydrogen, hydroxy, halogen, Ci-Ce- alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, C1-C6-alkoxy-Ci-Ce-alkyl, and a groups;R4is selected from the group consisting of hydrogen, amino, C1-C6-alkyl, hydroxy- C1-C6-alkyl, halo-C1-C6-alkyl, cyano-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, - (CHRL3)r-COORL2, -(CHRL3)r-CON(RL2)2, Ci-C6-alkyl-SO2-, Ci-C6-alkyl-. >3> Z~X / (R8)qkDJSO2NRL2-, and a group;R5is selected from the group consisting of halogen, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, and C1-C6-alkoxy-C1-C6-alkyl;R6is selected from the group consisting of halogen, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, and C1-C6-alkoxy-C1-C6-alkyl; andR7is selected from the group consisting of halogen, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, and C1-C6-alkoxy-C1-C6-alkyl;R8is selected from the group consisting of halogen, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, and 5- to 10- membered heteroaryl;each RL1is independently selected from the group consisting of hydrogen, Ci-Ce- alkyl, and C1-C6-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, hydroxy, C1-C6-alkyl, and C1-C6-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 or a tautomer thereof, wherein V is CH.

3. The compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:< Z— X / (R5)mR1is a groupA is selected from the group consisting of C6-C10-aryl and C3-C10-cycloalkyl; L1is a covalent bond;m is 0, 1, or 2; andR5is selected from the group consisting of C1-C6-alkoxy, C1-C6-alkoxy-Ci-Ce- alkyl, and halo-C1-C6-alkyl.

4. The compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:l_! / - C^AR1is a groupA is C6-C10-aryl;L1is a covalent bond;m is 2; andR5is C1-C6-alkoxy.

5. The compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:l <_! Z / -~X / (R5)rn( ^AR1is a groupA is phenyl;L1is a covalent bond;m is 2; andR5is methoxy.

6. The compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:A v<^a ubvR i r s / (R6)n2s g o p;B is selected from the group consisting of C6-C10-aryl, 5- to 10-membered heteroaryl and C3-C10-cycloalkyl;n is 0 or 1; andR6is selected from the group consisting of C1-C6-alkyl and C1-C6-alkoxy.

7. The compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:A<~> / (R6)nR2is a group;B is 5- to 6-membered heteroaryl;n is 1; andR6is C1-C6-alkoxy.

8. The compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:A<^v\B / (R6)nR2is a groups;B is pyridyl;n is 1; andR6is methoxy or ethoxy.

9. The compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:R3is selected from the group consisting of hydrogen, hydroxy and a groupC is 5- to 6-membered heteroaryl;L2is -CHRL1-;RL1is hydrogen; andp is 0.

10. The compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt or a tautomer thereof, wherein R3is hydrogen.

11. The compound of formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:R4is selected from the group consisting of hydrogen, amino, C1-C6-alkyl, hydroxy- C1-C6-alkyl, halo-C1-C6-alkyl, cyano-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, - (CHRL3)r-COORL2, -(CHRL3)r-CON(RL2)2, Ci-C6-alkyl-SO2-, Ci-C6-alkyl-SO2NRL2-, and a groupD is selected from the group consisting of C6-C10-aryl and 3- to 10-membered heterocyclyl;L3is a covalent bond or -(CHRL3)r-;q is 0 or 1;r is 1;R8is C1-C6-alkoxy;each RL2is independently selected from the group consisting of hydrogen and C1-C6-alkyl; andeach RL3is hydrogen.

12. The compound of formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:R4is selected from the group consisting of hydrogen, -CH2-COOH, and a groupD is C6-C10-aryl;L3is -(CHRL3)r-;q is 1;r is 1;R8is C1-C6-alkoxy; andRL3is hydrogen.

13. The compound of formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt or a tautomer thereof, wherein:R4is selected from the group consisting of hydrogen, –CH2-COOH, and a groupD is phenyl;L3is -(CHRL3)r-;q is 1;r is 1;R8is methoxy; andRL3is hydrogen.

14. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt or a tautomer thereof, wherein said compound of formula (I) is selected from: 3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-5H-imidazo[4,5-c]pyridin-4-one; 3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-5-[(4- methoxyphenyl)methyl]imidazo[4,5-c]pyridin-4-one;2-[3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-4-oxo-imidazo[4,5-c]pyridin-5- yl]acetic acid;3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-5-(2-hydroxyethyl)imidazo[4,5- c]pyridin-4-one;3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-5-(2-methoxyethyl)imidazo[4,5- c]pyridin-4-one;3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-5-methyl-imidazo[4,5-c]pyridin-4- one;3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-5-(2,2,2-trifluoroethyl)imidazo[4,5- c]pyridin-4-one;2-[3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-4-oxo-imidazo[4,5-c]pyridin-5- yl]acetonitrile;2-[3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-4-oxo-imidazo[4,5-c]pyridin-5- yl]-N-methyl-acetamide;5-(azetidin-3-yl)-3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)imidazo[4,5- c]pyridin-4-one;2-[3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-4-oxo-imidazo[4,5-c]pyridin-5- yl]-N, N-dimethyl-acetamide;5-amino-3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)imidazo[4,5-c]pyridin-4- one;N-[3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-4-oxo-imidazo[4,5-c]pyridin-5- yl]methanesulfonamide;3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-5-methylsulfonyl-imidazo[4,5- c]pyridin-4-one;2-(6-ethoxy-2-pyridyl)-3-(2-methoxyphenyl)-5H-imidazo[4,5-c]pyridin-4-one;3-(2,6-dimethoxyphenyl)-2-(1-methylpyrazol-3-yl)-5H-imidazo[4,5-c]pyridin-4-one; 2-cyclopentyl-3-(2,6-dimethoxyphenyl)-5H-imidazo[4,5-c]pyridin-4-one;2-(6-ethoxy-2-pyridyl)-3-phenyl-5H-imidazo[4,5-c]pyridin-4-one;8-(6-ethoxy-2-pyridyl)-7-(2-methoxyphenyl)hypoxanthine;3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-5H-pyrazolo[3,4-d]pyrimidin-4-one; 3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-5H-pyrazolo[4,3-c]pyridin-4-one; 3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-5H-pyrazolo[l,5-a]pyrazin-4-one; 3-(2,6-dimethoxyphenyl)-2-(6-ethoxy-2-pyridyl)-6H-imidazo[l,2-c]pyrimidin-5-one; 7-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-2-(2-pyrimidylmethyl)hypoxanthine; and7-(2,6-dimethoxyphenyl)-8-(6-ethoxy-2-pyridyl)-2-hydroxy -hypoxanthine.

15. The compound of formula (I) according to any one of claims 1 to 14, or a pharmaceutically acceptable salt or a tautomer thereof, for use as a therapeutically active substance.

16. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 14, or a pharmaceutically acceptable salt or a tautomer thereof, and a therapeutically inert carrier.

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