WO2010008777A2 - Fused azabicyclic pyridines - Google Patents

Abstract

Azabicyclic pyridine derivatives and pharmaceutically acceptable salts thereof are disclosed herein These compounds are useful as EP2 antagonists. Uses of these compounds and pharmaceutical compositions thereof are also disclosed.

Description

FUSED AZABICYCLIC PYRIDINES Field of the Invention

[0001] The invention relates to azabicyclic pyridine derivatives useful as EP2 antagonists.

BACKGROUND OF THE INVENTION

[0002] Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used to treat inflammatory pain conditions resulting from prevalent diseases such as rheumatoid arthritis, osteoarthritis and chronic low back pain. They are also frequently used to relieve pain resulting from conditions such as dysmenorrhoea, migraine, sprains and strains. The main mechanism of their analgesic action is the blockage of the cyclooxygenases (COX), which in turn inhibits the production of prostaglandins (PGs). Prostaglandin E₂ (PGE₂) is one of the PGs inhibited in this process. As a key mediator in inflammatory processes, it exerts its cellular effect through binding to four G-protein coupled receptors, EPi, EP₂, EP₃ and EP₄ (Sugimoto, Y. and Narumiya, S., J Biol Chem, 2007, 282(16), 11613-11617). The role of PGE₂ in the sensitization to pain (hyperalgesia) evoked by inflammation is well established (Park J. Y., et al, Clinical Immunology, 2006, 119(3), 229-240). Recently, the relative importance of the different PGE₂ receptor subtypes (i.e. EPi, EP₂, EP₃ and EP₄) to this process has been elucidated by receptor knock-out (Zeilhofer, H. C, and Brune K., Trends in Pharmacological Science, 2006, 27(9), 467-474) or antagonism by a small molecule (Hall, A., et al, Current Opinion in Drug Discovery & Development, 2007, 10(5), 597-612. Nakao, K., et al, J Pharmacol Exp Ther, 2007, 322; 686-694).

[0003] It appears that the role of EP₂ may be crucial in the pain process; mice that are ablated for the EP₂ gene (EP₂-/-) do not develop the hyperalgesia that results in normal mice from an intrathecal injection of PGE₂. Also, although these mice do display a shortlived hyperalgesia after peripheral inflammatory stimulus (zymosan A injection into the hind paw), they do not undergo the second, sustained hyperalgesic phase exhibited by normal mice (Reinold, H., et al, J Clin Invest, 2005, 115(3); 673-679).

[0004] Targeting a receptor sub-type downstream from COX may also eliminate the unwanted side effects associated with the current NSAIDs, such as gastrointestinal and renal toxicity and cardiovascular risks. In light of the strong evidence that links EP₂ to nociception and the potential benefits that sub-type selective EP₂ inhibitors may bring, antagonism of EP₂ may present an attractive approach for the treatment of various inflammatory pain conditions.

[0005] There is also evidence that EP₂ antagonists may be useful for the treatment of Alzheimer's disease (AD). Several large studies have found that long-term administration of NSAIDs is associated with a decreased incidence of AD (Szekely, CA. , et al, Neuroepidemiology, 2004, 23; 159-169. McGeer, P.L., et al, Neurology, 1996, 47; 425-432) and it was reported recently that ablation of EP₂ increases the clearance of amyloid β peptides from AD brain sections by mouse microglia (Liang, X., et al, J of Neuroscience, 2005, 25(44), 10180-10187). Ablation of EP₂ was also reported to suppress microglia- mediated neurotoxicity in vitro (Shie, F.-S., et al, Neurobiology, 2005, 166(4); 1163-1172). Therefore, a small molecule EP₂ antagonist that can cross the blood-brain barrier may be potentially useful to treat neuroinflammatory and neurodegenerative diseases such as AD.

[0006J EP₂ antagonists are thought to be useful for the treatment of elevated intraocular pressure and fertility disorders (WO 07/071456, Schering Aktinegesellschaft). Selective EP₂ antagonists are also valuable for PGE₂-mediated neuroinflammatory and neurodegenerative diseases such as Alzheimer's disease and multiple sclerosis. In short, EP2 antagonists are useful for any PGE₂-mediated inflammatory disease or pain conditions such as rheumatoid arthritis, osteoarthritis, acute gout, inflammatory arthropathies (e.g. ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome), dysmenorrhoea (painful menstruation), endometriosis, headache, migraines, postoperative pain, mild-to-moderate pain due to inflammation and tissue injury, back pain and sciatica, sprains, strains, rheumatism, dental pain, pain from kidney stones (renal colic), fever and other painful conditions, especially where there is inflammation.

SUMMARY OF THE INVENTION

[0007] There is provided a compound of general formulae Ia or Ib

Ia Ib

And pharmaceutically acceptable salts thereof, wherein

A is selected from the group consisting of oxygen and CH₂;

R¹ is selected from the group consisting of hydrogen and (C₁-C₆) alkyl optionally substituted with fluorine, (Ci-C₆) alkoxyl, (Ci-C₆) haloalkoxyl, hydroxyl, cyano, pyridinyl or (Ci-C₆) haloalkyl, with the proviso that R cannot be hydroxymethyl;

R^4a is selected from a group consisting of a) hydrogen, b) halogen, c) cyano, d) hydroxyl, e) (C]-C₆) alkyl optionally substituted with halogen or alkoxyl, f) (Ci-C₆) alkoxyl optionally substituted with halogen, g) aryloxyl, heterocyclyl, and aryl, wherein each aryloxyl, heterocyclyl or aryl is optionally substituted with one or more of halogen, cyano, (Ci-C₆) alkyl, (Ci-C₆) alkoxyl, (Cj-C₆) haloalkyl, (Ci-C₆) haloalkoxyl or cyanomethyl, or any combination thereof;

R⁴ is selected from a group consisting of a) hydrogen, b) halogen, c) cyano, d) hydroxyl, e) (Ci-C₆) alkyl optionally substituted with halogen or alkoxyl, f) (Ci-C₆) alkoxyl optionally substituted with halogen, g) aryloxyl, heterocyclyl, and aryl, wherein each aryloxyl, heterocyclyl or aryl is optionally substituted with one or more of halogen, cyano, (C 1-C₆) alkyl, (Ci-C₆) alkoxyl, (Ci-C₆) haloalkyl, (C]-C₆) haloalkoxyl or cyanomethyl, or any combination thereof;

R⁵ is chosen from H or (Ci-C₆) alkyl;

R⁶ is chosen from H, (CH₂)_nR⁷ and (Ci-C₆) alkyl optionally substituted with hydroxyl, alkoxyl, amino, alkylthio, cyano or halogen, or, when taken together with the nitrogen to which they are attached, R⁵ and R⁶ form a 4-12 membered, optionally substituted monocyclic or bicyclic nitrogen heterocycle; n is 0, 1 or 2; and

R⁷ is selected from the group consisting of optionally substituted carbocycle or heterocycle.

[0008] The disclosed compounds are inhibitors of EP₂ (as measured by the nethods disclosed herein) and are useful in situations where PGE₂ mediation is desired for. the treatment of various inflammatory pain conditions.

[0009] In another aspect, the invention relates to pharmaceutical compositions comprising a therapeutically effective amount of at least one compound of general formula Ia or Ib, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

[0010] In yet another aspect the present invention relates to a method of treating Alzheimer's disease, multiple sclerosis, elevated intraocular pressure or fertility disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of at least one compound of general formula Ia or Ib.

[0011] In yet another aspect the present invention relates to a method of treating inflammatory pain conditions in a subject in need thereof comprising administering to the subject a therapeutically effective amount of at least one compound of general formula Ia or Ib. or a pharmaceutically acceptable salt thereof. [0012] In yet another aspect, there is provided at least one compound of formula Ia or formula Ib or a pharmaceutically acceptable salt thereof for use in therapy.

[0013] In yet a another aspect there is provided at least one compound of formula Ia or formula Ib or a pharmaceutically acceptable salt thereof for use in the treatment of Alzheimer's disease, multiple sclerosis, elevated intraocular pressure or a fertility disorder.

[0014] In yet another aspect there is provided at least one compound of formula Ia or formula Ib or a pharmaceutically acceptable salt thereof for use in the treatment of inflammatory pain conditions.

[0015] In yet a further aspect there is provided at least one compound of formula Ia or formula Ib or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for the treatment of Alzheimer's disease, multiple sclerosis, elevated intraocular pressure or a fertility disorder.

[0016] In yet a further aspect there is provided at least one compound formula Ia or formula Ib or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for the treatment of inflammatory pain conditions.

[0017] In light of the strong evidence that links EP₂ to nociception and the potential benefits that sub-type selective EP₂ inhibitors may bring, antagonism of EP₂ may present an attractive approach for the treatment of various inflammatory pain conditions.

[0018] Exemplary disorders for treatment with EP₂ inhibitors include rheumatoid arthritis, osteoarthritis, acute gout, inflammatory arthropathies (e.g. ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome), dysmenorrhoea (painful menstruation), endometriosis, headache, migraines, postoperative pain, mild-to-moderate pain due to inflammation and tissue injury, back pain and sciatica, sprains, strains, rheumatism, dental pain, pain from kidney stones (renal colic), fever and other painful conditions, especially where there is inflammation. EP2 antagonists may therfore be useful in preventing and treating the above diseases and disorders related to inflammation.

[0019] Other indications in which the EP₂ antagonists are potentially useful include Alzheimer's disease, multiple sclerosis, elevated intraocular pressure or fertility disorder. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT [0020] Throughout this specification the substituents are defined when introduced and retain their definitions unless otherwise specified.

[0021] In a first aspect the invention relates to compounds having general formula

Ia or Ib, and pharmaceutically acceptable salts thereof:

Ia Ib

[0022] Where A is CH₂, the compounds are napthyridinones, and where A is oxygen, the compounds are pyridooxazinones.

[0023] In certain embodiments, R¹ is hydrogen or (C₁-C₆) alkyl optionally substituted with fluorine, (Cj-C₆) alkoxyl, (C₁-C₆) haloalkoxyl, hydroxyl, cyano, pyridinyl or (C]-C₆) haloalkyl, and in particular, R¹ may be methyl or ethyl. In other embodiments, R^4a or R^4b may be hydrogen; halogen; cyano; hydroxyl; (Ci-C₆) alkyl optionally substituted with halogen or alkoxyl; (C ₁-C₆) alkoxyl optionally substituted with halogen; or aryloxyl, heterocyclyl, or aryl, wherein each aryloxyl, heterocyclyl or aryl is optionally substituted with one or more of halogen, cyano, (Ci-C₆) alkyl, (Ci-C₆) alkoxyl, (C]-C₆) haloalkyl, (C₁- C₆) haloalkoxyl or cyanomethyl, or any combination thereof. In some preferred embodiments, R^4a or R^4b is optionally substituted aryl. For instance, R^4a may be phenyl optionally substituted with one or more of halogen, alkoxyl or (Ci-C₆) alkyl, or any combination thereof, or R^4b may be phenyl or pyrinidyl optionally substituted with one or more of halogen, alkoxyl or (C]-C₆) alkyl, or any combination thereof. [0024] In still other embodiments, R is chosen from hydrogen or (Ci-C₆) alkyl, and R⁶ is chosen from hydrogen, (CH₂)_nR⁷ and (Ci-C₆) alkyl optionally substituted with hydroxyl, alkoxyl, amino, alkylthio, cyano or halogen, wherein n can be zero, one or two, and R is an optionally substituted carbocycle or heterocycle. In one instance, R⁶ can be (CH₂)R⁷ wherein R⁷ is chosen from the group consisting of heterocyclyl and phenyl, each optionally substituted with one or more of halogen, (Ci-C₆) alkyl, (Ci-C₆) alkoxyl or hydroxyl, or any combination thereof. In other embodiments, R⁷ can be phenyl substituted with one or more (Ci-C₆) alkoxyl.

[0025] In yet other embodiments, R⁵ and R⁶ form a 4- to 12-membered, optionally substituted monocyclic or bicyclic nitrogen heterocycle, such as

wherein R and R are each independently chosen from the group consisting of hydrogen, alkoxyalkyl, alkoxyl, hydroxyl, alkyl, pyridinyl, pyrimidinyl, pyrazinyl, alkylaminoalkyl, optionally substituted phenyl, halogen, hydroxyalkyl and haloalkyl; R¹⁰ is chosen from acyl, hydrogen, aryl optionally substituted with one or more of halogen, alkoxyl or (Ci-C₆) alkyl, or any combination thereof, heterocyclyl optionally substituted with one or more of halogen, alkoxyl or (Ci-C₆) alkyl, or any combination thereof, and (Cj-C₆) alkyl optionally substituted with halogen or alkoxyl; and R¹¹ is chosen from the group consisting of hydrogen, alkoxyalkyl, alkoxyl, hydroxyl, alkyl, pyridinyl, pyrimidinyl, pyrazinyl, alkylaminoalkyl, halogen, hydroxyalkyl and haloalkyl.

[0026] In further embodiments, A is oxygen; R^4b is an aryl optionally substituted with one or more halogens and R⁵ and R⁶, when taken together with the nitrogen to which they are attached, form an alkoxyl- or alkoxyalkyl-substituted nitrogenous monocycle or bicycle. For instance, R^4b can be phenyl or pyridinyl substituted with one or more fluorine or chlorine atoms, or any combination thereof, and R⁵ and R⁶, taken together with the nitrogen to which they are attached, can be piperidine, tetrahydroisoquinoline or isoindoline substituted with methoxyl or alkoxyalkyl. In still other embodiments, A is CH₂, R^4b is an aryl optionally substituted with one or more halogens, and R⁵ and R⁶ form an alkoxyl- or alkoxyalkyl-substituted nitrogenous monocycle or bicycle. For instance, R^4b may be phenyl or pyridinyl substituted with one or more fluorine or chlorine atoms, methyl or methoxyl, and R⁵ and R⁶, taken together with the nitrogen to which they are attached, can be piperidine, tetrahydroisoquinoline or isoindoline substituted with methoxyl or alkoxyalkyl.

[0027] In yet other embodiments, R¹ is (Ci-C₆) alkyl optionally substituted with halogen, (C]-C₆) alkoxyl, (Ci-C₆) haloalkoxyl, hydroxyl, cyano, pyridinyl or (Ci-C₆) haloalkyl; R^4a is an aryl optionally substituted with one or more halogens, and R⁵ and R⁶, taken together with the nitrogen to which they are attached, form an alkoxyl- or alkoxyalkyl- substituted nitrogenous monocycle or bicycle. For instance, R¹ can be methyl or ethyl, R^4a can be phenyl optionally substituted with one or more fluorine or chlorine atoms, or any combination thereof, and R⁵ and R⁶, taken together with the nitrogen to which they are attached, may be tetrahydroisoquinoline or isoindoline substituted with methoxyl.

[0028] In yet another embodiment there is provided a compound of formula Ia and Ib, and pharmaceutically acceptable salts thereof, in which R¹ is selected from the group consisting of hydrogen; (Ci-C₆) alkyl which is linear or branched (e.g., (Ci-C₃) alkyl) optionally substituted with one, two or three substituents selected from halogen (e.g. fluoro) and cyano; and (C₂-C₆) alkyl which is linear or branched substituted with one, two or three (e.g., one) hydroxy.

In another embodiment R^4a is selected from a group consisting of hydrogen; halogen (Ci-C₆) alkyl which is linear or branched optionally substituted with one, two or three halogen; (C₃- C₇) cyclolalkyl (e.g., cyclohexyl or cyclopropyl) optionally substituted with one, two or three halogen (e.g., chloro, fluoro); (C₁-C₆) alkoxy which is linear or branched optionally substituted with one, two or three halogen (e.g. methoxy); aryloxy (e.g., O-phenyl), heteroaryl (e.g., furanyl, pyridinyl, thiophenyl) and aryl (e.g. phenyl), wherein each aryloxy, heteroaryl or aryl is optionally substituted with one or two substituents selected from the group consisting of halogen, cyano, (Ci-C₆) alkyl which is linear or branched and optionally substituted with one, two or three halogen, (Cj-C₆) alkoxyl which is linear or branched and optionally substituted with one two or three halogen, and cyanomethyl, with the proviso that R^4a is not unsubstituted pyridinyl or ortho-substituted phenyl. In a further embodiment R^4a is phenyl optionally substituted in the meta and/or para positions by one or two substituents selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, cyano, and cyanomethyl. In another embodiment R^4b is selected from a group consisting of hydrogen; halogen; (Ci-C₆) alkyl which is linear or branched optionally substituted with one, two or three halogen; (C₃-C₇) cyclolalkyl optionally substituted with one, two or three halogen; (C₁-C₆) alkoxy which is linear or branched optionally substituted with one, two or three halogen; aryloxy (e.g. O-phenyl), heteroaryl (e.g. furanyl, pyridinyl, thiophenyl) and aryl (e.g. phenyl), wherein each aryloxy, heteroaryl or aryl is optionally substituted with one or two substituents selected from the group consisting of halogen, cyano, (Ci-C₆) alkyl which is linear or branched and optionally substituted with one, two or three halogen (e.g. methyl, trifluromethyl, (Ci-C₆) alkoxyl which is linear or branched and optionally substituted with one two or three halogen (e.g. methoxy) and cyanomethyl,

In another embodiment R⁵ is selected from hydrogen or (Ci-C₆) alkyl (e.g. methyl and ethyl).

In another embodiment R⁶ is selected from the group consisting of hydrogen;

(Ci-C₆) alkyl which is linear or branched and optionally substituted with one, two or three substituents selected from the group consisting of hydroxy, halogen (e.g. fluoro), cyano, amino (e.g. NH₂), and (Ci-C₃) alkoxy;

(CH₂)_nR⁷ in which n is 0, 1 or 2 and R⁷ is selected from the group consisting of (C₃-C₇) cycloalkyl optionally substitiuted with one or two substituents selected from halogen (e.g. fluoro, chloro), (Ci-C₃) alkoxy, (Ci-C₃) alkyl which is linear or branched and optionally substituted by one, two or three halogen (e.g., trifluoromethyl); aryl (e.g., phenyl) optionally fused to a 5 to 7 membered non aromatic heterocyclic ring containing one or two heteoatoms selected from O, N, and S (e.g., a dioxolane ring) and optionally substituted by one, two or three substituents selected from hydroxy, halogen (e.g., fluoro, chloro), (Ci-C₃) alkoxy, (C]- C₃) alkyl which is linear or branched and optionally substituted by one, two or three halogen (e.g. methyl, trifluoromethyl), -SCH₃;

5 to 7 membered non aromatic heterocyclic ring containing one or two (e.g. one) heteroatoms selected from N, O and S (e.g. tetrahydrofuranyl, tetrahydropyranyl) optionally substituted by one, two or three substituents selected from hydroxy, halogen (e.g., fluoro, chloro), (Ci- C₃) alkoxy, (C₁-C₃) alkyl which is linear or branched and optionally substituted by one, two or three halogen (e.g. methyl, trifluoromethyl); and

5 to 7 membered heteroaryl ring containing one or two (e.g., one) heteroatoms selected from N, O and S (e.g., furanyl, pyridinyl) and optionally substituted by one, two or three substituents selected from hydroxy, halogen (e.g., fluoro, chloro), (Ci-C₃) alkoxy (e.g., methoxy), (Ci-C₃) alkyl which is linear or branched and optionally substituted by one, two or three halogen (e.g., methyl, trifluoromethyl).

In another embodiment, R⁵ and R⁶ when taken together with the nitrogen to which they are attached, form a 4-12 membered monocyclic or bicyclic heterocyclic ring optionally containing one or two further heteroatoms selected from N, S and O, and optionally substituted by one or two substituents selected from the group consisting of (Ci-C₆) alkyl which is linear or branched and optionally substituted by one, two, or three hydroxy, halogen , or amine groups e.g. NR'NR" wherein R' and R" are each independently hydrogen or (Ci- C₃) alkyl which is linear or branched e.g. NH₂ Or NHCH₃; (C₁-C₆) alkoxy which is linear or branched e.g. methoxy; hydroxy; (C₁-C₃) alkyl-O-(Ci-C₃) alkyl which is linear or branched; C(O)R^W in which R^w methyl or ethyl; and a 4-7 membered heteroaryl ring containing one or two N atoms (e.g. pyrimidinyl, pyrazinyl, pyridinyl).

Representative monocylic heterocyclic rings for R⁵ and R⁶ when taken together include azetidinyl, pyrrolidinyl, piperidinyl and hexahydroazepinyl.

Representative bicyclic heterocyclic rings for R⁵ and R⁶ when taken together include tetrahydroisoquinolinyl, isoindolinyl, tetrahydrobenzodiazepinyl, 4,5,6,7- tetrahydrothioeno[3,2-c]pyridinyl, and 5,6,7,8-tetrahydro-l ,6-naphthyridinyl. When substitution is permitted on an R group as defined, representative substituents may be selected from without limitation fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, cyano, cyanomethyl, NH_2, NHCH₃, -CH₂CH₂OH, -CH₂OH, -CH₂OCH₂CH₃, and CH₂OCH₃. Definitions

[0029] For convenience and clarity certain terms employed in the specification, examples and claims are described herein. Those terms retain their definitions whether alone or part of another group unless otherwise specified.

[0030] Alkyl is intended to include linear, branched, or cyclic hydrocarbon structures and combinations thereof. A combination would be, for example, cyclopropylmethyl. Lower alkyl refers to alkyl groups of from 1 to 6 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl (both n-propyl and isopropyl), butyl (including s-and t-butyl) and the like. Preferred alkyl groups are those of C₂₀ or below; more preferred are Cj-C₈ alkyl. Cycloalkyl is a subset of alkyl and includes cyclic hydrocarbon groups of from 3 to 8 carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl and the like.

[0031] Ci to C₂₀ hydrocarbon includes alkyl, cycloalkyl, polycycloalkyl, alkenyl, alkynyl, aryl and combinations thereof. Examples include benzyl, phenethyl, cyclohexylmethyl, camphoryl and naphthylethyl. Hydrocarbon refers to any substituent comprised of hydrogen and carbon as the only elemental constituents. The term "carbocycle" is intended to include ring systems in which the ring atoms are all carbon but of any oxidation state. Thus (C₃-Ci₀) carbocycle refers to such systems as cyclopropane, benzene and cyclohexene; (C₈-Ci₂) carbopolycycle refers to such systems as norbornane, decalin, indane and naphthalene. Carbocycle, not otherwise limited, refers to monocycles, bicycles and polycycles.

[0032] Alkoxy or alkoxyl refers to groups of from 1 to 8 carbon atoms of a straight, branched, cyclic configuration and combinations thereof attached to the parent structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like. Lower-alkoxy refers to groups containing one to four carbons. [0033] Heteroalkyl refers to alkyl residues in which one or more carbons (and their associated hydrogens) have been replaced by a heteroatom. For example, oxaalkyl refers to alkyl residues in which one or more carbons (and their associated hydrogens) have been replaced by oxygen. Examples include methoxypropoxy, 3,6,9-trioxadecyl and the like. The term oxaalkyl is intended as it is understood in the art [see Naming and Indexing of Chemical Substances for Chemical Abstracts, published by the American Chemical Society, 1)196, but without the restriction of f 127(a)], i.e. it refers to compounds in which the oxygen is bonded via a single bond to its adjacent atoms (forming ether bonds); it does not refer to doubly bonded oxygen, as would be found in carbonyl groups. Similarly, thiaalkyl and azaalkyl refer to alkyl residues in which one or more carbons have been replaced by sulfur or nitrogen, respectively. Examples include ethylaminoethyl and methylthiopropyl.

[0034] Acyl refers to formyl and to groups of 1, 2, 3, 4, 5, 6, 7 and 8 carbon atoms of a straight, branched, cyclic configuration, saturated, unsaturated and aromatic and combinations thereof, attached to the parent structure through a carbonyl functionality. One or more carbons in the acyl residue may be replaced by nitrogen, oxygen or sulfur as long as the point of attachment to the parent remains at the carbonyl. Examples include acetyl, benzoyl, propionyl, isobutyryl, t-butoxycarbonyl, benzyloxycarbonyl and the like. Lower- acyl refers to groups containing one to four carbons.

[0035] Aryl and heteroaryl mean a 5- or 6-membered aromatic or heteroaromatic ring containing 0-3 heteroatoms selected from O, N, or S; a bicyclic 9- or 10-membered aromatic or heteroaromatic ring system containing 0-3 heteroatoms selected from O, N, or S; or a tricyclic 13- or 14-membered aromatic or heteroaromatic ring system containing 0-3 heteroatoms selected from O, N, or S. The aromatic 6- to 14-membered carbocyclic rings include, e.g., benzene and naphthalene. The 5- to 10-membered aromatic heterocyclic rings include, e.g., imidazole, pyridine, indole, indoline, thiophene, benzopyranone, thiazole, furan, benzimidazole, benzodioxole, quinoline, isoquinoline, quinoxaline, pyrimidine, pyrazine, tetrazole and pyrazole.

[0036] Arylalkyl refers to a substituent in which an aryl residue is attached to the parent structure through alkyl. Examples are benzyl, phenethyl and the like. Heteroarylalkyl refers to a substituent in which a heteroaryl residue is attached to the parent structure through alkyl. Examples include, e.g., pyridinylmethyl, pyrimidinylethyl and the like. [0037] Heterocycle means a cycloalkyl or aryl residue in which from one to three carbons is replaced by a heteroatom selected from the group consisting of N, O and S. The nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. Examples of heterocycles include pyrrolidine, pyrazole, pyrrole, indole, quinoline, isoquinoline, tetrahydroisoquinoline, benzofuran, benzodioxan, benzodioxole (commonly referred to as methylenedioxy phenyl, when occurring as a substituent), tetrazole, morpholine, thiazole, pyridine, pyridazine, pyrimidine, thiophene, furan, oxazole, oxazoline, isoxazole, dioxane, tetrahydrofuran and the like. It is to be noted that heteroaryl is a subset of heterocycle in which the heterocycle is aromatic. Examples of heterocyclyl residues additionally include piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2- oxo-pyrrolidinyl, 2-oxoazepinyl, azepinyl, 4-piperidinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiamoφholinylsulfone, oxadiazolyl, triazolyl and tetrahydroquinolinyl. A nitrogenous heterocycle is a heterocycle containing at least one nitrogen in the ring; it may contain additional nitrogens, as well as other heteroatoms.

[0038] The term "carbocycle" is intended to include ring systems, including polycyclic structures, consisting entirely of carbon but of any oxidation state. Thus (C₃-Ci₀) carbocycle refers to such systems as cyclopropane, benzene and cyclohexene; (Cs-C]₂) carbopolycycle refers to such systems as norbornane, decalin, indane and naphthalene.

[0039] The terms "monocycle" and "bicycle" or "monocyclic" and "bicyclic" refer to carbocycles and heterocycles having one or two rings respectively. Preferred monocycles are 3, 4, 5, 6 or 7-membered rings, which may be aromatic, saturated or partially unsaturated. Non-limiting examples include cyclopropane, cyclopentane, cyclohexane, pyran, furan, tetrahydrofuran, tetrahydropyran, oxepane and phenyl. Preferred bicycles are those having from 8 to 12 ring atoms in total. Non-limiting examples include chroman, tetralin, naphthalene, benzofuran, indole, octahydropentalene and tetrahydrobenzo[b]oxepine. A particular embodiment comprises fused 5:6 and 6:6 systems.

[0040] Substituted alkyl, aryl, cycloalkyl, heterocyclyl etc. refer to alkyl, aryl, cycloalkyl, or heterocyclyl wherein up to three H atoms in each residue are replaced with halogen, haloalkyl, alkyl, acyl, alkoxyalkyl, hydroxyloweralkyl, phenyl, heteroaryl, benzenesulfonyl, hydroxy, loweralkoxy, haloalkoxy, carboxy, carboalkoxy (also referred to as alkoxycarbonyl), alkoxycarbonylamino, carboxamido (also referred to as alkylaminocarbonyl), cyano, carbonyl, acetoxy, nitro, amino, alkylamino, dialkylamino, mercapto, alkylthio, sulfoxide, sulfone, sulfonylamino, acylamino, amidino, aryl, benzyl, heterocyclyl, phenoxy, benzyloxy, heteroaryloxy, hydroxyimino, alkoxyimino, oxaalkyl, aminosulfonyl, trityl, amidino, guanidino, ureido, and benzyloxy. When the parent is a heterocycle that allows such substitution, the term also includes oxides, for example pyridine-N-oxide, thiopyran sulfoxide and thiopyran-S,S-dioxide. As mentioned above, two hydrogens on a single carbon may be replaced by a carbonyl to form an oxo derivative. Noteworthy oxo-substituted aryl residues include tetralone (3,4-dihydronaphthalen-l(2H)- one) and indanone (2,3-dihydroinden-l-one).

[0041] The term "optionally substituted with one or more of listed substituents can include any combination of those substituents. "Aryl optionally substituted with one or more of halogen or methyl" could include an aryl substituted with, for instance (but not limited to), one chlorine atom and two methyl groups or with a single chlorine atom.

[0042] The terms "halogen" and "halo" refer to fluorine, chlorine, bromine or iodine.

[0043] Some of the compounds described herein may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The present invention is meant to include all such possible isomers, as well as mixtures thereof, including racemic and optically pure forms. Optically active (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefmic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included. The configuration of any carbon-carbon double bond appearing herein is selected for convenience only and is not intended to designate a particular configuration; thus a carbon-carbon double bond depicted arbitrarily herein as trans may be Z, E or a mixture of the two in any proportion. [0044] The graphic representations of racemic, ambiscalemic and scalemic or enantiomerically pure compounds used herein are taken from Maehr J. Chem. Ed. 62, 114- 120 (1985): solid and broken wedges are used to denote the absolute configuration of a chiral element; wavy lines indicate disavowal of any stereochemical implication which the bond it represents could generate; solid and broken bold lines are geometric descriptors indicating the relative configuration shown but denoting racemic character; and wedge outlines and dotted or broken lines denote enantiomerically pure compounds of indeterminate absolute configuration. For example, the graphic representation

, of the two trans enantiomers

[0045] It will be recognized that the compounds of this invention can exist in radiolabeled form, i.e., the compounds may contain an unnatural ratio of one or more atoms containing an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Radioisotopes of hydrogen, carbon, phosphorous, fluorine, chlorine and iodine include ³H, ¹⁴C, ³⁵S, ¹⁸F, ³⁶Cl and ¹²⁵I, respectively. Compounds that contain those radioisotopes and/or other radioisotopes of other atoms are within the scope of this invention. Tritiated, i.e. ³H, and carbon-14, i.e., ¹⁴C, radioisotopes are particularly preferred for their ease in preparation and detectability. Radiolabeled compounds of this invention can generally be prepared by methods well known to those skilled in the art. Conveniently, such radiolabeled compounds can be prepared by carrying out the procedures disclosed in the Examples by substituting a readily available radiolabeled reagent for a non-radiolabeled reagent. Because of the high affinity for the EP2 enzyme active site, radiolabeled compounds of the invention are useful for EP2 assays. Chemical Synthesis

[0046] Terminology related to "protecting", "deprotecting" and "protected" functionalities occurs throughout this application. Such terminology is well understood by persons of skill in the art and is used in the context of processes that involve sequential treatment with a series of reagents. In that context, a protecting group refers to a group which is used to mask a functionality during a process step in which it would otherwise react, but in which reaction is undesirable. The protecting group prevents reaction at that step, but may be subsequently removed to expose the original functionality. The removal or "deprotection" occurs after the completion of the reaction or reactions in which the functionality would interfere. Thus, when a sequence of reagents is specified, as it is in the processes of the invention, the person of ordinary skill can readily envision those groups that would be suitable as "protecting groups". Suitable groups for that purpose are discussed in standard textbooks in the field of chemistry, such as Protective Groups in Organic Synthesis by T. W. Greene [John Wiley & Sons, New York, 1991], -which is incorporated herein by reference.

[0047] A comprehensive list of abbreviations utilized by organic chemists appears in the first issue of each volume of the Journal of Organic Chemistry. The list, which is typically presented in a table entitled "Standard List of Abbreviations", is incorporated herein by reference.

[0048] In general, the compounds of the present invention may be prepared by the methods illustrated in the general reaction schemes as, for example, described below, or by modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants that are in themselves known, but are not mentioned here. The starting materials, for example in the case of suitably substituted benzimidazole ring compounds, are either commercially available, synthesized as described in the examples or may be obtained by the methods well known to persons of skill in the art. [0049] The present invention further provides pharmaceutical compositions comprising as active agents, the compounds described herein.

[0050] As used herein a "pharmaceutical composition" refers to a preparation of one or more of the compounds described herein, or physiologically acceptable salts or solvates thereof, with other chemical components such as physiologically suitable carriers and excipients.

[0051] Pharmaceutical compositions for use in accordance with the present invention thus may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active compounds into preparations which, can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.

[0052] Compounds that inhibit EP2 can be formulated as pharmaceutical compositions and administered to a mammalian subject, such as a human patient in a variety of forms adapted to the chosen route of administration, i.e., orally or parenterally, by intravenous, intramuscular, topical, transdermal or subcutaneous routes.

[0053] For oral administration, the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for oral ingestion by a patient. Pharmacological preparations for oral use can be made using a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carbomethylcellulose; and/or physiologically acceptable polymers such as polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as cross- linked polyvinyl pyrrolidone, agar or alginic acid or a salt thereof such as sodium alginate.

[0054] In addition, enteric coating may be useful as it is may be desirable to prevent exposure of the compounds of the invention to the gastric environment. [0055] Pharmaceutical compositions, which can be used orally, include push-fit capsules made of gelatin as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules may contain the active ingredients in admixture with filler such as lactose, binders such as starches, lubricants such as talc or magnesium stearate and, optionally, stabilizers.

[0056] In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for the chosen route of administration.

[0057] For injection, the compounds of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's or Ringer's solution or physiological saline buffer. For transmucosal and transdermal administration, penetrants appropriate to the barrier to be permeated may be used in the composition. Such penetrants, including for example DMSO or polyethylene glycol, are known in the art.

[0058] For administration by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from a pressurized pack or a nebulizer with the use of a suitable propellant, e. g., dichlorodifluoromethane, trichlorofluoromethane, dichloro-tetrafluoroethane or carbon dioxide. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

[0059] Pharmaceutical compositions for parenteral administration include aqueous solutions of the active ingredients in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acids esters such as ethyl oleate, triglycerides or liposomes. Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilizers or agents, which increase the solubility of the compounds, to allow for the preparation of highly concentrated solutions.

[0060] The compounds of the present invention may also be formulated in rectal compositions such as suppositories or retention enemas, using, e.g., conventional suppository bases such as cocoa butter or other glycerides.

[0061] Depending on the severity and responsiveness of the condition to be treated, dosing can also be a single administration of a slow release composition, with course of treatment lasting from several days to several weeks or until cure is effected or diminution of the disease state is achieved. The amount of a composition to be administered will, of course, be dependent on many factors including the subject being treated, the severity of the affliction, the manner of administration, the judgment of the prescribing physician. The compounds of the invention may be administered orally or via injection at a dose from 0.001 to 2500 mg/kg per day. The dose range for adult humans is generally from 0.005 mg to 10 g/day. Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of compound of the invention which is effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg, usually around 10 mg to 200 mg. The precise amount of compound administered to a patient will be the responsibility of the attendant physician. However, the dose employed will depend on a number of factors, including the age and sex of the patient, the precise disorder being treated, and its severity. Also, the route of administration may vary depending on the condition and its severity.

[0062] As used herein, and as would be understood by the person of skill in the art, the recitation of "a compound" is intended to include salts, solvates and inclusion complexes of that compound. The term "solvate" refers to a compound of Formula I or II in the solid state, wherein molecules of a suitable solvent are incorporated in the crystal lattice. A suitable solvent for therapeutic administration is physiologically tolerable at the dosage administered. Examples of suitable solvents for therapeutic administration are ethanol and water. When water is the solvent, the solvate is referred to as a hydrate. In general, solvates are formed by dissolving the compound in the appropriate solvent and isolating the solvate by cooling or using an antisolvent. The solvate is typically dried or azeotroped under ambient conditions. Inclusion complexes are described in Remington: The Science and Practice of Pharmacy 19th Ed. (1995) volume 1, page 176-177, which is incorporated herein by reference. The most commonly employed inclusion complexes are those with cyclodextrins, and all cyclodextrin complexes, natural and synthetic, are specifically encompassed within the claims.

[0063] Compounds of formula Ia and Ib may exist in different physical forms. Such forms are within the scope of the present invention. Thus, the compounds of formula Ia and Ib may be in a crystalline or amorphous state. Furthermore, if crystalline, the compounds of formula Ia and Ib may exist in one or more polymorphic forms, which are included in the scope of the present invention. The most thermodynamically stable polymorphic form, at room temperature, of compounds of formula Ia and Ib is of interest.

[0064] Polymorphic forms of compounds of formula Ia and Ib may be characterized and differentiated using a number of conventional analytical techniques, including, but not limited to, X-ray powder diffraction (XRPD) patterns, infrared (IR) spectra, Raman spectra, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and solid state nuclear magnetic resonance (ssNMR).

[0065] The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases. When the compounds of the present invention are basic, salts may be prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids. Suitable pharmaceutically acceptable acid addition salts for the compounds of the present invention include acetic, benzenesulfonic (besylate), benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric acid, p-toluenesulfonic, and the like. When the compounds contain an acidic side chain, suitable pharmaceutically acceptable base addition salts for the compounds of the present invention include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.

[0066] The term "preventing" as used herein refers to administering a medicament beforehand to forestall or obtund an attack. The person of ordinary skill in the medical art (to which the present method claims are directed) recognizes that the term "prevent" is not an absolute term. In the medical art it is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or seriousness of a condition, and this is the sense intended herein.

[0067] It should be understood that in addition to the ingredients particularly mentioned above, the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.

[0068] The compositions may be presented in a packaging device or dispenser, which may contain one or more unit dosage forms containing the active ingredient. Examples of a packaging device include metal or plastic foil, such as a blister pack and a nebulizer for inhalation. The packaging device or dispenser may be accompanied by instructions for administration. Compositions comprising a compound of the present invention formulated in a compatible pharmaceutical carrier may also be placed in an appropriate container and labeled for treatment of an indicated condition. Indications

[0069] The compounds of the present invention are useful in inhibiting the activity of EP₂ or in inhibiting EP₂ mediated activity and may therefore be useful in the treatment of inflammatory diseases and of pain and complications arising therefrom. EP₂ antagonists may be useful for treating inflammatory arthropathies such as ankylosing spondylitis (spine and sacrum), psoriatic arthritis (skin and joints) and Reiter's syndrome (throughout the body, particularly in the spine and joints).

[0070] EP₂ antagonists may be useful for any PGE₂-mediated inflammatory disease or pain conditions such as rheumatoid arthritis, osteoarthritis, acute gout, dysmenorrhoea (painful menstruation), endometriosis, headache, migraines, postoperative pain, mild-to-moderate pain due to inflammation and tissue injury, back pain and sciatica, sprains, strains, rheumatism, dental pain, pain from kidney stones (renal colic), fever and other painful conditions, especially where there is inflammation.

[0071] Further evidence suggests that EP₂ antagonists may be useful for the treatment of neuroinflammatory and neurodegenerative diseases such as Alzheimer's disease (AD) and multiple sclerosis, as well as elevated intraocular pressure and fertility disorders. The following examples will further describe the invention, and are used for the purposes of illustration only, and should not be considered as limiting the invention being disclosed. Examples

[0072] The following abbreviations and terms have the indicated meaning throughout:

Ac = acetyl

ACN = acetonitrile

Boc = terf-butoxycarbonyl

Bu butyl

BuOH = butanol

CDCl ₃ = Deuterated chloroform

CDI = carbonyldiimidazole

CD₃OD = Deuterated methanol

Cone. = concentrated δ = NMR chemical shift referenced to tetramethylsilane

DCM = dichloromethane = methylene chloride = CH₂Cl₂

DCE = 1 ,2-dichloroethane

DEAD = diethyl azodicarboxylate

DIC = diisopropylcarbodiimide

DIEA = DIPEA=N,N-diisopropylethyl amine

DME = 1 ,2-dimethoxyethane

DMF = N,N-dimethylformamide

DMSO = dimethyl sulfoxide

Et ethyl

Et₂O = diethyl ether

EtOAc = ethyl Acetate

EDC = N-(3 -Dimethylaminopropyl)-N ' )ethylcarbodiimide

EtOH = ethanol

FCC = flash column chromatography h = hours

HOAc = acetic acid

HOBt = hydroxybenzotriazole i- = iso

/-PrOH = isopropanol=isopropyl alcohol m- = meta

Me = methyl

MeOH methanol = CH₃OH

MP = m.p.HVlelting point

Ms = mesylate

MS = mass spectrometry min = minutes

N = normal

NMR = Nuclear Magnetic Resonance

0- = ortho P- = para

Pd(dppf)₂Cl₂ = dichloro[ 1 , 1 '-bis(diphenylphosphinoferrocene]palladium

Ph = phenyl

PhOH = phenol

Pr = propyl

PS = polystyrene

PS-BEMP = 2-tert-butylimino-2-diethylami.no- 1 ,3-dimethyl-perhydro- 1 ,3 ,2- iazophosphorine on polystyrene

RT = room temperature sat. = saturated

S- = secondary t- = tert- = tertiary

TBDMS = t-butyldimethylsilyl

TEA = Et₃N=triethylamine

Tf triflate

TFA = trifluoroacetic acid

THF = tetrahydrofuran

TMS = trimethylsilyl

XPhos = 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

[0073] Examples below describe syntheses of certain precursors and intermediates of the invention.

The derivatives of the present invention are prepared by methods well known in the art of organic chemistry. See, for example, J. March, 'Advanced Organic Chemistry' 4th Edition, John Wiley and Sons. During synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This is achieved by means of conventional protecting groups, such as those described in T. W. Greene and P.G.M. Wutts 'Protective Groups in Organic Synthesis' 2nd Edition, John Wiley and Sons, 1991. The protective groups are optionally removed at a convenient subsequent stage using methods well known in the art.

Ia Ib [0074] Compounds of Formula Ia or Ib where A = O or A = CH₂ can be prepared using as starting materials the intermediates 1-3, 2-3, or 2-4 respectively. These can be prepared by the general synthetic sequences shown in Schemes 1 and 2. As illustrated in Scheme 1, 5-bromo-2-chloro-3-nitropyridine is reacted with an alkyl aminoacetate such as methyl (R = Me), ethyl (R = Et), or MButyl (R = t-Bu) aminoacetate in the presence of a suitable base such as DIPEA or TEA under standard reaction conditions to give intermediate 1-1. One example of suitable reaction conditions would be to run the reaction at reflux in a suitable solvent such as EtOH until the reaction is complete. The nitro group is reduced to give intermediate 1-2 using appropriate reaction conditions so as not to interfere with the aryl halide (bromo) or ester functionality. An example of appropriate conditions would be using an atmosphere of hydrogen gas, preferably at high pressure (such as 20 psi), in the presence of a suitable catalyst such as PtO_2. Another example of suitable conditions would be to reduce the nitro group with a metal, such as zinc in the presence of an acid catalyst, such as acetic acid, in a solvent such as THF. Finally, the desired intermediate 1-3 can be prepared from reaction of the intermediate 1-2 using an appropriate carbonylation reagent such as triphosgene or phosgene or CDI.

nitro reduction

1-1

1-2 1-3

Scheme 1

Scheme 2, illustrates the preparation of intermediates 2-3 (A = O) and 2-4 (A = CH₂). The requisite bromo intermediates 2-1 and 2-2 are either commercially available

A = O ^Or CH₂ A = O- 2-1

A = CH₂; 2-2

A = O; 2-3 A = CH₂; 2-4

Scheme 2

or prepared by bromination of commercially available 2H-pyrido[3,2-b][l,4]oxazin-3(4H)- one (A = O) or 3,4-dihydro-l,8-naphthyridin-2(lH)-one (A = CH₂). Suitable conditions for the bromination of 2H-pyrido[3,2-b][l,4]oxazin-3(4H)-one would be to react it with NBS in a solvent such as DMF. Intermediates 2-1 and 2-2 are then reacted with an appropriate alkyl bromoacetate using procedures well known in the art to provide intermediates 2-3 (A = O) and 2-4 (A = CH₂).

[0075] Compounds of Formula Ia (where R is alkyl, substituted alkyl, etc.), n = 0, and R ^a is aryl or heteroaryl, either optionally subsituted, can be prepared by the general four stage sequence shown in Scheme 3.

Scheme 3

[0076] First, intermediate 1-3 can be alkylated to give intermediate 3-1. One example of suitable conditions would be to treat intermediate 1-3 with a base, such as NaH, in an inert solvent, such as DMF, and to then treat the resultant anion with an alkylating substrate such as an alkylhalide. The ester intermediate 3-1 can be converted to the desired carboxylic acid 3-2 by a variety of reaction conditions well known in the art, depending on the nature of ester substituent defined by R. If R is methyl, or ethyl, for example, treatment of the ester with a suitable hydroxide reagent, such as LiOH, in a suitable solvent system such as aqueous MeOH, will provide the carboxylic acid 3-2. Alternatively, if R is t-Bu, then treatment with acid, such as TFA in a suitable solvent such as DCM, will give the carboxylic acid 3-2. Proper choice of the ester substituent (i.e. the R group) will be dictated by the nature of the R substituent. Reaction of intermediate 3-2 with a primary or secondary amine in the presence of a suitable amide bond coupling reagent gives the amide intermediate 3-3. One example of such a coupling reagent would be EDCI. The coupling reagent is added either alone or in the presence of an additive such as HOBt and in a suitable inert solvent such as dichloromethane, DMF, or a combination thereof. Finally, intermediate 3-3 is reacted with an aryl or heteroaryl boronic acid or boronate ester, under the appropriate Suzuki coupling conditions to give the desired pyridoimidazolone 3-4.

[0077] A further method by which the desired pyridoimidazolone products (3-4) can be obtained involves preparation of the intermediate boronate 4-1 which is prepared by reaction of bromide intermediate 3-3 with bis(pinacolato)diboron in the presence of a suitable catalyst such as PdCl₂(dppf) and a base such as KOAc in a suitable solvent such as DMSO or DMF (Scheme 4). This can then be coupled with an aryl or heteroaryl halide or triflate to give the desired pyridoimidazolone 3-4.

Scheme 4

[0078] Compounds of Formula I wherein A = O or CH₂ and R⁴ is an appropriately substituted aryl or heteroaryl can be prepared by the general three stage sequence shown in Scheme 5. First, the ester intermediates 2-3 (A = O) and 2-4 (A = CH₂) are converted to the carboxylic acid intermediates 5-1 and 5-2 using the same general procedures described above for the conversion of intermediate 3-1 to intermediate 3-2. Second, the carboxylic acid intermediates can be reacted with a primary or secondary amine using a wide variety of well known general amide coupling reaction conditions to give the amide intermediates 5-3 and 5-4. Finally, intermediates 5-3 and 5-4 are reacted with an aryl or heteroaryl boronic acid or boronate ester, under the appropriate Suzuki coupling conditions, which are well known by the artisan, to give the desired pyridooxazinones 5-5 (A = O) and dihydronapthpyridinones 5-6 (A = CH₂).

A = O; 2-3 . _, _ .

^A - ^CH»^{: M} A = §H₃;^"15-2

A = 0; 5-3 A = 0; 5-5

A = CH₂; 5-4 A = CH₂; 5-6

Scheme 5

[0079] It will be readily appreciated by one skilled in the art that the same general procedures illustrated in Scheme 4 and described for the conversion of intermediate 3-3, via intermediate 4-1, to the desired pyridoimidazolones (3-4) can be utilized for the preparation of the desired pyridooxazinones (5-5) and dihydronapthpyridinones (5-6) starting from the bromide intermediates 5-3 and 5-4.

[0080] It will also be readily appreciated by one skilled in the art that the compounds of general Formula Ib can be prepared using the general procedures and/or reaction sequences described above in any suitable order. For example, whereas the processes detailed above describe introduction of Ar groups later in the syntheses it will be recognized that, in some cases, the Ar groups can be introduced early by performing the Suzuki coupling reaction on the ester intermediates (e.g. intermediate 2-3) and then converting the esters to the desired amides.

EXAMPLES

The invention is further illustrated by the following examples. Synthesis of precursors and common intermediates Procedure I

INTERMEDIATE I.I : Ethyl 2-(6-bromo-2-oxo- 1 ,2-dihvdroimidazor4,5-blpyridin-3- vDacetate

a) Ethyl 2-(5-bromo-3-nitropyridin-2-ylamino)acetate

[0081] A mixture of 5-bromo-2-chloro-3-nitropyridine (10.00 g, 42.12 mmol), glycine ethyl ester*HCl (7.05 g, 50.5 mmol) and DIPEA (18.34 mL, 105.3 mmol) in EtOH (100 mL) was heated to reflux for 4 h. The mixture was cooled to room temperature, concentrated in vacuo and the residue taken up in EtOAc (300 mL). The organic layer was washed with sat. NH₄Cl (aq) (2 X 100 mL), H₂O (1 X 100 mL) and brine (1 X 100 mL). The organic phase was dried (Na₂SO₄), filtered and concentrated in vacuo to give ethyl 2-(5- bromo-3-nitropyridin-2-ylamino)acetate as brownish-yellow solid (12.36 g, 96%). Data: ¹H NMR (400 MHz, CDCl₃): δ 8.57 (d, IH), 8.45 (br s, IH), 8.43 (d, IH), 4.35 (d, 2H), 4.26 (q, 2H), 1.31 (t, IH) ppm. b) Ethyl 2-(6-bromo-2-oxo- 1 ,2-dihydroimidazo[4,5-b]pyridin-3-yl)acetate

[0082] A mixture of ethyl 2-(5-bromo-3-nitropyridin-2-ylamino)acetate (4.00 g, 13.15 mmol) and PtO₂ (400 mg) in THF (40 mL) was shaken in a Parr apparatus under a H₂ (g) atmosphere (20 psi) for 2 h. The mixture was filtered through a pad of Celite with THF rinses (2 X 40 mL) into a 500 mL round bottom flask. The filtrate was cooled to 0 ⁰C (ice bath) and Et₃N (4.58 mL, 32.88 mmol) was added. To the stirred mixture was added a solution of triphosgene (1.44 g, 4.87 mmol) in THF (20 mL), dropwise. After addition was complete, the cooling bath was removed and the mixture was stirred for an additional 16 h.

The mixture was then concentrated in vacuo, and the crude residue treated with sat. NH₄Cl

(aq) (200 mL) and extracted with EtOAc (3 X 200 mL). The combined organic extracts were washed with H₂O (1 X 100 mL) and brine (1 X 100 mL), dried (MgSO₄), filtered, and concentrated in vacuo. The resultant crude solid was triturated with Et₂O/hexanes to afford ethyl 2-(6-bromo-2-oxo-l , 2-dihydroimidazo[4, 5 -b]pyήdin-S-yl) acetate (INTERMEDIA TE

1.1) as gray solid (2.83 g, 72% for two steps).

Data: ¹H NMR (400 MHz, </₆-DMSO): δ 11.47 (s, IH), 8.05 (d, IH), 7.57 (d, IH), 4.61 (s,

2H), 4.14 (q, 2H), 1.19 (t, 3H) ppm, MS (ESI) m/z: 300 + 302 ([M+H]⁺).

Similarly prepared was:

INTERMEDIATE 1.2: Methyl 2-(6-bromo-2-oxo-l,2-dihydroimidazo[4,5-b]pyridin-3- yl)acetate (from glycine methyl ester*HCl)

Procedure II

INTERMEDIATE II.1 : Ethyl 2-(6-bromo- 1 -methy 1-2-oxo- 1 ,2-dihydroimidazo [4,5- b^~jpyridin-3-yl)acetate

[0083] To a mixture of ethyl 2-(6-bromo-2-oxo-l,2-dihydroimidazo[4,5- b]pyridin-3-yl)acetate (Intermediate Ll) (1.00 g, 3.33 mmol) and K₂CO₃ (1.38 g, 9.99 mmol) in acetone (10 mL) was added MeI (0.23 mL, 3.66 mmol) and the reaction mixture was stirred at room temperature for 16 h. The mixture was then concentrated in vacuo and the crude residue treated with H₂O (50 mL) and extracted with EtOAc (3 X 50 mL). The combined organic layers were washed with brine (1 X 50 mL), dried (Na₂SO₄), filtered and concentrated in vacuo to afford ethyl 2-(6-bromo-l-methyl-2-oxo-l,2-dihydroimidazo[4,5- b]pyridin-3-yl)acetate (INTERMEDIATE II I) as an off-white solid (0.99 g, 94%). Data: ¹H NMR (400 MHz, ^₆-DMSO): δ 8.07 (d, IH), 7.32 (d, IH), 4.70 (s, 2H), 4.23 (q, 2H), 3.43 (s, 3H), 1.28 (t, 3H) ppm, MS (ESI) m/z: 314 + 316 ([M+H]⁺). Similarly prepared was: INTERMEDIATE II.2: Ethyl 2-(6-bromo- 1 -ethyl-2-oxo- 1 ,2-dihydroimidazo[4,5-b1pyridin-

3-yHacetate (from INTERMEDIATE I.I and iodoethane)

Procedure HI

INTERMEDIATE III.1 : fert-butyl 2-(7-brorno-3-oxo-2,3-dihvdropyridor3,2-&T[1.41oxazin-4- yl)acetate

a) 7-Bromo-2H-pyrido|^"3 ,2-b] [ 1 ,41oxazin-3( 4H)-one

[0084] A mixture of 2H-pyrido[3,2-b][l,4]oxazin-3(4H)-one (5.0 g, 33.3 mmol) in DMF (75 mL) was stirred at r.t. and a solution of N-bromosuccinimide in DMF (25 mL) was added dropwise over a period of 40 min. The mixture was stirred at room temperature for 44 h after which the mixture was diluted with water (37 mL) producing a white precipitate. The mixture was cooled in a refrigerator for 2 h. The solid was filtered, washed with water (50 mL) and dried in vacuo to give 7-bromo-2H-pyrido[3,2-6][l,4]oxazin-3(4H)- one as a white solid (6.34 g, 83%).

Data: ¹H NMR (400 MHz, CDCl₃): δ 9.26 (bs, IH), 8.05 (d, IH), 7.42 (d, IH), 4.69 (s, 2H) ppm. MS (ESI) m/z: 229.0 ([M+H]⁺). b) fert-Butyl 2-(7-bromo-3-oxo-2,3-dihydropyrido|^~3,2-b1[l,4^"[oxazin-4-yl)acetate

[0085] To a mixture of 7-bromo-2H-pyrido[3,2-ό][l,4]oxazin-3(4H)-one (2.00 g, 8.74 mmol) in DMF (50 mL) and cooled to 0 ⁰C was added NaH (0.55 g, 13.1 mmol) and the mixture stirred for 0.5 h. To this was added tert-butyl bromoacetate (2.0 mL, 14.0 mmol) via syringe, the cooling bath was removed and the stirring continued 16 h. The reaction was quenched with NH₄Cl (aq) (20 mL), diluted with EtOAc (150 mL) and washed with H₂O (1

X 50 mL) and brine (1 X 50 mL), dried (MgSO₄), filtered, and concentrated in vacuo. The resultant crude solid was purified by flash chromatography to afford tert-butyl 2-(7-bromo-3- oxo-2,3-dihydropyrido[3,2-b][l,4]oxazin-4-yl)acetate (INTERMEDIATE III. J) as clear, yellow oil (2.91 g, 99%).

Data: ¹H NMR (400 MHz, J₆-DMSO): δ 8.01 (d, IH), 7.39 (d, IH), 4.74 (s, 2H), 4.71 (s,

2H), 1.46 (s, 9H) ppm, MS (ESI) m/z: 287.2 ([M+H]⁺).

Procedure IV

INTERMEDIATE IV.1 : tert-Butyl 2-(6-bromo-2-oxo-3 ,4-dihvdro- 1 ,8-naphthyridin- 1 (2HV vDacetate

Ό o^'

_'N^N, <P

Br'

[0086] A mixture of 6-bromo-3,4-dihydro-l,8-naphthyridin-2(lH)-one (0.46 g, 2.0 mmol), /ert-butylbromoacetate (360 μL, 2.4 mmol) and potassium carbonate (0.64 g, 4.4 mmol) in acetone (10 mL) was heated at reflux for 24 h. The mixture was then concentrated and the resulting residue treated with DCM (10 mL) and water (10 mL). The organic layer was dried (MgSO₄) and concentrated in vacuo to yield tert-butyl 2-(6-bromo-2-oxo-3,4- dihydro-l,8-naphthyridin-l(2H)-yl)acetate (INTERMEDIATE IV.1) as yellow solid. (0.64 g, 1.9 mmol, 94%)

Data: ¹H NMR (400MHz, CDCl₃): δ 8.20 (s, IH), 7.60 (s, IH), 4.70 (s, 2H), 2.95 (t, 2H), 2.75 (t, 2H), 1.40 (s, 9H) ppm. Synthesis of Examples According to the Invention EXAMPLE 1 a: N-butyl-2-( 1 -ethyl-Σ-oxo-ό-phenyl- 1 ,2-dihvdroimidazor4,5-blpyridin-3-

vDacetamide

a) Σ-fό-bromo-l-ethyl^-oxo-LZ-dihydroimidazo^.S-bjpyridin-S-vD-N-butylacetamide

[0087] A mixture of Ethyl 2-(6-bromo-l-ethyl-2-oxo-l,2-dihydroimidazo[4,5- b]pyridin-3-yl)acetate (INTERMEDIATE II.2) (0.30 g, 0.96 mmol), «-butylamine (0.5 mL) and sodium cyanide (5 mg, 0.10 mmol) in EtOH (2.6 mL) was heated to 150 ⁰C in a microwave for 60 min. The reaction mixture was cooled to room temperature, transferred to a separatory funnel and diluted with EtOAc (40 mL). The solution was washed with sat. NH₄Cl (aq) (1 X 20 mL), sat. NaHCO₃ (aq) (1 X 20 mL) and brine (1 X 20 mL). The organic phase was dried (MgSO₄), filtered and concentrated in vacuo to afford 2-(6-bromo-l-ethyl- 2-oxo-l,2-dihydroimidazo[4,5-b]pyridin-3-yl)-N-butylacetamide (328 mg, 96%). Data: ¹H NMR (400 MHz, CDCl₃): δ 8.09 (s, IH), 7.34 (s, IH), 6.01 (br s, IH), 4.58 (s, 2H), 3.94 (q, 2H), 3.27 (q, 2H), 1.46 (m, 2H), 1.34 (m, 5H), 0.90 (t, 3H) ppm; MS (ESI) m/z: 355.0 + 357.0 ([M+H]⁺).

b) N-butyl-2-(l-ethyl-2-oxo-6-phenyl-l,2-dihydroimidazo|^"4,5-b]pyridin-3-yl)acetamide

[0088] A 0.2-2 mL capacity microwave vessel was charged with the crude product from the previous step (20 mg, 0.056 mmol), phenylboronic acid (20 mg, 0.16 mmol) and EtOH (1.0 mL). To this was added 1 N K₂CO₃ (aq) (90 μL, 0.090 mmol) and PS- PPh₃-Pd (Biotage, -0.1 mmol/g, 35 mg, 0.0035 mmol). The vessel was tightly sealed and heated to 120 ⁰C for 20 min under microwave irradiation. After cooling, the reaction mixture was transferred to a pre-packed column of silica-carbonate (2 g, ~ 0.79 mmol/g) which had been conditioned with 1 : 1 DCM/MeOH. The eluent was collected via gravity elution and and the column washed with additional 1 : 1 DCM/MeOH (2 X 3 mL). The eluents were combined and concentrated in vacuo and the crude residue was purified by preparative HPLC to give N-butyl-2-(l-ethyl-2-oxo-6-phenyl-l,2-dihvdroimidazo[4,5-bJpyridin-3-yl)acetamide (EXAMPLE Ia) (16.5 mg, 83%)

Data: ¹HNMR (400 MHz, CDCl₃): δ 8.27 (d, IH), 7.56-7.39 (m, 6H), 6.23 (br s, IH, -NH), 4.72 (s, 2H), 4.03 (q, 2H), 3.29 (q, 2H), 1.50 (m, 2H), 1.41 (t, 3H), 1.33 (m, 2H), 0.90 (t, 3H) ppm, MS (ESI) m/z: 353.1 ([M+H]⁴).

Similarly prepared were EXAMPLES Ib-It (Table I) EXAMPLE 2a: N-(4-methylbenzyl)-2- (6-(3,5-dichlorophenyl)-l-methyl-2-oxo-l,2-dihydroimidazor4,5-b1pyridin-3-yl)acetamide

[0089] A mixture of 2-(6-(3,5-dichlorophenyl)-l-methyl-2-oxo-l ,2- dihydroimidazo[4,5-b]pyridin-3-yl)acetic acid (preparation described in EXAMPLE 1 1a, steps a and b) (21 mg, 0.060 mmol), PS-carbodiimide (Biotage, -1.42 mmol/g, 60 mg, 0.085 mmol) and HOBt*H₂O (9 mg, 0.067 mmol) in dichloromethane (0.9 mL) and dimethylformamide (0.1 mL) was agitated on an orbital shaker for 15 min. 4- methylbenzylamine (5 μL, 0.04 mmol) was added and the mixture agitated 16h. To the reaction mixture was added MP-carbonate resin (Biotage, -3.11 mmol/g, 150 mg, 0.47 mmol) and this was agitated for an additional 2h. The mixture was then filtered and the resins rinsed with dichloromethane (3x5 mL). The combined eluent was concentrated in vacuo to afford N-(4-methylbenzyl)-2-(6-(3, 5-dichlorophenyl)-l-methyl-2-oxo-l,2- dihydroimidazo[4,5-b]pyήdin-3-yl)acetamide (Example 2a) (15 mg, 83%). Data: ¹H NMR (400 MHz, ^₆-DMSO): δ 8.66 (t, IH, -NH), 8.38 (d, IH), 7.99 (d, IH), 7.85 (d, 2H), 7.62 (t, IH), 7.14 (m, 4H), 4.53 (s, 2H), 4.24 (d, 2H), 3.43 (s, 3H), 2.27 (s, 3H) ppm; MS (ESI) m/z: 455.0 + 457.0 ([M+H]⁺). Similarly prepared were EXAMPLES 2b-2s (Table 1)

EXAMPLE 3a: 2-(6-(3,5-dichlorophenyl)-l -ethyl-2-oxo-l ,2-dihydroimidazo[4,5-b]pyridin-

3 -vD-N-isopropylacetamide

a) ethyl 2-(6-(3,5-dichlorophenyD-l -ethyl-2-oxo-l, 2-dihydroimidazo[4,5-b]pyridin-3- vDacetate

[0090] A mixture of ethyl 2-(6-bromo-l-ethyl-2-oxo-l,2-dihydroimidazo[4,5- b]pyridin-3-yl)acetate (INTERMEDIATE II.2) (300 mg, 0.92 mmol), 3,5- dichlorobenzeneboronic acid (210 mg, 1.10 mmol), tetrakis(triphenylphosphine)palladium (0) (105 mg, 0.091 mmol) and potassium carbonate (250 mg, 1.81 mmol) in acetone :water (2:1, 5 mL) were heated at 80°C under argon atmosphere. The solution was concentrated in vacuo and the residue was taken up in DCM and washed with water. The organic layer was then dried (Na₂SO₄), filtered and concentrated in vacuo. Purification by FCC (SiO₂; elution with 1 :1 EtOAc/hexanes) gave ethyl 2-(6-(3,5-dichlorophenyl)-l -ethyl-2-oxo-l, 2- dihydroimidazo[4,5-b]pyridin-3-yl)acetate (180 mg, 51%)

Data: ¹H NMR (400 MHz, CDCl₃): δ 8.20 (s, IH), 7.45 (s, 2H), 7.38 (s, IH), 7.30 (s, IH), 4.80 (s, 2H), 4.25 (dd, 2H), 4.05 (dd, 2H), 1.45 (t, 3H), 1.30 (t, 3H) ppm. b) 2-(6-(3,5-dichlorophenyl)-l-ethyl-2-oxo-l,2-dihydroimidazo[4.5-b]pyridin-3-yl)acetic acid

[0091] To a solution of ethyl 2-(6-(3,5-dichlorophenyl)-l-ethyl-2-oxo-l,2- dihydroimidazo[4,5-b]pyridin-3-yl)acetate (100 mg, 0.25 mmol) in THF (2 mL), and MeOH (2 mL) was added IN LiOH (aq) (2 mL). The reaction mixture was stirred at 23 °C for 4 h. The mixture was then concentrated in vacuo and acidified to pH 3 with IN HCl (aq). The resulting precipitate was collected by filtration to give 2-(6-(3,5-dichlorophenyl)-l-ethyl-2- oxo-l,2-dihydroimidazo[4,5-b]pyridin-3-yl)acetic acid (76 mg, 83%) as a white solid. Data: ¹H NMR (400 MHz, ^-DMSO): δ 13.25 (br s, IH), 8.40 (s, IH), 8.10 (s, IH), 7.90 (s, 2H), 7.60 (s, IH), 4.60 (s, 2H), 4.00 (dd, 2H), 1.30 (t, 3H) ppm; MS (ESI) m/z: 365.9 + 367.9 (M+H⁺). c) 2-(6-(3,5-dichlorophenyl)-l-ethyl-2-oxo-l,2-dihydroimidazo[4,5-b]pyridin-3-yl)-N- isopropylacetamide

[0092] A solution of 2-(6-(3,5-dichlorophenyl)-l-ethyl-2-oxo-l,2- dihydroimidazo[4,5-b]pyridin-3-yl)acetic acid (20 mg, 0.05 mmol) in DCM (1 mL) was treated with oxalyl chloride (200 μL, excess) for 30 minutes. The solution was then concentrated in vacuo and the residue taken up in DCM (1.5 mL) and treated with Et₃N (100 μL, excess) and isopropyl amine (100 μL, excess) for 2 hours. The mixture was then concentrated in vacuo, taken up in DCM (5 mL) and washed with 0.5 N HCl (5 mL) and brine (5 mL). The organic layer was dried over Mg SO₄ and concentrated in vacuo to yield 2-(6-(3, 5-dichlorophenyl)-l-ethyl-2-oxo-l, 2-dihydroimidazo[4, 5-b]pyridin-3-yl)-N- isopropylacetamide (EXAMPLE 3a) (14 mg, 67%) as a white solid.

Data: ¹H NMR (400 MHz, CDCl₃): δ 8.10 (s, IH), 7.35 (s, 2H), 7.30 (s, IH), 7.38 (s, IH), 5.80 (br d, IH), 4.50 (s, 2H), 4.00 (m, IH), 3.90 (q, 2H), 1.30 (t, 3H), 1.05 (d, 6H) ppm; MS (ESI) m/z: 407.0 + 409.0 (M+H⁺ ). Similarly prepared were EXAMPLES 3b-3d (Table I) EXAMPLE 4a: 2-(6-(3,5-dichlorophenyl)-l -emyl-2-oxo-l ,2-dihydroimidazo|^"4,5-b]pyridin- 3-yl)-N-isobutylacetamide

[0093] To a solution of ethyl 2-(6-(3,5-dichlorophenyl)-l-ethyl-2-oxo-l,2- dihydroimidazo[4,5-b]pyridin-3-yl)acetate (20 mg, 0.047 mmol)in EtOH (0.3 niL) and THF(OJ niL) was added isobutyl amine (0.1 mL, 1.0 mmol, excess) and NaCN (1 mg, cat.). The solution was irradiated in a microwave at 16O⁰C for 3 hours. The solution was then concentrated in vacuo and the resulting oil taken up in DCM (5 mL) and washed with 0.5 N HCl (5 mL), 1 N KOH (5 mL) and brine (5 mL). The organic layer was dried over MgSO₄ and concentrated in vacuo to yield 2-(6-(3,5-dichlorophenyl)-l-ethyl-2-oxo-l,2- dihydroimidazo[4,5-b]pyridin-3-yl)-N-isobutylacetamide as an oil. (8 mg, 38%) Data: ¹H NMR (400 MHz, CDCl₃): δ 8.15 (s, IH), 7.40 (s, 2H), 7.30 (s, IH), 7.25 (s, IH), 6.2 (br t, IH), 4.65 (s, 2H), 4.00 (m, 2H), 3.10 (t, 2H), 2.75 (m, IH), 1.40 (t, 3H), 0.85 (d, 6H) ppm; MS (ESI) m/z: 421.0 + 422.9 (M+H⁺). Similarly prepared were EXAMPLES 4b-4h (Table I)

EXAMPLE 5a: N-butyl-2-(^"6-(3,5-dichlorophenyl)-2-oxo-l-propyl-1.2-dihydroimidazo[4,5- blpyridin-3 -vDacetamide

a) 2-(6-bromo-2-oxo- 1 ,2-dihydroimidazo[4,5-b1pyridin-3-ylVN-butylacetamide

[0094] A mixture of ethyl 2-(6-bromo-2-oxo- 1 ,2-dihydroimidazo[4,5-b]pyridin-3- yl)acetate (INTERMEDIATE I.I) (0.50 g, 1.67 mmol), rt-butylamine (2 mL) and NaCN (16 mg, 0.333 mmol) in EtOH (8 mL) was heated to 140 ⁰C in a microwave for 70 min. The reaction mixture was then cooled to room temperature, transferred to a separatory funnel and diluted with EtOAc (200 mL). The solution was washed with sat. NH₄Cl (aq) (1 X 100 mL), sat. NaHCO₃ (aq) (1 X 50 mL) and brine (1 X 50 mL). The organic phase was dried (Na₂SO₄), filtered and concentrated in vacuo to afford 2-(6-bromo-2-oxo-l,2- dihydroimidazo[4,5-b]pyridin-3-yl)-N-butylacetamide (546 mg, 100%). Data: ¹H NMR (400 MHz, d₆-OMSO): δ 1 1.34 (br s, IH), 8.12 (t, IH, -NH), 8.01 (d, IH), 7.51 (d, IH), 4.36 (s, 2H), 3.04 (q, 2H), 1.36 (m, 2H), 1.26 (m, 2H), 0.86 (t, 3H) ppm; MS (ESI) m/z: 327.0 + 329.0 ([M+H]⁺). b) 2-(6-bromo-2-oxo- 1 -propyl- 1 ,2-dihydroimidazor4,5 -blpyridin-3 -yl^*)-N-butylacetamide

[0095] A mixture of 2-(6-bromo-2-oxo-l,2-dihydroimidazo[4,5-b]pyridin-3-yl)- N-butylacetamide (20 mg, 0.061 mmol) and 2-ter/-butylimino-2-diethylamino-l,3-dimethyl- perhydro-l,3,2-diazaphosphorine on polystyrene (-2.2 mmol/g, 83 mg, 0.18 mmol) in ACN (0.4 mL) and DMF (0.1 mL) was heated to 50 ⁰C for 16 h with stirring in a tightly capped 1 dram screw top vial. The reaction mixture was cooled and then filtered through a medium frit with DCM rinses. The filtrate was concentrated in vacuo and the crude residue partitioned between EtOAc (3 X) and H₂O. The combined organic phases were dried (Na₂SO₄), filtered and concentrated in vacuo to give 2-(6-bromo-2-oxo- 1 -propyl- 1, 2- dihydroimidazo[4,5-b]pyridin-3-yl)-N-butylacetamide which was used in the next step without further purification. c) N-butyl-2-(6-(3,5-dichlorophenyl)-2-oxo-l-propyl-l,2-dihydroimidazo[4,5-b]pyridin-3- vDacetamide

[0096] A 0.2-2 mL capacity microwave vessel was charged with the crude product from the previous step, 3,5-dichlorophenylboronic acid (14 mg, 0.073 mmol) and EtOH (1.25 mL). To this was added 1 N K₂CO₃ (aq) (73 μL, 0.073 mmol) and PS-PPh₃-Pd (Biotage, 0.1 mmol/g, 31 mg, 0.0031 mmol). The vessel was tightly sealed and heated to 120 ⁰C for 20 min under microwave irradiation. After cooling the reaction mixture was transferred to a pre-packed column of Si-carbonate (2 g, 0.79 mmol/g) which had been conditioned with 1 : 1 DCM/MeOH. The eluent was collected via gravity elution and and the column washed with additional 1 :1 DCM/MeOH (2 X 3 mL). The eluents were combined and concentrated in vacuo and the crude residue purified by preparative HPLC to give N- butyl-2-(6-(3, 5-dichlorophenyl)-2-oxo- 1 -propyl- 1, 2-dihydroimidazo[4, 5-b]pyridin-3- yl)acetamide (EXAMPLE 5a) (16 mg, 59% for two steps from 2-(6-bromo-2-oxo-l,2- dihydroimidazo[4,5-b]pyridin-3-yl)-N-butylacetamide)

Data: ¹H NMR (400 MHz, CDCl₃): δ 8.18 (d, IH), 7.40 (d, 2H), 7.38 (t, IH), 7.30 (d, IH), 6.13 (br t, IH, -NH), 4.65 (s, 2H), 3.92 (t, 2H), 3.28 (q, 2H), 1.83 (m, 2H), 1.48 (m, 2H), 1.32 (m, 2H), 1.01 (t, 3H), 0.90 (t, 3H) ppm; MS (ESI) m/z: 435.0 + 436.9 ([M+H]⁺). Similarly prepared were EXAMPLES 5a-5d (see Table I)

EXAMPLE 6a: N-butyl-2-(6-(3,5-dichlorophenvn-2-oxo-l-(2,2,2-trifluoroethylVl,2- dihydroimidazo [4, 5 -blp yridin-3 - vDacetamide

a)N-butyl-2-r6-(3.5-dichlorophenyl)-2-oxo-l,2-dihydroimidazo[4,5-b]pyridin-3-yl)acetamide

[0097] A mixture of 2-(6-bromo-2-oxo-l,2-dihydroimidazo[4,5-b]pyridin-3-yl)- N-butylacetamide (preparation described above in Example 5a, step a) (100 mg, 0.306 mmol), 2 N Na₂CO₃ (aq) (0.18 mL, 0.367 mmol), 3,5-dichlorophenylboronic acid (70 mg, 0.367 mmol) and Pd(PPh₃ )₄ (18 mg, 0.0153 mmol) in dioxane (5 mL) was heated to reflux for 0.5 h. More 2 N Na₂CO₃ (aq) (0.18 mL, 0.367 mmol), and heating at reflux was continued for 16 h. After cooling to room temperature, the reaction mixture was partitioned between EtOAc (50 mL) and sat. NH₄Cl (aq) (20 mL) in a separatory funnel. The organic phase was washed with sat. NaHCO₃ (aq) (1 X 20 mL) and brine (1 X 20 mL), dried (Na₂SO₄), filtered and concentrated in vacuo. The crude residue was purified by FCC (SiO₂; elution with EtOAc) to give N-butyl-2-(6-(3,5-dichlorophenyl)-2-oxo-l,2- dihydroimidazo[4,5-b]pyridin-3-yl)acetarnide (19 mg, 16%) as an off-white solid, b) N-butyl-2-(6-(3,5-dichlorophenyl)-2-oxo-l-(2.2.2-trifluoroethyl)-l,2- dihydroimidazo [4, 5 -b]pyridin-3 -vDacetamide

[0098] A mixture of N-butyl-2-(6-(3,5-dichlorophenyl)-2-oxo-l,2- dihydroimidazo[4,5-b]pyridin-3-yl)acetamide (10 mg, 0.0259 mmol), PS-BEMP (40 mg), and 2-bromo-l,l,l,-trifluoroethane (50 μL) in DMF (0.4 mL) was stirred for 16 h at 23 ⁰C in a tightly capped 1 dram screw-top vial. The screw top was removed and additional 2-bromo- 1,1,1-trifluoroethane (0.40 mL) was added. The vial was tightly capped, and the reaction mixture was continued to stir at room temperature for an additional 24 h. The mixture was then filtered to remove the PS-BEMP resin with DCM rinses. The eluent was concentrated in vacuo , and the crude residue purified by FCC (SiO₂; elution with 2:1 hexanes/EtOAc then 1 :1 hexanes/EtOAc) to afford N-butyl-2-(6-(3,5-dichlorophenyl)-2-oxo-l-(2,2,2- trifluoroethyl)-l,2-dihydroimidazo[4,5-b]pyridin-3-yl)acetamide (EXAMPLE 6a) (1.3 mg, 11%).

Data: ¹H NMR (400 MHz, CDCl₃): δ 8.25 (d, IH), 7.39 (m, 4H), 5.94 (br t, IH, -NH), 4.67 (s, 2H), 4.55 (q, 2H), 3.30 (q, 2H), 1.50 (m, 2H), 1.33 (m, 2H), 0.91 (t, 3H) ppm; MS (ESI) m/z: 474.9 + 477.0 ([M+H]⁺).

EXAMPLE 7a: N-butyl-2-(6-(3 ,5-dichlorophenvD- 1 -isopropyl-2-oxo- 1.2- dihvdroimidazor4,5-blpyridin-3-yl)acetamide

[0099] A mixture of N-butyl-2-(6-(3,5-dichlorophenyl)-2-oxo-l,2- dihydroimidazo[4,5-b]pyridin-3-yl)acetamide (preparation described above in Example 6a, step a) (10 mg, 0.026 mmol), PS-BEMP (40 mg) and 2-bromopropane (50 μL) in DMF (0.40 mL) was heated to 50 ⁰C in a tightly capped screw-top 1 dram vial for 16 h. The mixture was cooled to room temperature and filtered to remove the PS-BEMP resin, and the resin rinsed with DCM, MeOH, then DCM. The combined eluent and rinses were concentrated in vacuo, and the crude residue purified by FCC (SiO₂; elution with 1 : 1 EtOAc/hexanes) to give N- butyl-2-(6-(3, 5-dichlorophenyl)-l-isopropyl~2-oxo-l, 2-dihydroimidazo[4, 5-b]pyridin-3- yl)acetamide (EXAMPLE 7a) (8 mg, 73%) as a white solid.

Data: ¹H NMR (400 MHz, CDCl₃): δ 8.16 (d, IH), 7.43-7.35 (m, 4H), 6.10 (br t, IH, -NH), 4.76 (septet, IH), 4.62 (s, 2H), 3.26 (q, 2H), 1.56 (d, 6H), 1.47 (m, 2H), 1.30 (m, 2H), 0.88 (t, 3H) ppm; MS (ESI) m/z: 435.0 + 437.0 ([M+H]⁺).

EXAMPLE 8a: N-butyl-2-(l -(cvanomethyl)-6-(3.5-dichlorophenyP)-2-oxo- 1.2- dihydroimidazor4,5-b1pyridin-3-yl)acetarnide

[0100] A mixture of N-butyl-2-(6-(3,5-dichlorophenyl)-2-oxo-l,2- dihydroimidazo[4,5-b]pyridin-3-yl)acetamide (prepared as described above in Example 6a, step a) (24 mg, 0.061 mmol), PS-BEMP (2.2 mmol/g, 83 mg, 0.183 mmol), and bromoacetonitrile (5 μL, 0.0732 mmol) in ACN (0.5 mL) and DMF (0.1 mL) was stirred for 16 h at 23 ⁰C in a tightly capped 1 dram screw-top vial. The mixture was then filtered to remove the PS-BEMP resin rinsing with DCM (2X) and THF (2X) and the combined eluent and rinses were concentrated in vacuo. The crude residue was purified by preparative HPLC to give N-butyl-2-(l-(cyanomethyl)-6-(3, 5-dichlorophenyl)-2-oxo- 1 , 2-dihydroimidazo [4, 5- b]pyridin-3-yl)acetamide (EXAMPLE 8a) (9 mg, 35%).

Data: ¹H NMR (400 MHz, CDCl₃): δ 8.25 (s, IH), 7.50 (s, IH), 7.43-7.37 (m, 3H), 6.38 (br t, IH, -NH), 4.90 (s, 2H), 4.64 (s, 2H), 3.27 (q, 2H), 1.49 (m, 2H), 1.33 (m, 2H), 0.90 (t, 3H) ppm; MS (ESI) m/z: 432.0 + 434.0 ([M+H]⁺).

EXAMPLE 9a: N-butyl-2-(6-(3-chloro-5-fluorophenyn-l-methyl-2-oxo-1.2- dihydroimidazo [4,5 -blpyridin-3 -vPacetamide

a) 2-(6-bromo-l-methyl-2-oxo-l, 2-dihydroimidazo |^"4,5-b^"|pyridin-3-yl)-N-butylacetamide

[0101] Ethyl 2-(6-bromo-l -methyl-2-oxo-l ,2-dihydroimidazo[4,5-b]pyridin-3- yl)acetate (INTERMEDIATE ILl) (60 mg, 0.19 mmol) was reacted with butylamine using the same general procedure described in EXAMPLE 5a, step a, to give 2-(6-bromo-l- methyl-2-oxo-l,2-dihydroimidazo[4,5-b]pyridin-3-yl)-N-butylacetamide (48 mg, 74%). Data: MS (ESI) m/z: 341.3 + 343.1 ([M+H]⁺). b) N-butyl-2-(6-(3-chloro-5-fluorophenyl)-l-methyl-2-oxo-l,2-dihydroimidazof4,5- b]pyridin-3-yl)acetamide

[0102] 2-(6-bromo-l -methyl-2-oxo-l, 2-dihydroimidazo[4,5-b]pyridin-3-yl)-N- butylacetamide (23 mg, 0.068 mmol) was coupled with 3-chloro-5-fluorophenylboronic acid (18 mg, 0.10 mmol) using the same general procedure described in EXAMPLE 5a, step c. Purification of the crude product by preparative HPLC gave N-butyl-2-(6-(3-chloro-5- fluorophenyl)- 1 -methyl-2 -oxo-1 , 2-dihydroimidazo[4, 5-b]pyridin-3-yl)acetamide (EXAMPLE

Po) (15mg, 58%).

Data: ¹H NMR (400 MHz, CDCl₃): δ 8.21 (s, IH), 7.32 (m, 2H), 7.16-7.10 (m, 2H), 6.07

(br t, IH, -NH), 4.65 (s, 2H), 3.50 (s, 3H), 3.28 (q, 2H), 1.49 (pentet, 2H), 1.32 (sextet, 2H),

0.90 (t, 3H) ppm; MS (ESI) m/z: 391.5 + 393.5 ([M+H]⁺).

EXAMPLE 1 Oa: 6-(3-chloro-5-fluorophenyl)-3-(2-(^'5-methoxyisoindolin-2-ylV2-oxoethylV

1 -methyl- 1 H-imidazo[4,5-b^"|pyridin-2(3H)-one

a) 2-(6-bromo-l-methyl-2-oxo-l,2-dihydroimidazo[4,5-b1pyridin-3-yl)acetic acid

[0103] To a suspension of ethyl 2-(6-bromo-l-methyl-2-oxo-l,2- dihydroimidazo[4,5-b]pyridin-3-yl)acetate (INTERMEDIATE ILl) (0.41 g, 1.31 mmol) in MeOH (6 mL), H₂O (2 mL) and THF (2 mL) was added LiOH*H₂O (164 mg, 3.92 mmol) and the reaction mixture was stirred at 23 ⁰C for 0.5 h. The mixture was concentrated in vacuo, partitioned between H₂O and Et₂O. The aqueous phase was acidified with 2 N HCl (aq) to pH3 and then extracted with EtOAc (3X). The organic layers were combined, dried (Na₂SO₄), filtered and concentrated in vacuo to afford 2-(6-bromo-l-methyl-2-oxo-l,2- dihydroimidazo[4,5-b]pyridin-3-yl)acetic acid (374 mg, 100%) which was used without further purification directly in the next step.

Data: ¹H NMR (400 MHz, d₆-DMSO): δ 13.22 (br s, IH, -OH), 8.08 (d, IH), 7.88 (d, IH), 4.55 (s, 2H), 3.37 (s, 3H) ppm; MS (ESI) m/z: 286.1 + 288.1 ([M+H]⁺). b) 6-bromo-3-(2-(5-methoxyisoindolin-2-ylV2-oxoethyl)-l-methyl-lH-imidazo[4,5- blpyridin-2(3H)-one

[0104] To a mixture of 2-(6-bromo-l-methyl-2-oxo-l,2-dihydroimidazo[4,5- b]pyridin-3-yl)acetic acid (368 mg, 1.29 mmol), 5-methoxyisoindoline*HCl (239 mg, 1.29 mmol) and TEA (0.22 mL, 1.55 mmol) in DCM (9 mL) were added EDCI (297 mg, 1.55 mmol) and HOBt* H₂O (290 mg, 1.55 mmol) and the reaction mixture was stirred at 23 ⁰C for 16 h. The mixture was concentrated in vacuo and the crude residue was partitioned between 3:1 DCM//-PrOH and sat. NH₄Cl (aq). The organic phase was washed with sat. NaHCO₃ (aq) (IX) and brine (IX), dried (Na₂SO₄), filtered and concentrated in vacuo. The crude solid was triturated with EtOAc/hexanes and collected by filtration to give 6-bromo-3- (2-(5-methoxyisoindolin-2-yl)-2-oxoethyl)-l -methyl- lH-imidazo[4,5-b]pyridin-2(3H)-one (368 mg, 68%) as a tan solid.

Data: ¹H NMR (400 MHz, d₆-OMSO, 1.1 :1 mixture of amide rotamers): δ 8.06 (d, IH), 7.88 (d, IH), 7.27 (d, IH), 6.96-6.88 (m, 2H), 5.01 and 4.96 (2 s, 2H), 4.81 and 4.81 (2 s, 2H), 4.62 and 4.57 (2 s, 2H), 3.77 and 3.76 (2 s, 3H), 3.39 (s, 3H) ppm; MS (ESI) m/z: All 2 + 419.2 ([M+H]⁺). c) 6-(3 -chloro-5 -fluorophenyl)-3 -(2-(5-methoxyisoindolin-2-yl^*)-2-oxoethyl)- 1 -methyl- 1 H- imidazo[4,5-b]pyridin-2(3H)-one

[0105] 6-bromo-3-(2-(5-methoxyisoindolin-2-yl)-2-oxoethyl)-l-methyl-lH- imidazo[4,5-b]pyridin-2(3H)-one (30 mg, 0.072 mmol) was coupled with 3-chloro-5- fluorophenylboronic acid (18 mg, 0.10 mmol) using the same general procedure described in EXAMPLE 5a, step c. Purification by preparative HPLC gave 6-(3-chloro-5-fluorophenyl)- 3-(2-(5-methoxyisoindolin-2-yl)-2-oxoethyl)-l-methyl-lH-imidazo[4,5-b]pyridin-2(3H)-one (EXAMPLE i føj (31 mg, 91 %).

Data: ¹H NMR (400 MHz, CDCl₃, 1.1 :1 mixture of amide rotamers): δ 8.16 (d, IH), 7.31 (m, 2H), 7.20 (m, IH), 7.14 (m, IH), 7.09 (m, IH), 6.88-6.82 (m, 2H), 4.97 and 4.94 (2 s, 2H), 4.85 (s, 2H), 4.80 and 4.76 (2 s, 2H), 3.83 and 3.81 (2 s, 3H), 3.50 (s, 3H) ppm; MS (ESI) m/z: 467.3+ 469.2 ([M+H]⁺). Similarly prepared were EXAMPLES 10b- 1Od (see Table I) EXAMPLE 1 Ia: 6-O,5-dichlorophenylV3-(2-(7-methoxy-3Λ-dihvdroisoquinolin-2qiL)-viy 2-oxoethylH -methyl- lH-imidazoF4,5-b1pyridin-2(3H)-one

a) Ethyl 2-(6-(3,5-dichlorophenyl)- 1 -methyl-2-oxo-l ,2-dihydroimidazo[4,5-b]pyridin-3- vDacetate

[0106] A mixture of ethyl 2-(6-bromo-l -methyl-2-oxo-l, 2-dihydroimidazo[4, 5- b]pyridin-3-yl)acetate (INTERMEDIATE ILl) (0.50 g, 1.59 mmol), K₃PO₄ (1.01, 4.77 mmol) and 3,5-dichlorophenylboronic acid (455 mg, 2.39 mmol) in toluene (8 mL) was degassed by bubbling argon through for 5 min. To this was added Pd(PPh₃)₄ (92 mg, 0.080 mmol) and the resultant mixture was heated to 90 ⁰C under argon atmosphere for 20 h. The mixture was cooled and partitioned between EtOAc and sat. NaHCO₃ (aq). The aqueous phase was extracted twice more with EtOAc and the organic layers were combined, washed with brine (IX), dried (Na₂SO₄), filtered and concentrated in vacuo. The crude residue was purified by FCC (SiO₂; gradient elution with 10% EtOAc/hexanes to 50% EtOAc/hexanes) to afford ethyl 2-(6-(3,5-dichlorophenyl)-l -methyl-2-oxo-l, 2-dihydroimidazo[4,5-b]pyridin-3- yl)acetate (200 mg, 33%). Data: MS (ESI) m/z: 380.0 + 382.0 ([M+H]⁺). b) 2-(6-(3,5-dichlorophenyl^')-l-methyl-2-oxo-l,2-dihydroimidazo[4,5-b1pyridin-3-yl)acetic acid

[0107] To a suspension of ethyl 2-(6-(3,5-dichlorophenyl)-l-methyl-2-oxo-l,2- dihydroimidazo[4,5-b]pyridin-3-yl)acetate (171 mg, 0.45 mmol) in MeOH (3 mL), H₂O (1 mL) and THF (1 mL) was added LiOH⁺H₂O (57 mg, 1.35 mmol) and the resultant reaction mixture stirred for 0.5 h. Additional THF (1 mL) was added and stirring was continued for 1 h. The mixture was then concentrated in vacuo, diluted with H₂O (40 mL) and washed with Et₂O (1 X 20 mL). The aqueous phase was acidified with 2 N HCl (aq) to pH 3 and extracted with EtOAc (3X). The combined organic layers were dried (Na₂SO₄), filtered and concentrated in vacuo to give 2-(6-(3,5-dichlorophenyl)-l-methyl-2-oxo-l,2- dihydroimidazo[4,5-b]pyridin-3-yl)acetic acid (158 mg, 100%) as a white solid which was used directly in the next step without further purification. c) 6-(3,5-dichlorophenyl)-3-(2-(7-methoxy-3,4-dihvdroisoquinolin-2(lH)-yl)-2-oxoethyl)-l- methyl- 1 H-imidazo [4,5 -b1pyridin-2(3 H)-one

[0108] A mixture of 2-(6-(3,5-dichlorophenyl)-l-methyl-2-oxo-l,2- dihydroimidazo[4,5-b]pyridin-3-yl)acetic acid (39 mg, 0.11 mmol), PS-carbodiimide (Biotage, -1.42 mmol/g, 60 mg, 0.085 mmol) and hydroxybenzotriazole (9 mg, 0.067 mmol) in dichloromethane (0.9 mL) and dimethylformarnide (0.1 mL) was agitated on an orbital shaker for 15 min. 7-methoxy-l,2,3,4-tetrahydroisoquinoline*HCl (15 mg, 0.074 mmol) and TEA (12 μL, 0.089 mmol) were then added and the mixture agitated for an additional 16 h. To the reaction mixture was added MP-carbonate resin (Biotage, -2.9 mmol/g, 255 mg, 0.74 mmol) and this was agitated for an additional 2 h. The mixture was then filtered and the resins rinsed with dichloromethane (3 X 5 mL). The combined eluent was concentrated in vacuo and the crude product purified by preparative HPLC to afford 6-(3,5-dichlorophenyl)- 3-(2-(7-methoxy-3,4-dihydroisoquinolin-2(lH)-yl)-2-oxoethyl)-l-methyl-lH-imidazo[4,5- b]pyridin-2(3H)-one (EXAMPLE Ha) (14 mg, 38%).

Data: ¹H NMR (400 MHz, CDCl₃, 1.5:1 mixture of amide rotamers): δ 8.17 (d, IH), 7.41 (d, 2H), 7.37 (t, IH), 7.32 (m, IH), 7.09 (d, IH), 6.79 (m, IH), 6.67 (m, IH), 4.95 and 4.93 (2 s, 2H), 4.73 and 4.70 (2 s, 2H), 3.84-3.78 (m, 5H), 3.51 (s, 3H), 2.97 and 2.81 (2 t, 2H) ppm;

MS (ESI) m/z: 497.3+ 499.2 ([M+H]⁺).

Similarly prepared was EXAMPLE l ib (see Table I)

EXAMPLE 12a: 7-(4-chloropwidin-2-yl)-4-(2-(5-methoxyisoindolin-2-ylV2-oxoethylV2H- pyrido [3 ,2-bl \ 1 ,4^"|oxazin-3 (4H)-one

a) 2-(7-bromo-3-oxo-2,3-dihydropyrido[3,2-bl[l ,41oxazin-4-yl)acetic acid o

OH

^N N O

[0109] tert-Butyl 2-(7-bromo-3-oxo-2,3-dihydropyrido[3,2-b][l ,4]oxazin-4- yl)acetate (INTERMEDIATE III.l) (200 mg, 0.58 mmol) was treated with 50% TFA/DCM (5 niL) and allowed to stand for 16 h at 23 ⁰C. This was then concentrated in vacuo to give 2-(7-bromo-3-oxo-2,3-dihydropyrido[3,2-b][l,4]oxazin-4-yl)acetic acid (167 mg, 100%) which was used directly in the next step without further purification. b) 7-bromo-4-(2-(5 -methylisoindolin-2-yl)-2-oxoethyl)-2H-pyrido [3 ,2-b] [ 1 ,41oxazin-3 (4H)- one

[0110] 2-(7-bromo-3-oxo-2,3-dihydropyrido[3,2-b][l,4]oxazin-4-yl)acetic acid (47 mg, 0.16 mmol) was coupled with 5-methylisoindoline*HCl (33 mg, 0.20 mmol) using the same general procedure described in EXAMPLE 10a, step b giving 7-bromo-4-(2-(5- methylisoindolin-2-yl)-2-oxoethyl)-2H-pyrido[3,2-b][l,4]oxazin-3(4H)-one which was used directly in the next step without further purification.

Data: MS (ESI) m/z: 402.1 + 404.1 ([M+H]⁺). c) 7-(4-chloropyridin-2-yl)-4-(2-(5-methylisoindolin-2-yl^')-2-oxoethyl)-2H-pyridor3,2- b] \ 1 ,41oxazin-3C4HVone

[0111] A mixture of the crude product from step b above, 4-chloro-2-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (31 mg, 0.20 mmol), CsF (30 mg, 0.20 mmol) in DME (2 mL) was degassed by bubbling argon through for 5 min. To this was added Pd(PPh₃ )₄ (19 mg, 0.016 mmol) and the resultant mixture was heated to 80 ⁰C under argon atmosphere for 72 h. The mixture was cooled to room temperature and then partitioned between EtOAc (3 X 4 mL) and H₂O (4 mL). The combined organic layers were dried (Na₂SO₄), filtered and concentrated in vacuo. The crude residue was purified by FCC (SiO₂; elution with 3:1 EtOAc/hexanes) giving 24 mgs of semipure material which was further purified by preparative HPLC to afford 7-(4-chloropyridin-2-yl)-4-(2-(5-methylisoindolin-2- yl)-2-oxoethyl)-2H-pyrido[3,2-b][l,4]oxazin-3(4H)-one (EXAMPLE 12a) (15 mg, 21% for 2 steps) as a white solid.

Data: ¹H NMR (400 MHz, CDCl₃, mixture of amide rotamers): δ 8.45 (d, IH), 8.19 (d, IH), 7.47 (m, 2H), 7.36 (dd, IH), 7.22-7.13 (m, 3H), 5.02 (s, 2H), 4.98 (s, 2H), 4.86 (s, 2H), 4.81(s, 2H), 2.39 and 2.38 (2 s, 3H) ppm; MS (ESI) m/z: 435.1 + 437.1 ([M+H]⁺). Similarly prepared were EXAMPLES 12b- 12c (see Table I)

EXAMPLE 13a: 7-(5-chloropyridin-3-ylV4-(2-(7-methoxy-3,4-dihydroisoquinolin-2(lH)- vπ-2-oxoethyl)-2H-pyrido[3.2-b][l,41oxazin-3(4H)-one

a) 7-bromo-4-(2-(7-methoxy-3 ,4-dihvdroisoquinolin-2C 1 HV yl>2-oxoethyl)-2H-pyrido F3.2- bi r 1 ,41oxazin-3 (4H)-one

[0112] 2-(7-bromo-3 -oxo-2,3 -dihydropyrido[3 ,2-b] [ 1 ,4]oxazin-4-y l)acetic acid (120 mg, 0.42 mmol), which was prepared using the general procedure described in Example 12a, was coupled with 7-methoxy-l,2,3,4-tetrahydroisoquinoline*HCl (100 mg, 0.50 mmol) using the general procedure described in EXAMPLE 10a, step b giving 7-bromo-4-(2-(7- methoxy-3,4-dihydroisoquinolin-2(lH)-yl)-2-oxoethyl)-2H-pyrido[3,2-b][l,4]oxazin-3(4H)- one (150 mg, 83%) which was used directly in the next step without further purification. Data: MS (ESI) m/z: 432.1 + 434.1 ([M+H]⁺). b) 7-(5-chloropyridin-3 -yl)-4-(2-(7-methoxy-3 ,4-dihvdroisoquinolin-2( 1 H)- yl)-2-oxoethyl)- 2H-pyridor3.2-biri.41oxazin-3(4HVone

[0113] 7-bromo-4-(2-(7-methoxy-3,4-dihydroisoquinolin-2(l H)-yl)-2-oxoethyl)- 2H-pyrido[3,2-b][l,4]oxazin-3(4H)-one (58 mg, 0.13 mmol) was coupled with 5- chloropyridin-3-ylboronic acid (32 mg, 0.40 mmol) using the same general reaction conditions as desribed in Example l la, step a. After the appropriate aqueous work-up the crude material was purified by FCC (SiO₂; elution with 3:1 EtOAc/hexanes) to afford 7-(5- chloropyridin-3-yl)-4-(2-(7-methoxy-3,4-dihydroisoquinolin-2(lH)-yl)-2-oxoethyl)-2H- pyrido[3,2-b][l,4]oxazin-3(4H)-one (EXAMPLE 13a) (9 mg, 15%).

Data: ¹H NMR (400 MHz, CDCl₃, 1.4:1 mixture of amide rotamers): δ 8.64 (d, IH), 8.57 (d, IH), 8.11-8.08 (m, IH), 7.78 (app t, IH), 7.42 (d, IH), 7.12-7.09 (m, IH), 6.83-6.76 (m, IH), 6.71-6.66 (m, IH), 5.07 and 5.06 (2 s, 2H), 4.84 (s, 2H), 4.77 and 4.71 (2 s, 2H), 3.85- 3.79 (m, 2H), 3.82 and 3.78 (2 s, 3H), 2.99 and 2.82 (2 t, 2H) ppm; MS (ESI) m/z: 465.1 + 467.1 ([M+H]⁺).

Similarly prepared were EXAMPLES 13b- 13d (see Table I)

EXAMPLE 14a: 7-(4-chloropyridin-2-yl)-4-(2-(7-methoxy-3 ,4-dihvdroisoquinolin-2( 1 HV yl)-2-oxoethylV2H-pyrido [3 ,2-bl [ 1.41oxazin-3 (4HVone

a) tert-butyl 2-(7-(4-chloropyridin-2-yl)-3-oxo-2,3-dihydropyridor3,2-b][l,41oxazin-4- vQacetate

[0114] tert-Butyl 2-(7-bromo-3-oxo-2,3-dihydropyrido[3,2-b][l,4]oxazin-4- yl)acetate (INTERMEDIATE III.l) (200 mg, 0.58 mmol) and 4-chloro-2-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (110 mg, 0.70 mmol) were coupled following the same general procedure as described for EXAMPLE 12a, step c, except that the reaction was run in THF instead of DME. After the appropriate aqueous work up the crude product was purified by FCC (SiO₂; elution with 4:1 hexanes/EtOAc then 2:1 hexanes/EtOAc) giving 7-bromo-4-(2-(7-methoxy-3,4-dihydroisoquinolin-2(lH)-yl)-2-oxoethyl)-2H-pyrido[3,2- b][l,4]oxazin-3(4H)-one (204 mg, 47%) as a tan solid. Data: MS (ESI) m/z: 376.1 + 377.8 ([M+H]⁺). b) 2-(7-(4-chloropyridin-2-yl)-3-oxo-2,3-dihydropyrido[3,2-b1[l ,4]oxazin-4-yl)acetic acid

[0115] 7-bromo-4-(2-(7-methoxy-3,4-dihydroisoquinolin-2(lH)-yl)-2-oxoethyl)- 2H-pyrido[3,2-b][l,4]oxazin-3(4H)-one (204 mg, 0.54 mmol) was treated with 50% TFA/DCM (5 mL) and allowed to stand for 16 h. This was then concentrated in vacuo giving 2-(7-(4-chloropyridin-2-yl)-3-oxo-2,3-dihydropyrido[3,2-b][l,4]oxazin-4-yl)acetic acid (173 mg, 100%) as a tan solid which was used in the next step without further purification. c) 7-(4-chloropyridin-2-yl^')-4-(2-(^'7-methoxy-3,4-dihvdroisoquinolin-2(^'lH)-yl^')-2-oxoethylV 2H-pyridor3,2-bl[l,41oxazin-3(4HVone

[0116] 2-(7-(4-chloropyridin-2-yl)-3-oxo-2,3-dihydropyrido[3,2-b][l,4]oxazin-4- yl)acetic acid (70 mg, 0.22 mmol) and 7-methoxy-l ,2,3,4-tetrahydroisoquinoline*HCl (52 mg, 0.26 mmol) were coupled using the general procedure described EXAMPLE 10a, step b to afford, after purification by FCC (SiO₂; elution with 3:1 EtOAc/hexanes), 7-(4- chloropyridin-2-yl)-4-(2-(7-methoxy-3,4-dihydroisoquinolin-2(lH)-yl)-2-oxoethyl)-2H- pyrido[3,2-b][l,4]oxazin-3(4H)-one (EXAMPLE 14a) (58 mg, 57%).

Data: ¹H NMR (400 MHz, CDCl₃, 1.4:1 mixture of amide rotamers): δ 8.44 (d, IH), 8.17 and 8.14 (2 d, IH), 7.46 (m, 2H), 7.35 (dd, IH), 7.12-7.09 (m, IH), 6.83-6.76 (m, IH), 6.71- 6.66 (m, IH), 5.07 and 5.06 (2 s, 2H), 4.85 (s, 2H), 4.76 and 4.71 (2 s, 2H), 3.85-3.79 (m, 2H), 3.82 and 3.78 (2 s, 3H), 2.99 and 2.82 (2 t, 2H) ppm; MS (ESI) m/z: 465.0 + 467.0 ([M+H]⁺). Similarly prepared were EXAMPLES 14a- 14c (see Table I)

EXAMPLE 15 a: 7-(3.5-dichlorophenyl)-4-(2-(4-(hvdroxymethyl)piperidin- 1 -ylV2- oxoethylV2H-pyridor3,2-birK41oxazin-3(4H)-one

a) tert-butyl 2-(7-(3,5-dichlorophenyl)-3-oxo-23-dihydropyrido[3,2-b^"|(T,41oxazin-4- vDacetate

[0117] tert-Butyl 2-(7-bromo-3-oxo-2,3-dihydropyrido[3,2-b][l,4]oxazin-4- yl)acetate (INTERMEDIATE III.l) (1.19 g, 3.47 mmol) and 3,5-dichlorophenylboronic acid (1.32 g, 6.94 mmol) were coupled utilizing the general procedure as described for EXAMPLE 11a, step a. After the appropriate aqueous work up, the crude product was purified by FCC (SiO₂; elution with 6:1 hexanes/EtOAc) giving 0.90 g of semipure material which was then further purified by recrystallization from EtOAc/hexanes to afford tert-butyl 2-(7-(3,5-dichlorophenyl)-3-oxo-2,3-dihydropyrido[3,2-b][l,4]oxazin-4-yl)acetate (0.61 g, 0.43 mmol) as a white solid. Data: MS (ESI) m/z: 376.1 + 377.8 ([M+H]⁺). b) 2-(7-(3,5-dichlorophenyl)-3-oxo-2,3-dihvdropyrido[3,2-b^"|[l ,41oxazin-4-yl)acetic acid

[0118] tert-Butyl 2-(7-(3,5-dichlorophenyl)-3-oxo-2,3-dihydropyrido[3,2- b][l,4]oxazin-4-yl)acetate (204 mg, 0.50 mmol) was treated with 4N HCl in dioxane and allowed to stand for 16 h resulting in the formation of a white precipitate. The volatiles were removed in vacuo giving 2-(7-(3,5-dichlorophenyl)-3-oxo-2,3-dihydropyrido[3,2- b][l,4]oxazin-4-yl)acetic acid as a white solid which was used without further purification in the next step. c) 7-(3 ,5-dichlorophenyI>4-(2-(4-(hydroxymethyl)piperidin- 1 -yl)-2-oxoethyl)-2H- pyrido [3 ,2-b] [ 1 ,41oxazin-3 (4HVone

[0119] 2-(7-(3,5-Dichlorophenyl)-3-oxo-2,3-dihydropyrido[3,2-b][l,4]oxazin-4- yl)acetic acid (59 mg, 0.17 mmol) was coupled with 4-piperidinemethanol (21 mg, 0.18 mmol) using the general procedure described in EXAMPLE 10a, step b. The crude product was recrystallized from EtOH to afford 7-(3,5-dichlorophenyl)-4-(2-(4-

(hydroxymethyl)pipeήdin-l-yl)-2-oxoethyl)-2H-pyrido[3,2-b][l,4]oxazin-3(4H)-one

(EXAMPLE 15a) (35 mg, 47%) as a white solid.

Data: mp 215-217 ⁰C (EtOH); ¹H NMR (400 MHz, CDCl₃): δ 8.10 (d, IH), 7.38-7.36 (m,

4H), 4.99 (m, 2H), 4.81 (s, 2H), 4.58 (br d, IH), 3.97 (br d, IH), 3.56, (q, 2H), 3.20 (td, IH),

2.67 (td, IH), 3.87 (br d, IH), 1.86-1.73 (m, 2H), 1.45-1.34 (m, 2H), 1.26-1.16 (m, IH) ppm;

MS (ESI) m/z: 449.9 + 451.8 ([M+H]⁺).

Similarly prepared were EXAMPLES 15a-15d (see Table I)

EXAMPLE 16a: 7-(3-chloro-4-fluorophenylV4-(2-(4-(ethoxymethvnpiperidin- 1 -yl)-2- oxoethyl V2H-pyrido [32-b] [ 1.41oxazin-3(4HVone

a) fer/-butyl 2-(7-(3-chloro-4-fluorophenyl)-3-oxo-2,3-dihydropyridor3,2-b][L4]oxazin-4- vDacetate

[0120] tert-Butyl 2-(7-bromo-3-oxo-2,3-dihydropyrido[3,2-b][l ,4]oxazin-4- yl)acetate (INTERMEDIATE III.l) (2.03 g, 5.92 mmol) was coupled with 3-chloro-4- fluorophenylboronic acid (2.06 g, 1 1.8 mmol) following the general procedure described in EXAMPLE 11a, step a. After the usual work up, the crude product was purified by FCC (SiO₂; elution with 7:1 hexanes/EtOAc) to give tert-butyl 2-(7-(3-chloro-4-fluorophenyl)-3- oxo-2,3-dihydropyrido[3,2-b][l,4]oxazin-4-yl)acetate (1.56 g, 67%) as a white solid.

Data: MS (ESI) m/z: 337.2, 339.2 ([M+H]⁺). b) 2-(7-(3-chloro-4-fluorophenyl)-3-oxo-2,3-dihvdropyrido[3,2-b1[l,4]oxazin-4-yl)acetic acid

[0121] A mixture of tert-butyl 2-(7-(3-chloro-4-fluorophenyl)-3-oxo-2,3- dihydropyrido[3,2-b][l,4]oxazin-4-yl)acetate (1.33 g, 3.39 mmol) in 4M HCl/dioxane (24 mL) was stirred at 23 ⁰C for 36 h. This was then cooled in at 5 ⁰C in a refrigerator for overnight 16 h and the resultant white precipitate was collected by filtration. The filter cake was rinsed with 1 :1 ether/hexane and air dried. The solid was further dried in vacuo to provide 2-(7-(3-chloro-4-fluorophenyl)-3-oxo-2,3-dihydropyrido[3,2-b][l,4]oxazin-4- yl)acetic acid (1.15 g, 100%) as a white solid. This was used in the next step without further purification. c) 7-(3 -chloro-4-fluorophenyl V4-(2-(4-(ethoxymethyl)piperidin- 1 -yl)-2-oxoethyl)-2H- pyrido[3,2-b]|T.4^"|oxazin-3(4H)-one

[0122] A mixture of 2-(7-(3-chloro-4-fluorophenyl)-3-oxo-2,3- dihydropyrido[3,2-b][l,4]oxazin-4-yl)acetic acid (61 mg, 0.18 mmol), EDCI (46 mg, 0.24 mmol) and HOBt*H₂O (30 mg, 0.25 mmol) in DMF/DCM (1 :1, 2 mL) was stirred at 23 ⁰C for 5 min. 4-(ethoxymethyl)piperidine (25 mg, 0.21 mmol) was then added and stirring was continued for 18 h. The reaction mixture was then concentrated in vacuo and the crude residue purified by preparative HPLC directly to provide 7-(3-chloro-4-fluorophenyl)-4-(2- (4-(ethoxymethyl)piperidin-l-yl)-2-oxoethyl)-2H-pyrido[3,2-b][l,4]oxazin-3(4H)-one (EXAMPLE 16a) (20.4 mg, 25%) as a white solid.

Data: IH NMR (400 MHz, CDCl₃): δ 8.07 (d, IH), 7.53 (dd, IH), 7.40-7.33 (m, 2H), 7.21 (t, IH), 4.98 (d, 2H), 4.81 (s, 2H), 4.55 (d, IH), 3.95 (d, IH), 3.49 (q, 2H), 3.31 (m, 2H), 3.19 (td, IH), 2.67 (td, IH), 1.97-1.81 (m, 2H), 1.76 (d, IH), 1.37 (m, IH), 1.22 (m, IH),

1.21 (t, 3H) ppm; MS (ESI) m/z: 462.1 + 464.2 ([M+H]⁺).

Similarly prepared were EXAMPLES 16b- 16f (Table I)

EXAMPLE 17a: 7-(3,5-dichlorophenyl)-4-(2-(4-methylpiperidin-l-ylV2-oxoethylV2H- pyridor3,2-biπ,41oxazin-3(4H)-one

a) tert-butγ\ 2-(7-(3,5-dichlorophenyl)-3-oxo-2,3-dihvdropyrido[3,2-b][l,41oxazin-4- vDacetate

[0123] A mixture of tert-butyl 2-(7-bromo-3-oxo-2,3-dihydropyrido[3,2- b][l,4]oxazin-4-yl)acetate (INTERMEDIATE III.l) (0.15 mg, 0.70 mmol), 3,5- dichlorophenylboronic acid (200 mg, 1.05 mmol) and potassium phosphate (450 mg, 2.10 mmol) in toluene (3 mL) was purged by bubbling argon through for 10 min. To this mixture was added Pd(PPh₃)₄ (84 mg, 0.073 mmol) and the resultant mixture was refluxed with stirring under an argon atmosphere for 16 h. After cooling to room temperature, the mixture was partitioned between EtOAc and NH₄Cl (aq). The organic layer was then washed with water (IX) and brine (IX), dried (MgSO₄), filtered and concentrated in vacuo. The crude residue was purified by FCC to afford tert-butyl 2-(7-(3,5-dichlorophenyl)-3-oxo-2,3- dihydropyrido[3,2-b][l,4]oxazin-4-yl)acetate (200 mg, 70%).

Data: IH NMR (400 MHz, CDCl₃): δ 8.14 (d, IH), 7.38 (m, 4H), 4.79 (s, 2H), 4.79 (s, 2H), 1.48 (s, 9H) ppm; MS (ESI) m/z: 409.2 + 411.2 ([M+H]⁺). b) 2-(7-(3,5-dichlorophenyl)-3-oxo-2,3-dihvdropyrido[3,2-b][l ,41oxazin-4-yl)acetic acid

[0124] ter t-Buty 1 2-(7-(3 ,5 -dichlorophenyl)-3 -oxo-2,3 -dihydropyrido [3,2- b][l,4]oxazin-4-yl)acetate (200 mg, 0.49 mmol) was treated with 4M HCl/dioxane (8 mL) and stirred at 23 ⁰C for 16 h. The volatiles were removed in vacuo to provide 2-(7-(3,5- dichlorophenyl)-3-oxo-2,3-dihydropyrido[3,2-b][l,4]oxazin-4-yl)acetic acid (174 mg, 100%) which was used in the next step without further purification. Data: MS (ESI) m/z: 353.0 + 355.0 ([M+H]⁺). c) 7-(3.5-dichlorophenyl)-4-(2-(4-methylpiperidin-l-yl)-2-oxoethyl)-2H-pyridor3,2- b] [ 1 ,4]oxazin-3 (4HV one

[0125] A mixture of 2-(7-(3,5-dichlorophenyl)-3-oxo-2,3-dihydropyrido[3,2- b][l,4]oxazin-4-yl)acetic acid (0.15 g, 0.42 mmol), PS-carbodiimide (Biotage, -1.42 mmol/g, 37 mg, 0.053 mmol) and HOBt⁺H₂O (8 mg, 0.060 mmol) in DCM (1 mL) and dimethylforamide (0.1 mL) was agitated on an orbital shaker at r.t. for 30 min. A 1 M solution of 4-methylpiperidine (37 μL, 0.037 mmol) was then added, and agitation was continued for 8 h. MP-carbonate (Biotage, ~3.11 mmol/g, 150 mg, 0.2 mmol) was added and agitation was continued for 2 h. The mixture was then filtered to remove the resins rinsing with dichloromethane (3 X 2mL). The eluent was concentrated in vacuo to provide tert-butyl 2-(7-(S, 5-dichlorophenyl)-3-oxo-2, 3 -dihydropyrido [3, 2-bJfl, 4] oxazin-4-yl) acetate (EXAMPLE Ua) (10 mg, 57%).

Data: Data: IH NMR (400 MHz, CDCl₃): δ 8.11 (d, IH), 7.37 (m, 4H), 5.98 (m, 2H), 4.82 (s, 2H), 4.51 (d, IH), 3.90 (d, IH), 3.17 (t, IH), 2.65 (t, IH), 1.84 -1.64 (m, 2H), 1.37 -1.09 (m, 3H), 1.00 (d, 3H) ppm; MS (ESI) m/z: 434.2 + 436.2 ([M+H]⁺). Similarly prepared were EXAMPLES 17b-17au (see Table I)

EXAMPLE 18a: 7-(3,5-dichlorophenylV4-(2-(5-methoxyisoindolin-2-vn-2-oxoethvn-2H- ^pyridor3,2-biri,41oxazin-3⁽4HVone

a) 2-(7-bromo-3-oxo-2,3-dihydropyrido[3,2-b]π ,4]oxazin-4-yDacetic acid

[0126] A mixture tert-butyl 2-(7-bromo-3-oxo-2,3-dihydropyrido[3,2- b][l,4]oxazin-4-yl)acetate (INTERMEDIATE III.1) (565 mg, 1.65 mmol) in 4M HCl/dioxane (10 mL) was stirred at r.t. for 16 h. The volatiles were removed in vacuo to afford 2-(7-bromo-3-oxo-2,3-dihydropyrido[3,2-b][l,4]oxazin-4-yl)acetic acid (450 mg, 98%) as a white solid which was used in the next step without further purification, b) 7-bromo-4-(2-(5 -methoxyisoindolin-2-yl)-2-oxoethyl)-2H-pyrido [3 ,2-b] [ 1 ,4]oxazin-

3(4H)-one

[0127] A mixture of 2-(7-bromo-3-oxo-2,3-dihydropyrido[3,2-b][l,4]oxazin-4- yl)acetic acid (250 mg, 0.87 mmol), PS-carbodiimide (1.05 g, 1.35 mmol) and HOBt*H₂O (200 mg, 1.48 mmol) in DMF (7.5 mL) was agitated on an orbital shaker at r.t. for 30 min. To this was added TEA (0.25 mL, 1.79 mmol) and 5-methoxyisoindoline (140 mg, 0.75 mmol) and agitation on the orbital shaker was continued for 16 h. To the mixture was added MP-carbonate resin (Biotage, — 3.11 mmol/g, 1.5 g, 4.67 mmol) and this was agitated for 2 h. The reaction mixture was then filtered to remove the resins, rinsing with DCM (3X5 mL).

The eluent was concentrated in vacuo and the crude residue purified by FCC (SiO₂; elution with 4:1 hexanes/EtOAc) to provide 7-bromo-4-(2-(5-methoxyisoindolin-2-yl)-2-oxoethyl)-

2H-pyrido[3,2-b][l,4]oxazin-3(4H)-one (290 mg, 79%) as a white solid.

Data: IH NMR (400 MHz, CDCl₃): δ 7.97 (d, IH), 7.39 (d, IH), 7.20 (dd, IH), 6.86 (m,

2H) 4.93 (s, 4H), 4.80 (s, 4H), 3.82 (s, 3H) ppm; MS (ESI) m/z: 418.1 ([M+H]⁺). c) 7-(3.5-dichlorophenylV4-(2-f5-methoxyisoindolin-2-yl)-2-oxoethylV2H-pyrido[3,2- biπ,41oxazin-3(4HVone

[0128] A mixture of 7-bromo-4-(2-(5-methoxyisoindolin-2-yl)-2-oxoethyl)-2H- pyrido[3,2-b][l,4]oxazin-3(4H)-one (200 mg, 0.70 mmol), 3,5-dichlorophenylboronic acid (110 mg, 0.84 mmol) and potassium phosphate (345 mg, 2.10 mmol) in toluene (4 mL) was degassed by bubbling argon through for 15 min. To this was added Pd(PPh₃ )₄ (100 mg, 70 μmol) and the reaction mixture was refluxed with stirring under an argon atmosphere for 16 h. After cooling to room temperature the mixture was filtered through a pad of Celite to remove the solids and the filtrate concentrated in vacuo. The crude residue was purified by preparative HPLC to afford 7-(3,5-dichlorophenyl)-4-(2-(5-methoxyisoindolin-2-yl)-2- oxoethyl)-2H-pyrido[3,2-b][l,4]oxazin-3(4H)-one (EXAMPLE 18a) (42 mg, 12%) as a white solid.

Data: ¹H NMR (400 MHz, CDCl₃): δ 8.38 (d, IH), 7.89 (d, IH), 7.82 (m, 2H), 7.61 (app t, IH), 7.28 (m, IH), 6.96 (m, IH), 6.90 (m, IH), 5.01-4.91 (m, 4H), 4.63 and 4.58 (2 s, 2H), 3.77 and 3.76 (2 s, 2H); MS (ESI) m/z: 484.1 + 486.1 ([M+H]⁺). Similarly prepared were EXAMPLES 18b- 18c (see Table I)

EXAMPLE 19a: 1 -(2-(7-methoxy-3.4-dihydroisoquinolin-2( 1 HV ylV 2-oxoethylV 6-phenyl- 3 ,4-dihvdro- 1 ,8-naphthyridin-2( 1 HVone

a) 2-(6-bromo-2-oxo-3 ,4-dihydro- 1 ,8-naphthyridin- 1 (2H)-yl)acetic acid

[0129] tert-Butyl 2-(6-bromo-2-oxo-3,4-dihydro-l,8-naphthyridin-l(2H)- yl)acetate

[0130] (INTERMEDIATE IV.1) (0.45 g, 1.3 mmol) was treated with 4N HCl/dioxane (1OmL) for 18 hours. The solution was then concentrated in vacuo to yield 2- (6-bromo-2-oxo-3,4-dihydro-l,8-naphthyridin-l(2H)-yl)acetic acid which was used without further purification.

Data: ¹H NMR (400 MHz, d6-DMSO): δ 12.75 (br s, IH), 8.30 (s, IH), 7.90 (s, IH), 4.60

(s, 2H), 3.90 (t, 2H), 3.65 (t, 2H) ppm; MS (ESI) m/z: 285.1 + 287.1 (M+H⁺). b) 6-bromo-l-(2-(7-methoxy-3,4-dihydroisoquinolin-2(lHVyl)-2-oxoethyl)-3,4-dihvdro-l,8- naphthyridin-2( 1 HVone

[0131] To 2-(6-bromo-2-oxo-3,4-dihydro-l,8-naphthyridin-l(2H)-yl)acetic acid (1.7 g, 5.8 mmol) in DCM (15 mL) was added HOBt (0.86 g, 6.4 mmol), EDCI (1.3 g, 6.4 mmol) and Et₃N (1.8 mL, 12.8 mmol). After 5 minutes 7-methoxy-tetrahydroisoquinoline (1.2 g, 5.8 mmol) was added and the mixture was stirred for 18 hours. The mixture was concentrated in vacuo and the residue was taken up in DCM (20 mL) and washed with 0.5N HCl (20 mL) and sat. NaHCO₃ (20 mL). The organic layer was dried over MgSO₄ and concentrated in vacuo to yield 6-bromo-l-(2-(7-methoxy-3,4-dihydroisoquinolin-2(lH)-yl)- 2-oxoethyl)-3,4-dihydro-l,8-naphthyridin-2(lH)-one as a foam. (2.1 g, 5.0 mmol, 85%) Data: ¹H NMR (400 MHz, CDCl₃): δ 8.15 (m, IH), 7.55 (s, IH), 7.05 (d, IH), 6.70-6.80 (m,lH), 6.60-6.70 (d, IH), 5.05 (s, 2H), 4.70-4.60 (d, 2H), 3.85-3.70 (m, 7H), 2.95 (m, 2H), 2.75 (m, 2H) ppm. c) 1 -(2-(7-methoxy-3 ,4-dihydroisoquinolin-2( 1 HVylV2-oxoethvD-6-phenyl-3 ,4-dihydro- 1,8- naphthyridin^C 1 HVone

[0132] 6-bromo-l-(2-(7-methoxy-3,4-dihydroisoquinolin-2(lH)-yl)-2-oxoethyl)- 3,4-dihydro-l,8-naphthyridin-2(lH)-one (40 mg, 0.093 mmol) was coupled with phenylboronic acid using the general procedure described in EXAMPLE Ia, step b. Purification by preparative HPLC gave l-(2-(7-methoxy-3,4-dihydroisoquinolin-2(lH)-yl)-2- oxoethyl)-6-phenyl-3,4-dihydro-l,8-naphthyridin-2(lH)-one (EXAMPLE 19a) (28 mg, 70%). Data: ¹H NMR (400 MHz, CDCl₃, 1.4:1 mixture of amide rotamers): δ 8.33 (m, IH), 7.66 (m, IH), 7.52-7.50 (m, 2H), 7.44 (t, 2H), 7.36 (m, IH), 7.10-7.07 (m, IH), 6.80-6.75 (m, IH), 6.70-6.65 (m, IH), 5.13 and 5.12 (2 s, 2H), 4.78 and 4.71 (2 s, 2H), 3.84-3.81 (m, 2H), 3.82 and 3.77 (2 s, 3H), 3.08-2.79 (m, 6H) ppm; MS (ESI) m/z: 428.2 (M+H⁺). Similarly prepared wasEXAMPLE 19b (see Table I)

EXAMPLE 20a: 6-(3-chiorophenylVl -(2-(5-methoxyisoindolin-2-ylV2-oxoethylV3,4- dihydro- 1 ,8-naphthyridin-2( 1 HVone

a) 6-bromo-l-(2-(5-methoxyisoindolin-2-yl)-2-oxoethyl^*)-3,4-dihydro-l,8-naphthyridin-

2(1 HVone

[0133] To a solution of 2-(6-bromo-2-oxo-3,4-dihydro-l,8-naphthyridin-l(2H)- yl)acetic acid (0.44 g, 1.3 mmol) (prepared as described in EXAMPLE 19a, step a) in DCM (10 niL) was added HOBt (0.19 g, 1.4 mmol), EDCI (0.27 g, 1.4 mmol) and Et₃N (0.6 mL, 4.3 mmol). After 5 minutes 6-methoxy-isoindoline (0.26 g, 1.4 mmol) was added. The solution was stirred at 25 °C for 18 hours. The solution was then concentrated in vacuo and the residue taken up in DCM (20 mL) and washed with 0.5 N HCl (20 mL), 1 N KOH (20 mL) and brine (20 mL). The organic layer was dried over MgSO₄ and concentrated in vacuo to yield 6-bromo-l-(2-(5-methoxyisoindolin-2-yl)-2-oxoethyl)-3,4-dihydro-l,8-naphthyridin- 2(lH)-one as a tan solid. (0.50g, 92%).

Data: ¹H NMR (400 MHz, CDCl₃): δ 8.22 (s, IH), 7.65 (s, IH), 7.20 (d, IH), 6.90 (d,lH), 6.85 (s, IH), 5.00 (s, 2H), 4.90 (d, 2H), 4.75 (d, 2H), 3.85 (s, 3H), 3.00 (m, 2H), 2.85 (m, 2H) ppm. b) 6-(3-chlorophenyl)-l-(2-(5-methoxyisoindolin-2-yl)-2-oxoethyl)-3,4-dihydro-l,8- naphthyridin-2( 1 H)-one

[0134] 6-bromo-l-(2-(5-methoxyisoindolin-2-yl)-2-oxoethyl)-3,4-dihydro-l,8- naphthyridin-2(lH)-one (0.1 g, 0.24 mmol), 3-chlorobenzeneboronic acid (56 mg, 0.36 mmol), potassium carbonate (0.1 g, 0.72 mmol) and tetrakistriphenylphosphine palladium (14 mg, 0.012 mmol) were combined in acetone: water (3 mL, 2:1) and heated at 80⁰C under Ar for 1.5 hours. The solution was then concentrated in vacuo. The residue was then taken up in DCM (10 mL) and washed with water (10 mL). The organic layer was then concentrated in vacuo and the residue purified by preparative HPLC. The resulting oil was then taken up in DCM (10 mL) and washed with 1 N KOH (10 mL). The organic layer was dried over K₂CO₃ and concentrated in vacuo to yield 6-(3-chlorophenyl)-l-(2-(5- methoxyisoindolin-2-yl)-2-oxoethyl)-3, 4-dihydro-l, 8-naphthyridin-2(lH)-one (EXAMPLE 20a) (55 mg, 50%).

Data: ¹H NMR (400 MHz, CDCl₃): δ 8.35 (s, IH), 7.7 (s, IH), 7.50 (s, IH), 7.30-7.40 (m, 3H), 7.20 (d,lH), 6.80-6.85 (m, 2H), 5.10 (s, 2H), 4.95 (d, 2H), 4.75 (d, 2H), 3.85 (s, 3H), 3.10 (m, 2H), 2.85 (m, 2H) ppm; MS (ESI) m/z: 448.1 + 450.1 (M+H⁺) Similarly prepared were EXAMPLES 20b-20i

EXAMPLE 21a: 6-(3 -chloro-4-fluorophenyl)- 1 -(2-(5-methoxyisoindolin-2-yl)-2-oxoethyl)- 3,4-dihydro-l,8-naphthyridin-2(lH)-one

a) tert-butyl 2-(6-(3-chloro-4-fluorophenyl)-2-oxo-3,4-dihvdro-1.8-naphthyridin-l(2HV vDacetate

[0135] A solution tert-Butyl 2-(6-bromo-2-oxo-3,4-dihydro-l,8-naphthyridin- l(2H)-yl)acetate

[0136] (INTERMEDIATE IV.1) (0.20 g, 0.59 mmol), 3-chloro-4- fluorobenzeneboronic acid (0.16 g, 0.89 mmol), potassium carbonate (0.25 g, 1.8 mmol) and tetrakis(triphenylphosphine) palladium (0) (70 mg, 0.061 mmol) were combined in acetonerwater (3 mL, 2:1) and heated at 80°C under Ar for 4 hours. The solution was then concentrated in vacuo. The residue was then taken up in DCM (10 mL) and washed with water (10 mL). The organic layer was then concentrated in vacuo and the residue purified on a silica gel column, eluting with EtOAc:hexanes (1 :1) to yield tert-butyl 2-(6-(3-chloro-4- fluorophenyl)-2-oxo-3,4-dihydro-l,8-naphthyridin-l(2H)-yl)acetate (0.13 g, 56%) as an oil Data: ¹H NMR (400 MHz, CDCl₃): δ 8.30 (s, IH), 7.60 (s, IH), 7.55 (m, IH), 7.35 (m, IH), 7.20 (m, IH), 4.80 (s, 2H), 2.95 (t, 2H), 2.75 (t, 2H), 1.45 (s, 9H) ppm. b) 2-(6-(3-chloro-4-fluorophenyl)-2-oxo-3,4-dihydro- 1 ,8-naphthyridin- 1 (2H)-yl)acetic acid

[0137] tert-Butyl 2-(6-(3-chloro-4-fluorophenyl)-2-oxo-3,4-dihydro- 1 ,8- naphthyridin-l(2H)-yl)acetate was treated with 4N HCl/dioxane for 18 hours. The solution was then concentrated in vacuo to yield 2-(6-(3-chloro-4-fluorophenyl)-2-oxo-3,4-dihydro- l,8-naphthyridin-l(2H)-yl)acetic acid which was used in the next step without further purification. c) 6-(3 -chloro-4-fluorophenyiy 1 -(2-(5-methoxyisoindolin-2-yl)-2-oxoethyl)-3 ,4-dihydro- 1,8- naphthyridin-2( 1 H)-one

[0138] A mixture of the crude product from the previous step, 2-(6-(3-chloro-4- fluorophenyl)-2-oxo-3,4-dihydro-l,8-naphthyridin-l(2H)-yl)acetic acid, EDCI (69 mg, 0.36 mmol), HOBt*H₂O (49 mg, 0.36 mmol) and Et₃N (140 μL, 1.0 mmol) in DCM (4 mL) was stirred for 5 min. Then 6-methoxyisoindoline (74 mg, 0.40 mmol) was added and stirring was continued for 18 h. The solution was concentrated in vacuo and the residue taken up in DCM (5 mL) and washed with 0.5 N HCl (5 mL) and 1 N KOH (5 mL). The organic layer was dried (Na₂SO₄), filtered and concentrated in vacuo and the crude residue purified by FCC (SiO₂; elution with 1 :1 EtOAc/hexanes) to yield 6-(3-chloro-4-fluorophenyl)-l-(2-(5- methoxyisoindolin-2-yl)-2-oxoethyl)-3, 4-dihydro-l, 8-naphthyridin-2(lH)-one (EXAMPLE 21a) (70 mg, 21% for 2 steps)

Data: ¹H NMR (400 MHz, CDCl₃): δ 8.30 (s, IH), 7.60 (s, IH), 7.55 (m, IH), 7.35 (m, IH), 7.25 7.15 (m, 2H), 6.90-6.75 (m, 2H), 5.05 (s, 2H), 4.95 (d, 2H), 4.75 (d, 2H), 3.80 (s, 3H), 3.05 (m, 2H), 2.80 (m, 2H). MS (ESI) m/z: 466.2 + 468.1 (M+H⁺) Similarly prepared were EXAMPLES 21b-21ab (see Table I)

EXAMPLE 22a: N-butyl-2-f6-f3>dichlorophenyl)-2-oxo-3,4-dihvdro-l .8-naphthyridin- 1 (2H)-yl)acetamide

a) tert-butyl 2-(6-(3,5-dichlorophenyl)-2-oxo-3,4-dihydro-l,8-naphthyridin-l(2H^')-yDacetate

[0139] A solution tert-Butyl 2-(6-bromo-2-oxo-3,4-dihydro-l,8-naphthyridin- l(2H)-yl)acetate

(INTERMEDIATE IV.1) (0.64 g, 1.9 mmol), 3,5-dichlorobenzeneboronic acid (0.43 g, 2.3 mmol), potassium carbonate (0.8 g, 5.7 mmol) and tetrakis(triphenylphosphine)palladium (0) (110 mg, 0.095 mmol) were combined in acetone:water (15 mL, 2:1) and heated at 80°C under Ar for 18 hours. The solution was then concentrated in vacuo. The residue was then taken up in DCM (20 mL) and washed with water (20 mL). The organic layer was then concentrated in vacuo and the residue purified on a silica gel column, eluting with EtOAc:hexanes (1 :2) to yield tert-butyl 2-(6-(3,5-dichlorophenyl)-2-oxo-3,4-dihydro-l,8- naphthyridin-l(2H)-yl)acetate as yellow solid. (0.52 g, 67%)

Data: ¹H NMR (400 MHz, CDCl₃): δ 8.35 (s, IH), 7.60 (s, IH), 7.40 (s, 2H), 7.35 (s, IH), 4.80 (s, 2H), 3.05 (t, 2H), 2.8 (t, 2H), 1.45 (s, 9H) ppm; MS (ESI) m/z: 351.4 + 353.2 (MH⁺-

b) 2-(6-(3,5-dichlorophenyl)-2-oxo-3,4-dihvdro-l,8-naphthyridin-l(2H)-yl)acetic acid

[0140] A solution of tert-butyl 2-(6-(3,5-dichlorophenyl)-2-oxo-3,4-dihydro-l,8- naphthyridin-l(2H)-yl)acetate (0.52 g, 1.3 mmol) in DCM (5 niL) was treated with 4N HCl/dioxane (5 mL) for 18 hours. The solution was then concentrated in vacuo and the residue triturated with diethyl ether/hexanes (1:1) to yield 2-(6-(3,5-dichlorophenyl)-2-oxo- 3,4-dihydro-l,8-naphthyridin-l(2H)-yl)acetic acid as a tan solid. (0.45 g, 100%) Data: ¹H NMR (400 MHz, d₆-OMSO): δ 8.65 (s, IH), 8.15 (s, IH), 7.85 (s, 2H), 7.60 (s, IH), 4.70 (s, 2H), 3.0 (t, 2H), 2.75 (t, 2H) ppm; MS (ESI) m/z: 351.4 + 353.2 (M+H⁺). c) N-butyl-2-(6-(3,5-dichlorophenylV2-oxo-3.4-dihvdro-l,8-naphthyridin-l(2H)- vDacetamide

[0141] 2-(6-(3,5-dichlorophenyl)-2-oxo-3,4-dihydro-l,8-naphthyridin-l(2H)- yl)acetic acid, HOBt (10 mg, 0.07 mmol), Et₃N (7 μL, 0.07 mmol), N-butylamine (50 μL of a 1 M solution in DCM) and PS-carbodiimide resin (70 mg, 1.42 mmol/g, 0.10 mmol) were combined in DCM (1 ml) and gently agitated for 6 hours. MP-carbonate resin (160 mg, 3.11 mmol/g) was then added and gently agitated for 18 hours. The solution was then filtered and concentrated in vacuo to yield N-butyl-2-(6-(3,5-dichlorophenyl)-2-oxo-3,4-dihydro-l,8- naphthyridin-l(2H)-yl)acetamide as an oil. (23 mg, 94%)

Data: ¹H NMR (400 MHz, CDCl₃): δ 8.40 (s, IH)₅ 7.65 (s, IH), 7.40 (s, 2H), 7.38 (s, IH), 5.80 (br t, IH), 4.85 (s, 2H), 3.35 (t, 2H), 3.05 (t, 2H), 2.80 (t, 2H), 1.45 (2, 2H), 1.35 (m, 2H), 0.90 (t, 3H) ppm; MS (ESI) m/z: 408.2 + 410.3 (M+H⁺). Similarly prepared was EXAMPLE 22b (see Table I)

EXAMPLE 23 a: 6-(4-chlorophenyl V 1 -f 2-(7-methoxy-3.4-dihydroisoquinolin-2( 1 HVylV2- oxoethyl ^*)- 3 ,4-dihydro- 1 , 8-naphthyridin-2( 1 H)-one

[0142] A mixture of 6-bromo- 1 -(2-(7-methoxy-3 ,4-dihydroisoquinolin-2( 1 H)-yl)- 2-oxoethyl)-3,4-dihydro-l,8-naphthyridin-2(lH)-one (prepared as described in EXAMPLE 25a, steps a and b) (30 mg, 0.070 mmol), 4-chlorophenylboronic acid (16 mg, 0.11 mmol), tetrakis(triphenylphosphine)palladium (0) (9.0 mg, 0.0078 mmol) in a degassed 2 M aqueous solution of sodium carbonate (0.32 mL, 0.63 mmol) and DME (1.3 mL) was heated and stirred in a sealed vessel to 80 ⁰C for 0.5 h. The reaction mixture was then cooled to room temperature, transferred to a separatory funnel and partitioned between 25 mL EtOAc and a saturated aqueous solution of sodium bicarbonate. The organic phase was separated, dried (Na₂SO₄), and concentrated in vacuo. The residue was purified by preparative HPLC to give 6-(4-chlorophenyl)- 1 -(2-(7-methoxy-3 ,4-dihydroisoquinolin-2( 1 H)-yl)-2-oxoethy l)-3 ,4- dihydro-l,8-naphthyridin-2(lH)-one (20 mg, 62%).

Data: ¹H NMR (400 MHz, CDCl₃, mixture of amide rotamers, ratio 1.4 to 1.0): δ 8.30 and 8.28 (2 d, IH), 7.62 (dd, IH), 7.43 (dd, 4H), 7.09 (d, IH), 6.78 (dt, IH), 6.68 (dd, IH), 5.11 (s, 2H), 4.78 and 4.70 (2 s, 2H), 3.84-3.78 (m, 5H), 3.05 (t, 2H), 2.98 (t, IH), 2.86-2.80 (m, 3H) ppm; MS (ESI) m/z: 462.0 + 463.9 ([M+H]⁺). Similarly prepared were EXAMPLES 23b-23i (see Table I)

EXAMPLE 24a: l-(2-(7-methoxy-3.4-dihvdroisoquinolin-2(lHVyl)-2-oxoethyl)-6-

(pyridin-2-yl)-3,4-dihydro-l,8-naphthyridin-2(lH)-one

[0143] A mixture of 6-bromo-l-(2-(7-methoxy-3,4-dihydroisoquinolin-2(lH)-yl)- 2-oxoethyl)-3,4-dihydro-l,8-naphthyridin-2(lH)-one (INTERMEDIATE 25b) (40 mg, 0.093 mmol), 6-phenyl-2-(pyridin-2-yl)-l,3,6,2-dioxazaborocane (75 mg, 0.19 mmol), palladium acetate (3.2 mg, 0.0048 mmol), triphenylphosphine (4.9 mg, 0.019 mmol), copper iodide (7.1 mg, 0.037 mmol), potassium carbonate (26 mg, 0.19 mmol) in degassed THF (1 mL) was stirred and heated in a sealed vessel at 80 ⁰C for 2 h. The reaction mixture was then cooled to room temperature, filtered and purified by preparative HPLC to give l-(2-(7-methoxy-3,4- dihydroisoquinolin-2(lH)-yl)-2-oxoethyl)-6-(pyridin-2-yl)-3,4-dihydro-l,8-naphthyridin- 2(lH)-one (13.7 mg, 34%).

Data: ¹H NMR (400 MHz, CDCl₃, mixture of amide rotamers, ratio 1.4 to 1.0): δ 8.34 and 8.31 (2 d, IH), 7.66 (d, IH), 7.41 (m, IH), 7.29 (d, IH), 7.21 (d, IH), 7.10 (d, IH), 7.06 (ddd, IH), 6.81 and 6.77 (2 dd, IH), 6.70 and 6.66 (2 d, IH), 5.13 and 5.12 (2 s, 2H), 4.79 and 4.71

(2 s, 2H), 3.85-3.80 (m, 2H), 3.82 and 3.78 (2 s, 3H), 3.10-3.03 (m, 2H), 2.99 and 2.81 (2 t,

2H), 2.88-2.82 (m, 2H) ppm; MS (ESI) m/z: 429.1 ([M+H]⁺).

Similarly prepared was EXAMPLE 24b (see Table I)

EXAMPLE 25a: 1 -(2-(7-memoxy-3,4-dihydroisoquinolin-2(lH)-yl)-2-oxoethyl)-6-phenoxy-

3,4-dihvdro- 1 ,8-naphthyridin-2( 1 HVone

a) 6-bromo-l -(2-(7-methoxy-3,4-dihvdroisoquinolin-2(l H)-yl)-2-oxoethyl)-3,4-dihydro-l ,8- naphthyridin-2( 1 H)-one

[0144] To a solution of 2-(6-bromo-2-oxo-3,4-dihydro-l,8-naphthyridin-l(2H)- yl)acetic acid (1.7 g, 5.8 mmol) (prepared as described in EXAMPLE 19a, step a) in DCM (15 mL) was added HOBt (0.86 g, 6.4 mmol), EDCI (1.3 g, 6.4 mmol) and Et₃N (1.8 mL, 12.8 mmol). After 5 minutes 7-methoxy-tetrahydroisoquinoline (1.2 g, 5.8 mmol) was added and the mixture was stirred for 18 hours and concentrated in vacuo. The residue was taken up in DCM (20 mL) and washed with 0.5 N HCl (20 mL) and sat. NaHCO₃ (20 mL). The organic layer was dried over MgSO₄ and concentrated in vacuo to yield 6-bromo-l-(2-(7- methoxy-3,4-dihydroisoquinolin-2(lH)-yl)-2-oxoethyl)-3,4-dihydro-l,8-naphthyridin-2(lH)- one as a foam. (2.1 g, 85%) Data: ¹H NMR (400 MHz, CDCl₃): δ 8.15 (m, IH), 7.55 (s, IH), 7.05 (d, IH), 6.70-6.80 (m,lH), 6.60-6.70 (d, IH), 5.05 (s, 2H), 4.70-4.60 (d, 2H), 3.85-3.70 (m, 7H), 2.95 (m, 2H), 2.75 (m, 2H) ppm. b) 1 -(2-(7-methoxy-3 ,4-dihydroisoquinolin-2( 1 H)-yl)-2-oxoethyl)-6-phenoxy-3 ,4-dihydro- 1 ,8-naphthyridin-2( 1 H)- one

[0145] 6-bromo-l-(2-(7-methoxy-3,4-dihydroisoquinolin-2(lH)-yl)-2-oxoethyl)- 3,4-dihydro-l,8-naphthyridin-2(lH)-one (50 mg, 0.12 mmol), phenol (12 mg, 0.13 mmol), cesium carbonate (1 18 mg, 0.36 mmol) and tetrakis(acetonitrile)copper (II) hexafluorophosphate (45 mg, 0.12 mmol) were combined in dry pyridine (1 mL) and heated to 100°C under Ar for 4 hours. The mixture was then concentrated in vacuo and purified by preparative HPLC to yield l-(2-(7-methoxy-3,4-dihydroisoquinolin-2(lH)-yl)-2-oxoethyl)-6- phenoxy-3,4-dihydro-l,8-naphthyridin-2(lH)-one (EXAMPLE 25a) (17 mg, 32%) as an oil.

Data: ¹H NMR (400 MHz, CDCl₃, mixture of amide rotamers): δ 7.90 (d, IH), 7.35 (m, 2H), 7.20-7.05 (m, 3H), 6.95 (d, 2H), 6.80-6.70 (m, IH), 6.65 (m, IH) 5.05 (s, 2H), 4.75-4.65 (d, 2H), 3.85-3.70 (m, 7H), 2.95 (m, 2H), 2.75 (m, 2H) ppm; MS (ESI) m/z: AAA2 (M+H⁺) Similarly prepared was EXAMPLES 25b-25f (see Table I) EXAMPLE 26a: 4-(^'2-(^'5-methoxyisoindolin-2-yl)-2-oxoethyl)-7-(4-methvbyridin-2-yl)-2H-

Pyridor3.2-biπ.41oxazin-3(4H)-one*HCl

a) tert-butyl 2-(7-(4-methylpyridin-2-yl)-3-oxo-23-dihvdropyridor3,2-biπ,41oxazin-4- yPacetate

[0146] A suspension of tert-Butyl 2-(7-bromo-3-oxo-2,3-dihydropyrido[3,2- b][l,4]oxazin-4-yl)acetate (INTERMEDIATE III.l) (203 mg, 0.59 mmol), 4-methyl-2- pyridine-boronic acid N-phenyldiethanolamine ester (334 mg, 1.18 mmol), PPh₃ (31 mg, 0.12 mmol), Pd(OAc)₂ (20 mg, 0.030 mmol), K₂CO₃ (163 mg, 1.18 mmol) and CuI (45 mg, 0.24 mmol) in THF (2.5 mL) was heated to 80 ⁰C thermally in a tightly sealed 2-5 mL capacity microwave vessel for 24 h. After cooling to room temperature, the mixture was filtered through a short pad of Celite with EtOAc rinses. This was then concentrated in vacuo and the crude residue was purified by FCC (SiO₂; elution with 3:1 hexanes/EtOAc) to give tert- butyl 2-(7-(4-methylpyridin-2-yl)-3-oxo-2,3-dihydropyrido[3,2-b][l,4]oxazin-4-yl)acetate (74 mg, 35%).

Data: MS (ESI) m/z: 356.2 (M+H⁺) b) 2-(7-(4-methylpyridin-2-ylV3-oxo-2,3-dihvdropyrido[3,2-biri.41oxazin-4-vπacetic acid*HCl

[0147] tert-Butyl 2-(7-(4-methylpyridin-2-yl)-3-oxo-2,3-dihydropyrido[3,2- b][l,4]oxazin-4-yl)acetate (74 mg, 0.21 mmol) was treated with 4 N HCl/dioxane (5 mL) and this was allowed to stand for 16 h at room temperature. The volatiles with then removed in vacuo to give 2-(7-(4-methylpyridin-2-yl)-3-oxo-2,3-dihydropyrido[3,2-b][l,4]oxazin-4- yl)acetic acid*HCl which was used directly in the next step without further purification, c) 4-(2-(5-rnethoxyisoindolin-2-yl)-2-oxoethyπ-7-(4-rnethylpyridin-2-ylV2H-pyrido[3.2- biπ,41oxazin-3(4HVone*HCl [0148] 2-(7-(4-methylpyridin-2-yl)-3-oxo-2,3-dihydropyrido[3,2-b][l,4]oxazin-4- yl)acetic acid*HCl from above was couple with 5-methoxyisoindoline*HCl (46 mg, 0.25 mmol) using the same general amide coupling procedure described in EXAMPLE 10a, step b. The crude product thus obtained was purified by FCC (SiO₂; elution with 2:1 EtOAc/hexanes then 3:1 EtOAc/hexanes). The material was then dissolved in EtOH/DCM and to this was added 4 N HCl/dioxane (0.5 mL) with stirring. After stirring for 10 min, the volatiles were removed in vacuo and the crude solid was triturated with Et₂O to afford 4-(2- (5-methoxyisoindolin-2-yl)-2-oxoethyl)-7-(4-methylpyridin-2-yl)-2H-pyrido[3,2- b][l,4]oxazin-3(4H)-one*HCl (EXAMPLE 26a) (64 mg, 66% for 2 steps) as a tan solid. Data: ¹H NMR (400 MHz, CDCl₃, mixture of amide rotamers, ratio 1.1:1.0): δ 8.72 (d, IH), 8.68 (s, IH), 8.16 (d, IH), 7.81 (s, IH), 7.61 (d, IH), 7.22 and 7.20 (2 d, IH), 6.87 (dd, IH), 6.85 and 6.83 (2 d, IH), 5.01 (s, 2H), 4.98 and 4.95 (2 s, 2H), 4.87 (s, 2H), 4.79 and 4.75 (2 s, 2H), 3.83 and 3.82 (2 s, 3H), 2.70 (s, 3H) ppm; MS (ESI) m/z: 431.1 (M+H⁺) Similarly prepared was EXAMPLE 26b (see Table I)

EXAMPLE 27a: 6-butyl- 1 -(2-(7-methoxy-3 ,4-dihydroisoquinolin-2( 1 H)- yl)-2-oxoethyl)- 3 ,4-dihvdro- 1 ,8-naphthyridin-2( 1 HVone

[0149] A 0.5-2.0 mL capacity microwave vessel was charged with 6-bromo-l-(2- (7-methoxy-3,4-dihydroisoquinolin-2(lH)-yl)-2-oxoethyl)-3,4-dihydro-l,8-naphthyridin- 2(lH)-one (prepared as described in EXAMPLE 25a, steps a and b) (40 mg, 0.093 mmol) and Pd(dppf)Cl₂*DCM (8 mg, 0.0093 mmol), flushed with argon and then tightly sealed with a crimp-top septa. To this was added a 0.5 M solution of butylzinc bromide in THF (2 mL) via syringe, and then the mixture was heated to 160 ⁰C in a microwave for 10 min. After cooling to room temperature, the mixture was partitioned between EtOAc (3 X 4 mL) and 0.5 N HCl (aq) (4 mL). The combined organic layers were washed with sat. NaHCO₃ (aq) (5 mL), dried (Na₂SO₄), filtered and concentrated in vacuo. The crude residue was purified by FCC (SiO₂; elution with 2:1 EtOAc/ hexanes then 3:1 EtOAc/hexanes) to afford 6-butyl-l-(2- (7-methoxy-3, 4-dihydroisoquinolin-2(lH)-yl)-2-oxoethyl)-3, 4-dihydro-l, 8-naphthyridin-

2(lH)-one (EXAMPLE 27a) (16 mg, 42%).

Data: ¹H NMR (400 MHz, CDCl₃, mixture of amide rotamers, ratio 1.4:1.0): δ 7.91 (m, IH),

7.26 (m, IH, partially obscured by solvent peak), 7.07 (m, IH), 6.77 (m, IH), 6.66 (m, IH),

5.06 and 5.05 (2 s, 2H), 4.75 and 4.68 (2 s, 2H), 3.83-3.78 (m, 2H), 3.81 and 3.77 (2 s, 3H),

2.95 (m, 3H), 2.79-2.74 (m, 3H), 2.51 (m, 2H), 1.54 (m, 2H), 1.34 (m, 2H), 0.92 (t, 3H) ppm;

MS (ESI) m/z: 431.1 (M+H⁺)

Similarly prepared were EXAMPLES 27b-27c (see Table I)

EXAMPLE 28a 6-cvclopropyl-l-(2-(7-methoxy-3,4-dihvdroisoquinolin-2(lH)-yl)-2- oxoethyl)-3,4-dihvdro-l,8-naphthyridin-2(lH)-one

[0150] Based on Tetrahedron Letters, 23, 2002, 6987-6990 Wallace, D. J. et. al, a mixture of 6-bromo- 1 -(2-(7-methoxy-3 ,4-dihydroisoquinolin-2( 1 H)-yl)-2-oxoethyl)-3 ,4- dihydro-l,8-naphthyridin-2(lH)-one (INTERMEDIATE 25b) (50 mg, 0.12 mmol), 2- cyclopropyl-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (25 mg, 0.15 mmol), palladium acetate (3.9, 0.0058 mmol), potassium phosphate (86 mg, 0.41 mmol), and tricyclohexylphosphine (3.3 mg, 0.012 mmol) in a degassed solution of toluene (1 mL) and water (0.050 mL) was heated and stirred in a sealed vessel at 100 ⁰C for 16 h. The reaction mixture was then cooled to room temperature, transferred to a separatory funnel and partitioned between EtOAc and a saturated aqueous solution of sodium bicarbonate. The organic phase was separated, dried (Na₂SO₄), and concentrated in vacuo. The residue was purified by preparative RP HPLC to give 6-cyclopropyl-l-(2-(7-methoxy-3, 4-dihydroisoquinolin-2(lH)-yl)-2-oxoethyl)-3, 4- dihydro-l,8-naphthyridin-2(lH)-one (EXAMPLE 28a) (21 mg, 46%).

Data: ¹H NMR (400 MHz, CDCl₃, mixture of amide rotamers, ratio 1.6 to 1.0): δ 8.00 and 7.98 (2 d, IH), 7.21 (dd, IH), 7.08 (d, IH), 6.78 (dt, IH), 6.67 (dd, IH), 5.10 (m, 2H), 4.75 and 4.68 (2 s, 2H), 3.81-3.78 (m, 5H), 2.99-2.96 (m, 3H), 2.81-2.78 (m, 3H), 1.85 (m, IH), 0.99 (dt, 2H), 0.67 (dt, 2H) ppm, MS (ESI) m/z: 392.0 ([M+H]⁺). EXAMPLE 29a: 1 -(2-(7-methoxy-3 ,4-dihydroisoquinolin-2f 1 HVvIV 2-oxoethylV 3 A- dihydro- 1 ,8-naphthyridin-2d HVone

[0151] 6-bromo-l-(2-(7-methoxy-3,4-dihydroisoquinolin-2(lH)-yl)-2-oxoethyl)- 3,4-dihydro-l,8-naphthyridin-2(lH)-one (50 mg, 0.12 mmol), piperidine (13 μL, 0.13 mmol), X-PHOS ( 3 mg, 0.0063 mmol), Pd(OAc)₂ (4 mg, 0.0059 mmol), and Cs₂CO₃ (43 mg, 0.14 mmol) were combined in toluene:ter/-butanol (4:1, 0.50 mL). The mixture was heated at 7O⁰C under Ar for 18 hours. The mixture was then concentrated in vacuo, taken up in DCM (5 mL) and washed with sat NaHCO₃ (5 mL). The organic layer was then concentrated in vacuo and the residue purified by preparative HPLC to yield l-(2-(7-methoxy-3,4- dihydroisoquinolin-2(lH)-yl)-2-oxoethyl)-3,4-dihydro-l,8-naphthyridin-2(lH)-one (EXAMPLE 29a) as an undesired byproduct.

Data: ¹H NMR (400 MHz, CDCl₃, mixture of amide rotamers): δ 8.15-8.11 (m, 1 H), 7.49 (d, 1 H), 7.08 (d, 1 H), 6.92 (dd, 1 H), 6.79-6.74 (m, 1 H), 6.66 (d, 1 H), 5.10 (s, 2 H), 4.76 and 4.68 (s, 2 H), 3.80-3.76 (m, 5 H), 3.00-2.96 (m, 3 H), 2.81-2.78 (m, 3 H)) ppm; MS (ESI) m/z: 352.2 (M+H⁺).

EXAMPLE 30a: 7-bromo-4-(2-(7-hvdroxy-3,4-dihvdroisoquinolin-2(l HVylV2-oxoethylV 2H-pyridor3,2-biri,41oxazin-3(4HVone

[0152] 2-(7-bromo-3-oxo-2,3-dihydropyrido[3,2-b][l ,4]oxazin-4-yl)acetic acid (200 mg, 0.70 mmol), which was prepared using the general procedure described in Example 12a, was coupled with l,2,3,4-tetrahydroisoquinolin-7-ol*HBr (192 mg, 0.84 mmol) using the general procedure described in EXAMPLE 10a, step b. The crude product was purified by FCC (SiO2; elution with 2% MeOH/DCM) to afford 7-bromo-4-(2-(7-hydroxy-3,4- dihydroisoquinolin-2( 1 H)-yl)-2-oxoethyl)-2H-pyrido[3 ,2-b] [ 1 ,4]oxazin-3 (4H)-one (228 mg, 78%).

Data: IH NMR (400 MHz, CDC13, mixture of amide rotamers, ratio 1.8:1.0): δ 7.93 (d, IH), 7.36 (d, IH), 7.01-6.97 (m, IH), 6.67 and 6.61 (m, IH), 6.56 (m, IH), 6.16 and 5.64 (2 s, IH), 5.30 (s, 2H), 4.98 (s, 2H), 4.81 and 4.79 (2 s, 2H), 4.65 and 4.61 (2 s, 2H), 3.79 and 3.75 (2 t, 2H), 2.92 and 2.77 (2 t, 2H) ppm; MS (ESI) mix: 418.0 + 420.0 ([M+H]+). EXAMPLE 31 a: 7-bromo-4-(2-(7-ethoxy-3 ,4-dihydroisoquinolin-2( 1 H)-yl)-2-oxoethyl)-2H- pyrido[3,2-b][l,4]oxazin-3(4H)-one

[0153] PS-TBD resin (255 mg, 1.24 mmol/g, 3 eq) was incubated with a solution of 7-bromo-4-(2-(7-hydroxy-3,4-dihydroisoquinolin-2(lH)-yl)-2-oxoethyl)-2H-pyrido[3,2- b][l,4]oxazin-3(4H)-one (44 mg, 0.11 mmol) in THF (0.5 mL) for 1 h. A solution of ethyl iodide in THF (0.25 M, 0.38 mL, 1 eq) was added followed by the addition of additional THF (1 mL). The reaction mixture was stirred gently for 16 h at ambient temperature. More ethyl iodide in THF (0.25 M, 0.38 mL, 1 eq) was added and the mixture was stirred at ambient temperature for an additional 24 h. The reaction mixture was then filtered to remove the PS-TBD resin, rinsing with small portions of DCM. The filtrate was concentrated in vacuo and the crude residue was taken up in EtOAc (4 mL). This was filtered through an isolute HM-N SPE column (3 mL capacity) prewetted with 1 N NaOH (aq) (2 mL), collecting the eluent by gravity filtration. The SPE column was eluted with additional EtOAc (2 X 4 mL). The combined eluents were concentrated in vacuo and the crude residue purified by FCC (SiO2; elution with 2:1 hexanes/EtOAc) to provide 7-bromo-4-(2-(7-ethoxy- 3 ,4-dihydroisoquinolin-2( 1 H)-yl)-2-oxoethyl)-2H-pyrido [3 ,2-b] [ 1 ,4]oxazin-3 (4H)-one (2 mg, 4%).

Data: IH NMR (400 MHz, CDC13, mixture of amide rotamers, ratio 1.4:1.0): δ 7.96 and 7.94 (2 d, IH), 7.38 (d, IH), 7.09-7.06 (m, IH), 6.80-6.74 (m, IH), 6.67 (m, IH), 4.99 and 4.98 (2 s, 2H), 4.78 (s, 2H), 4.71 and 4.68 (2 s, 2H), 4.03 and 4.00 (2 q, 2H), 3.81 and 3.77 (2 t, 2H), 2.96 and 2.80 (2 t, 2H), 1.42 and 1.39 (2 t, 3H) ppm; MS (ESI) m/z: 446 + 448 ([M+H]+). Similarly prepared was EXAMPLE 31b (see Table I) EP2 Antagonist Assay

[0154] The ability of compounds to antagonize EP2 was assessed using a cell- based, functional assay. In this assay, cells that over-express EP2 were treated with PGE₂ in the absence and presence of several concentrations of the compounds, and cAMP responses were measured using a LANCE® cAMP Detection Kit (PerkinElmer Life and Analytical Sciences, Inc., Waltham, MA). The assay utilized derivatives of 293EBNA cells (Invitrogen Corp., Carlsbad, CA) into which an episomal expression vector containing the human EP2 gene has been previously transfected. The cells were maintained in flasks containing DMEM supplemented with 10% heat inactivated fetal calf serum, 100 units/ml penicillin, 100 μg/ml streptomycin, 2 mM GlutaMAX-I (Invitrogen) and 250 μg/ml Hygromycin.

[0155] To perform the assay, cells were harvested using a Versene-containing cell dissociation buffer and were resuspended at a concentration of 2.5xlO⁵ cells/ml in Ix HBSS containing 5mM HEPES, 0.1% bovine serum albumin and 1% dimethyl sulfoxide (Buffer A). Ten microliters of cells were added to each well of a 384- well assay plate, followed by lOμl of test compound, diluted in Buffer A. Ten microliters of Buffer A containing 0.549nM PGE2, 1% anti-cAMP antibody (included in Perkin Elmer LANCE™ cAMP Kit) and 120 μM Rolipram was then added to each well, and the assay plate was incubated for 1 hour at 25⁰C. After the incubation, lOμl of Detection Buffer (included in the kit) was added to each well, and the assay plate was incubated for a further 3 hours at 25°C. After the 3 hour incubation, the assay plate was read in an appropriate instrument (e.g., the PerkinElmer Victor, EnVision or ViewLux) (excitation at 320 or 340 nm; emission at 615 and 665 nm).

[0156] Some comparative examples are shown below. All of the IC₅₀ ⁵S for EP2 are below 10 μM. Potency of compound is further divided into three groups: +++, IC₅₀ < 10OnM; ++, IC₅₀ > 10OnM to < 1 μM; +, IC₅₀ > 1 μM to < 10 μM.

(m, (m,

t, (m, (m,

(br (m, ppm

(s,

(t, (m,

(s, (d,

t, (s,

( (s,

(m, (2 (2 1,

(d, (s,

3H)

(m,

IH),

(m, 1

0.90

t, (m, (m,

(s,

4.50

t, (m (t,

(m,

(d, 4.98

IH),

4.82 3H)

(s,

(s, (s,

(m,

(2

(2 s, (

1

2H)

(s, (2

(2 (2 (2 s, (

(s, (m,

4.78

2H),

(2

and 2H)

(2

4.74 (2

(2 s, 2H), 2H)

(2

(2 s,

(2 (2 and 4.72

(2

(2 s, (2

(s,

(s,

(s,

(2 (m,

IH), (2

s, and

(2

4.82 3H)

(s,

(s, s, 2H), 1.0):

4.77 (2

m,

(m,

(dd, s, 2H), 1.42

4.81 and

(2

d, 2H), (2

(2

4.81

ppm

(s,

(2 and (2

(2 m,

(2 (t,

ppm

(2

(2

(2

7.83 dd,

s, (2

7.69 dd,

s, (2

m,

s, (2

(2 d,

Claims

WHAT IS CLAIMED IS:

1. A compound of formula Ia or Ib, and pharmaceutically acceptable salts thereof:

Ia Ib wherein

A is selected from the group consisting of oxygen and CH₂;

R¹ is selected from the group consisting of hydrogen and (C₁-C₆) alkyl optionally substituted with fluorine, (Ci-C₆) alkoxyl, (Ci-C₆) haloalkoxyl, hydroxyl, cyano, pyridinyl or (Ci-C₆) haloalkyl, with the proviso that R¹ cannot be hydroxymethyl;

R^4a is selected from a group consisting of a) hydrogen, b) halogen, c) cyano, d) hydroxyl, e) (C₁-C₆) alkyl optionally substituted with halogen or alkoxyl, f) (C₁-C₆) alkoxyl optionally substituted with halogen, g) aryloxyl, heterocyclyl, and aryl, wherein each aryloxyl, heterocyclyl or aryl is optionally substituted with one or more of halogen, cyano, (C]-C₆) alkyl, (Ci-C₆) alkoxyl, (Cj-C₆) haloalkyl, (C₁-C₆) haloalkoxyl or cyanomethyl, with the proviso that R^4a is not pyridinyl or ortho- substituted phenyl; R^4b is selected from a group consisting of a) hydrogen, b) halogen, c) cyano, d) hydroxy 1, e) (Ci-C₆) alkyl optionally substituted with halogen or alkoxyl, f) (C₁-C₆) alkoxyl optionally substituted with halogen, g) aryloxyl, heterocyclyl, and aryl, wherein each aryloxyl, heterocyclyl or aryl is optionally substituted with one or more of halogen, cyano, (Ci-C₆) alkyl, (C₁-C₆) alkoxyl, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxyl or cyanomethyl;

R⁵ is selected from the group consiting of H or (Ci-C₆) alkyl;

R⁶ is selected from the group consiting of H, (CH₂)_nR⁷ and (Ci-C₆) alkyl optionally substituted with hydroxyl, alkoxyl, amino, alkylthio, cyano or halogen, or, when taken together with the nitrogen to which they are attached, R⁵ and R⁶ form a 4-12 membered, optionally substituted monocyclic or bicyclic nitrogen heterocycle; n is 0, 1 or 2; and

R⁷ is selected from the group consisting of optionally substituted carbocycle or heterocycle; with the proviso that when R⁵ and R⁶, together with the nitrogen to which they are attached, form a monocycle, then the monocycle is not substituted with phenyl.

2. A compound according to claim 1 wherein A is CH₂.

3. A compound according to claim 1 wherein A is oxygen.

4. A compound according to any one of claims 1 to 3 wherein R¹ is (Ci-C₆) alkyl.

5. A compound according to any one of claims 1 to 4 wherein R^4a or R^4b is optionally substituted aryl.

6. A compound according to claim 5 wherein R^4a or R is optionally substituted phenyl.

7. A compound according to claim 5 wherein R^4b is optionally substituted pyridinyl.

8. A compound according to any one of claims 1 to 4 wherein R^4a or R^4b is optionally substituted (Ci-C₆) alkyl.

9. A compound according to any one of claims 1 to 4 wherein R^4a or R^4b is optionally substituted aryloxyl.

10. A compound according to claim 5 wherein the aryl is optionally substituted with a substituent chosen from one or more of (Ci-C₆) alkyl, halogen, (Ci-C₆) alkoxyl and cyano.

11. A compound according to any of claims 1 to 10 where at least one of R⁵ and R⁶ is not hydrogen.

12. A compound according to any of claims 1 to 10 wherein R⁵ and R⁶ form a 4- to 12-membered, optionally substituted monocyclic or bicyclic nitrogen heterocycle.

13. A compound according to claim 12 wherein the heterocycle is chosen from the group consisting of

wherein R and R are each independently chosen from the group consisting of hydrogen, alkoxyalkyl, alkoxyl, hydroxyl, alkyl, pyridinyl, pyrimidinyl, pyrazinyl, alkylaminoalkyl, optionally substituted phenyl, halogen, hydroxyalkyl and haloalkyl;

R¹⁰ is chosen from acyl, hydrogen, aryl optionally substituted with halogen, alkoxyl or (Ci-

C₆) alkyl, heterocyclyl optionally substituted with halogen, alkoxyl or (C)-C₆) alkyl, and

(Ci-C₆) alkyl optionally substituted with halogen or alkoxyl, with the proviso that R¹⁰ cannot be phenyl or alkoxy methyl; and

R¹¹ is chosen from the group consisting of hydrogen, alkoxyalkyl, alkoxyl, hydroxyl, alkyl, pyridinyl, pyrimidinyl, pyrazinyl, alkylaminoalkyl, halogen, hydroxyalkyl and haloalkyl.

14. A compound according to claim 13 wherein the heterocycle is chosen from

wherein R¹¹ is hydroxyl, (C₁-C₆) alkoxyl, (C₁-C₆) alkyl or alkoxyalkyl; and R⁹ is hydrogen.

15. A compound according to claim 14 wherein the heterocycle is

wherein q is zero or one.

16. A compound according to claim 11 wherein R⁵ is hydrogen and R⁶ is optionally substituted (C₁-C₆) alkyl.

17. A compound according to claim 11 wherein R⁵ is hydrogen and R⁶ is (CH₂)_nR⁷.

18. A compound according to claim 17 wherein n is one and R⁷ is chosen from the group consisting of heterocycle and phenyl, each optionally substituted with one or more of halogen, (Ci-C₆) alkyl, (C]-C₆) alkoxyl or hydroxyl.

19. A compound according to claim 18 wherein the phenyl is optionally substituted with one or more (CrC₆) alkoxyl.

20. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to any one of claims 1 to 19

21. Use of a compound according to any of claims 1-19 for treating a disorder which is dependent upon inhibition OfEP₂.

22. The use according to claim 21 wherein said disorder is a PGE₂-mediated inflammatory pain condition.

23. The use according to claim 22 wherein said disorder is selected from osteoarthritis, acute gout, inflammatory arthropathy, dysmenorrhoea, endometriosis, headache, migraine, postoperative pain, back pain, sciatica, sprains, strains, rheumatism, dental pain, kidney stones and fever.

24. The use according to claim 23 wherein said inflammatory arthropathy is chosen from ankylosing spondylitis, psoriatic arthritis and Reiter's syndrome.

25. The use according to claim 21 wherein said disorder is chosen from the group consisting of Alzheimer's disease, multiple sclerosis, elevated intraocular pressure and fertility disorders.

26. The use of a compound according to any one of claims 1 to 19 for treating a PGE₂-mediated inflammatory pain condition.

27. A compound selected from the grouip consisting of: N~butyl-2-(l-ethyl-2-oxo-6-phenyl-l,2-dihydroimidazo[4,5-bJpyridin-3- yl)acetamide,

N-butyl-2-(l-ethyl-6-(3-methoxyphenyl)-2-oxo-l,2-dihydroimidazo[4,5- b]pyridin-3 -yl)acetamide,

N-butyl-2-(l-ethyl-2-oxo-6-m-tolyl-l,2-dihydroimidazo[4,5-b]pyridin-3- yl)acetamide,

N-butyl-2-(l-ethyl-2-oxo-6-(3-(trifluoromethoxy)phenyl)-l,2- dihydroimidazo[4,5-b]pyridin-3-yl)acetamide,

N-butyl-2-(l-ethyl-2-oxo-6-p-tolyl-l,2-dihydroimidazo[4,5-b]pyridin-3- yl)acetamide,

N-butyl-2-( 1 -ethyl-2-oxo-6-(3-(trifluoromethyl)phenyl)- 1 ,2- dihydroimidazo[4,5-b]pyridin-3-yl)acetamide,

N-butyl-2-(l-ethyl-6-(4-fluorophenyl)-2-oxo-l,2-dihydroimidazo[4,5- b]pyridin-3-yl)acetamide,

N-butyl-2-(6-(3-(cyanomethyl)phenyl)- 1 -ethyl-2-oxo- 1 ,2- dihydroimidazo[4,5-b]pyridin-3-yl)acetamide,

N-butyl-2-(6-(2-chloropyridin-4-yl)-l -ethyl-2-oxo- l,2-dihydroimidazo[4,5- b]pyridin-3 -yl)acetamide ,

N-butyl-2-(6-(3,4-dichlorophenyl)-l-ethyl-2-oxo-l,2-dihydroimidazo[4,5- b]pyridin-3 -yl)acetamide,

N-butyl-2-(6-(3 -cyanophenyl)- 1 -ethyl-2-oxo- 1 ,2-dihydroimidazo[4,5 - b]pyridin-3-yl)acetamide, N-butyl-2-(6-(3 -chlorophenyl)- 1 -ethyl-2-oxo- 1 ,2-dihydroimidazo [4,5 - b]pyridin-3 -yl)acetamide,

N-butyl-2-(6-(3-chloro-5-fluorophenyl)- 1 -ethyl-2-oxo- 1 ,2- dihydroimidazo [4, 5 -b]pyridin-3 -yl)acetamide,

N-butyl-2-(l-ethyl-6-(fiiran-3-yl)-2-oxo-l,2-dihydroimidazo[4,5-b]pyridin- 3-yl)acetamide,

N-butyl-2-( 1 -ethyl-2-oxo-6-(thiophen-3 -yl)- 1 ,2-dihydroimidazo[4,5 - b]pyridin-3 -yl)acetamide,

2-(6-(3 ,5-dichlorophenyl)- 1 -ethyl-2-oxo- 1 ,2-dihydroimidazo [4,5 -b]pyridin- 3 -y l)-N-(3 -hydroxy-3 -methylbutyl)acetamide,

N-butyl-2-(6-(4-chlorophenyl)-l-ethyl-2-oxo-l,2-dihydroimidazo[4,5- b]pyridin-3-yl)acetamide,

N-butyl-2-(l-ethyl-6-(3-fluorophenyl)-2-oxo-l,2-dihydroimidazo[4,5- b]pyridin-3-yl)acetamide,

N-butyl-2-(6-(3,5-difluorophenyl)-l -ethyl-2-oxo- 1 ,2-dihydroimidazo [4,5- b]pyridin-3 -yl)acetamide,

N-(2-cyclopropylethyl)-2-(6-(3 ,5-dichlorophenyl)- 1 -ethyl-2-oxo- 1 ,2- dihydroimidazo [4,5 -b]pyridin-3 -yl)acetamide,

N-(4-methylbenzyl)-2-(6-(3,5-dichlorophenyl)-l-methyl-2-oxo-l,2- dihydroimidazo[4,5-b]pyridin-3-yl)acetamide,

3-(2-(azepan-l-yl)-2-oxoethyl)-6-(3,5-dichlorophenyl)-l-methyl-lH- imidazo[4,5-b]pyridin-2(3H)-one,

N-(4-hydroxybenzyl)-2-(6-(3 ,5-dichlorophenyl)- 1 -methyl-2-oxo- 1 ,2- dihydroimidazo[4,5-b]pyridin-3-yl)acetamide,

6-(3 , 5 -dichloropheny I)- 1 -methyl-3 -(2-oxo-2-(pyrrolidin- 1 -yl)ethyl)- 1 H- imidazo [4,5 -b]pyridin-2(3 H)-one,

N-(4-methoxyphenethyl)-2-(6-(3,5-dichlorophenyl)-l-methyl-2-oxo-l,2- dihydroimidazo[4,5-b]pyridin-3-yl)acetamide, '

6-(3,5-dichlorophenyl)-l-methyl-3-(2-(4-methylpiperidin-l-yl)-2-oxoethyl)- lH-imidazo[4,5-b]pyridin-2(3H)-one, 6-(3 ,5-dichlorophenyl)-3 -(2-(isoindolin-2-yl)-2-oxoethy I)- 1 -methyl- 1 H- imidazo[4,5-b]pyridin-2(3H)-one,

N-(4-(methylthio)benzyl)-2-(6-(3,5-dichlorophenyl)-l-methyl-2-oxo-l,2- dihydroimidazo[4,5-b]pyridin-3-yl)acetamide,

N-(3-methoxybenzyl)-2-(6-(3,5-dichlorophenyl)-l-methyl-2-oxo-l,2- dihydroimidazo [4,5 -b]pyridin-3 -yl)acetamide,

N-(4-fluorobenzyl)-2-(6-(3 ,5 -dichlorophenyl)- 1 -methyl-2-oxo- 1 ,2- dihydroimidazo [4,5 -b]pyridin-3 -yl)acetamide,

2-(6-(3, 5 -dichlorophenyl)- 1 -methyl-2-oxo- 1, 2-dihydroimidazo[4,5- b]pyridin-3-yl)-N-((5-methylfuran-2-yl)methyl)acetamide_s

N-(2-methoxybenzyl)-2-(6-(3,5-dichlorophenyl)- 1 -methyl-2-oxo- 1 ,2- dihydroimidazo[4,5-b]pyridin-3-yl)acetamide,

N-(benzo[d] [ 1 ,3 ]dioxol-5-ylmethyl)-2-(6-(3,5-dichlorophenyl)- 1 -methyl-2- oxo-l,2-dihydroimidazo[4,5-b]pyridin-3-yl)acetamide,

6-(3 ,5-dichlorophenyl)-3-(2-(4-methoxypiperidin- 1 -yl)-2-oxoethyl)- 1 - methyl- 1 H-imidazo [4,5 -b]pyridin-2(3 H)-one,

6-(3,5-dichlorophenyl)-3-(2-(3,4-dihydroisoquinolin-2(lH)-yl)-2-oxoethyl)- 1 -methyl- 1 H-imidazo[4,5-b]pyridin-2(3H)-one,

2-(6-(3 , 5 -dichlorophenyl)- 1 -methyl-2-oxo- 1 ,2-dihydroimidazo [4,5- b]pyridin-3-yl)-N-(furan-2-ylmethyl)acetamide,

2-(6-(3 ,5 -dichlorophenyl)- 1 -methyl-2-oxo- 1 ,2-dihydroimidazo [4,5 - b]pyridin-3-yl)-N-((6-methoxypyridin-3-yl)methyl)acetamide,

2-(6-(3,5-dichlorophenyl)-l-methyl-2-oxo-l,2-dihydroimidazo[4,5- b]pyridin-3-yl)-N-phenylacetamide,

2-(6-(3 ,5 -dichlorophenyl)- 1 -methyl-2-oxo- 1 ,2-dihydroimidazo[4,5 - b]pyridin-3-yl)-N-(pyridin-4-ylmethyl)acetamide,

2-(6-(3,5-dichlorophenyl)-l-ethyl-2-oxo-l,2-dihydroimidazo[4,5-b]pyridin- 3-yl)-N-isopropylacetamide,

2-(6-(3,5-dichlorophenyl)-l-methyl-2-oxo-l,2-dihydroimidazo[4,5- b]pyridin-3 -yl)-N-(3 -hydroxypropyl)acetamide, N-(2-cyclopropylethyl)-2-(6-(3 ,5-dichlorophenyl)- 1 -methyl-2-oxo- 1 ,2- dihydroimidazo[4,5-b]pyridin-3-yl)acetamide,

N-butyl-2-(6-(3,5-dichlorophenyl)-l-ethyl-2-oxo-l,2-dihydroimidazo[4,5- b]pyridin-3-yl)-N-methylacetamide,

2-(6-(3,5-dichlorophenyl)-l-ethyl-2-oxo-l,2-dihydroimidazo[4,5-b]pyridin- 3-yl)-N-isobutylacetamide,

2-(6-(3 ,5-dichlorophenyl)- 1 -ethyl-2-oxo- 1 ,2-dihydroimidazo [4,5 -bjpyridin- 3-yl)-N-(4,4,4-trifluorobutyl)acetamide,

2-(6-(3,5-dichlorophenyl)-l-ethyl-2-oxo-l,2-dihydroimidazo[4,5-b]pyridin- 3-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide,

2-(6-(3,5-dichlorophenyl)-l-ethyl-2-oxo-l,2-dihydroimidazo[4,5-b]pyridin- 3-yl)-N-(3-methoxypropyl)acetamide,

2-(6-(3,5-dichlorophenyl)-l-ethyl-2-oxo-l,2-dihydroimidazo[4,5-b]pyridin- 3-yl)-N-propylacetamide,

N-(4-aminobutyl)-2-(6-(3,5-dichlorophenyl)-l-ethyl-2-oxo-l,2- dihydroimidazo[4,5-b]pyridin-3-yl)acetamide,

N-(cyclohexylmethyl)-2-(6-(3,5-dichlorophenyl)-l-ethyl-2-oxo-l,2- dihydroimidazo[4,5-b]pyridin-3-yl)acetamide,

2-(6-(3,5-dichlorophenyl)-l-ethyl-2-oxo-l,2-dihydroimidazo[4,5-b]pyridin- 3 -y l)-N-isopentylacetamide,

N-butyl-2-(6-(3,5-dichlorophenyl)-2-oxo-l-propyl-l,2-dihydroimidazo[4,5- b]pyridin-3 -yl)acetamide,

N-butyl-2-(6-(3,5-dichlorophenyl)-l-methyl-2-oxo-l,2-dihydroimidazo[4,5- b]pyridin-3 -yl)acetamide,

N-butyl-2-(6-(3 ,5-dichlorophenyl)- 1 -isobutyl-2-oxo- 1 ,2- dihydroimidazo [4,5 -b]pyridin-3 -yl)acetamide,

N-butyl-2-(6-(3 ,5-dichlorophenyl)- 1 -(2-hydroxyethyl)-2-oxo- 1 ,2- dihydroimidazo[4,5-b]pyridin-3-yl)acetamide,

N-butyl-2-(6-(3,5-dichlorophenyl)-2-oxo-l-(2,2,2-trifluoroethyl)-l,2- dihydroimidazo[4,5-b]pyridin-3-yl)acetamide, N-butyl-2-(6-(3,5-dichlorophenyl)-l-isopropyl-2-oxo-l,2- dihydroimidazo[4,5-b]pyridin-3-yl)acetamide,

N-butyl-2-( 1 -(cyanomethyl)-6-(3 ,5-dichlorophenyl)-2-oxo- 1 ,2- dihydroimidazo [4,5 -b]pyridin-3 -yl)acetamide,

N-butyl-2-(6-(3-chloro-5-fluorophenyl)- 1 -methyl-2-oxo- 1 ,2- dihydroimidazo[4,5-b]pyridin-3-yl)acetamide,

6-(3-chloro-5-fluorophenyl)-3-(2-(5-niethoxyisoindolin-2-yl)-2-oxoethyl)- 1 -methyl- 1 H-imidazo [4,5 -b]pyridin-2(3 H)-one,

6-(3-chloro-4-fluorophenyl)-3-(2-(5-methoxyisoindolin-2-yl)-2-oxoethyl)- l-methyl-lH-imidazo[4,5-b]pyridin-2(3H)-one,

6-(3,5-dichlorophenyl)-3-(2-(5-methoxyisoindolin-2-yl)-2-oxoethyl)-l- methyl- 1 H-imidazo[4,5-b]pyridin-2(3H)-one,

6-(3-chlorophenyl)-3-(2-(5-methoxyisoindolin-2-yl)-2-oxoethyl)-l-methyl- lH-imidazo[4,5-b]pyridin-2(3H)-one,

6-(3,5-dichlorophenyl)-3-(2-(7-methoxy-3,4-dihydroisoquinolin-2(lH)-yl)- 2-oxoethyl)- 1 -methyl- 1 H-imidazo[4,5-b]pyridin-2(3H)-one,

6-(3,5-dichlorophenyl)-3-(2-(6-methoxy-3,4-dihydroisoquinolin-2(lH)-yl)- 2-oxoethyl)- 1 -methyl- 1 H-imidazo[4,5-b]pyridin-2(3H)-one,

7-(4-chloropyridin-2-yl)-4-(2-(5-methylisoindolin-2-yl)-2-oxoethyl)-2H- pyrido[3,2-b][l,4]oxazin-3(4H)-one,

7-(2-chloropyridin-4-yl)-4-(2-(7-methoxy-3 ,4-dihydroisoquinolin-2( 1 H)- yl)-2-oxoethyl)-2H-pyrido [3 ,2-b] [ 1 ,4]oxazin-3 (4H)-one,

7-(6-chloropyridin-2-yl)-4-(2-(7-methoxy-3 ,4-dihydroisoquinolin-2( 1 H)- y l)-2-oxoethyl)-2H-pyrido [3 ,2-b] [ 1 ,4] oxazin-3 (4H)-one,

7-(5-chloropyridin-3-yl)-4-(2-(7-methoxy-3,4-dihydroisoquinolin-2(lH)- yl)-2-oxoethyl)-2H-pyrido[3,2-b][l,4]oxazin-3(4H)-one,

7-(3 -chloro-4-fluorophenyl)-4-(2-(4-methylpiperidin- 1 -yl)-2-oxoethyl)-2H- pyrido[3 ,2-b] [ 1 ,4]oxazin-3(4H)-one,

N-butyl-2-(7-(3,5-dichlorophenyl)-3-oxo-2,3-dihydropyrido[3,2- b] [ 1 ,4]oxazin-4-yl)acetamide, 7-(3-chloro-5-fluorophenyl)-4-(2-(4-methylpiperidin-l-yl)-2-oxoethyl)-2H- pyrido [3 ,2-b] [ 1 ,4]oxazin-3 (4H)-one,

7-(4-chloropyridin-2-yl)-4-(2-(7-methoxy-3 ,4-dihydroisoquinolin-2( 1 H)- yl)-2-oxoethyl)-2H-pyrido[3 ,2-b] [ 1 ,4]oxazin-3 (4H)-one,

7-(4-chloropyridin-2-yl)-4-(2-(6-methoxy-3 ,4-dihydroisoquinolin-2( 1 H)- yl)-2-oxoethyl)-2H-pyrido[3 ,2-b] [ 1 ,4]oxazin-3 (4H)-one,

7-(4-chloropyridin-2-yl)-4-(2-(5-methoxyisoindolin-2-yl)-2-oxoethyl)-2H- pyrido [3 ,2-b] [ 1 ,4]oxazin-3 (4H)-one,

7-(3,5-dichlorophenyl)-4-(2-(4-(hydroxymethyl)piperidin-l-yl)-2- oxoethyl)-2H-pyrido[3,2-b][l,4]oxazin-3(4H)-one,

7-(3,5-dichlorophenyl)-4-(2-(4-hydroxypiperidin-l-yl)-2-oxoethyl)-2H- pyrido [3 ,2-b] [ 1 ,4]oxazin-3 (4H)-one,

7-(3,5-dichlorophenyl)-4-(2-(5-methylisoindolin-2-yl)-2-oxoethyl)-2H- pyrido [3 ,2-b] [ 1 ,4]oxazin-3 (4H)-one,

7-(3-chloro-4-fluorophenyl)-4-(2-(5-methoxyisoindolin-2-yl)-2-oxoethyl)- 2H-pyrido[3,2-b][l,4]oxazin-3(4H)-one,

7-(3-chloro-4-fluorophenyl)-4-(2-(4-(ethoxymethyl)piperidin-l-yl)-2- oxoethyl)-

2H-pyrido[3,2-b][l,4]oxazin-3(4H)-one,

7-(3 -chloro-4-fluorophenyl)-4-(2-(4-(2-hydroxyethyl)piperidin- 1 -yl)-2- oxoethyl)-2H-pyrido[3,2-b][l,4]oxazin-3(4H)-one,

7-(3-chloro-4-fluorophenyl)-4-(2-(4-hydroxyazepan-l-yl)-2-oxoethyl)-2H- pyrido [3 ,2-b] [ 1 ,4]oxazin-3 (4H)-one,

7-(3-chloro-4-fluorophenyl)-4-(2-(5,6-dimethoxyisoindolin-2-yl)-2- oxoethyl)-2H-pyrido [3 ,2-b] [ 1 ,4]oxazin-3 (4H)-one,

7-(3 -chloro-4-fluorophenyl)-4-(2-(4-((methy lamino)methyl)piperidin- 1 -yl)- 2-oxoethy l)-2H-pyrido [3 ,2-b] [ 1 ,4] oxazin-3 (4H)-one,

7-(3-chloro-5-fluorophenyl)-4-(2-(7-methoxy-3,4-dihydroisoquinolin- 2(lH)-yl)-2-oxoethyl)-2H-pyrido[3,2-b][l,4]oxazin-3(4H)-one, 7-(3,5-dichlorophenyl)-4-(2-(4-methylpiperidin-l-yl)-2-oxoethyl)-2H- pyrido [3 ,2-b] [ 1 ,4]oxazin-3 (4H)-one,

7-(3 ,5-dichlorophenyl)-4-(2-oxo-2-(4-(pyrimidin-2-yl)piperazin- 1 -yl)ethyl)- 2H-pyrido[3,2-b][l,4]oxazin-3(4H)-one,

7-(3 ,5-dichlorophenyl)-4-(2-oxo-2-(4-(pyridin-4-yl)piperazin- 1 -yl)ethyl)- 2H-pyrido [3 ,2-b] [ 1 ,4]oxazin-3(4H)-one,

7-(3,5-dichlorophenyl)-4-(2-oxo-2-(piperidin-l-yl)ethyl)-2H-pyrido[3,2- b] [ 1 ,4]oxazin-3 (4H)-one,

7-(3,5-dichlorophenyl)-4-(2-(3-methylpiperidin-l-yl)-2-oxoethyl)-2H- pyrido [3 ,2-b] [ 1 ,4]oxazin-3 (4H)-one,

7-(3,5-dichlorophenyl)-4-(2-(6-methoxy-3,4-dihydroisoquinolin-2(lH)-yl)- 2-oxoethyl)-2H-pyrido[3,2-b][l,4]oxazin-3(4H)-one,

7-(3 ,5-dichlorophenyl)-4-(2-oxo-2-(4-(pyridin-2-yl)piperazin- 1 -yl)ethyl)- 2H-pyrido[3,2-b][l,4]oxazin-3(4H)-one,

7-(3-chlorophenyl)-4-(2-(5-methoxyisoindolin-2-yl)-2-oxoethyl)-2H- pyrido [3 ,2-b] [ 1 ,4]oxazin-3 (4H)-one,

7-(3,5-dichlorophenyl)-4-(2-(4,4-difluoropiperidin-l-yl)-2-oxoethyl)-2H- pyrido[3 ,2-b] [ 1 ,4]oxazin-3 (4H)-one,

7-(3,5-dichlorophenyl)-4-(2-(4,4-dimethylρiperidin-l-yl)-2-oxoethyl)-2H- pyrido[3 ,2-b] [ 1 ,4]oxazin-3 (4H)-one,

7-(3-chlorophenyl)-4-(2-(7-methoxy-3,4-dihydroisoquinolin-2(lH)-yl)-2- oxoethyl)-2H-pyrido[3,2-b][l,4]oxazin-3(4H)-one,

7-(3-chlorophenyl)-4-(2-(6-methoxy-3,4-dihydroisoquinolin-2(lH)-yl)-2- oxoethyl)-2H-pyrido[3,2-b][l,4]oxazin-3(4H)-one,

7-(3,5-dichlorophenyl)-4-(2-(3,4-dihydroisoquinolin-2(lH)-yl)-2-oxoethyl)- 2H-pyrido[3,2-b][l,4]oxazin-3(4H)-one,

7-(3,5-dichlorophenyl)-4-(2-(6-hydroxy-3,4-dihydroisoquinolin-2(lH)-yl)- 2-oxoethyl)-2H-pyrido [3 ,2-b] [ 1 ,4]oxazin-3(4H)-one,

7-(3,5-dichlorophenyl)-4-(2-(7-methoxy-3,4-dihydroisoquinolin-2(lH)-yl)- 2-oxoethyl)-2H-pyrido[3 ,2-b] [1 ,4]oxazin-3(4H)-one, 7-(3,5-dichlorophenyl)-4-(2-(6-fluoro-3,4-dihydroisoquinolin-2(lH)-yl)-2- oxoethyl)-2H-pyrido[3,2-b][l,4]oxazin-3(4H)-one,

7-(3,5-dichlorophenyl)-4-(2-(4-hydroxy-4-methylpiperidin-l-yl)-2- oxoethyl)-2H-pyrido[3,2-b][l,4]oxazin-3(4H)-one,

7-(3 ,5-dichlorophenyl)-4-(2-(4-(2-hydroxypropan-2-yl)piperidin- 1 -yl)-2- oxoethy l)-2H-pyrido [3 ,2-b] [ 1 ,4]oxazin-3 (4H)-one,

7-(3,5-dichlorophenyl)-4-(2-oxo-2-(4-(2,2,2-trifluoroethyl)piperazin-l- yl)ethyl)-2H-pyrido[3,2-b][l,4]oxazin-3(4H)-one,

4-(2-(4-chloroisoindolin-2-yl)-2-oxoethyl)-7-(3,5-dichlorophenyl)-2H- pyrido [3 ,2-b] [ 1 ,4]oxazin-3 (4H)-one,

7-(3 ,5-dichlorophenyl)-4-(2-oxo-2-(4-(pyrazin-2-yl)piperazin- 1 -yl)ethyl)- 2H-pyrido[3,2-b][l,4]oxazin-3(4H)-one,

7-(3,5-dichlorophenyl)-4-(2-(4-(methoxymethyl)piperidin-l-yl)-2- oxoethyl)-2H-pyrido[3 ,2-b] [ 1 ,4]oxazin-3(4H)-one,

7-(3,5-dichlorophenyl)-4-(2-(3,4-dihydroquinolin-l(2H)-yl)-2-oxoethyl)- 2H-pyrido[3,2-b][l,4]oxazin-3(4H)-one,

7-(3 ,5 -dichlorophenyl)-4-(2-(4-methylpiperazin- 1 -yl)-2-oxoethyl)-2H- pyrido [3 ,2-b] [ 1 ,4]oxazin-3(4H)-one,

7-bromo-4-(2-(5-methoxyisoindolin-2-yl)-2-oxoethyl)-2H-pyrido[3,2- b] [ 1 ,4]oxazin-3(4H)-one,

7-(3 ,5-dichlorophenyl)-4-(2-(7-hydroxy-3 ,4-dihydroisoquinolin-2( 1 H)-yl)- 2-oxoethyl)-2H-pyrido[3,2-b][l,4]oxazin-3(4H)-one,

7-(3,5-dichlorophenyl)-4-(2-(5-fluoroisoindolin-2-yl)-2-oxoethyl)-2H- pyrido[3,2-b][l,4]oxazin-3(4H)-one,

4-(2-(6-chloro-3,4-dihydroisoquinolin-2(lH)-yl)-2-oxoethyl)-7-(3,5- dichloropheny l)-2H-pyrido [3 ,2-b] [ 1 ,4] oxazin-3 (4H)-one,

N-(4-methoxybenzyl)-2-(7-(3,5-dichlorophenyl)-3-oxo-2,3- dihydropyrido [3 ,2-b] [ 1 ,4]oxazin-4-yl)acetamide,

7-(3 ,5 -dichloropheny l)-4-(2-(6-methyl-3 ,4-dihydroisoquinolin-2( 1 H)-yl)-2- oxoethyl)-2H-pyrido[3 ,2-b] [ 1 ,4]oxazin-3 (4H)-one, 4-(2-(4-acetylpiperazin-l-yl)-2-oxoethyl)-7-(3,5-dichlorophenyl)-2H- pyrido [3 ,2-b] [ 1 ,4]oxazin-3 (4H)-one,

7-(3,5-dichlorophenyl)-4-(2-(indolin-l-yl)-2-oxoethyl)-2H-pyrido[3,2- bj [ 1 ,4]oxazin-3 (4H)-one,

7-(3 ,5-dichloropheny l)-4-(2-(4-methoxypiperidin- 1 -yl)-2-oxoethyl)-2H- pyrido [3 ,2-b] [ 1 ,4] oxazin-3 (4H)-one,

7-(3 ,5-dichloropheny l)-4-(2-(3 -ethylazetidin- 1 -y l)-2-oxoethyl)-2H- pyrido [3 ,2-b] [ 1 ,4]oxazin-3(4H)-one,

7-(3,5-dichlorophenyl)-4-(2-oxo-2-(4-(trifluoromethyl)piperidin-l- yl)ethyl)-2H-pyrido[3 ,2-b] [ 1 ,4]oxazin-3(4H)-one,

7-(3 ,5-dichlorophenyl)-4-(2-(2-methylpiperidin- 1 -yl)-2-oxoethyl)-2H- pyrido [3 ,2-b] [ 1 ,4]oxazin-3(4H)-one,

7-(3,5-dichlorophenyl)-4-(2-(isoindolin-2-yl)-2-oxoethyl)-2H-pyrido[3,2- b][l,4]oxazin-3(4H)-one,

7-(3,5-dichlorophenyl)-4-(2-(5-methylindolin-l-yl)-2-oxoethyl)-2H- pyrido[3 ,2-b] [ 1 ,4]oxazin-3(4H)-one,

7-(3,5-dichlorophenyl)-4-(2-(2,3-dihydro-lH-benzo[e][l,4]diazepin-4(5H)- yl)-2-oxoethyl)-2H-pyrido [3 ,2-b] [ 1 ,4]oxazin-3 (4H)-one,

2-(7-(3 ,5 -dichlorophenyl)-3 -oxo-2,3 -dihydropyrido[3 ,2-b] [ 1 ,4]oxazin-4-yl)- N-(3-hydroxy-3-methylbutyl)acetamide,

7-(3,5-dichlorophenyl)-4-(2-(5-methoxyisoindolin-2-yl)-2-oxoethyl)-2H- pyrido [3 ,2-b] [ 1 ,4]oxazin-3(4H)-one,

7-(3-chloro-5-fluorophenyl)-4-(2-(5-methoxyisoindolin-2-yl)-2-oxoethyl)- 2H-pyrido[3,2-b][l,4]oxazin-3(4H)-one,

7-(3-chloro-4-fluorophenyl)-4-(2-(7-methoxy-3,4-dihydroisoquinolin- 2( 1 H)-yl)-2-oxoethyl)-2H-pyrido[3,2-b] [ 1 ,4]oxazin-3(4H)-one,

1 -(2-(7-methoxy-3 ,4-dihydroisoquinolin-2( 1 H)-yl)-2-oxoethyl)-6-phenyl- 3 ,4-dihydro- 1 ,8-naphthyridin-2( 1 H)-one,

6-(4-chloropyridin-2-yl)- 1 -(2-(7-methoxy-3 ,4-dihydroisoquinolin-2( 1 H)- yl)-2-oxoethyl)-3,4-dihydro-l,8-naphthyridin-2(lH)-one, 6-(3 -chloro-4-fluorophenyl)- 1 -(2-(7-methoxy-3 ,4-dihydroisoquinolin- 2( 1 H)-yl)-2-oxoethyl)-3 ,4-dihydro- 1 ,8-naphthyridin-2( 1 H)-one,

6-bromo- 1 -ethyl-3 -(2-(7-methoxy-3 ,4-dihydroisoquinolin-2( 1 H)-yl)-2- oxoethyl)- 1 H-imidazo[4,5-b]pyridin-2(3H)-one,

6-(3-chlorophenyl)-l-ethyl-3-(2-(5-methoxyisoindolin-2-yl)-2-oxoethyl)- lH-imidazo[4,5-b]pyridin-2(3H)-one,

6-(3-chloro-5-fluorophenyl)-l-ethyl-3-(2-(5-methoxyisoindolin-2-yl)-2- oxoethyl)-lH-imidazo[4,5-b]pyτidin-2(3H)-one,

N-butyl-2-(6-(3,5-dichlorophenyl)-l-ethyl-2-oxo-l,2-dihydroimidazo[4,5- b]pyridin-3 -yl)acetamide,

6-(3-chloro-4-fluorophenyl)-l-ethyl-3-(2-(5-methoxyisoindolin-2-yl)-2- oxoethyl)-lH-imidazo[4,5-b]pyridin-2(3H)-one,

6-(3,5-dichlorophenyl)-l-ethyl-3-(2-(5-methoxyisoindolin-2-yl)-2- oxoethyl)-lH-imidazo[4,5-b]pyridin-2(3H)-one,

6-(3-chlorophenyl)-l-(2-(5-methoxyisoindolin-2-yl)-2-oxoethyl)-3,4- dihydro-l,8-naphthyridin-2(lH)-one,

6-(3-chlorophenyl)-l-(2-(7-methoxy-3,4-dihydroisoquinolin-2(lH)-yl)-2- oxoethyl)-3 ,4-dihydro- 1 , 8-naphthyridin-2( 1 H)-one,

6-(3-chloro-4-fluorophenyl)-l-(2-(5-methoxyisoindolin-2-yl)-2-oxoethyl)- 3,4-dihydro-l,8-naphthyridin-2(lH)-one,

7-(3-chloro-4-fluorophenyl)-4-(2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)- yl)-2-oxoethyl)-2H-pyrido[3,2-b][l,4]oxazin-3(4H)-one,

7-(3-chloro-4-fluorophenyl)-4-(2-(3,4-dihydroisoquinolin-2(lH)-yl)-2- oxoethy l)-2H-pyrido [3 ,2-b] [ 1 ,4] oxazin-3 (4H)-one,

6-(4-chloropyridin-2-yl)- 1 -(2-(5 -methoxyisoindolin-2-yl)-2-oxoethyl)-3 ,4- dihydro- 1 ,8-naphthyridin-2( 1 H)-one,

(S)-2-(6-(3,5-dichlorophenyl)-l-methyl-2-oxo-l,2-dihydroimidazo[4,5- b]pyridin-3-yl)-N-((tetrahydrofuran-2-yl)methyl)acetamide,

6-(3 ,5-dichlorophenyl)- 1 -(2-(7-methoxy-3 ,4-dihydroisoquinolin-2( 1 H)-yl)- 2-oxoethyl)-3 ,4-dihydro- 1 ,8-naphthyridin-2( 1 H)-one, 6-(3,5-dichlorophenyl)-l-(2-(isoindolin-2-yl)-2-oxoethyl)-3,4-dihydro-l,8- naphthyridin-2( 1 H)-one,

N-(2-cyanoethyl)-2-(6-(3 ,5-dichlorophenyl)- 1 -methyl-2-oxo- 1 ,2- dihydroimidazo[4,5-b]pyridin-3-yl)acetamide,

6-(3 ,5-dichlorophenyl)- 1 -(2-(7-hydroxy-3 ,4-dihydroisoquinolin-2( 1 H)-yl)- 2-oxoethyl)-3 ,4-dihydro- 1 ,8-naphthyridin-2( 1 H)-one,

6-(3 ,5-dichlorophenyl)- 1 -(2-(6-methoxy-3 ,4-dihydroisoquinolin-2( 1 H)-yl)- 2-oxoethyl)-3 ,4-dihydro- 1 ,8-naphthyridin-2( 1 H)-one,

6-(3,5-dichlorophenyl)-l-(2-(4-(hydroxymethyl)piperidin-l-yl)-2- oxoethyl)-3,4-dihydro- 1 ,8-naphthyridin-2( 1 H)-one,

N-(4-methoxybenzyl)-2-(6-(3 ,5-dichlorophenyl)-2-oxo-3 ,4-dihydro- 1,8- naphthyridin- 1 (2H)-yl)-N-methylacetamide,

6-(3,5-dichlorophenyl)-l-ethyl-3-(2-oxo-2-(piperidin-l-yl)ethyl)-lH- imidazo[4,5-b]pyridin-2(3H)-one,

6-(3,5-dichlorophenyl)-l-(2-(4-methylpiperidin-l-yl)-2-oxoethyl)-3,4- dihydro- 1 , 8 -naphthyridin-2( 1 H)-one,

2-(6-(3,5-dichlorophenyl)-l-methyl-2-oxo-l,2-dihydroimidazo[4,5- b]pyridin-3-yl)-N-(2-methylbutyl)acetamide,

(R)-2-(6-(3,5-dichlorophenyl)-l-methyl-2-oxo-l,2-dihydroimidazo[4,5- b]pyridin-3-yl)-N-((tetrahydrofuran-2-yl)methyl)acetamide,

2-(6-(3,5-dichlorophenyl)-l-methyl-2-oxo-l,2-dihydroimidazo[4,5- b]pyridin-3-yl)-N-ρentylacetamide,

2-(6-(3,5-dichlorophenyl)-l-methyl-2-oxo-l,2-dihydroimidazo[4,5- b]pyridin-3-yl)-N-isopentylacetamide,

2-(6-(3 ,5-dichlorophenyl)- 1 -methyl-2-oxo- 1 ,2-dihydroimidazo [4,5 - b]pyridin-3-yl)-N-phenethylacetamide,

N-(4-methoxybenzyl)-2-(6-(3,5-dichlorophenyl)-l-methyl-2-oxo-l,2- dihydroimidazo[4,5-b]pyridin-3-yl)acetamide,

N-(cyclohexylmethyl)-2-(6-(3 ,5-dichlorophenyl)- 1 -methyl-2-oxo- 1 ,2- dihydroimidazo [4,5 -b]pyridin-3 -y l)acetamide, 6-(3 ,5 -dichloropheny I)- 1 -(2-(3 ,4-dihydroisoquinolin-2( 1 H)-yl)-2-oxoethyl)- 3,4-dihydro- 1 ,8-naphthyridin-2( 1 H)-one,

6-(3 ,5 -dichloropheny I)- 1 -(2-(4-(methoxymethyl)piperidin- 1 -yl)-2- oxoethyl)-3 ,4-dihydro- 1 ,8-naphthyridin-2( 1 H)-one,

7-(3,5-dichlorophenyl)-4-(2-(2-methoxy-7,8-dihydro- 1 ,6-naphthyridin- 6(5H)-yl)-2-oxoethyl)-2H-pyrido[3,2-b][l,4]oxazin-3(4H)-one,

6-(3 ,5-dichloropheny I)- 1 -(2-(6-hydroxy-3 ,4-dihydroisoquinolin-2( 1 H)-yl)- 2-oxoethyl)-3 ,4-dihydro- 1 ,8-naphthyridin-2( 1 H)-one,

2-(6-(3,5-dichlorophenyl)-l-methyl-2-oxo-l,2-dihydroimidazo[4,5- b]pyridin-3 -yl)-N-(3 -hydroxy-3 -methylbutyl)acetamide,

2-(6-(3,5-dichlorophenyl)-l-methyl-2-oxo-l,2-dihydroimidazo[4,5- b]pyridin-3-yl)-N-(pentan-2-yl)acetamide,

N-butyl-2-(6-(3,5-dichlorophenyl)-2-oxo-3,4-dihydro-l,8-naphthyridin- l(2H)-yl)acetamide,

(S)-2-(6-(3 ,5-dichlorophenyl)-2-oxo-3 ,4-dihydro- 1 ,8-naphthyridin- 1 (2H)- yl)-N-(2,3 -dihydro- 1 H-inden- 1 -yl)acetamide,

6-(4-chlorophenyl)- 1 -(2-(7-methoxy-3 ,4-dihydroisoquinolin-2( 1 H)-yl)-2- oxoethyl)-3 ,4-dihydro- 1 , 8-naphthyridin-2( 1 H)-one,

6-(2-chlorophenyl)- 1 -(2-(7-methoxy-3 ,4-dihydroisoquinolin-2( 1 H)-yl)-2- oxoethyl)-3 ,4-dihydro- 1 , 8-naphthyridin-2( 1 H)-one,

3-(8-(2-(7-methoxy-3,4-dihydroisoquinolin-2(lH)-yl)-2-oxoethyl)-7-oxo- 5,6,7,8-tetrahydro-l,8-naphthyridin-3-yl)benzonitrile,

1 -(2-(7-methoxy-3 ,4-dihydroisoquinolin-2( 1 H)-yl)-2-oxoethyl)-6-m-tolyl- 3,4-dihydro-l,8-naphthyridin-2(lH)-one,

6-(3-fluorophenyl)- 1 -(2-(7-methoxy-3 ,4-dihydroisoquinolin-2( 1 H)-yl)-2- oxoethyl)-3,4-dihydro-l,8-naphthyridin-2(lH)-one,

1 -(2-(7-methoxy-3 ,4-dihydroisoquinolin-2( 1 H)-yl)-2-oxoethyl)-6-(pyridin- 3-yl)-3,4-dihydro-l,8-naphthyridin-2(lH)-one,

1 -(2-(7-methoxy-3 ,4-dihydroisoquinolin-2( 1 H)-yl)-2-oxoethyl)-6-(pyridin- 3-yl)-3,4-dihydro-l,8-naphthyridin-2(lH)-one, 1 -(2-(7-methoxy-3 ,4-dihydroisoquinolin-2( 1 H)-yl)-2-oxoethyl)-6-(pyridin- 4-yl)-3,4-dihydro-l,8-naphthyridin-2(lH)-one,

1 -(2-(7-methoxy-3 ,4-dihydroisoquinolin-2( 1 H)-yl)-2-oxoethyl)-6- (pyrimidin-5-yl)-3,4-dihydro-l,8-naphthyridin-2(lH)-one, l-(2-(7-methoxy-3,4-dihydroisoquinolin-2(lH)-yl)-2-oxoethyl)-6-(pyridin- 2-yl)-3,4-dihydro-l ,8-naphthyridin-2(l H)-one,

4-(2-(5-methoxyisoindolin-2-yl)-2-oxoethyl)-7-(6-methylpyridin-2-yl)-2H- pyrido[3,2-b][l,4]oxazin-3(4H)-one,

1 -(2-(7-methoxy-3 ,4-dihydroisoquinolin-2( 1 H)-yl)-2-oxoethyl)-6-phenoxy- 3 ,4-dihydro- 1 ,8-naphthyridin-2( 1 H)-one,

1 -(2-(7-methoxy-3 ,4-dihydroisoquinolin-2( 1 H)-yl)-2-oxoethyl)-6-(m- tolyloxy)-3,4-dihydro-l,8-naphthyridin-2(lH)-one,

1 -(2-(7-methoxy-3 ,4-dihydroisoquinolin-2( 1 H)-yl)-2-oxoethyl)-6-(4- methoxyphenoxy)-3 ,4-dihydro- 1 ,8-naphthyridin-2( 1 H)-one,

6-(4-chlorophenoxy)- 1 -(2-(7-methoxy-3 ,4-dihydroisoquinolin-2( 1 H)-yl)-2- oxoethy l)-3 ,4-dihydro- 1 , 8-naphthyridin-2( 1 H)-one,

1 -(2-(7-methoxy-3 ,4-dihydroisoquinolin-2( 1 H)-yl)-2-oxoethyl)-6-(p- tolyloxy)-3 ,4-dihydro- 1 ,8-naphthyridin-2( 1 H)-one,

1 -(2-(7-methoxy-3 ,4-dihydroisoquinolin-2( 1 H)-yl)-2-oxoethyl)-6-(o- toly loxy)-3 ,4-dihydro- 1 , 8-naphthyridin-2( 1 H)-one,

4-(2-(5-methoxyisoindolin-2-yl)-2-oxoethyl)-7-(4-methylpyridin-2-yl)-2H- pyrido[3,2-b][l,4]oxazin-3(4H)-one,

4-(2-(7-methoxy-3 ,4-dihydroisoquinolin-2( 1 H)-yl)-2-oxoethyl)-7-(4- methylpyridin-2-yl)-2H-pyrido[3,2-b][l,4]oxazin-3(4H)-one,

6-butyl- 1 -(2-(7-methoxy-3 ,4-dihydroisoquinolin-2( 1 H)-yl)-2-oxoethyl)-3 ,4- dihydro- 1 ,8-naphthyridin-2( 1 H)-one,

6-tert-butyl- 1 -(2-(7-methoxy-3 ,4-dihydroisoquinolin-2( 1 H)-yl)-2-oxoethyl)- 3,4-dihydro- 1 ,8-naphthyridin-2( 1 H)-one,

6-cyclohexyl- 1 -(2-(7-methoxy-3 ,4-dihydroisoquinolin-2( 1 H)-yl)-2- oxoethyl)-3 ,4-dihydro- 1 , 8-naphthyridin-2( 1 H)-one, 6-cyclopropyl- 1 -(2-(7-methoxy-3,4-dihydroisoquinolin-2( 1 H)-yl)-2- oxoethyl)-3 ,4-dihydro- 1 ,8-naphthyridin-2( 1 H)-one,

1 -(2-(7-methoxy-3 ,4-dihydroisoquinolin-2( 1 H)-yl)-2-oxoethyl)-3 ,4- dihydro-l,8-naphthyridin-2(lH)-one,

7-bromo-4-(2-(7-hydroxy-3 ,4-dihydroisoquinolin-2( 1 H)-yl)-2-oxoethyl)- 2H-pyrido[3 ,2-b] [ 1 ,4]oxazin-3(4H)-one,

7-bromo-4-(2-(7-ethoxy-3 ,4-dihydroisoquinolin-2( 1 H)-yl)-2-oxoethyl)-2H- pyrido [3 ,2-b] [ 1 ,4]oxazin-3 (4H)-one,

4-(2-(7-(benzy loxy)-3 ,4-dihydroisoquinolin-2( 1 H)-yl)-2-oxoethyl)-7- bromo-2H-pyrido[3,2-b][l,4]oxazin-3(4H)-one, and the pharmaceutically accept salts thereof.