Amidopyrimidone derivatives

Abstract

The present invention relates to compounds of formula I or II: TIFF2023531021000211.tif85170[where, X 1 , X 3 , R 1 , R 2 , R 3 , R 4 , and R 5 is as described herein], and pharmaceutically acceptable salts thereof. The present invention further relates to the preparation of compounds of formula I, pharmaceutical compositions containing them, and their use as medicaments.

Description

[Technical Field]

[0001] The present invention provides compounds that are inhibitors of human methionine adenosyltransferase 2A (Mat2A) for use in treating, preventing and / or delaying the progression of cancer. Summary of the Invention

[0002] The present invention relates to compounds of formula I or II: TIFF0007749602000001.tif78170[In the formula, X 1 is either N or CH, X 3 is N or CR 3 Either The dotted line is R 5 represents a single bond when is oxo, or R 5 represents a double bond when is -NH2, R 1 is one or more, in particular one to three, more particularly one or two substituents R 1a (C1-C6) alkyl optionally substituted with one or more, in particular one to three, more particularly one or two substituents R 1b (C1-C6)alkoxy optionally substituted with one or more, in particular one to three, more particularly one or two substituents R 1a halo(C1-C6)alkyl optionally substituted with one or more, in particular one to three, more particularly one or two substituents R 1b halo(C1-C6)alkoxy optionally substituted with one or more, in particular one to three, more particularly one or two substituents R 1c (C3-C8)cycloalkyl optionally substituted with one or more, in particular one to three, more particularly one or two substituents R 1d heteroaryl optionally substituted with one or more, in particular one to three, more particularly one or two substituents R 1eor one or more, in particular one to three, more in particular one or two, substituents R 1f phenyl optionally substituted with R 1a and R 1b are each independently selected from (C-C)cycloalkyl, hydroxyl, heteroaryl, heterocycloalkyl, and phenyl, where heteroaryl, heterocycloalkyl, or phenyl may contain one or more, particularly one to three, more particularly one or two, substituents R 1g may be substituted with R 1c , R 1d , R 1e and R 1f are each independently selected from halogen, oxo, cyano, hydroxyl, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy-(C1-C6)alkyl, heteroaryl, heterocycloalkyl, and phenyl; R 1g are each independently selected from halogen, cyano, hydroxyl, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl-(C1-C6)alkyl, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, hydroxy(C1-C6)alkyl, and (C1-C6)alkoxy-(C1-C6)alkyl; R 2 is hydrogen, halogen, amino, (C1-C6) alkyl, (C1-C6) alkoxy, halo(C1-C6) alkyl, halo(C1-C6) alkoxy, one or more, in particular one to three, more in particular one or two substituents R 2a (C3-C6)cycloalkyl optionally substituted with one or more, in particular one to three, more particularly one or two substituents R 2b(C3-C6)cycloalkyl-(C1-C6)alkyl optionally substituted with one or more, in particular one to three, more particularly one or two substituents R 2c (C3-C6)cycloalkyl-(C1-C6)alkoxy optionally substituted with one or more, in particular one to three, more particularly one or two substituents R 2d Heterocycloalkyl optionally substituted with NR 2f R 2g or one or more, in particular one to three, more particularly one or two substituents R 2e phenyl optionally substituted with R 2a , R 2b , R 2c , R 2d and R 2e are each independently selected from halogen, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, and halo(C1-C6)alkoxy; R 2f and R 2g are each independently selected from hydrogen or (C1-C6) alkyl; R 3 is hydrogen, halogen, cyano, amino, (C1-C6) alkyl, (C1-C6) alkoxy, halo(C1-C6) alkyl, halo(C1-C6) alkoxy, one or more, in particular one to three, more in particular one or two substituents R 3a (C3-C6)cycloalkyl optionally substituted with one or more, in particular one to three, more particularly one or two substituents R 3b (C3-C6)cycloalkyl-(C1-C6)alkyl optionally substituted with one or more, in particular one to three, more particularly one or two substituents R 3c (C3-C6)cycloalkyl-(C1-C6)alkoxy optionally substituted with one or more, in particular one to three, more particularly one or two substituents R 3dor one or more, in particular one to three, more in particular one or two, substituents R 3e phenyl optionally substituted with R 3a , R 3b , R 3c , R 3d and R 3e are each independently selected from halogen, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, and halo(C1-C6)alkoxy; R 4 is hydrogen, cyano, hydroxy, halogen, amino, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, (C1-C6)alkoxy-(C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, one or more, in particular one to three, more in particular one or two substituents R 4a (C3-C6)cycloalkyl optionally substituted with one or more, in particular one to three, more particularly one or two substituents R 4b (C3-C6)cycloalkyl-(C1-C6)alkyl optionally substituted with one or more, in particular one to three, more particularly one or two substituents R 4c (C3-C6)cycloalkyl-(C1-C6)alkoxy optionally substituted with one or more, in particular one to three, more particularly one or two substituents R 4d heterocycloalkyl optionally substituted with -COR 4a or -CONR 4b R 4c and R 4a , R 4b , R 4c and R 4d are each independently selected from hydrogen and (C1-C6) alkyl; R 5 is -NH2 or oxo] and pharmaceutically acceptable salts thereof.

[0003] In particular, the present invention provides compounds of formula I or II: TIFF0007749602000002.tif78170[In the formula, X 1 is either N or CH, X 3 is N or CR 3 Either The dotted line is R 5 represents a single bond when is oxo, or R 5 represents a double bond when is -NH2, R 1 is one or more, in particular one to three, more particularly one or two substituents R 1a (C1-C6) alkyl optionally substituted with one or more, in particular one to three, more particularly one or two substituents R 1b (C1-C6)alkoxy optionally substituted with one or more, in particular one to three, more particularly one or two substituents R 1a halo(C1-C6)alkyl optionally substituted with one or more, in particular one to three, more particularly one or two substituents R 1b halo(C1-C6)alkoxy optionally substituted with one or more, in particular one to three, more particularly one or two substituents R 1c (C3-C8)cycloalkyl optionally substituted with one or more, in particular one to three, more particularly one or two substituents R 1d heteroaryl optionally substituted with one or more, in particular one to three, more particularly one or two substituents R 1e or one or more, in particular one to three, more in particular one or two, substituents R 1f phenyl optionally substituted with R 1a and R 1bare each independently selected from (C-C)cycloalkyl, hydroxyl, heteroaryl, heterocycloalkyl, and phenyl, where heteroaryl, heterocycloalkyl, or phenyl may contain one or more, particularly one to three, more particularly one or two, substituents R 1g may be substituted with R 1c , R 1d , R 1e and R 1f are each independently selected from halogen, oxo, cyano, hydroxyl, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy-(C1-C6)alkyl, heteroaryl, heterocycloalkyl, and phenyl; R 1g are each independently selected from halogen, cyano, hydroxyl, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl-(C1-C6)alkyl, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, hydroxy(C1-C6)alkyl, and (C1-C6)alkoxy-(C1-C6)alkyl; R 2 is hydrogen, halogen, amino, (C1-C6) alkyl, (C1-C6) alkoxy, halo(C1-C6) alkyl, halo(C1-C6) alkoxy, one or more, in particular one to three, more in particular one or two substituents R 2a (C3-C6)cycloalkyl optionally substituted with one or more, in particular one to three, more particularly one or two substituents R 2b (C3-C6)cycloalkyl-(C1-C6)alkyl optionally substituted with one or more, in particular one to three, more particularly one or two substituents R 2c(C3-C6)cycloalkyl-(C1-C6)alkoxy optionally substituted with one or more, in particular one to three, more particularly one or two substituents R 2d or one or more, in particular one to three, more in particular one or two, substituents R 2e phenyl optionally substituted with R 2a , R 2b , R 2c , R 2d and R 2e are each independently selected from halogen, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, and halo(C1-C6)alkoxy; R 3 is hydrogen, halogen, cyano, amino, (C1-C6) alkyl, (C1-C6) alkoxy, halo(C1-C6) alkyl, halo(C1-C6) alkoxy, one or more, in particular one to three, more in particular one or two substituents R 3a (C3-C6)cycloalkyl optionally substituted with one or more, in particular one to three, more particularly one or two substituents R 3b (C3-C6)cycloalkyl-(C1-C6)alkyl optionally substituted with one or more, in particular one to three, more particularly one or two substituents R 3c (C3-C6)cycloalkyl-(C1-C6)alkoxy optionally substituted with one or more, in particular one to three, more particularly one or two substituents R 3d or one or more, in particular one to three, more in particular one or two, substituents R 3e phenyl optionally substituted with R 3a , R 3b , R 3c , R 3d and R 3eare each independently selected from halogen, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, and halo(C1-C6)alkoxy; R 4 is hydrogen, cyano, hydroxy, halogen, amino, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, (C1-C6)alkoxy-(C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, one or more, in particular one to three, more in particular one or two substituents R 4a (C3-C6)cycloalkyl optionally substituted with one or more, in particular one to three, more particularly one or two substituents R 4b (C3-C6)cycloalkyl-(C1-C6)alkyl optionally substituted with one or more, in particular one to three, more particularly one or two substituents R 4c (C3-C6)cycloalkyl-(C1-C6)alkoxy optionally substituted with one or more, in particular one to three, more particularly one or two substituents R 4d heterocycloalkyl optionally substituted with -COR 4a or -CONR 4b R 4c and R 4a , R 4b , R 4c and R 4d are each independently selected from hydrogen and (C1-C6) alkyl; R 5 is -NH2 or oxo] and pharmaceutically acceptable salts thereof. DETAILED DESCRIPTION OF THE INVENTION

[0004] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below.

[0005] All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.

[0006] The nomenclature used in this application is based on IUPAC systematic nomenclature unless otherwise indicated.

[0007] Any open valence appearing on a carbon, oxygen, sulfur or nitrogen atom in the structures herein indicates the presence of a hydrogen, unless otherwise indicated.

[0008] When referring to the number of substituents, the term "one or more" refers to a range from one substituent to the highest possible number of substitutions, i.e., from the replacement of one hydrogen to the replacement of all hydrogens by substituents; particularly "one or more" refers to one, two, or three; most particularly "one or more" refers to one or two.

[0009] The term "substituent" refers to an atom or group of atoms that replaces a hydrogen atom of a parent molecule.

[0010] The term "substituted" indicates that the specified group bears one or more substituents. Any group can have multiple substituents, and when a variety of possible substituents are provided, the substituents are independently selected and need not be the same. The term "unsubstituted" means that the specified group bears no substituents. The term "optionally substituted" means that the specified group is unsubstituted or substituted with one or more substituents independently selected from a group of possible substituents. When indicating the number of substituents, the term "one or more" refers to a range from one substituent to the highest possible number of substitutions, i.e., replacement of one hydrogen by a substituent to replacement of all hydrogens.

[0011] The term "amino," as used herein, refers to a group of the formula -NR'R'', where R' and R'' are independently hydrogen, (C1-C6)alkyl, halo(C1-C6)alkyl, or (C3-C6)cycloalkyl. Alternatively, R' and R'' can be taken together with the nitrogen to which they are attached to form a heterocycloalkyl. The term "primary amino" refers to a group where R' and R'' are both hydrogen. The term "secondary amino" refers to a group where R' is hydrogen and R'' is a group other than hydrogen, particularly where R'' is (C1-C6)alkyl. The term "secondary amino" refers to a group where R' and R'' are both other than hydrogen, particularly where R' and R'' are both (C1-C6)alkyl. Particular secondary and tertiary amines are methylamine, ethylamine, propylamine, isopropylamine, phenylamine, benzylamine, dimethylamine, diethylamine, dipropylamine, and diisopropylamine, with amino most particularly referring to ethylamine.

[0012] "Halo" or "halogen" means fluoro, chloro, bromo or iodo, especially chloro or fluoro.

[0013] "Hydroxy" refers to the group --OH.

[0014] "(C1-C6) alkyl" refers to a branched or straight hydrocarbon chain such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, and hexyl.

[0015] "(C1-C6)alkoxy" refers to a group of the formula -OR a In the formula, R a is a (C1-C6) alkyl moiety as defined herein. Examples of (C1-C6) alkoxy moieties include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like.

[0016] The term "(C3-C8)cycloalkyl" refers to a monovalent saturated monocyclic hydrocarbon group having from 3 to 6 ring carbon atoms. Examples of monocyclic (C3-C8)cycloalkyl are cyclopropyl, sucrobanil, cyclopentyl, cyclohexyl, or cycloheptyl. A particular example of (C3-C6)cycloalkyl is cyclopropyl.

[0017] "(C3-C6)cycloalkyl-(C1-C6)alkyl" refers to a (C1-C6)alkyl as defined above that is substituted with one or more (C3-C6)cycloalkyl groups, in particular one (C3-C6)cycloalkyl group. More particularly, "(C3-C6)cycloalkyl-(C1-C6)alkyl" refers to Points to TIFF0007749602000003.tif22170.

[0018] The term "perhalo(C1-C3)alkyl" means a (C1-C3)alkyl group as defined above, in which all hydrogen atoms have been replaced with halogen atoms. More particularly, "(C1-C3)perhaloalkyl" is a (C1-C3)perfluoroalkyl, most preferably trifluoromethyl.

[0019] "Halo-(C1-C6)alkyl" refers to (C1-C6)alkyl as defined above substituted with one or more halogen atoms, particularly one to three halogen atoms. More particularly, halo-(C1-C6)alkyl is chloro- and fluoro-(C1-C6)alkyl. In some particular embodiments, halo-(C1-C6)alkyl refers to perhalo(C1-C3)alkyl as defined herein. Most particularly, halo-(C1-C6)alkyl is trifluoromethyl, difluoromethyl, or fluoromethyl.

[0020] "Halo-(C1-C6)alkoxy" refers to (C1-C6)alkoxy as defined above substituted with one or more halogen atoms, particularly one to three halogen atoms. More particularly, halo-(C1-C6)alkoxy is chloro- and fluoro-(C1-C6)alkoxy. In some particular embodiments, halo-(C1-C6)alkoxy refers to perhalo(C1-C3)alkoxy, such as trifluoromethoxy or difluoromethoxy.

[0021] "Hydroxy-(C1-C6)alkyl" refers to a (C1-C6)alkyl as defined above that is substituted with one or more hydroxy groups, particularly one hydroxy group. More particularly, hydroxy-(C1-C6)alkyl refers to methyl hydroxide or ethyl hydroxide.

[0022] "(C1-C6)alkoxy-(C1-C6)alkyl" refers to a (C1-C6)alkyl as defined above that is substituted with one or more (C1-C6)alkoxy groups as defined herein, in particular one (C1-C6)alkoxy group. More particularly, (C1-C6)alkoxy-(C1-C6)alkyl refers to -CH2-O-CH3 or -CH2CH2-O-CH3.

[0023] "Halo-(C1-C6)alkoxy" refers to alkoxy as defined above substituted with one or more halogen atoms, particularly one to three halogen atoms. More particularly, halo-(C1-C6)alkoxy is chloro- and fluoro-(C1-C6)alkoxy.

[0024] "Heteroaryl" means a monovalent monocyclic or bicyclic moiety of 5 to 12 ring atoms having at least one aromatic ring containing 1, 2, or 3 ring heteroatoms each independently selected from N, O, or S (preferably N or O), the remaining ring atoms being C, and it is understood that the point of attachment of the heteroaryl moiety is on the aromatic ring. More specifically, the term heteroaryl includes, but is not limited to, pyridinyl, furanyl, thienyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, tetrahydrobenzofuranyl, isobenzofuranyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, indolyl, isoindolyl, benzoxazolyl, quinolyl, tetrahydroquinolinyl, isoquinolyl, benzimidazolyl, benzisoxazolyl, or benzothienyl, imidazo[1,2-a]-pyridinyl, imidazo[2,1-b]thiazolyl, and derivatives thereof. "N-heteroaryl" specifically refers to heteroaryl as defined above containing at least one nitrogen atom. The point of attachment of the N-heteroaryl to the rest of the molecule can be via a nitrogen or carbon ring atom. Examples of N-heteroaryl are pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl.

[0025] The terms "heterocycloalkyl" or "heterocyclic" refer to a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system of 4 to 9 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, and S, with the remaining ring atoms being carbon. Examples of heterocycloalkyl are pyrrolidinyl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxolane, 1,4-dioxepanyl, oxepanyl, 1,1-dioxo-thiomorphol-4-yl, azepanyl, diazepanyl, homopiperazinyl, or oxazepanyl. More specifically, heterocycloalkyl refers to dihydrofuryl, 1,3-dioxolyl, dihydropyryl, dihydrothiophyl, dihydropyrazolyl, dihydroisoxazolyl, tetrahydropyridyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, 3,4-dihydro-2H-1,4-oxazinyl, 3,4-dihydro-2H-1,4-thiazyl, 1,2,3,4-tetrahydropyrazyl.

[0026] The term "therapeutically effective amount" refers to an amount of a compound or molecule of the invention that, when administered to a subject, (i) treats or prevents a particular disease, condition, or disorder, (ii) attenuates, ameliorate, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. A therapeutically effective amount will vary depending on the compound, the condition being treated, the severity of the disease being treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending physician or veterinarian, and other factors.

[0027] "Optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and the description includes instances where the event or circumstance occurs and instances where it does not occur. For example, "an aryl group optionally substituted with an alkyl group" means that the alkyl may, but need not, be present, and the description includes situations where the aryl group is substituted with an alkyl group and situations where the aryl group is not substituted with an alkyl group.

[0028] The term "individual" or "subject" refers to a mammal. Mammals include, but are not limited to, livestock animals (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats). In certain embodiments, the individual or subject is a human.

[0029] The terms "compound(s) of this invention" and "compound(s) of the present invention" refer to the compounds disclosed herein as well as their stereoisomers, tautomers, solvates, and salts (e.g., pharmaceutically acceptable salts).

[0030] When the compounds of the present invention are solid, it will be understood by those skilled in the art that these compounds, as well as solvates and salts thereof, may exist in different solid forms, particularly different crystalline forms, all of which are intended to be within the scope of the present invention and specific formula.

[0031] The term "pharmaceutically acceptable salt" means a salt that is not biologically or otherwise undesirable. Pharmaceutically acceptable salts include both acid and base addition salts.

[0032] The term "pharmaceutically acceptable acid addition salt" refers to a pharmaceutically acceptable salt formed with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and the like, and an organic acid selected from the aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid.

[0033] The term "pharmaceutically acceptable base addition salt" refers to a pharmaceutically acceptable salt formed with an organic or inorganic base. Examples of acceptable inorganic bases include sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperidine, N-ethylpiperidine, and polyamine resins.

[0034] The term "active pharmaceutical ingredient" (or "API") refers to a compound or molecule in a pharmaceutical composition that has a specific biological activity.

[0035] The terms "pharmaceutical composition" and "pharmaceutical formulation" (or "formulation") are used interchangeably and refer to a mixture or solution containing a therapeutically effective amount of an active pharmaceutical ingredient together with pharmaceutically acceptable excipients, to be administered to a mammal, e.g., a human, in need of treatment.

[0036] The terms "pharmaceutically acceptable excipient," "pharmaceutically acceptable carrier," and "therapeutically inactive excipient" can be used interchangeably and refer to any pharmaceutically acceptable ingredient in a pharmaceutical composition that has no therapeutic activity and is non-toxic to a subject to which it is administered, such as, for example, a disintegrant, binder, filler, solvent, buffer, isotonicity agent, stabilizer, antioxidant, surfactant, carrier, diluent, or lubricant used in formulating a pharmaceutical product.

[0037] The terms "treating" or "treatment" of a medical condition include inhibiting the medical condition, i.e., halting the occurrence of the medical condition or its clinical symptoms, or alleviating the medical condition, i.e., causing a temporary or permanent regression of the medical condition or its clinical symptoms.

[0038] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space are called "isomers." Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers." When a compound has an asymmetric center, for example, when carbon atoms are bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center, described by the Cahn-Ingold-Prelog R- and S-ordering rules, or by the way the molecule rotates the plane of polarized light, called dextrorotatory or levorotatory (i.e., (+) or (-) isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0039] The compound of formula I or II can have one or more asymmetric centers or asymmetric axes.Unless otherwise indicated, the description or naming of a particular compound in this specification and claims is intended to include individual enantiomers, atropisomers and their mixtures, racemic or otherwise, and individual epimers, atropisomers and their mixtures.Methods for determining stereochemistry and separating stereoisomers are well known in the art (see the discussion in Chapter 4 of "Advanced Organic Chemistry", 4th Edition, J. March, John Wiley and Sons, New York, 1992).

[0040] Certain compounds may exhibit tautomerism. Tautomeric compounds can exist as two or more interconvertible species. The prototypical tautomer results from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and attempts to isolate individual tautomers usually produce mixtures whose chemical and physical properties match those of the compound. The position of the equilibrium depends on the chemical features within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates, whereas in phenols, the enol form predominates. Common protic tautomers include keto / enol (-C(=O)-CH-⇔-C(-OH)=CH-), amide / imidic acid (-C(=O)-NH-⇔-C(-OH)=N-), and amidine (-C(=NR)-NH-⇔-C(-NHR)=N-) tautomers. The latter two are particularly common in heteroaryl and heterocyclic rings, and the present invention encompasses all tautomeric forms of the compounds.

[0041] It has now been found that the present compounds of Formula I or II are inhibitors of Mat2A and as such may be utilized therapeutically for the treatment of cancer diseases including lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, esophageal carcinoma, glioblastoma multiforme, and mesothelioma.

[0042] These compounds are potent inhibitors of human methionine adenosyltransferase II alpha (MAT2A). MAT2A and MAT1A (methionine adenosyltransferase I alpha) are two genes that encode methionine adenosyltransferase activity, thereby generating S-adenosylmethionine (SAM), the principal methyl group donor in cells. MAT1A is a liver-specific SAM-generating enzyme, whereas MAT2A is widely expressed outside the liver. MAT2A was found to complex with MAT2B, an allosteric regulator of MAT2A, which acts like a variable resistor for MAT2A enzymatic activity. Upon binding of MAT2B to MAT2A, MAT2A undergoes a conformational change, increasing its affinity for methionine and SAM. The net effect is that MAT2A, when bound to MAT2B, becomes more active at low concentrations of methionine but is inhibited at high concentrations of methionine.

[0043] Loss-of-function mutations in tumor suppressor genes are important in the molecular pathogenesis of cancer. However, successful targeting of tumor suppressor genes has been elusive, primarily because mutant proteins cannot be directly inhibited for therapeutic benefit, whereas restoration of mutant function (such as that of mutant p53) has only been possible to date. Recent clinical successes of PARP in patients with BRCA1 / 2 deficiency have demonstrated that targeting conditional synthetic lethals (CSLs) resulting from loss-of-function mutations in tumor suppressor genes is a clinically validated approach for cancer treatment. CSLs are not only effective against tumor suppressor genes, but can also extend to genes located within the same genetic region as the tumor suppressor gene, eliminating them if the region is deleted. Methylthioadenosine phosphorylase (MTAP), one such gene, is located close to the tumor suppressor gene CDKN2A and is deleted in approximately 15% of all cancers. MTAP deletion is found in approximately 53% of glioblastoma multiforme (GBM), approximately 25% of pancreatic adenocarcinoma (PDAC), approximately 25% of melanoma, approximately 23% of lung squamous cell carcinoma, approximately 20% of head and neck squamous cell carcinoma, and approximately 15% of lung adenocarcinoma, including, but not limited to, this deletion occurs across multiple indications, many of which represent areas of high unmet medical need due to limited effective treatments. For glioblastoma, median survival is 14 months, and the latest approved treatments have not significantly extended overall survival (OS), with the standard of care (SoC) remaining unchanged for over a decade. The same is true for the majority of patients with PDAC, whose OS is less than one year. MTAP deletion is a truncal event that occurs early in tumor development and is believed to persist throughout all tumor progression, including metastasis. Therefore, its deletion represents an alteration that is not affected by tumor heterogeneity, genetic background, or resistance to any clinically approved drugs. The CSL relationship identifying MTAP deficiency appears to represent a true Achilles heel of multiple tumor indications.

[0044] MTAP is located close to the tumor suppressor gene CDKN2A on chromosome 9. When CDKN2A is deleted, MTAP is frequently co-deleted. Its deletion is considered a bystander effect and phenotypically neutral. MTAP is fundamental to the intracellular adenine and methionine salvage pathway. The methionine salvage pathway feeds into the SAM synthesis pathway. SAM levels are a key regulator of cancer cell proliferation, and large changes (increases or decreases) in SAM concentration lead to cell cycle arrest, so cancer cell proliferation must be tightly controlled. The importance of SAM levels to cancerous growth lies in the central role of protein, DNA, and RNA methylation, which acts as a checkpoint for cell health. Cells deficient in MTAP accumulate methylthioadenosine (MTA) and decarboxylated SAM (dcSAM) without adversely affecting the levels of any salvaged metabolites / products, including SAM. This accumulation creates a new stress in cells where, due to structural similarities, MTA acts as a competitive inhibitor of SAM-dependent responses. Deletion of MTAP forces cells to adapt to the novel MTA / SAM paradigm without any loss of viability, whereas MTAP-competent cells do not. This adaptation creates a strong dependency on methionine adenosyltransferase II alpha 2 (MAT2A), one of the enzymes that generates SAM in MTAP-deficient cells. This relationship between MTAP deletion and MAT2A-dependent conditional synthetic lethality (CSL) was confirmed in three large-scale shRNA screens (Marjon Cell Reports 2016, Kryukov Science 2016, and Mavrakis Science 2016).

[0045] Targeting MAT2A with small molecule inhibition is likely to benefit genetically defined patient populations that represent many areas of high unmet medical need.

[0046] The object of the present invention is the use of compounds of formula I or II for preparing medicaments for the treatment, prevention and / or delay of cancer, in particular lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, esophageal carcinoma, glioblastoma multiforme and mesothelioma, more particularly for the treatment of cancer, including lung adenocarcinoma, lung squamous cell carcinoma, pancreatic adenocarcinoma, glioblastoma multiforme and head and neck squamous cell carcinoma, the manufacture thereof and medicaments based on compounds of formula I or II according to the invention.

[0047] A further object of the present invention are all forms of optically pure enantiomers, racemates or diastereomeric mixtures of the compounds of formula I or II.

[0048] In particular, the present invention provides compounds of formula I: TIFF0007749602000004.tif75170[In the formula, X 1 is either N or CH, X 3 is N or CR 3 Either The dotted line is R 5 represents a single bond when is oxo, or R 5 represents a double bond when is -NH2, R 1 is one or more, in particular one to three, more particularly one or two substituents R 1a (C1-C6) alkyl optionally substituted with one or more, in particular one to three, more particularly one or two substituents R 1b (C1-C6)alkoxy optionally substituted with one or more, in particular one to three, more particularly one or two substituents R 1c (C3-C8)cycloalkyl optionally substituted with one or more, in particular one to three, more particularly one or two substituents R 1d heteroaryl optionally substituted with one or more, in particular one to three, more particularly one or two substituents R 1eor one or more, in particular one to three, more in particular one or two, substituents R 1f phenyl optionally substituted with R 1a and R 1b are each independently selected from (C-C)cycloalkyl, hydroxyl, heteroaryl, heterocycloalkyl, and phenyl, where heteroaryl, heterocycloalkyl, or phenyl may contain one or more, particularly one to three, more particularly one or two, substituents R 1g may be substituted with R 1c , R 1d , R 1e and R 1f are each independently selected from halogen, cyano, oxo, hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy-(C1-C6)alkyl, heteroaryl, heterocycloalkyl, and phenyl; R 1g are each independently selected from halogen, cyano, hydroxyl, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, hydroxy(C1-C6)alkyl, and (C1-C6)alkoxy-(C1-C6)alkyl; R 2 is hydrogen, halogen, amino, (C1-C6) alkyl, (C1-C6) alkoxy, halo(C1-C6) alkyl, halo(C1-C6) alkoxy, one or more, in particular one to three, more in particular one or two substituents R 2a (C3-C6)cycloalkyl optionally substituted with one or more, in particular one to three, more particularly one or two substituents R 2b(C3-C6)cycloalkyl-(C1-C6)alkyl optionally substituted with one or more, in particular one to three, more particularly one or two substituents R 2c (C3-C6)cycloalkyl-(C1-C6)alkoxy optionally substituted with one or more, in particular one to three, more particularly one or two substituents R 2d or one or more, in particular one to three, more in particular one or two, substituents R 2e phenyl optionally substituted with R 2a , R 2b , R 2c , R 2d and R 2e are each independently selected from halogen, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, and halo(C1-C6)alkoxy; R 3 is hydrogen, halogen, cyano, amino, (C1-C6) alkyl, (C1-C6) alkoxy, halo(C1-C6) alkyl, halo(C1-C6) alkoxy, one or more, in particular one to three, more in particular one or two substituents R 3a (C3-C6)cycloalkyl optionally substituted with one or more, in particular one to three, more particularly one or two substituents R 3b (C3-C6)cycloalkyl-(C1-C6)alkyl optionally substituted with one or more, in particular one to three, more particularly one or two substituents R 3c (C3-C6)cycloalkyl-(C1-C6)alkoxy optionally substituted with one or more, in particular one to three, more particularly one or two substituents R 3d or one or more, in particular one to three, more in particular one or two, substituents R 3e phenyl optionally substituted with R 3a , R 3b , R 3c , R 3dand R 3e are each independently selected from halogen, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, and halo(C1-C6)alkoxy; R 4 is hydrogen, cyano, hydroxy, halogen, amino, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, (C1-C6)alkoxy-(C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, one or more, in particular one to three, more in particular one or two substituents R 4a (C3-C6)cycloalkyl optionally substituted with one or more, in particular one to three, more particularly one or two substituents R 4b (C3-C6)cycloalkyl-(C1-C6)alkyl optionally substituted with one or more, in particular one to three, more particularly one or two substituents R 4c (C3-C6)cycloalkyl-(C1-C6)alkoxy optionally substituted with one or more, in particular one to three, more particularly one or two substituents R 4d is heterocycloalkyl optionally substituted with R 4a , R 4b , R 4c and R 4d are each independently selected from hydrogen and (C1-C6) alkyl; R 5 is -NH2 or oxo] and pharmaceutically acceptable salts thereof.

[0049] In certain embodiments, the present invention provides a compound of formula I': TIFF0007749602000005.tif76170[where, X 1 , X 3 , R 1 , R 2 and R 4 is as defined herein.

[0050] In certain embodiments, the present invention provides a compound of formula I″: TIFF0007749602000006.tif78170[where, X 1 , X 3 , R 1 , R 2 and R 4 is as defined herein.

[0051] Furthermore, certain X 1 , X 3 , R 1 , R 1a , R 1b , R 1c , R 1d , R 1e , R 1r , R 1g , R 2 , R 2a , R 2b , R 2c , R 2d , R 2e , R 3 , R 3a , R 3b , R 3c , R 3d , R 3e , R 4 , R 4a , R 4b , R 4c , R 4d , and R 5 All embodiments relating to the other X disclosed herein may be combined with any other X 1 , X 3 , R 1 , R 1a , R 1b , R 1c , R 1d , R 1e , R 1r , R 1g , R 2 , R 2a , R 2b , R 2c , R 2d , R 2e , R 3 , R 3a , R 3b , R 3c , R3d , R 3e , R 4 , R 4a , R 4b , R 4c , R 4d , and R 5 It should be understood that the present invention can be combined with any other embodiment related to the present invention.

[0052] Certain embodiments of the present invention are compounds of formula I, I' or I'' wherein X 3 is CR 3 [is] related to.

[0053] Certain embodiments of the present invention are compounds of formula I, I' or I'' wherein X 1 is N].

[0054] Other particular embodiments of the present invention are compounds of formula I, I' or I'' wherein X 1 is CH].

[0055] Certain embodiments of the present invention are compounds of formula I, I', I'' wherein R 1 is one R 1a (C1-C6) alkyl optionally substituted with one R 1c (C3-C6)cycloalkyl optionally substituted with one or two R 1d heteroaryl optionally substituted with one R 1e heterocycloalkyl optionally substituted with, or one or two R 1f and more particularly, phenyl optionally substituted by R 1 is one R 1a (C1-C3) alkyl optionally substituted with one R 1c (C3-C6)cycloalkyl optionally substituted with one R 1d pyrazolyl, optionally substituted with one R 1d indazolyl, optionally substituted with one R 1d Indolyl, optionally substituted with one R 1dbenzo[d]oxazolyl optionally substituted with one R 1d benzo[d]thiazolyl optionally substituted with one R 1d benzo[d]imidazolyl optionally substituted with one R 1d dioxepanyl optionally substituted with one R 1d oxazolyl optionally substituted with one R 1d thiazolyl optionally substituted with one R 1d pyridinyl, optionally substituted with one R 1d pyrimidinyl, optionally substituted with one R 1e dihydropyrrolo[1,2-c]imidazolyl optionally substituted with one R 1e oxepanyl optionally substituted with one R 1e dihydro-indolyl optionally substituted with one R 1e 1,4-dioxepanyl optionally substituted with one R 1e tetrahydrofuranyl optionally substituted with one R 1e tetrahydropyranyl optionally substituted with one R 1e piperidinyl, optionally substituted with one R 1e oxaspiro[2.5]octanyl optionally substituted with one R 1e dihydrobenzofuranyl optionally substituted by, or one or two R 1f and more specifically, phenyl optionally substituted with R 1 is R 1a (C1-C3) alkyl optionally substituted with one R 1c cyclopentyl, indazol-4-yl, optionally substituted with one R 1d pyrazolyl, optionally substituted with one R 1d oxazolyl optionally substituted with one R 1d thiazolyl optionally substituted with one or two R 1d pyridinyl, optionally substituted with one R 1d pyrimidinyl, oxepanyl, tetrahydrofuranyl, optionally substituted with one R1e tetrahydropyranyl optionally substituted with one R 1e piperidinyl, oxaspiro[2.5]octanyl, 2,3-dihydrobenzofuranyl or one or two R 1f and even more specifically, phenyl optionally substituted with R 1 is one or two R 1d pyridinyl, oxaspiro[2.5]octanyl, 2,3-dihydrobenzofuranyl, optionally substituted with one R 1e tetrahydropyranyl optionally substituted with one or two R 1f and most particularly tetrahydropyranyl optionally substituted with one (C1-C3) alkyl, and more particularly alpha methyl.

[0056] Certain embodiments of the present invention are compounds of formula I, I′ or I″, wherein R 1 is one R 1a (C1-C6) alkyl optionally substituted with one R 1c (C3-C6)cycloalkyl optionally substituted with one or two R 1d heteroaryl optionally substituted with one R 1e heterocycloalkyl optionally substituted with, or one or two R 1f phenyl, which may be substituted by R 1 is one R 1a (C1-C3) alkyl optionally substituted with one R 1c (C3-C6)cycloalkyl optionally substituted with one R 1d pyrazolyl, optionally substituted with one R 1d oxazolyl optionally substituted with one R 1d thiazolyl optionally substituted with one or two R 1d pyridinyl, optionally substituted with one R 1d pyrimidinyl, optionally substituted with one R 1etetrahydrofuranyl optionally substituted with one R e tetrahydropyranyl optionally substituted with one R 1e piperidinyl, optionally substituted with one R 1e oxaspiro[2.5]octanyl optionally substituted with one R 1e 2,3-dihydrobenzofuranyl optionally substituted by one or two R 1f and more particularly, phenyl optionally substituted by R 1 is R 1a (C1-C3) alkyl optionally substituted with one R 1c cyclopentyl optionally substituted with one R 1d pyrazolyl, optionally substituted with one R 1d oxazolyl optionally substituted with one R 1d thiazolyl optionally substituted with one or two R 1d pyridinyl, optionally substituted with one R 1d pyrimidinyl, tetrahydrofuranyl, tetrahydropyranyl, optionally substituted with one R 1e piperidinyl, oxaspiro[2.5]octanyl, 2,3-dihydrobenzofuranyl or one or two R 1f and more specifically, phenyl optionally substituted with R 1 is one or two R 1d pyridinyl, tetrahydropyranyl or one or two R 1f and phenyl optionally substituted by.

[0057] Certain embodiments of the present invention are compounds of formula I, I′ or I″, wherein R 1 is one or two R 1d Heteroaryl optionally substituted with (at least one R 1d is ortho-substituted), one R 1d heterocycloalkyl alpha-substituted with one or two R 1fphenyl substituted with (at least one R 1f is ortho-substituted), and in particular R 1 is one or two R 1d pyridinyl substituted with (at least one R 1d is ortho-substituted), one R 1e tetrahydrofuranyl substituted with (at least one R 1e is replaced by alpha), one R 1e alpha-substituted tetrahydropyranyl, oxaspiro[2.5], or one R 1e and more specifically, 2,3-dihydrobenzofuranyl substituted with R 1 is one R 1e alpha-substituted tetrahydrofuranyl, one R 1e alpha-substituted tetrahydropyranyl, oxaspiro[2.5]octanyl, or one R 1e and more specifically, 2,3-dihydrobenzofuranyl substituted with R 1 is one R 1e is tetrahydropyranyl alpha-substituted by

[0058] A more particular embodiment of the present invention is a compound of formula I, I' or I'' wherein R 1 is one or two R 1d heteroaryl optionally substituted with one R 1e heterocycloalkyl optionally substituted with, or one or two R 1f and phenyl optionally substituted by.

[0059] Certain embodiments of the present invention are compounds of formula I, I′ or I″, wherein R 1a and R 1b are each independently selected from heteroaryl, heterocycloalkyl, and phenyl, particularly R 1a is selected from tetrahydrofuranyl, pyridinyl, oxetanyl or oxazolyl.

[0060] Certain embodiments of the present invention are compounds of formula I, I′ or I″, wherein R 1c , R 1d , R 1e and R 1f are each independently selected from halogen, oxo, cyano, hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl and halo(C1-C6)alkoxy, particularly R 1c , R 1d , R 1e and R 1f are each independently selected from chloro, fluoro, oxo, cyano, hydroxy, (C1-C3)alkyl, (C1-C3)alkoxy, and halo(C1-C3)alkyl, more specifically, R 1c , R 1d , R 1e and R 1f are each independently cyano, chloro, and (C1-C3) alkyl, most particularly R 1d are each independently selected from cyano, chloro and methyl.

[0061] Certain embodiments of the present invention are compounds of formula I, I′ or I″, wherein R 1are 2,3-dihydrobenzofuranyl, 2-hydroxycyclopentyl, 3-hydroxycyclopentyl, 1-(tetrahydrofuran-2-yl)ethyl, 1-tetrahydrofuran-3-yl-ethyl, 1-pyridin-2-yl-ethyl, oxepan-3-yl, 1,4-dioxepan-6-yl, dihydro-1H-indol-4-yl, 1-(oxetan-3-yl)ethyl, 1-(oxazol-5-yl)ethyl, indazol-4-yl, oxaspiro[2.5]octanyl, 4-methyloxazol-5-yl, 2-methoxy-phenyl, 3-methyl-phenyl, 2-methyl-phenyl, 3-fluoro-2-methoxyphenyl, 2-methylbenzonitrile, 2-methoxybenzonitrile, 2-ethoxybenzonitrile, 2-chlorophenyl, 3-chlorophenyl, 4-fluoro-2-methylphenyl, 3-fluoro-2-methylphenyl, 3-fluorophenyl, 2-fluorophenyl, 2,6-difluorophenyl, 2,3-dimethylphenyl, phenyl, 2,3-difluorophenyl, 2-fluoro-3-methylphenyl, 3-methoxyphenyl, 3,5-difluorophenyl, 3,4-difluorophenyl, 2-trifluoromethyl-phenyl, 3-(fluoromethyl)-2-methylphenyl, 3-ethylphenyl, 3-chloro-2-fluorophenyl, 2-chloro-5-fluorophenyl, 2-chloro-4-fluorophenyl, 2,3-dichlorophenyl, benzo[d]oxazole-4 -yl, benzo[d]imidazolyl, benzo[d]thiazol-7-yl, 2-oxopiperidin-4-yl, 2-methylpyrazol-3-yl, 1-ethyl-1H-pyrazol-5-yl, 2-methylpyridin-3-yl, picolinonitrile, 2-methoxypyridin-3-yl, 2-(trifluoromethyl)pyridin-3-yl, 4-methylpyridin-3-yl, 4-fluoro-2-methoxypyridin-3-yl, indolyl, 2-chloropyridin-3-yl, 6-methylpyridin-3-yl, 2 ...2-methylpyridin-3-yl, 2-methylpyridin-3-yl, 2-methylpyridin-3-yl, 2-methylpyridin-3-yl, 2-methylpyridin-3-yl, 2-methylpyridin-3-yl, 2-methylpyridin-3-yl, 2-methylpyridin-3-yl, 2-methylpyridin-3-yl, 2-methylpyridin-3-yl, 2-methylpyridin-3-yl, 2-methylpyridin-3-yl, 2-methylpyridin-3-yl, 2-methylpyridin-3-yl, 2- thoxypyridin-2-yl, 4-methylpyrimidin-5-yl, trifluoromethoxypyridin-2-yl, dihydrobenzofuranyl, tetrahydrofuranyl, 4-methyltetrahydrofuran-3-yl, methyl-tetrahydro-2H-pyran-3-yl, 6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4-yl or 4-methylthiazol-5-yl, in particular R. 1is 2,3-dihydrobenzofuranyl, oxaspiro[2.5]octanyl, oxepan-3-yl, 3-methyl-phenyl, 2-methyl-phenyl, 2-methylbenzonitrile, 2-chlorophenyl, phenyl, 2-methylpyridin-3-yl, 4-methylpyridin-3-yl, 4-2-chloropyridin-3-yl, 2-methyl-tetrahydro-2H-pyran-3-yl, or 4-methylpyrimidin-5-yl, most particularly R 1 is 2-methyl-tetrahydro-2H-pyran-3-yl].

[0062] Certain embodiments of the present invention are compounds of formula I, I′ or I″, wherein R 1 are 2,3-dihydrobenzofuranyl, 2-hydroxycyclopentyl, 3-hydroxycyclopentyl, 1-(tetrahydrofuran-2-yl)ethyl, 1-tetrahydrofuran-3-yl-ethyl, 1-pyridin-2-yl-ethyl, 1-(oxetan-3-yl)ethyl, 1-(oxazol-5-yl)ethyl, oxaspiro[2.5]octanyl, 4-methyloxazol-5-yl, 2-methoxy-phenyl, 3-methyl-phenyl, 2-methyl-phenyl, 3-fluoro-2-methoxyphenyl, 2-methylbenzonitrile, 2-methoxybenzonitrile, 2-ethoxybenzonitrile, 2-chlorophenyl, 3-methoxyphenyl, 3,5-difluorophenyl phenyl, 3-ethylphenyl, 2-oxopiperidin-4-yl, 2-methylpyrazol-3-yl, 1-ethyl-1H-pyrazol-5-yl, 2-methylpyridin-3-yl, picolinonitrile, 2-methoxypyridin-3-yl, 2-(trifluoromethyl)pyridin-3-yl, 4-methylpyridin-3-yl, 4-fluoro-2-methoxypyridin-3-yl, 2-chloropyridin-3-yl, 6-methoxypyridin-2-yl, 4-methylpyrimidin-5-yl, tetrahydrofuranyl, 4-methyltetrahydrofuran-3-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4-yl or 4-methylthiazol-5-yl, in particular R 1is 2,3-dihydrobenzofuranyl, oxaspiro[2.5]octane, 3-methyl-phenyl, 2-methyl-phenyl, 2-methylbenzonitrile, 2-chlorophenyl, phenyl, 2-methylpyridin-3-yl, 4-methylpyridin-3-yl, 4, 2-chloropyridin-3-yl or 4-methylpyrimidin-5-yl].

[0063] Another embodiment of the present invention is a compound of formula I, I' or I'' wherein R 2 is halogen, (C1-C6) alkyl, (C1-C6) alkoxy, halo(C1-C6) alkyl, halo(C1-C6) alkoxy, one R 2a (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkoxy, optionally substituted with one or two R 2d Heterocycloalkyl optionally substituted with NR 2f R 2g or phenyl, especially R 2 is halogen, (C1-C6) alkyl, (C1-C6) alkoxy, halo(C1-C6) alkyl, halo(C1-C6) alkoxy, one R 2a (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkoxy, optionally substituted with one or two R 2d or phenyl, more specifically R 2 is halogen, (C1-C3) alkyl, (C1-C3) alkoxy, halo(C1-C3) alkyl, halo(C1-C3) alkoxy, one R 2a cyclopropyl, optionally substituted with one R 2a cyclobutyl optionally substituted with one R 2a cyclopentyl optionally substituted with (C3-C6)cycloalkyl-(C1-C3)alkoxy, 4,5-dihydrofuran-3-yl, 7-azabicyclo[2.2.1]heptan-7-yl, 3-azabicyclo[2.2.1]heptan-3-yl, one or two R 2dtetrahydropyranylazetidinyl, or phenyl, optionally substituted by R 2 is halogen, (C1-C3)alkyl, (C1-C3)alkoxy, halo(C1-C3)alkyl, halo(C1-C3)alkoxy, cyclopropyl optionally substituted with halogen, or (C1-C3)alkyl, cyclobutyl, cyclopentyl, cyclopropyloxy, 4,5-dihydrofuran-3-yl, 7-azabicyclo[2.2.1]heptan-7-yl, 3-azabicyclo[2.2.1]heptan-3-yl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl optionally substituted with one or two (C1-C3)alkyl, and even more particularly, R 2 is halo(C1-C3)alkyl, halo(C1-C3)alkoxy, cyclopropyl optionally substituted with halogen, or (C1-C3)alkyl, most particularly R 2 is trifluoromethyl, difluoromethoxy, trifluoromethoxy or cyclopropyl.

[0064] Another embodiment of the present invention is a compound of formula I, I' or I'' wherein R 2a , R 2b , R 2c , R 2d , and R 2e are each independently selected from halogen and (C1-C6) alkyl, particularly R 2a , R 2b , R 2c , R 2d , and R 2e are each independently selected from halogen and (C-C) alkyl, more specifically, R 2a , R 2b , R 2c , R 2d , and R 2e are each independently selected from chloro, fluoro and methyl.

[0065] Another embodiment of the present invention is a compound of formula I, I' or I'' wherein R 2f and R2g are each independently selected from hydrogen or (C1-C3) alkyl, particularly R 2f and R 2g wherein one of the groups is hydrogen and the other is (C1-C3) alkyl.

[0066] Yet another embodiment of the present invention is a compound of formula I, I' or I'' wherein R 3 is hydrogen, halogen or cyano, especially R 3 is hydrogen, chloro, fluoro or cyano, more specifically R 3 is hydrogen].

[0067] Yet another embodiment of the present invention is a compound of formula I, I' or I'' wherein R 3a , R 3b , R 3c , R 3d and R 3e are each independently selected from halogen and (C1-C3) alkyl.

[0068] A further embodiment of the present invention is a compound of formula I, I′ or I″, wherein R 4 is hydrogen, cyano, halogen, (C1-C6) alkyl, (C1-C6) alkoxy or -CONR 4b R 4c and especially R 4 is hydrogen, cyano, chloro, fluoro or (C1-C3) alkyl, more specifically R 4 is hydrogen].

[0069] A further embodiment of the present invention is a compound of formula I, I′ or I″, wherein R 4b or R 4c is hydrogen].

[0070] Yet another embodiment of the present invention is a compound of formula I, I' or I'' wherein R 5 is -NH2].

[0071] Particular compounds of formula I of the present invention are those selected from the group consisting of: 4-Amino-7-cyclopropyl-1-(o-tolyl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-7-cyclopropyl-1-(2-methoxyphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-7-(tert-butyl)-1-(o-tolyl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-1-(2-methoxyphenyl)-7-phenylpyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-7-(3,3-difluoroazetidin-1-yl)-1-(o-tolyl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-7-cyclopropyl-1-(tetrahydrofuran-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-7-cyclopropyl-1-(2-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-7-cyclopropyl-1-(2-oxopiperidin-4-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-7-cyclopropyl-1-((cis)-2-methyltetrahydrofuran-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-7-cyclopropyl-1-(o-tolyl)pyrido[4,3-d]pyrimidin-2(1H)-one 4-Amino-7-cyclopropyl-1-(2-methylpyridin-3-yl)quinazolin-2-one 4-Amino-7-cyclopropyl-1-(2-methylphenyl)quinazolin-2-one 7-Cyclopropyl-1-(2-methylphenyl)quinazoline-2,4-dione 4-Amino-7-cyclopropyl-1-(o-tolyl)pyrimido[4,5-d]pyrimidin-2(1H)-one 7-Cyclopropyl-1-(2-methylpyridin-3-yl)quinazoline-2,4-dione 4-Amino-7-cyclopropyl-1-(2-methoxypyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-7-cyclopropyl-6-fluoro-1-(2-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 7-Cyclopropyl-1-(2-methylphenyl)pyrido[2,3-d]pyrimidine-2,4-dione 3-(4-amino-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)picolinonitrile 4-Amino-7-cyclopropyl-1-(oxan-3-yl)pyrido[2,3-d]pyrimidin-2-one 4-Amino-7-cyclopropyl-1-[1-(oxolan-3-yl)ethyl]pyrido[2,3-d]pyrimidin-2-one 4-Amino-7-cyclopropyl-1-(3-fluoro-2-methoxyphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one 3-(4-amino-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)-2-methylbenzonitrile 4-Amino-1-(2-methylpyridin-3-yl)-7-propan-2-ylpyrido[2,3-d]pyrimidin-2-one 4-Amino-7-cyclopropyl-1-(2,3-dihydrobenzofuran-4-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-6-chloro-7-cyclopropyl-1-(2-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 3-(4-amino-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)-2-methoxybenzonitrile 3-(4-amino-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)-2-ethoxybenzonitrile 4-Amino-7-cyclopropyl-1-(1-(tetrahydrofuran-2-yl)ethyl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-1-(2-methylpyridin-3-yl)-7-(oxetan-3-yl)quinazolin-2(1H)-one 7-Cyclopropyl-1-(2-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4-dione 4-Amino-7-((1RS,2RS)-2-methylcyclopropyl)-1-(2-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-7-cyclopentyl-1-(2-methyl-3-pyridyl)pyrido[2,3-d]pyrimidin-2-one 4-Amino-7-cyclopropyl-1-((1SR,2RS)-2-hydroxycyclopentyl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-2-cyclopentyl-7-(o-tolyl)pyrazolo[3,4-d]pyrimidin-6-one; Formic acid 4-Amino-7-cyclopentyl-1-(4-methylpyrimidin-5-yl)pyrido[2,3-d]pyrimidin-2-one 4-Amino-7-cyclopropyl-1-(3-fluoro-2-methylphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-7-cyclopropyl-1-[(3R)-oxan-3-yl]pyrido[2,3-d]pyrimidin-2-one 4-Amino-7-cyclopropyl-1-[(3S)-oxan-3-yl]pyrido[2,3-d]pyrimidin-2-one 4-Amino-7-cyclopropyl-1-(4-methyltetrahydrofuran-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-7-cyclopropyl-2-oxo-1-(o-tolyl)-1,2-dihydropyrido[2,3-d]pyrimidine-5-carboxamide 4-Amino-1-(2-methoxy-3-pyridyl)-7-tetrahydropyran-2-yl-pyrido[2,3-d]pyrimidin-2-one 4-Amino-7-[(1S,4R)-3-azabicyclo[2.2.1]heptan-3-yl]-1-(2-methylpyrazol-3-yl)pyrido[2,3-d]pyrimidin-2-one; Formic acid 4-Amino-1-(2-methylpyridin-3-yl)-7-(trifluoromethyl)quinazolin-2-one 4-Amino-7-cyclopropyl-1-[rac(2R,3S)-2-methyloxolan-3-yl]pyrido[2,3-d]pyrimidin-2-one 4-Amino-7-cyclobutyl-1-(2-methyl-3-pyridyl)pyrido[2,3-d]pyrimidin-2-one; Formic acid 4-Amino-7-cyclopropyloxy-1-(2-methylpyridin-3-yl)quinazolin-2-one 4-Amino-1-(2-methylpyridin-3-yl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-7-[(7-azabicyclo[2.2.1]heptan-7-yl]-1-(4-methylthiazol-5-yl)pyrido[2,3-d]pyrimidin-2-one; Formic acid 4-Amino-7-cyclopropyl-1-(3-hydroxycyclopentyl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-7-(difluoromethoxy)-1-(2-methylpyridin-3-yl)quinazolin-2(1H)-one 4-Amino-7-(difluoromethyl)-1-(2-methylpyridin-3-yl)quinazolin-2(1H)-one 4-Amino-7-[(1R,2S)-2-fluorocyclopropyl]-1-(2-methyl-3-pyridyl)pyrido[2,3-d]pyrimidin-2-one 4-Amino-7-cyclopropyl-1-(2-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile 3-(4-amino-7-isopropyl-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)-2-methoxybenzonitrile 4-Amino-7-cyclopropyl-2-oxo-1-(o-tolyl)-1,2-dihydropyrido[2,3-d]pyrimidine-5-carbonitrile 4-Amino-7-methoxy-1-(2-methylpyridin-3-yl)quinazolin-2(1H)-one 4-amino-1-(2-methylpyridin-3-yl)-7-(trifluoromethoxy)quinazolin-2(1H)-one 4-Amino-7-(4,5-dihydrofuran-3-yl)-1-(2-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-1-(2-methylpyridin-3-yl)-7-(tetrahydrofuran-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-7-cyclopropyl-1-(2-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2-one 4-Amino-7-cyclopropyl-1-(2-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2-one 4-Amino-7-cyclopropyl-1-(4-methylthiazol-5-yl)pyrido[2,3-d]pyrimidin-2-one 4-Amino-7-cyclopropyl-1-(4-methylpyrimidin-5-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-7-cyclopropyl-1-(2-(trifluoromethyl)pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-7-cyclopropyl-1-(2-methylpyrazol-3-yl)pyrido[2,3-d]pyrimidin-2-one 4-Amino-7-cyclopropyl-1-(2,3-dihydrobenzofuran-4-yl)quinazolin-2(1H)-one (R)-4-Amino-1-(tetrahydro-2H-pyran-3-yl)-7-(trifluoromethyl)quinazolin-2(1H)-one 4-Amino-7-cyclopropyl-1-(4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-7-ethyl-1-(2-methylpyridin-3-yl)quinazolin-2(1H)-one 4-Amino-7-[(1S,2R)-2-fluorocyclopropyl]-1-[(3R)-tetrahydropyran-3-yl]pyrido[2,3-d]pyrimidin-2-one 4-Amino-7-cyclopropyl-1-(4-methyloxazol-5-yl)pyrido[2,3-d]pyrimidin-2-one 3-(4-amino-6-chloro-7-isopropyl-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)-2-methoxybenzonitrile 4-Amino-7-cyclopropyl-1-((R)-1-((S)-tetrahydrofuran-3-yl)ethyl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-7-cyclopropyl-1-((R)-1-((R)-tetrahydrofuran-3-yl)ethyl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-7-(2-fluoropropan-2-yl)-1-(2-methylpyridin-3-yl)quinazolin-2-one 4-Amino-5-methoxy-1-(2-methylpyridin-3-yl)-7-(trifluoromethyl)quinazolin-2(1H)-one 4-Amino-7-cyclopropyl-1-(4-fluoro-2-methoxypyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-5-fluoro-1-(2-methylpyridin-3-yl)-7-(trifluoromethyl)quinazolin-2(1H)-one 4-Amino-7-cyclopropyl-1-(1-ethyl-1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-7-chloro-1-(o-tolyl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-7-cyclopropyl-1-(2,3-dihydrobenzofuran-7-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 1-Amino-4-(2-methoxyphenyl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one 4-Amino-1-(2-chlorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2-one 4-Amino-7-cyclopropyl-1-[(1R)-1-[(3S)-oxolan-3-yl]ethyl]pyrido[2,3-d]pyrimidin-2-one 4-Amino-7-cyclopropyl-1-[(1R)-1-[(3R)-oxolan-3-yl]ethyl]pyrido[2,3-d]pyrimidin-2-one 3-(4-amino-6-chloro-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)-2-methoxybenzonitrile 4-Amino-7-cyclopropyl-1-(4-oxaspiro[2.5]octan-8-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-6-chloro-7-cyclopropyl-1-(2-methoxypyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-7-cyclopropyl-1-(4-fluoro-2-methylphenyl)pyrido[2,3-d]pyrimidin-2-one 4-Amino-7-cyclopropyl-1-(3-ethylphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-7-cyclopropyl-1-(m-tolyl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-7-cyclopropyl-1-(3,5-difluorophenyl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-7-cyclopropyl-1-(6-methoxypyridin-2-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-7-cyclopropyl-1-(3-methoxyphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-7-cyclopropyl-1-(2,3-difluorophenyl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-7-cyclopropyl-1-phenylpyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-7-cyclopropyl-1-(1-(oxazol-5-yl)ethyl)pyrido[2,3-d]pyrimidin-2(1H)-one 3-(4-amino-2-oxo-7-(trifluoromethyl)quinazolin-1(2H)-yl]-2-methylbenzonitrile 3-(4-amino-2-oxo-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-1(2H)-yl)-2-methylbenzonitrile 4-Amino-7-cyclopropyl-1-(2,6-difluorophenyl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-7-cyclopropyl-1-(2-fluorophenyl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-7-cyclopropyl-1-(3-fluorophenyl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-7-cyclopropyl-1-[1-(oxetan-3-yl)ethyl]pyrido[2,3-d]pyrimidin-2-one 4-Amino-7-(difluoromethoxy)-1-(2-methylphenyl)pyrido[2,3-d]pyrimidin-2-one 4-Amino-7-cyclopropyl-1-(1-pyridin-2-ylethyl)pyrido[2,3-d]pyrimidin-2-one 4-Amino-1-(2-methyl-3-pyridyl)-7-(2,2,2-trifluoroethyl)quinazolin-2-one hydrochloride 4-Amino-7-cyclopropyl-1-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-1-(2-chloropyridin-3-yl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-2-cyclopentyl-7-(2-methyl-3-pyridyl)pyrazolo[3,4-d]pyrimidin-6-one 4-Amino-5-chloro-1-(2-methylpyridin-3-yl)-7-(trifluoromethyl)quinazolin-2(1H)-one 4-Amino-1-(3-fluoro-2-methylphenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-7-cyclopropyl-1-(1H-indol-4-yl)pyrido[2,3-d]pyrimidin-2-one 4-Amino-7-cyclopropyl-1-[6-(trifluoromethoxy)pyridin-2-yl]pyrido[2,3-d]pyrimidin-2-one 4-Amino-1-(2,3-dihydrobenzofuran-4-yl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-1-(3-chloro-2-fluorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2-one 4-Amino-1-(2,3-dihydro-1-benzofuran-4-yl)-7-(trifluoromethoxy)quinazolin-2-one 4-Amino-1-(3-fluoro-2-methylphenyl)-7-(trifluoromethoxy)quinazolin-2-one 3-[4-amino-2-oxo-7-(trifluoromethoxy)quinazolin-1-yl]-2-methylbenzonitrile 4-Amino-7-cyclopropyl-1-(2,3-dihydro-1H-indol-4-yl)pyrido[2,3-d]pyrimidin-2-one 4-Amino-1-(2-chloro-5-fluorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2-one 4-Amino-1-(2-chloro-4-fluorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-7-cyclopropyl-1-(2,5-difluorophenyl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-7-(ethylamino)-1-(o-tolyl)quinazolin-2-one 4-Amino-1-(3-chlorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2(1H)-one 3-(4-amino-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)benzonitrile 4-Amino-7-(difluoromethoxy)-1-(4-oxaspiro[2.5]octan-8-yl)quinazolin-2(1H)-one 1-amino-4-(2-chlorophenyl)-6-(trifluoromethyl)pyrido[1,2-c]pyrimidin-3-one 4-Amino-1-(benzo[d]oxazol-4-yl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-7-cyclopropyl-1-(3,4-difluorophenyl)pyrido[2,3-d]pyrimidin-2(1H)-one 3-(4-amino-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)-2-methylbenzonitrile 3-(4-amino-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)-2-methylbenzonitrile 4-Amino-7-(difluoromethoxy)-1-(o-tolyl)quinazolin-2(1H)-one 3-(4-amino-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)-2-chlorobenzonitrile 4-Amino-7-cyclopropyl-1-[(8S)-4-oxaspiro[2.5]octan-8-yl]pyrido[2,3-d]pyrimidin-2-one 4-Amino-7-cyclopropyl-1-[(8R)-4-oxaspiro[2.5]octan-8-yl]pyrido[2,3-d]pyrimidin-2-one 4-Amino-1-(1H-benzo[d]imidazol-4-yl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-7-cyclopropyl-1-(1H-indazol-4-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-7-cyclopropyl-1-(2,3-dimethylphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-1-(2-chloropyridin-3-yl)-7-(difluoromethoxy)quinazolin-2(1H)-one 4-Amino-1-(2-chloropyridin-3-yl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-1-(2-chloropyridin-3-yl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-7-(difluoromethoxy)-1-(m-tolyl)quinazolin-2(1H)-one 4-Amino-7-(difluoromethoxy)-1-(2-fluoro-3-methylphenyl)quinazolin-2(1H)-one 4-Amino-7-cyclopropyl-1-[2-(trifluoromethyl)phenyl]pyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-7-cyclopropyl-1-(3-(fluoromethyl)-2-methylphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-1-(2-chloro-3-methylphenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2-one 4-Amino-1-(3-chloro-2-methylphenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2-one 4-Amino-7-cyclopropyl-1-(2,3-dichlorophenyl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-7-cyclopropyl-1-(2-fluoro-3-methylphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one 3-(4-amino-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)-2-fluorobenzonitrile (S)-4-Amino-7-cyclopropyl-1-(oxepan-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (R)-4-Amino-7-cyclopropyl-1-(oxepan-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-7-cyclopropyl-1-(3-hydroxy-2-methylphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-7-(difluoromethoxy)-1-(3-fluoro-2-methylphenyl)quinazolin-2(1H)-one 4-Amino-7-cyclopropyl-1-[rac(2S,3S)-2-methyltetrahydropyran-3-yl]pyrido[2,3-d]pyrimidin-2-one 4-Amino-1-(benzo[d]thiazol-7-yl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-7-cyclopropyl-1-((2S,3R)-2-methyltetrahydro-2H-pyran-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-7-cyclopropyl-1-((2R,3S)-2-methyltetrahydro-2H-pyran-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (-)-4-Amino-1-(2-chloro-3-fluorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2(1H)-one (+)-4-Amino-1-(2-chloro-3-fluorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2(1H)-one (-)-4-Amino-1-(2-chlorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2(1H)-one (+)-4-Amino-1-(2-chlorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-7-cyclopropyl-6-(difluoromethoxy)-1-(o-tolyl)pyrido[2,3-d]pyrimidin-2-one 4-Amino-7-cyclopropyl-1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)pyrido[2,3-d]pyrimidin-2-one; Formic acid 4-(2-chlorophenyl)-6-cyclopropyl-1-imino-pyrido[1,2-c]pyrimidin-3-one; Formic acid 4-Amino-7-cyclopropyl-1-[2-(trifluoromethoxy)phenyl]pyrido[2,3-d]pyrimidin-2-one 4-Amino-1-(2-chloro-3-pyridyl)-7-(trifluoromethoxy)quinazolin-2-one 4-Amino-7-cyclopropyl-1-(6-(difluoromethoxy)pyridin-2-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-7-cyclopropyl-1-(1,4-dioxepan-6-yl)pyrido[2,3-d]pyrimidin-2-one 4-Amino-7-cyclopropyl-1-(3-fluoro-2-methylphenyl)quinazolin-2-one

[0072] Particular compounds of formula I of the present invention are those selected from the group consisting of: 4-Amino-7-cyclopropyl-1-(o-tolyl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-7-cyclopropyl-1-(2-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 3-(4-amino-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)-2-methylbenzonitrile 4-Amino-7-cyclopropyl-1-(2,3-dihydrobenzofuran-4-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-7-cyclopropyl-1-(3-fluoro-2-methylphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-7-cyclopropyl-1-(oxan-3-yl)pyrido[2,3-d]pyrimidin-2-one 4-Amino-7-(difluoromethoxy)-1-(2-methylpyridin-3-yl)quinazolin-2(1H)-one 4-amino-1-(2-methylpyridin-3-yl)-7-(trifluoromethoxy)quinazolin-2(1H)-one 4-Amino-7-cyclopropyl-1-(2,3-dihydrobenzofuran-4-yl)quinazolin-2(1H)-one 4-Amino-7-cyclopropyl-1-(2,3-dihydrobenzofuran-7-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-1-(2-chlorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2-one 4-Amino-7-cyclopropyl-1-(4-oxaspiro[2.5]octan-8-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-1-(2-chloropyridin-3-yl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-7-(difluoromethoxy)-1-(2-methylphenyl)pyrido[2,3-d]pyrimidin-2-one 3-(4-amino-2-oxo-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-1(2H)-yl)-2-methylbenzonitrile 4-Amino-7-cyclopropyl-1-(m-tolyl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-7-cyclopropyl-1-[(8S)-4-oxaspiro[2.5]octan-8-yl]pyrido[2,3-d]pyrimidin-2-one 4-Amino-7-cyclopropyl-1-[(8R)-4-oxaspiro[2.5]octan-8-yl]pyrido[2,3-d]pyrimidin-2-one (R)-4-Amino-7-cyclopropyl-1-(oxepan-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-7-cyclopropyl-1-((2S,3R)-2-methyltetrahydro-2H-pyran-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

[0073] In another embodiment, the present invention provides a compound according to Formula I, I', I'' or II described herein for use as a therapeutically active substance.

[0074] In yet another embodiment, the present invention provides a compound according to formula I, I', I" or II as described herein for the treatment, prevention and / or delay of progression of cancer, particularly lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, esophageal carcinoma, glioblastoma multiforme, and mesothelioma, more particularly lung adenocarcinoma, lung squamous cell carcinoma, pancreatic adenocarcinoma, glioblastoma multiforme, and head and neck squamous cell carcinoma.

[0075] In another embodiment, the present invention provides the use of a compound of formula I or II, a compound according to formula I, I', I" or II as described herein for the treatment, prevention and / or delay of progression of cancer, particularly lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, esophageal carcinoma, glioblastoma multiforme, and mesothelioma, more particularly lung adenocarcinoma, lung squamous cell carcinoma, pancreatic adenocarcinoma, glioblastoma multiforme, and head and neck squamous cell carcinoma.

[0076] In one aspect, the present application provides a method for treating a Mat2A disorder in a subject having a Mat2A-associated disorder, the method comprising administering a therapeutically effective amount of any of the above-mentioned compounds to a subject in need thereof.

[0077] In another embodiment, the present invention provides a method for the treatment, prevention and / or delay of progression of cancer, particularly lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, esophageal carcinoma, glioblastoma multiforme, and mesothelioma, more particularly lung adenocarcinoma, lung squamous cell carcinoma, pancreatic adenocarcinoma, glioblastoma multiforme, and head and neck squamous cell carcinoma, more particularly the treatment, comprising administering an effective amount of a compound according to Formula I, I', I'' or II as described herein.

[0078] In certain embodiments, the present invention provides a method for the treatment, prevention and / or delay of progression of cancer, particularly lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, esophageal carcinoma, glioblastoma multiforme, and mesothelioma, more particularly lung adenocarcinoma, lung squamous cell carcinoma, pancreatic adenocarcinoma, glioblastoma multiforme, and head and neck squamous cell carcinoma, more particularly the treatment, comprising administering an effective amount of a compound according to Formula I, I', I'' or II as described herein.

[0079] In particular, the Mat2A disorder or Mat2A-associated disease is cancer, particularly lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, esophageal carcinoma, glioblastoma multiforme, and mesothelioma, more particularly lung adenocarcinoma, lung squamous cell carcinoma, pancreatic adenocarcinoma, glioblastoma multiforme, and head and neck squamous cell carcinoma.

[0080] In some particular embodiments of the present invention, atropoisomerism is avoided, resulting in chirally stable compounds.

[0081] In one aspect, the application provides a pharmaceutical composition comprising a compound of any one of the above embodiments mixed with at least one pharmaceutically acceptable carrier, such as an excipient or diluent.

[0082] In another embodiment, the present invention provides the use of a compound of formula I, I', I'' or II in the preparation of a medicament for the treatment, prevention and / or delay of progression of a disease associated with Mat2A, more particularly for the treatment.

[0083] In yet another embodiment, the present invention provides a medicament comprising a compound of formula I, I', I" or II or a pharmaceutically acceptable salt thereof as described herein and a therapeutically inert carrier, which is also an object of the present invention as well as a process for their preparation which comprises formulating one or more compounds of formula I, I', I" or II and / or a pharmaceutically acceptable salt thereof, and optionally one or more other therapeutically valuable substances, together with one or more therapeutically inert carriers, into a galenical dosage form.

[0084] Another embodiment provides pharmaceutical compositions or medicaments comprising a compound of the invention and a therapeutically inactive carrier, diluent or pharmaceutically acceptable excipient, and methods of using the compounds of the invention to prepare such compositions and medicaments.

[0085] The composition is formulated, dosed and administered in a manner consistent with good medical practice.The factors that should be considered in this regard include the specific disorder that is treated, the specific mammal that is treated, the clinical condition of each patient, the cause of the disorder, the delivery site of the drug, the method of administration, the administration schedule and other factors that are known to medical professionals.For example, this amount may be below the amount that is toxic to normal cells or mammals as a whole.

[0086] The compounds of the present invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural, and intranasal, and, if desired for local treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

[0087] The compounds of the present invention can be administered in any convenient dosage form, such as tablets, coated tablets, dragees, powders, capsules (hard and soft gelatin capsules), solutions (i.e., injectable solutions), dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, eye drops, ear drops, etc. Such compositions may contain ingredients commonly used in pharmaceutical preparations, such as diluents, carriers, pH adjusters, sweeteners, fillers, and additional active agents.

[0088] Typical formulations are prepared by mixing the compound of the present invention with pharmaceutically acceptable carriers or additives.Suitable pharmaceutically acceptable carriers and additives are well known to those skilled in the art, and are described in detail in, for example, Ansel, Howard C. et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R. et al., Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005.Pharmaceutical acceptable carriers can be either solid or liquid.Solid formulations include powders, tablets, pills, capsules, cachets, suppositories and dispersible granules. A solid carrier can be one or more substances that may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or encapsulating materials. In powders, the carrier is generally a finely divided solid that is mixed with the finely divided active ingredient. In tablets, the active ingredient is generally mixed with a carrier having the necessary binding capacity in appropriate proportions and compacted into the desired shape and size. Powders and tablets preferably contain from about one (1) percent to about seventy (70) percent of the active compound. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low-melting waxes, cocoa butter, and the like.

[0089] The dosage at which the compounds of the present invention can be administered may vary within wide limits and will, of course, be adapted to the individual requirements of each particular case. In general, for oral administration, a daily dosage of about 0.01 to 1000 mg of a compound of formula I, I', I" or II per person should be appropriate, although the upper limit mentioned above can also be exceeded if necessary.

[0090] An example of a suitable oral dosage form is a tablet containing about 100 mg to 500 mg of a compound of the present invention, blended with about 30 to 90 mg of anhydrous lactose, about 5 to 40 mg of croscarmellose sodium, about 5 to 30 mg of polyvinylpyrrolidone (PVP) K30, and about 1 to 10 mg of magnesium stearate. The powdered ingredients are first mixed together and then mixed with a solution of PVP. The resulting composition can be dried, granulated, mixed with magnesium stearate, and compressed into tablet form using conventional equipment.

[0091] An example of an aerosol formulation can be prepared by dissolving 10 to 100 mg of the compound of the present invention in a suitable buffer solution, such as phosphate buffer, and adding an isotonicity agent, such as sodium chloride, if desired. The solution may be filtered, for example, using a 0.2 μm filter, to remove impurities and contaminants.

[0092] Thus, one embodiment includes a pharmaceutical composition comprising a compound according to the invention as described herein or a stereoisomer thereof. A further embodiment includes a pharmaceutical composition comprising a compound according to the invention as described herein or a stereoisomer thereof, together with a pharmaceutically acceptable carrier or excipient.

[0093] The compounds of the present invention can be used either alone or in combination with other drugs for the treatment, prevention and / or delay of progression of Mat2A-related diseases, in particular cancer, specifically lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, esophageal carcinoma, glioblastoma multiforme, and mesothelioma, more specifically lung adenocarcinoma, lung squamous cell carcinoma, pancreatic adenocarcinoma, glioblastoma multiforme, and head and neck squamous cell carcinoma.

[0094] Certain embodiments of the present invention relate to pharmaceutical compositions comprising a compound of formula I, I', I" or II as described above or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients for use in the treatment, prevention and / or delay of progression of cognitive impairment associated with cancer, particularly lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, esophageal carcinoma, glioblastoma multiforme, and mesothelioma, more particularly lung adenocarcinoma, lung squamous cell carcinoma, pancreatic adenocarcinoma, glioblastoma multiforme, and head and neck squamous cell carcinoma.

[0095] Another embodiment includes a pharmaceutical composition comprising a compound according to the invention as described herein for use in the treatment, prevention and / or delay of progression, more particularly in the treatment, of a Mat2A associated disease.Another embodiment includes a pharmaceutical composition comprising a compound according to the invention as described herein for use in the treatment, prevention and / or delay of progression, more particularly in the treatment, of a Mat2A associated disease.

[0096] In another embodiment, the present invention provides for the preparation of a compound of formula I, I', I'' or II as described herein.

[0097] The preparation of compounds of formula I, I', I" or II of the present invention can be carried out by sequential or convergent synthetic routes. The syntheses of the present invention are shown in the following general schemes. The skills required to carry out the reactions and purification of the resulting products are known to those skilled in the art. When mixtures of enantiomers or diastereomers are produced in the reactions, these enantiomers or diastereomers can be separated by the methods described herein or by methods known to those skilled in the art, such as chiral chromatography or crystallization.

[0098] Furthermore, the compounds of the present invention can be prepared from commercially available starting materials or by using common synthetic techniques and procedures known to those skilled in the art. Suitable reaction schemes for preparing such compounds are outlined below. The substituents and indices used in the following process descriptions have the significance given herein. Further examples can be found in the specific examples detailed below.

[0099] General scheme More specifically, compounds of Formula I, I', or I'' and intermediates thereto can be prepared according to Scheme 1 or 2 and as described in the specific examples.

[0100] X 1 is N and X 3 is CR 3 where X is halogen (especially chloro or fluoro) and R 5 is NH2 and R 1 , R 2 , R 3 and R 4 The subgroup of compounds of formula I or I', where is as defined above, can be prepared as outlined in Scheme 1 below. TIFF0007749602000007.tif116170

[0101] 2,6-Dihalo-3-nitrile pyridine A can be reacted at the 6-position with a boronic acid or boronate ester in a Suzuki-Miyaura-type reaction using a palladium catalyst such as Pd(dppf)ClCHCl and excess base such as KCO in a solvent such as dioxane or water at elevated temperatures, or with an amine in a SnAr-type reaction using excess base (e.g., DIPEA, KCO) in a polar solvent such as DMF, DMA, or NMP at elevated temperatures (Condition A) to give 2-halo-3-nitrile pyridine B. Alternatively, pyridine B can be synthesized by cyclization of intermediate VII with 2-cyanoacetamide using a base (e.g., NaOEt) in a polar solvent such as DMF at elevated temperatures to give the corresponding hydroxypyridine VIII (Condition G). Hydroxypyridine VIII can be converted to pyridine B using a dehydrating reagent such as POCl at elevated temperatures. The halogen at the 2-position of pyridine B can be converted with amines or anilines in a Hartwig-Buchwald-type reaction using a palladium catalyst system such as Pd(OAc) / xantphos or xphos and excess base such as CsCO in a solvent such as dioxane or toluene at elevated temperatures, or in a SnAr-type reaction using excess base (e.g., DIPEA, KCO) in a polar solvent such as DMF, DMA, or NMP at elevated temperatures (Condition B) to give substituted pyridines C. The NH group of pyridine C can be cyclized with ammonia in a polar solvent such as MeOH at ambient temperature (Condition C), followed by activation with an isocyanate reagent, e.g., trichloroacetylisocyanate, in a chlorinated nonpolar solvent such as DCM at ambient or elevated temperatures.

[0102] Alternatively, the halogen at the 2-position of pyridine B can be converted to an amine moiety using ammonolysis reaction conditions, such as using ammonia in a polar solvent (e.g., MeOH) at elevated temperature and pressure, to give pyridine intermediate VI (conditions D), or the 5-position of intermediate V can be reacted with an electrophilic halogenating reagent (such as NBS) in a chlorinated solvent (e.g., DCM or CHCl3) at ambient or elevated temperature to give pyridine VI (conditions E). Pyridine VI can then be reacted with a haloarene in a Hartwig-Buchwald type reaction using a palladium catalyst system such as Pd(OAc) / xantphos or xphos and excess base such as CsCO in a solvent such as dioxane or toluene at elevated temperatures (conditions F), or in a SnAr type reaction using excess base (e.g., DIPEA, KCO) in a polar solvent such as DMF, DMA, NMP at elevated temperatures (conditions B) to provide substituted pyridine C, which can be converted to the final aminopyrimidone IV using conditions previously described.

[0103] X 1 is CH and X 3 is CR 3 where X is halogen (especially chloro or fluoro) and R 5 is NH2 and R 1 , R 2 , R 3 and R 4 The subgroup of compounds of formula I or I', where is as defined above, can be prepared as outlined in Scheme 2 below. TIFF0007749602000008.tif50170

[0104] The halogen at the 2-position of aryl nitrile IX (X = Br or Cl) can be converted with amines or anilines in a Hartwig-Buchwald-type reaction using a palladium catalyst system such as Pd(OAc)2 / xantphos or xphos and excess base such as Cs2CO3 in a solvent such as dioxane or toluene at elevated temperatures, or in a SnAr-type reaction using excess base (e.g., DIPEA, K2CO3) in a polar solvent such as DMF, DMA, or NMP at elevated temperatures (Condition I) to give substituted aryl nitrile X. The NH group of intermediate X can be cyclized with ammonia in a polar solvent such as MeOH at ambient temperature (Condition C), followed by activation with an isocyanate reagent, e.g., trichloroacetylisocyanate, in a chlorinated nonpolar solvent such as DCM at ambient or elevated temperatures. TIFF0007749602000009.tif131170

[0105] Dihalides XII (X = Br, I) can be selectively metallated by lithium-halogen exchange at the 2-position with nBuLi in THF at low temperature (-78 °C) (European Journal of Inorganic Chemistry, 2014, 4734), resulting in the reaction of the organolithium with an aldehyde to give XIII. Oxidation to the ketone with standard oxidizing reagents (e.g., MnO, Dess-Martin periodinane) generates ketone XIV, which can be further derivatized by Suzuki coupling with boronic acids to give R. 2 can be incorporated into product XV. Reaction with tosMIC in dimethoxyethane and a strong base (e.g., potassium tert-butoxide) at ambient temperature affords nitrile XVI. Mild hydrolysis under acidic conditions (e.g., sulfuric acid:acetic acid = 1:4) at 40 °C affords carboxamide XVIII. Cyclization with thiophosgene in ethanol under basic conditions (sodium ethoxide) affords XIX, which can be directly alkylated with iodomethane in an alcoholic solvent (e.g., ethanol) to afford thioether XX. Reaction with ammonia at elevated temperature (50 °C in a sealed tube) affords final product XXI.

[0106] Alternatively, nitrile XVI can be prepared by reacting SVII (X=Cl) with an appropriate nitrile in a polar solvent (eg, DMF) under strong basic (eg, sodium hydroxide) conditions. General Procedure TIFF0007749602000010.tif37170[where, X 1 is N and X 3 is halogen (especially chloro or fluoro), and R 2 , R 3 and R 4 is as defined above]

[0107] General Procedure A1: Suzuki-Miyaura Type Cross Coupling To 2,6-dihalo-3-nitrile pyridine A dissolved in dioxane / water (4:1 ratio, 0.1–0.2 M), K2CO3 (3 equiv.) was added, followed by the boronic acid or ester (1.5 equiv.). The resulting reaction mixture was sonicated and degassed by bubbling argon through it. Pd(dppf)2Cl2·CHCl2 complex (0.05–0.2 equiv.) was added, and the reaction mixture was heated to 100 °C until LCMS indicated complete consumption of pyridine starting material A (0.5–16 h). The reaction was then diluted with EtOAc, washed with brine, dried over Na2SO4, and concentrated. The crude product B may be purified using flash silica gel chromatography.

[0108] General Procedure A2: SnAr-type reactions To a solution of 2,6-dihalo-3-nitrilepyridine A in THF (0.1-0.2 M) was added DIPEA (2 equiv.) and a secondary amine (1.1 equiv.). The reaction was stirred at ambient or elevated temperature until LCMS indicated complete consumption of the pyridine starting material A (up to 16 h). The reaction was then diluted with EtOAc, washed with brine, dried over Na2SO4, and concentrated. The crude product B may be purified using flash silica gel chromatography. TIFF0007749602000011.tif41170

[0109] [where, X 1 is N and X 3 is CR 3 where X is halogen (especially chloro or fluoro) and R 2 , R 3 and R 4 is as defined above]

[0110] General Procedure B1: Hartwig-Buchwald Cross-Coupling To 2-halo-3-nitrile pyridine B dissolved in dioxane (0.1–0.2 M) was added CsCO (3 equiv.), followed by an amine or aniline (1.5–3 equiv.). The resulting reaction mixture was sonicated and degassed by bubbling argon through it. Pd(OAc) (0.1 equiv.) and a ligand (xantphos or xphos, 0.2 equiv.) were added, and the reaction mixture was heated to 100 °C until LCMS indicated complete consumption of the pyridine starting material B (0.5–16 h). The reaction was then diluted with EtOAc, washed with brine, dried over NaSO, and concentrated. The crude product C may be purified using flash silica gel chromatography.

[0111] General Procedure B2: SnAr-type reactions To 2-halo-3-nitrile pyridine B dissolved in NMP (0.1-0.2 M) was added DIPEA or TEA (3 equiv.) and a primary amine (1.2-2 equiv.). The reaction mixture was heated to 100-210 °C until LCMS indicated complete consumption of the pyridine starting material A (1-8 h). The reaction was then diluted with EtOAc, washed with brine, dried over Na2SO4, and concentrated. The crude product C may be purified using flash silica gel chromatography.

[0112] General Procedure C: Preparation of Aminopyrimidone TIFF0007749602000012.tif41170[where, X 1 is N and X 3 is CR 3and R 5 is NH2 and R 2 , R 3 and R 4 is as defined above]

[0113] To a solution of pyridine intermediate C in DCM or DCE (0.1–0.2 M), trichloroacetyl isocyanate (2.2 equiv.) was added, and the resulting reaction mixture was stirred at ambient or elevated temperature until LCMS indicated complete consumption of the pyridine starting material C and the formation of the 2,2,2-trichlorocarbamoylacetamide intermediate (1–16 h). Next, ammonia in methanol (7 M, 100–200 equiv.) was added, and the resulting reaction mixture was stirred at ambient temperature until LCMS indicated complete conversion of the aminopyrimidone product IV (1–16 h). The reaction was then diluted with EtOAc, washed with brine, dried over NaSO, and concentrated. The crude product IV may be purified using flash silica gel chromatography or preparative HPLC.

[0114] General Procedures G and H: Pyridine Synthesis TIFF0007749602000013.tif36170[where, X 1 is N and X 3 is CR 3 and R 4 is H and R 2 and R 3 is as defined above]

[0115] To a DMF (0.2-0.4 M) solution of VII (prepared with modifications according to the procedure in J. Med. Chem. 2011, 54, 7974-7985), 2-cyanoacetamide (3 equiv.) and NaOEt (3 equiv.) as a base were added. The resulting reaction mixture was heated to 100 °C until LCMS indicated complete consumption of the starting material VII (approximately 16 h). The reaction mixture was then diluted with EtOAc, washed with brine, dried over Na2SO4, and concentrated. The crude product VIII may be purified using flash silica gel chromatography.

[0116] In the subsequent step, hydroxypyridine VIII was dissolved in POCl3 (10-20 equiv.), and the resulting reaction mixture was heated to 100 °C until LCMS indicated complete consumption of starting material VIII (approximately 16 h). The reaction mixture was then concentrated under reduced pressure, diluted with EtOAc, and filtered. The organic layer was diluted with water and extracted several times with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The crude chloropyridine product B may be purified using flash silica gel chromatography.

[0117] General Procedure D: Ammonolysis TIFF0007749602000014.tif42170[where, X 1 is N, X is halogen (especially chloro or fluoro), and X 3 is CH and R 2 and R 4 is as defined above]

[0118] A solution of pyridine IIa in dioxane (0.4-0.6 M) was heated to 100 °C under NH atmosphere and pressure until LCMS indicated complete consumption of starting material IIa (approximately 2 days). The reaction was then concentrated to dryness. The crude product V may be purified using flash silica gel chromatography.

[0119] General Procedure E: Pyridine Synthesis: Halogenation TIFF0007749602000015.tif45170[where, X 1 is N, X is halogen (especially chloro or fluoro), and X 3 is CH and R 2 and R 4 is as defined above]

[0120] To a solution of aminopyridine V in DMF, DCM, or CHCl (0.1–0.2 M) was added NCS or NBS reagent (1.1–1.5 equiv.), and the resulting reaction mixture was stirred in the dark at ambient temperature (for NBS) or heated to 60 °C until LCMS indicated complete consumption of starting material V. The reaction was then diluted with EtOAc, washed with brine, dried over NaSO, and concentrated. The crude product VI could be used in the next step without further purification or purified using flash silica gel chromatography.

[0121] General Procedure F: Reverse Hartwig-Buchwald Cross-Coupling TIFF0007749602000016.tif48170[where, X 1 is N, X is halogen (especially chloro or fluoro), and R 2 and R 4 is as defined above]

[0122] To 2-amino-3-nitrilepyridine VI dissolved in dioxane (0.1–0.2 M), CsCO (3 equiv.) was added, followed by haloarene (1.5–3 equiv.). The resulting reaction mixture was sonicated and degassed by bubbling argon through it. Pd(OAc) (0.05–0.1 equiv.) and a ligand (xantphos or xphos, 0.1–0.2 equiv.) were added, and the reaction mixture was heated to 100 °C until LCMS indicated complete consumption of the pyridine starting material VI (0.5–16 h). The reaction was then diluted with EtOAc, washed with brine, dried over NaSO, and concentrated. The crude product C may be purified using flash silica gel chromatography.

[0123] General Procedure I1: Hartwig-Buchwald Cross-Coupling TIFF0007749602000017.tif45170[where, X 1 is CH, X is halogen (especially chloro or fluoro), and X 3 is CH and R 2 and R4 is as defined above]

[0124] To haloarene nitrile XI dissolved in dioxane (0.1–0.2 M) was added CsCO (3 equiv.), followed by an amine or aniline (1.5–3 equiv.). The resulting reaction mixture was sonicated and degassed by bubbling argon through it. Pd(OAc) (0.1 equiv.) and a ligand (xantphos or xphos, 0.2 equiv.) were added, and the reaction mixture was heated to 90–100 °C until LCMS indicated complete consumption of starting material XI (0.5–16 h). The reaction was then diluted with EtOAc, washed with brine, dried over NaSO, and concentrated. The crude product X may be purified using flash silica gel chromatography.

[0125] General Procedure I2: SnAr-Type Reactions To haloarene nitrile XI dissolved in NMP (0.1-0.2 M) was added DIPEA or TEA (3 equiv.) and a primary amine (1.2-2 equiv.). The reaction mixture was stirred at ambient temperature or heated to 140-210 °C until LCMS indicated complete consumption of the pyridine starting material XI (1-8 h). The reaction was then diluted with EtOAc, washed with brine, dried over Na2SO4, and concentrated. The crude product X may be purified using flash silica gel chromatography.

[0126] A particular embodiment of the present invention is a compound of formula (I') as defined in accordance with the present invention, wherein X 1 , X 3 , R 1 , R 2 and R 4 is as defined herein] and pharmaceutically acceptable salts thereof, which comprises cyclizing a compound of formula (Ia') by activation with an isocyanate reagent, for example, trichloroacetylisocyanate, in a chlorinated non-polar solvent such as DCM at ambient or elevated temperature, followed by addition of ammonia in a polar solvent such as MeOH at ambient temperature (Condition C), to give a compound of formula (I'), as shown in Scheme 4. TIFF0007749602000018.tif82170

[0127] These compounds were investigated according to the tests set out below.

[0128] Determination of Mat2A activity Measurement of Mat2A inhibition is performed in an absorbance-based assay in a 384-well format.

[0129] Recombinant human Mat2a (12.5 nM) and serially diluted compounds in DMSO (concentration range: 10 μM to 508 pM) or control (DMSO) are incubated for 15 minutes at room temperature (RT) in assay buffer containing 50 mM HEPES (pH 7.5), 50 mM KCl, 50 mM MgCl2, 0.01% Tween 20, and 10 mM DTT. The reaction is initiated by adding the combined substrates ATP and methionine to a final concentration of 100 μM each. Final assay conditions are 12.5 nM Mat2A, 100 μM ATP and methionine substrates, and 2% DMSO. After 120 minutes of incubation at room temperature, the reaction is stopped by adding Biomol Green. After 30 minutes of equilibration at room temperature, the absorbance signal is measured at λ = 635 nm using a multiplate reader (BMG Pherastar reader or equivalent). TIFF0007749602000019.tif255170TIFF0007749602000020.tif255170TIFF00077496020 00021.tif255170TIFF0007749602000022.tif255170TIFF0007749602000023.tif183170

[0130] Experimental part The following examples are given by way of illustration of the present invention and should not be considered as limiting the scope of the invention, but merely as representative thereof.

[0131] overview Analysis method HPLC (Method LCMS_fastgradient) Column: Agilent Zorbax Eclipse Plus C18, Rapid Resolution HT, 2.1 x 30 mm, 1.8 μm, part number 959731-902 Solvent A: Water with 0.01% formic acid; Solvent B: Acetonitrile (MeCN)

[0132] gradient: TIFF0007749602000024.tif47170

[0133] Abbreviation The following abbreviations were used in the experimental section: Ar = argon; nBuLi = n-butyllithium; DCM = dichloromethane; DIPEA = diisopropylethylamine; DMSO = dimethyl sulfoxide; DMF = dimethylformamide; EtOH = ethanol; EtOAc = ethyl acetate; HCl = hydrochloric acid; HPLC = high performance liquid chromatography; LDA = Lithium diisopropylamide; LiHMDS = lithium bis(trimethylsilyl)amide; mCPBA = metachloroperbenzoic acid; MOM = methoxymethyl; NMP = N-methyl-2-pyrrolidone; SEM = [2-(trimethylsilyl)ethoxy)methyl]acetal; TBTU = 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate; THF = tetrahydrofuran; TEMPO = 2,2,6,6-tetramethylpiperidinyloxyl; TBAF = tetra-n-butylammonium fluoride; TLC = thin layer chromatography;

[0134] Starting materials Basic chemicals and solvents were purchased and used as is without further purification. Some intermediates are commercially available or can be synthesized using methods known in the art.

[0135] Intermediates Intermediate 1: 6-Cyclopropyl-2-(o-tolylamino)nicotinonitrile TIFF0007749602000025.tif45170

[0136] Title compound ([M+H] + 250.2) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS[1198475-35-2]) by reaction with o-toluidine (CAS[95-35-4]) using Pd(OAc)2 as catalyst and xphos as ligand (General Procedure B1).

[0137] Intermediate 2: 6-cyclopropyl-2-((2-methoxyphenyl)amino)nicotinonitrile TIFF0007749602000026.tif46170

[0138] Title compound ([M+H] + 266.2) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS[1198475-35-2]) by reaction with o-anisidine (CAS[90-04-0]) using Pd(OAc)2 as catalyst and xphos as ligand (General Procedure B1).

[0139] Intermediate 3: 6-(tert-butyl)-2-(o-tolylamino)nicotinonitrile TIFF0007749602000027.tif45170

[0140] Title compound ([M+H] +266.2) was prepared from 6-(tert-butyl)-2-chloronicotinonitrile (CAS[4138-20-9]) by reaction with o-toluidine (CAS[95-35-4]) using Pd(OAc)2 as catalyst and xphos as ligand (General Procedure B1).

[0141] Intermediate 4: 2-((2-methoxyphenyl)amino)-6-phenylnicotinonitrile TIFF0007749602000028.tif45170

[0142] Title compound ([M+H] + 302.2) was prepared from 2-chloro-6-phenylnicotinonitrile (CAS[43083-14-3]) by reaction with o-anisidine (CAS[90-04-0]) using Pd(OAc)2 as catalyst and xphos as ligand (General Procedure B1).

[0143] Intermediate 5: 6-(3,3-difluoroazetidin-1-yl)-2-(o-tolylamino)nicotinonitrile TIFF0007749602000029.tif47170

[0144] Step 1: 2-chloro-6-(3,3-difluoroazetidin-1-yl)nicotinonitrile 2-chloro-6-(3,3-difluoroazetidin-1-yl)nicotinonitrile ([M+H] + 230.0) was prepared by the reaction of 2,6-dichloronicotinonitrile (CAS [40381-90-6]) with 3,3-difluoroazetidine hydrochloride (CAS [288315-03-7]) using DIPEA as the base at 80 °C.

[0145] Step 2: 6-(3,3-difluoroazetidin-1-yl)-2-(o-tolylamino)nicotinonitrile Title compound ([M+H] +301.1) was prepared from 2-chloro-6-(3,3-difluoroazetidin-1-yl)nicotinonitrile by reaction with o-toluidine (CAS[95-35-4]) using Pd(OAc)2 as catalyst and xphos as ligand (General Procedure B1).

[0146] Intermediate 6: 6-Cyclopropyl-2-((tetrahydrofuran-3-yl)amino)nicotinonitrile TIFF0007749602000030.tif44170

[0147] Title compound ([M+H] + 230.3) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS[1198475-35-2]) by reaction with tetrahydrofuran-3-amine (CAS[88675-24-5]) at 120° C. using DIPEA as the base (General Procedure B2).

[0148] Intermediate 7: 6-cyclopropyl-2-((2-methylpyridin-3-yl)amino)nicotinonitrile TIFF0007749602000031.tif46170

[0149] Title compound ([M+H] + 251.2) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS[1198475-35-2]) by reaction with 3-amino-2-methylpyridine (CAS[3430-10-2]) using Pd(OAc)2 as catalyst and xphos as ligand (General Procedure B1).

[0150] Intermediate 8: 4-Cyclopropyl-2-(2-methylanilino)benzonitrile TIFF0007749602000032.tif44170

[0151] Title compound ([M+H] +249.2) was prepared from 2-bromo-4-cyclopropylbenzonitrile (CAS[1237130-18-5]) by reaction with o-toluidine (CAS[95-35-4]) at 120 °C using Pd(OAc) as catalyst and DPPF as ligand and KOtBu as base in toluene (General Procedure I1).

[0152] Intermediate 9: 6-cyclopropyl-2-((2-methoxypyridin-3-yl)amino)nicotinonitrile TIFF0007749602000033.tif46170

[0153] Title compound ([M+H] + 267.2) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS[1198475-35-2]) by reaction with o-anisidine (CAS[90-04-0]) using Pd(OAc)2 as catalyst and xphos as ligand (General Procedure B1).

[0154] Intermediate 10: 6-cyclopropyl-5-fluoro-2-((2-methylpyridin-3-yl)amino)nicotinonitrile TIFF0007749602000034.tif45170

[0155] Step 1: 2-chloro-6-cyclopropyl-5-fluoronicotinonitrile 2-Chloro-6-cyclopropyl-5-fluoronicotinonitrile ([M+H] + 197.0) was prepared by the reaction of 2,6-dichloro-5-fluoronicotinonitrile (CAS[82671-02-1]) with cyclopropylboronic acid (CAS[411235-57-9]) using Pd(dppf)2Cl2·CH2Cl2 as catalyst and K2CO3 as base (General Procedure A1).

[0156] Step 2: 6-cyclopropyl-5-fluoro-2-((2-methylpyridin-3-yl)amino)nicotinonitrile Title compound ([M+H] + 269.2) was prepared from 2-chloro-6-cyclopropyl-5-fluoronicotinonitrile by reaction with 3-amino-2-methylpyridine (CAS [3430-10-2]) using Pd(OAc) as catalyst and xphos as ligand (General Procedure B1).

[0157] Intermediate 11: 3-((3-cyano-6-cyclopropylpyridin-2-yl)amino)picolinonitrile TIFF0007749602000035.tif46170

[0158] Title compound ([M+H] + 262.3) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS[1198475-35-2]) by reaction with 3-amino-2-cyanopyridine (CAS[42242-11-5]) using Pd(OAc)2 as catalyst and xphos as ligand (General Procedure B1).

[0159] Intermediate 12: 6-Cyclopropyl-2-(oxan-3-ylamino)pyridine-3-carbonitrile TIFF0007749602000036.tif46170

[0160] Title compound ([M+H] + 244.3) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) by reaction with tetrahydro-2H-pyran-3-amine at 200° C. using DIPEA as a base (General Procedure B2).

[0161] Intermediate 13: 6-Cyclopropyl-2-[1-(oxolan-3-yl)ethylamino]pyridine-3-carbonitrile TIFF0007749602000037.tif44170

[0162] Title compound ([M+H] +258.2) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS[1198475-35-2]) by reaction with 1-(tetrahydrofuran-3-yl)ethan-1-amine hydrochloride (CAS[1803592-17-7]) using NMP as solvent and DIPEA as base at 210°C / MW (General Procedure B2).

[0163] Intermediate 14: 6-Cyclopropyl-2-((3-fluoro-2-methoxyphenyl)amino)nicotinonitrile TIFF0007749602000038.tif46170

[0164] Title compound ([M+H] + 284.2) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS[1198475-35-2]) by reaction with 3-fluoro-2-methoxyaniline (CAS[437-83-2]) using Pd(OAc)2 as catalyst and xphos as ligand (General Procedure B1).

[0165] Intermediate 15: 2-((3-cyano-2-methylphenyl)amino)-6-cyclopropylnicotinonitrile TIFF0007749602000039.tif52170

[0166] Title compound ([M+H] + 275.3) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS[1198475-35-2]) by reaction with 3-amino-2-methylbenzonitrile (CAS[69022-35-1]) using Pd(OAc)2 as catalyst and xphos as ligand (General Procedure B1).

[0167] Intermediate 16: 2-[(2-methylpyridin-3-yl)amino]-6-propan-2-ylpyridine-3-carbonitrile TIFF0007749602000040.tif46170

[0168] Title compound ([M+H] + 253.2) was prepared from 2-chloro-6-isopropylnicotinonitrile (CAS[108244-44-6]) by reaction with 3-amino-2-methylpyridine (CAS[3430-10-2]) at 120 °C using Pd(OAc)2 as catalyst and DPPF as ligand and KOtBu as base in toluene (General Procedure B1).

[0169] Intermediate 17: 6-Cyclopropyl-2-((2,3-dihydrobenzofuran-4-yl)amino)nicotinonitrile TIFF0007749602000041.tif47170

[0170] Title compound ([M+H] + 278.3) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS[1198475-35-2]) by reaction with 3-amino-2-methylbenzonitrile (CAS[69022-35-1]) using Pd(OAc)2 as catalyst and xphos as ligand (General Procedure B1).

[0171] Intermediate 18: 5-chloro-6-cyclopropyl-2-((2-methylpyridin-3-yl)amino)nicotinonitrile TIFF0007749602000042.tif46170

[0172] Step 1: 2,5-Dichloro-6-cyclopropyl-pyridine-3-carbonitrile 2,5-Dichloro-6-cyclopropyl-pyridine-3-carbonitrile ([M+H] + 213.1) was prepared by the reaction of 2,5,6-trichloronicotinonitrile (CAS[40381-92-8]) with cyclopropylboronic acid (CAS[411235-57-9]) using Pd(dppf)2Cl2·CH2Cl2 as catalyst and K2CO3 as base (General Procedure A1).

[0173] Step 2: 5-chloro-6-cyclopropyl-2-((2-methylpyridin-3-yl)amino)nicotinonitrile Title compound ([M+H] + 285.2) was prepared from 2,5-dichloro-6-cyclopropyl-pyridine-3-carbonitrile by reaction with 3-amino-2-methylpyridine (CAS [3430-10-2]) using Pd(OAc) as catalyst and xphos as ligand (General Procedure B1).

[0174] Intermediate 19: 2-((3-cyano-2-methoxyphenyl)amino)-6-cyclopropylnicotinonitrile TIFF0007749602000043.tif51170

[0175] Title compound ([M+H] + 291.2) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS[1198475-35-2]) by reaction with 3-amino-2-methoxybenzonitrile (CAS[725718-10-5]) using Pd(OAc)2 as catalyst and xphos as ligand (General Procedure B1).

[0176] Intermediate 20: 2-((3-cyano-2-ethoxyphenyl)amino)-6-cyclopropylnicotinonitrile TIFF0007749602000044.tif52170

[0177] Title compound ([M+H] + 305.2) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) by reaction with 3-amino-2-ethoxybenzonitrile (CAS [1823514-97-1]) using Pd(OAc) as catalyst and xphos as ligand (General Procedure B1).

[0178] Intermediate 21: 6-Cyclopropyl-2-(1-tetrahydrofuran-2-ylethylamino)pyridine-3-carbonitrile TIFF0007749602000045.tif43170

[0179] Title compound ([M+H] + 258.4) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS[1198475-35-2]) by reaction with 1-(tetrahydrofuran-2-yl)ethanamine (CAS[92071-57-3]) using NMP as solvent and DIPEA as base at 210 °C / MW (General Procedure B2).

[0180] Intermediate 22: 2-((2-methylpyridin-3-yl)amino)-4-(oxetan-3-yl)benzonitrile TIFF0007749602000046.tif46170

[0181] Step 1: 2-chloro-4-(oxetan-3-yl)benzonitrile To a mixture of (3-chloro-4-cyanophenyl)boronic acid (197 mg, 1.09 mmol) and trans-2-aminocyclohexanol hydrochloride (5 mg, 0.03 mmol) in 2-propanol (2 mL) was added 2 M sodium bis(trimethylsilyl)amide in THF (544 μL, 1.09 mmol). The reaction mixture was degassed, and 3-iodooxetane (47 μL, 0.54 mmol) and nickel(II) iodide (10 mg, 0.03 mmol) were added. The resulting reaction was stirred in a sealed tube at 80 °C, then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and evaporated to dryness. The crude reaction mixture was purified by flash column chromatography to give the product (16 mg, 14%) as a white solid. ([M+H] + 192.9)

[0182] Step 2: 2-((2-methylpyridin-3-yl)amino)-4-(oxetan-3-yl)benzonitrile Title compound ([M+H] +266.2) was prepared from 2-chloro-4-(oxetan-3-yl)benzononitrile by reaction with 3-amino-2-methylpyridine (CAS[3430-10-2]) using Pd2(dba)3 as catalyst, xantphos as ligand, and Cs2CO3 as base in dioxane at 100 °C (General Procedure I1).

[0183] Intermediate 23: 6-((1RS,2RS)-2-methylcyclopropyl)-2-((2-methylpyridin-3-yl)amino)nicotinonitrile TIFF0007749602000047.tif46170

[0184] Step 1: 2-Hydroxy-6-(2-methylcyclopropyl)nicotinonitrile 2-Hydroxy-6-(2-methylcyclopropyl)nicotinonitrile ([M+H] + 175.0) was prepared by the reaction of (E)-3-(dimethylamino)-1-(2-methylcyclopropyl)prop-2-en-1-one (prepared by a modified procedure in J. Med. Chem. 2011, 54, 7974-7985) with 2-cyanoacetamide (CAS[107-91-5]) using NaOMe as the base (general procedures G and H).

[0185] Step 2: 2-chloro-6-((1RS,2RS)-2-methylcyclopropyl)nicotinonitrile 2-chloro-6-((1RS,2RS)-2-methylcyclopropyl)nicotinonitrile ([M+H] + 193.1) was prepared by reaction of 2-hydroxy-6-(2-methylcyclopropyl)nicotinonitrile with POCl3 (general procedures G and H).

[0186] Step 3: 6-((1RS,2RS)-2-methylcyclopropyl)-2-((2-methylpyridin-3-yl)amino)nicotinonitrile Title compound ([M+H] +265.3) was prepared from 2-chloro-6-((1RS,2RS)-2-methylcyclopropyl)nicotinonitrile by reaction with 3-amino-2-methylpyridine (CAS[3430-10-2]) using Pd(OAc)2 as catalyst and xphos as ligand (General Procedure B1).

[0187] Intermediate 24: 6-Cyclopropyl-2-[[(1SR,2RS)-2-triethylsilyloxycyclopentyl]amino]pyridine-3-carbonitrile TIFF0007749602000048.tif51170

[0188] Step 1: 6-Cyclopropyl-2-(((1SR,2RS)-2-hydroxycyclopentyl)amino)nicotinonitrile Title compound ([M+H] + 244.3) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS[1198475-35-2]) by reaction with (1SR,2RS)-2-aminocyclopentanol hydrochloride (CAS[137254-03-6]) using NMP as solvent and DIPEA as base at 210 °C / MW (General Procedure B2).

[0189] Step 2: 6-Cyclopropyl-2-[[(1SR,2RS)-2-triethylsilyloxycyclopentyl]amino]pyridine-3-carbonitrile To a 2 mL container of 6-cyclopropyl-2-(((1SR,2RS)-2-hydroxycyclopentyl)amino)nicotinonitrile (79 mg, 325 μmol) in DCE (2 mL) was added DIPEA (57 μL, 325 μmol), chlorotriethylsilane (60 μL, 357 μmol), and DMAP (48 mg, 390 μmol), and the reaction mixture was stirred at room temperature for 1 hour. The 6-cyclopropyl-2-[[(1SR,2RS)-2-triethylsilyloxycyclopentyl]amino]pyridine-3-carbonitrile intermediate was carried on directly to the next step without isolation. ([M+H] + 358.5)

[0190] Intermediate 25: 6-Cyclopropyl-2-((3-fluoro-2-methylphenyl)amino)nicotinonitrile TIFF0007749602000049.tif46170

[0191] Title compound ([M+H] + 268.3) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS[1198475-35-2]) by reaction with 3-fluoro-2-methylaniline (CAS[443-86-7]) using Pd(OAc)2 as catalyst and Xantphos as ligand (General Procedure B1).

[0192] Intermediate 26: 6-Cyclopropyl-2-[[(3R)-oxan-3-yl]amino]pyridine-3-carbonitrile TIFF0007749602000050.tif44170

[0193] Title compound ([M+H] + 244.3) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS[1198475-35-2]) by reaction with (R)-tetrahydro-2H-pyran-3-amine hydrochloride (CAS[1315500-31-2]) using NMP as the solvent and DIPEA as the base at 210°C / MW (General Procedure B2).

[0194] Intermediate 27: 6-Cyclopropyl-2-[[(3S)-oxan-3-yl]amino]pyridine-3-carbonitrile TIFF0007749602000051.tif46170

[0195] Title compound ([M+H] +244.3) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS[1198475-35-2]) by reaction with (S)-tetrahydro-2H-pyran-3-amine hydrochloride (CAS[1071829-81-6]) using NMP as the solvent and DIPEA as the base at 210°C / MW (General Procedure B2).

[0196] Intermediate 28: 6-Cyclopropyl-2-((4-methyltetrahydrofuran-3-yl)amino)nicotinonitrile TIFF0007749602000052.tif44170

[0197] Title compound ([M+H] + 244.1) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) by reaction with 4-methyltetrahydrofuran-3-amine (CAS [1527863-66-6]) using NMP as solvent and DIPEA as base at 120 °C (General Procedure B2).

[0198] Intermediate 29: 2-[(2-methylpyridin-3-yl)amino]-4-(trifluoromethyl)benzonitrile TIFF0007749602000053.tif47170

[0199] Title compound ([M+H] + 278.2) was prepared from 2-bromo-4-(trifluoromethyl)benzonitrile (CAS[35764-15-9]) by reaction with 3-amino-2-methylpyridine (CAS[3430-10-2]) at 120 °C using Pd(OAc)2 as catalyst and DPPF as ligand and KOtBu as base in toluene (General Procedure I1).

[0200] Intermediate 30: 6-Cyclopropyl-2-[[(2SR,3RS)-2-methyltetrahydrofuran-3-yl]amino]pyridine-3-carbonitrile TIFF0007749602000054.tif44170

[0201] Step 1: (2SR,3SR)-2-methyltetrahydrofuran-3-yl 4-methylbenzenesulfonate To a colorless solution of 2-methyldihydrofuran-3(2H)-one (967 μL, 10.0 mmol) in THF (40 mL) was added L-Selectride (1 M in THF, 13 mL, 13.0 mmol) dropwise at −78° C. The resulting reaction mixture was stirred at −78° C. for 1 h, after which 1 M NaOH was added and the mixture was allowed to warm to room temperature. The aqueous phase was washed with DCM and then carefully concentrated in vacuo. The residual semi-solid was suspended in DCM / MeOH (9:1) and filtered. The filtrate was concentrated in vacuo, resuspended in DCM, filtered through Dicalite, and concentrated to give crude (2SR,3SR)-2-methyltetrahydrofuran-3-ol, which was used directly. At 0°C, 4-methylbenzenesulfonyl chloride (853 mg, 4.47 mmol) was added to a solution of (2SR,3SR)-2-methyltetrahydrofuran-3-ol (457 mg, 4.5 mmol) and TEA (1.25 mL, 9.0 mmol) in DCM (16 mL), and the resulting reaction mixture was stirred at room temperature until TLC showed complete consumption of the starting material. The reaction mixture was diluted with DCM and washed twice with water. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography to give (2SR,3SR)-2-methyltetrahydrofuran-3-yl 4-methylbenzenesulfonate (374 mg, 33%) as a colorless oil. 1 H NMR (CDCl3, 300 MHz) δ 7.8-7.8 (m, 2H), 7.35 (dd, 2H, J=0.6, 8.5 Hz), 4.9-5.0 (m, 1H, J=2.0, 3.7, 5.6 Hz), 3.9-4.0 (m, 1H), 3.86 (dq, 1H, J=3.7, 6.3 Hz), 3.72 (dt, 1H, J=5.4, 8.7 Hz), 2.46 (s, 3H), 2.0-2.3 (m, 2H), 1.20 (d, 3H, J=6.2 Hz))

[0202] Step 2: (2SR,3RS)-2-methyltetrahydrofuran-3-amine acetate To a solution of (2SR,3SR)-2-methyltetrahydrofuran-3-yl 4-methylbenzenesulfonate (374 mg, 1.46 mmol) in DMF (2 mL) was added sodium azide (285 mg, 4.38 mmol). The mixture was heated at 80 °C for 72 h until TLC showed complete consumption of the starting material. The reaction was diluted with EtO and washed twice with a minimal amount of water. 20 mL of MeOH was added to the mixture, and most of the EtO was evaporated at 600 mbar (40 °C). The methanol solution was acidified with acetic acid (418 μL, 7.3 mmol), 10% Pd-C (16 mg, 146 μmol) was added, and the mixture was placed under a H atmosphere (balloon) and stirred for 16 h until TLC and LCMS showed complete consumption of the starting material. The reaction mixture was filtered and concentrated to give (2SR,3RS)-2-methyltetrahydrofuran-3-amine acetate (224 mg, 91%) as a colorless gum. ([M+H] + 102.1)

[0203] Step 3: 6-Cyclopropyl-2-[[(2SR,3RS)-2-methyltetrahydrofuran-3-yl]amino]pyridine-3-carbonitrile Title compound ([M+H] + 244.2) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) by reaction with (2SR,3RS)-2-methyltetrahydrofuran-3-amine acetate in NMP at 210 °C using DIPEA as the base (General Procedure B2).

[0204] Intermediate 31: 4-Cyclopropyloxy-2-[(2-methylpyridin-3-yl)amino]benzonitrile TIFF0007749602000055.tif45170

[0205] Title compound ([M+H] +266.2) was prepared from 2-bromo-4-cyclopropoxybenzonitrile by reaction with 3-amino-2-methylpyridine (CAS[3430-10-2]) using Pd2(dba)3 as catalyst, xantphos as ligand, and Cs2CO3 as base in dioxane at 100 °C (General Procedure I1).

[0206] Intermediate 32: 2-((2-methylpyridin-3-yl)amino]-6-(trifluoromethyl)nicotinonitrile TIFF0007749602000056.tif47170

[0207] Title compound ([M+H] + 279.2) was prepared from 2-chloro-6-(trifluoromethyl)nicotinonitrile (CAS[386704-06-9]) by reaction with 3-amino-2-methylpyridine (CAS[3430-10-2]) using Pd(OAc)2 as catalyst and Xantphos as ligand (General Procedure B1).

[0208] Intermediate 33: 6-Cyclopropyl-2-[[(rac(1S)-3-triethylsilyloxycyclopentyl]amino]pyridine-3-carbonitrile TIFF0007749602000057.tif61170

[0209] Step 1: 6-Cyclopropyl-2-[[3-hydroxycyclopentyl]amino]pyridine-3-carbonitrile Title compound ([M+H] + 244.3) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS[1198475-35-2]) by reaction with 3-aminocyclopentan-1-ol (CAS[1279032-31-3]) using NMP as solvent and DIPEA as base at 210 °C (General Procedure B2).

[0210] Step 2: 6-Cyclopropyl-2-[[(rac(1S)-3-triethylsilyloxycyclopentyl]amino]pyridine-3-carbonitrile To a solution of 6-cyclopropyl-2-((3-hydroxycyclopentyl)amino)nicotinonitrile (50 mg, 205 μmol) in DCE (1.3 mL) was added TEA (286 μL, 2.05 mmol), chlorotriethylsilane (55.2 μL, 329 μmol), and DMAP (30 mg, 247 μmol). The reaction mixture was stirred at room temperature for 1 h, then diluted with DCM and washed twice with water. The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography to give the desired product (74 mg, 100%) as a colorless oil. ([M+H] + 358.4)

[0211] Intermediate 34: 4(Difluoromethoxy)-2-[(2-methylpyridin-3-yl)amino]benzonitrile TIFF0007749602000058.tif47170

[0212] Title compound ([M+H] + 276.3) was prepared from 2-bromo-4-(difluoromethoxy)benzonitrile (CAS[1261818-72-7]) by reaction with 3-amino-2-methylpyridine (CAS[3430-10-2]) using Pd2(dba)3 as catalyst, xantphos as ligand, and Cs2CO3 as base in dioxane at 100 °C (General Procedure I1).

[0213] Intermediate 35: 4(Difluoromethyl)-2-((2-methylpyridin-3-yl)amino)benzonitrile TIFF0007749602000059.tif45170

[0214] Step 1: 2-Bromo-4-(difluoromethyl)benzonitrile To a solution of 2-bromo-4-formylbenzonitrile (218 mg, 1.04 mmol) in DCM (5 mL) was added 1 M DAST in DCM (302 μL, 2.28 mmol) at room temperature. After stirring for 2 h, the reaction was quenched with saturated NaHCO3 solution (3 mL) and extracted with DCM. The combined organic layers were washed with brine, dried over MgSO4, and concentrated to give 2-bromo-4-(difluoromethyl)benzonitrile (202 mg, 80% yield) as a brown oil. 1 H NMR (DMSO-d6, 300 MHz) d ppm 8.09 - 8.15 (m, 2 H) 7.73 - 7.86 (m, 1 H) 6.90 - 7.37 (m, 1 H))

[0215] Step 2: 4-(Difluoromethyl)-2-((2-methylpyridin-3-yl)amino)benzonitrile Title compound ([M+H] + 260.2) was prepared from 2-bromo-4-(difluoromethyl)benzonitrile (CAS[1261580-17-9]) by reaction with 3-amino-2-methylpyridine (CAS[3430-10-2]) using Pd2(dba)3 as catalyst, xantphos as ligand, and Cs2CO3 as base in dioxane at 100 °C (General Procedure I1).

[0216] Intermediate 36: 6-[(1RS,2SR)-2-fluorocyclopropyl]-2-[(2-methyl-3-pyridyl)amino]pyridine-3-carbonitrile TIFF0007749602000060.tif46170

[0217] Step 1: 6-((trans)-2-fluorocyclopropyl)-2-hydroxynicotinonitrile 6-((trans)-2-fluorocyclopropyl)-2-hydroxynicotinonitrile ([M+H] +179.0) was prepared by the reaction of 3-(dimethylamino)-1-((trans)-2-fluorocyclopropyl)prop-2-en-1-one (prepared by a modified procedure from J. Med. Chem. 2011, 54, 7974-7985) with 2-cyanoacetamide (CAS[107-91-5]) using NaOMe as the base (general procedures G and H).

[0218] Step 2: 2-chloro-6-((trans)-2-fluorocyclopropyl)nicotinonitrile 2-chloro-6-((trans)-2-fluorocyclopropyl)nicotinonitrile ( 1 H NMR (CDCl3, 300 MHz) δ 7.8-7.9 (m, 1H), 7.3-7.3 (m, 1H), 4.8-5.1 (m, 1H), 2.49 (d, 1H, J=1.6 Hz), 1.6-1.8 (m, 1H), 1.5-1.6 (m, 1H)) was prepared by the reaction of 6-((trans)-2-fluorocyclopropyl)-2-hydroxynicotinonitrile with POCL3 (general procedures G and H).

[0219] Step 3: 6-[(1RS,2SR)-2-fluorocyclopropyl]-2-[(2-methyl-3-pyridyl)amino]pyridine-3-carbonitrile Title compound ([M+H] + 269.0) was prepared from 2-chloro-6-((trans)-2-fluorocyclopropyl)nicotinonitrile by reaction with 3-amino-2-methylpyridine (CAS[3430-10-2]) using Pd(OAc)2 as catalyst and Xantphos as ligand (General Procedure B1).

[0220] Intermediate 37: 2-Cyclopropyl-6-((2-methylpyridin-3-yl)amino)pyridine-3,5-dicarbonitrile TIFF0007749602000061.tif45170

[0221] Step 1: 2-Amino-6-cyclopropylnicotinonitrile Title compound ([M+H] + 160.1) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) using general procedure D.

[0222] Step 2: 2-Amino-5-bromo-6-cyclopropylnicotinonitrile Title compound ([M+H] + 238.0) was prepared from 2-amino-6-cyclopropylnicotinonitrile and NBS in CHCl3 (General Procedure E).

[0223] Step 3: 2-Amino-6-cyclopropylpyridine-3,5-dicarbonitrile To a solution of 2-amino-5-bromo-6-cyclopropylnicotinonitrile (21 mg, 0.088 mmol) in DMF (0.5 mL) was added Zn(CN) (11 mg, 0.088 mmol) and Pd(PPh) (3 mg, 0.0026 mmol). The reaction was heated in a microwave at 150° C. for 1 hour, after which additional portions of Zn(CN) (11 mg, 0.088 mmol) and Pd(PPh) (10 mg, 0.0088 mmol) were added. The reaction was stirred in a microwave at 150° C. for an additional 30 minutes. The reaction was quenched with water and extracted with EtOAc. The reaction was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO, and concentrated. 2-Amino-6-cyclopropylpyridine-3,5-dicarbonitrile was purified by flash column chromatography to give 2-amino-6-cyclopropylpyridine-3,5-dicarbonitrile as a white solid. ([M+H] + 185.2)

[0224] Step 4: 2-Cyclopropyl-6-((2-methylpyridin-3-yl)amino)pyridine-3,5-dicarbonitrile Title compound ([M+H] +276.3) was prepared from 2-amino-6-cyclopropylpyridine-3,5-dicarbonitrile by reaction with 3-bromo-2-methylpyridine (CAS [38749-79-0]) using Pd2(dba)3 as catalyst and Xantphos as ligand (General Procedure F).

[0225] Intermediate 38: 2-((3-cyano-2-methoxyphenyl)amino)-6-cyclopropylnicotinonitrile TIFF0007749602000062.tif50170

[0226] Title compound ([M+H] + 291.2) was prepared from 2-chloro-6-(propan-2-yl)pyridine-3-carbonitrile (CAS[108244-44-6]) by reaction with 3-amino-2-methoxybenzonitrile (CAS[725718-10-5]) using Pd(OAc)2 as catalyst and xphos as ligand (General Procedure B1).

[0227] Intermediate 39: 4-Methoxy-2-((2-methylpyridin-3-yl)amino)benzonitrile TIFF0007749602000063.tif47170

[0228] Title compound ([M+H] + 240.2) was synthesized from 2-bromo-4-methoxybenzonitrile (CAS [140860-51-1]) with Pd(OAc) as catalyst, DPPF as ligand, and KO as base in toluene. t Prepared by reaction with 3-amino-2-methylpyridine (CAS [3430-10-2]) at 120° C. using Bu (general procedure I1).

[0229] Intermediate 40: 2-((2-methylpyridin-3-yl)amino)-4-(trifluoromethoxy)benzonitrile TIFF0007749602000064.tif46170

[0230] Title compound ([M+H] + 294.2) was prepared from 2-bromo-4-(trifluoromethoxy)benzonitrile (CAS[1214334-83-4]) by reaction with 3-amino-2-methylpyridine (CAS[3430-10-2]) using Pd(OAc) as catalyst, Xantphos as ligand, and CsCO as base in dioxane at 100 °C (General Procedure I1).

[0231] Intermediate 41: 6-(4,5-dihydrofuran-3-yl)-2-((2-methylpyridin-3-yl)amino)nicotinonitrile TIFF0007749602000065.tif46170

[0232] Step 1: 2-chloro-6-(2,3-dihydrofuran-4-yl)pyridine-3-carbonitrile Title compound ([M+H] + 207.1) was prepared by the reaction of 2,6-dichloronicotinonitrile (CAS[40381-90-6]) with 2-(4,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAS[1046812-03-6]) using Pd(dppf)2Cl2·CH2Cl2 complex as catalyst and K2CO3 as base at 80 °C (General Procedure A1).

[0233] Step 2: 6-(4,5-dihydrofuran-3-yl)-2-((2-methylpyridin-3-yl)amino)nicotinonitrile Title compound ([M+H] + 279.2) was prepared from 2-chloro-6-(4,5-dihydrofuran-3-yl)nicotinonitrile by reaction with 3-amino-2-methylpyridine (CAS[3430-10-2]) using Pd(OAc)2 as catalyst and Xantphos as ligand (General Procedure B1).

[0234] Intermediate 42: 6-Cyclopropyl-2-((4-methylpyrimidin-5-yl)amino)nicotinonitrile TIFF0007749602000066.tif46170

[0235] Title compound ([M+H] + 252.2) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS[1198475-35-2]) by reaction with 5-amino-4-methylpyrimidine (CAS[3438-61-7]) using Pd(OAc)2 as catalyst and Xantphos as ligand (General Procedure B1).

[0236] Intermediate 43: 6-Cyclopropyl-2-((2-(trifluoromethyl)pyridin-3-yl)amino)nicotinonitrile TIFF0007749602000067.tif46170

[0237] Title compound ([M+H] + 305.2) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS[1198475-35-2]) by reaction with 2-(trifluoromethyl)pyridin-3-amine (CAS[106877-32-1]) using Pd(OAc)2 as catalyst and Xantphos as ligand (General Procedure B1).

[0238] Intermediate 44: 6-Cyclopropyl-2-[(2-methylpyrazol-3-yl)amino]pyridine-3-carbonitrile TIFF0007749602000068.tif43170

[0239] Title compound ([M+H] + 240.1) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS[1198475-35-2]) by reaction with 1-methyl-1H-pyrazol-5-ylamine (CAS[1192-21-8]) using Pd(OAc)2 as catalyst and Xantphos as ligand (General Procedure B1).

[0240] Intermediate 45: 4-Cyclopropyl-2-((2,3-dihydrobenzofuran-4-yl)amino)benzonitrile TIFF0007749602000069.tif46170

[0241] Title compound ([M+H] + 277.2) was prepared from 2-bromo-4-cyclopropylbenzonitrile (CAS[1237130-18-5]) by reaction with 2,3-dihydrobenzofuran-4-amine (CAS[61090-37-7]) at 100 °C using Pd(OAc)2 as catalyst and Xantphos as ligand (General Procedure I1).

[0242] Intermediate 46: (R)-2-((tetrahydro-2H-pyran-3-yl)amino)-4-(trifluoromethyl)benzonitrile TIFF0007749602000070.tif46170

[0243] Title compound ([M+H] + 271.2) was prepared from 2-bromo-4-(trifluoromethyl)benzonitrile (CAS[35764-15-9]) by reaction with (R)-tetrahydro-2H-pyran-3-amine hydrochloride (CAS[1315500-31-2]) at 90 °C using Pd(OAc)2 as catalyst and Xantphos as ligand (General Procedure I1).

[0244] Intermediate 47: 6-cyclopropyl-2-((4-methylpyridin-3-yl)amino)nicotinonitrile TIFF0007749602000071.tif46170

[0245] Title compound ([M+H] +251.2) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS[1198475-35-2]) by reaction with 3-amino-4-methylpyridine (CAS[3430-27-1]) using Pd(OAc)2 as catalyst and Xantphos as ligand (General Procedure B1).

[0246] Intermediate 48: 4-Ethyl-2-((2-methylpyridin-3-yl)amino)benzonitrile TIFF0007749602000072.tif46170

[0247] Title compound ([M+H] + 238.2) was prepared from 2-bromo-4-ethylbenzonitrile (CAS[38678-87-4]) by reaction with 3-amino-2-methylpyridine (CAS[3430-10-2]) at 100 °C using Pd(OAc)2 as catalyst and Xantphos as ligand (General Procedure I1).

[0248] Intermediate 49: 6-[(1SR,2RS)-2-fluorocyclopropyl]-2-[[(3R)-tetrahydropyran-3-yl]amino]pyridine-3-carbonitrile TIFF0007749602000073.tif46170

[0249] Step 1: 6-((trans)-2-fluorocyclopropyl)-2-hydroxynicotinonitrile 6-((trans)-2-fluorocyclopropyl)-2-hydroxynicotinonitrile ([M+H] + 179.0) was prepared by the reaction of 3-(dimethylamino)-1-((trans)-2-fluorocyclopropyl)prop-2-en-1-one (prepared by a modified procedure from J. Med. Chem. 2011, 54, 7974-7985) with 2-cyanoacetamide (CAS[107-91-5]) using NaOMe as the base (general procedures G and H).

[0250] Step 2: 2-chloro-6-((trans)-2-fluorocyclopropyl)nicotinonitrile 2-Chloro-6-((trans)-2-fluorocyclopropyl)nicotinonitrile (H NMR (CDCl, 300 MHz) δ 7.8-7.9 (m, 1H), 7.3-7.3 (m, 1H), 4.8-5.1 (m, 1H), 2.49 (d, 1H, J=1.6 Hz), 1.6-1.8 (m, 1H), 1.5-1.6 (m, 1H)) was prepared by the reaction of 6-((trans)-2-fluorocyclopropyl)-2-hydroxynicotinonitrile with POCL (general procedures G and H).

[0251] Step 3: 6-[(1SR,2RS)-2-fluorocyclopropyl]-2-[[(3R)-tetrahydropyran-3-yl]amino]pyridine-3-carbonitrile Title compound ([M+H] + 260.0) was prepared from 2-chloro-6-((trans)-2-fluorocyclopropyl)nicotinonitrile by reaction with (R)-tetrahydro-2H-pyran-3-amine hydrochloride (CAS [1315500-31-2]) at 80 °C using Pd(OAc) as catalyst and Xantphos as ligand (General Procedure I1).

[0252] Intermediate 50: 6-Cyclopropyl-2-[(4-methyloxazol-5-yl)amino]pyridine-3-carbonitrile TIFF0007749602000074.tif44170

[0253] Step 1: tert-butyl N-(3-cyano-6-cyclopropyl-2-pyridyl)-N-(4-methyloxazol-5-yl)carbamate Title compound ([M+H] +341.1) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS[1198475-35-2]) by reaction with tert-butyl N-(4-methyloxazol-5-yl)carbamate (CAS[3403-45-0]) using Pd(OAc)2 as catalyst and Xantphos as ligand (General Procedure B1).

[0254] Step 2: 6-cyclopropyl-2-[(4-methyloxazol-5-yl)amino]pyridine-3-carbonitrile A mixture of tert-butyl N-(3-cyano-6-cyclopropyl-2-pyridyl)-N-(4-methyloxazol-5-yl)carbamate (50 mg, 0.150 mmol) in TFA:DCM = 1:1 (3.0 mL) was stirred at 25 °C for 2 hours, after which saturated aqueous NaHCO was added. The reaction mixture was extracted with DCM (20 mL × 2), and the combined organic layers were dried over NaSO, filtered, and concentrated in vacuo to give crude 6-cyclopropyl-2-[(4-methyloxazol-5-yl)amino]pyridine-3-carbonitrile (40 mg, 108%) as a pale yellow solid. ([M+H] + 241.1)

[0255] Intermediate 51: 6-Cyclopropyl-2-[(4-methylthiazol-5-yl)amino]pyridine-3-carbonitrile TIFF0007749602000075.tif43170

[0256] Step 1: tert-butyl N-(4-methylthiazol-5-yl)carbamate To a solution of 4-methylthiazole-5-carboxylic acid (600 mg, 4.19 mmol) in tBuOH (15 mL) was added TEA (2.34 mL, 16.76 mmol) and diphenylphosphoryl azide (1.73 g, 6.29 mmol). The reaction mixture was stirred at 20° C. for 15 minutes and then heated to 80° C. for 2 hours. The reaction mixture was poured into saturated aqueous NaHCO (30 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (30 mL), dried over NaSO, and concentrated in vacuo to give crude tert-butyl N-(4-methylthiazol-5-yl)carbamate (400 mg, 44%) as a yellow solid. ([M+H] + 215.1)

[0257] Step 2: 4-Methylthiazol-5-amine hydrochloride To a solution of tert-butyl N-(4-methylthiazol-5-yl)carbamate (400 mg, 1.87 mmol) in DCM (5 mL) was added HCl (4 M in dioxane, 2.0 mL, 8 mmol). The reaction was stirred at 25° C. for 12 h until TLC and LCMS indicated complete consumption of the starting material. The reaction mixture was concentrated in vacuo to give crude 4-methylthiazol-5-amine hydrochloride (200 mg, 71%) as a yellow solid. ([M+H] + 115.1)

[0258] Step 3: 6-Cyclopropyl-2-[(4-methylthiazol-5-yl)amino]pyridine-3-carbonitrile Title compound ([M+H] + 256.9) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) by reaction with 4-methylthiazol-5-amine hydrochloride at 100 °C using Pd(OAc) as catalyst and Xantphos as ligand (General Procedure B1).

[0259] Intermediate 52: 6-Cyclopropyl-4-(o-tolylamino)nicotinonitrile TIFF0007749602000076.tif45170

[0260] Step 1: 4-chloro-6-cyclopropylnicotinonitrile Title compound ([M+H] + 179.1) was prepared by the reaction of 4,6-dichloronicotinonitrile (CAS[166526-03-0]) with cyclopropylboronic acid (CAS[411235-57-9]) using Pd(dppf)2Cl2·CH2Cl2 complex as catalyst and K2CO3 as base at 90 °C (similar to general procedure A1).

[0261] Step 2: 6-Cyclopropyl-4-(o-tolylamino)nicotinonitrile Title compound ([M+H] + 250.2) was prepared from 4-chloro-6-cyclopropylnicotinonitrile by reaction with o-toluidine (CAS[95-35-4]) at 100 °C using Pd(OAc) as catalyst and xphos as ligand (similar to general procedure B1).

[0262] Intermediate 53: 6-Cyclobutyl-2-[(2-methyl-3-pyridyl)amino]pyridine-3-carbonitrile TIFF0007749602000077.tif44170

[0263] Step 1: 2-chloro-6-cyclobutyl-pyridine-3-carbonitrile To a 40 mL vial equipped with a stir bar was added bromocyclobutane (1171 mg, 8.67 mmol), 2,6-dichloronicotinonitrile (1000 mg, 5.78 mmol), Ir[dF(CF3)ppy]2(dtbpy)(PF6) (65 mg, 0.060 mmol), NiCl2·dtbbpy (12 mg, 0.030 mmol), tris(trimethylsilyl)silane (1437 mg, 5.78 mmol), and Na2CO3 (1225 mg, 11.56 mmol) in DME (30 mL). The vial was sealed and placed under nitrogen. The reaction was stirred and irradiated with a 34 W blue LED lamp (7 cm distance) using a cooling fan to maintain the reaction temperature at 25 °C for 14 h. Ethyl acetate (30 mL) and brine (20 mL) were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (30 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. Purification by reverse-phase preparative HPLC afforded 2-chloro-6-cyclobutyl-pyridine-3-carbonitrile (100 mg, 9%) as a white solid. ([M+H] + 193.0)

[0264] Step 2: Cyclobutyl-2-[(2-methyl-3-pyridyl)amino]pyridine-3-carbonitrile Title compound ([M+H] + 265.2) was prepared from 2-chloro-6-cyclobutyl-pyridine-3-carbonitrile by reaction with 3-amino-2-methylpyridine (CAS [3430-10-2]) using Pd(OAc)2 as catalyst and xphos as ligand (General Procedure B1).

[0265] Intermediate 54: 2-[(2-methoxy-3-pyridyl)amino]-6-tetrahydropyran-2-yl-pyridine-3-carbonitrile TIFF0007749602000078.tif46170

[0266] Step 1: 2-chloro-6-(3,4-dihydro-2H-pyran-6-yl)pyridine-3-carbonitrile Title compound ( 1H NMR (DMSO-d6, 400 MHz) δ = 8.43 (d, J = 8.2 Hz, 1H), 7.61 (d, J = 8.2 Hz, 1H), 6.24 (t, J = 4.3 Hz, 1H), 4.20 - 4.16 (m, 2H), 2.30 - 2.24 (m, 2H), 1.90 - 1.83 (m, 2H)) was prepared by the reaction of 2,6-dichloronicotinonitrile (CAS[40381-90-6]) with 2-(3,4-dihydro-2H-pyran-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAS[1025707-93-0]) using Pd(dppf)Cl·CHCl complex as catalyst and KCO as base at 80 °C (General Procedure A1).

[0267] Step 2: 6-(3,4-dihydro-2H-pyran-6-yl)-2-[(2-methoxy-3-pyridyl)amino]pyridine-3-carbonitrile Title compound ([M+H] + 309.1) was prepared from 2-chloro-6-(3,4-dihydro-2H-pyran-6-yl)pyridine-3-carbonitrile by reaction with o-anisidine (CAS[90-04-0]) using Pd(OAc)2 as catalyst and Xantphos as ligand at 80 °C (General Procedure B1).

[0268] Step 3: 2-[(2-methoxy-3-pyridyl)amino]-6-tetrahydropyran-2-yl-pyridine-3-carbonitrile A mixture of 6-(3,4-dihydro-2H-pyran-6-yl)-2-[(2-methoxy-3-pyridyl)amino]pyridine-3-carbonitrile (600 mg, 1.95 mmol) and 10% Pd / C (1.95 mmol) in THF (120 mL) was stirred under a H balloon at 30° C. for 1 hour, then filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 2-[(2-methoxy-3-pyridyl)amino]-6-tetrahydropyran-2-yl-pyridine-3-carbonitrile (150 mg, 25%) as a white solid.1 H NMR (DMSO-d6, 6.98 (d, J = 7.9 Hz, 1H), 4.28 (dd, J = 2.3, 11.1 Hz, 1H), 4.07 - 4.00 (m, 1H), 3.92 (s, 3H), 3.54 (br d, J = 3.2 Hz, 1H), 1.95 (br dd, J = 2.6, 13.1 Hz, 1H), 1.84 (br s, 1H), 1.71 - 1.58 (m, 1H), 1.57 - 1.48 (m, 2H), 1.36 (br s, 1H))

[0269] Intermediate 55: 6-Cyclopentyl-2-[(4-methylpyrimidin-5-yl)amino]pyridine-3-carbonitrile TIFF0007749602000079.tif46170

[0270] Step 1: 2-chloro-6-(cyclopenten-1-yl)pyridine-3-carbonitrile Title compound ([M+H] + 205.0) was prepared by the reaction of 2,6-dichloronicotinonitrile (CAS[40381-90-6]) with 1-cyclopentenylboronic acid pinacol ester (CAS[287944-10-9]) using Pd(dppf)2Cl2·CH2Cl2 complex as catalyst and K2CO3 as base at 80 °C (General Procedure A1).

[0271] Step 2: 6-(cyclopenten-1-yl)-2-[(4-methylpyrimidin-5-yl)amino]pyridine-3-carbonitrile Title compound ( 1 H NMR (DMSO-d6, 400 MHz) δ = 9.03 (s, 1H), 8.85 (s, 1H), 8.69 (s, 1H), 8.05 (d, J = 8.1 Hz, 1H), 7.05 (d, J = 7.9 Hz, 1H), 6.53 (d, J = 1.7 Hz, 1H), 4.03 (q, J = 7.1 Hz, 5H), 2.48 - 2.44 (m, 3H), 2.34 (s, 3H), 1.99 (s, 7H), 1.92 - 1.81 (m, 2H), 1.17 (t, J = 7.1 Hz, 8H)) was prepared from 2-chloro-6-(cyclopenten-1-yl)pyridine-3-carbonitrile by reaction with 5-amino-4-methylpyrimidine (CAS [3438-61-7] using Pd(OAc) as catalyst and Xantphos as ligand at 80 °C (General Procedure B1).

[0272] Step 3: 6-Cyclopentyl-2-[(4-methylpyrimidin-5-yl)amino]pyridine-3-carbonitrile To a solution of 6-(cyclopenten-1-yl)-2-[(4-methylpyrimidin-5-yl)amino]pyridine-3-carbonitrile (350 mg, 1.26 mmol) in THF (70 mL) was added 10% Pd / C (0.26 mmol). After the mixture was stirred under a H atmosphere (balloon) at 20° C. for 1 h, it was filtered and concentrated under reduced pressure to give crude 6-cyclopentyl-2-[(4-methylpyrimidin-5-yl)amino]pyridine-3-carbonitrile (480 mg, quant.) as a white solid. ([M+H] + 280.0)

[0273] Intermediate 56: 6-Cyclopentyl-2-[(2-methyl-3-pyridyl)amino]pyridine-3-carbonitrile TIFF0007749602000080.tif46170

[0274] Step 1: 2-chloro-6-(cyclopenten-1-yl)pyridine-3-carbonitrile Title compound ([M+H] +205.0) was prepared by the reaction of 2,6-dichloronicotinonitrile (CAS[40381-90-6]) with 1-cyclopentenylboronic acid pinacol ester (CAS[287944-10-9]) using Pd(dppf)2Cl2·CH2Cl2 complex as catalyst and K2CO3 as base at 80 °C (General Procedure A1).

[0275] Step 2: 6-(cyclopenten-1-yl)-2-[(2-methyl-3-pyridyl)amino]pyridine-3-carbonitrile Title compound ([M+H] + 277.2) was prepared from 2-chloro-6-(cyclopenten-1-yl)pyridine-3-carbonitrile by reaction with 3-amino-2-methylpyridine (CAS [3430-10-2]) using Pd(OAc) as catalyst and Xantphos as ligand (General Procedure B1).

[0276] Step 3: 6-Cyclopentyl-2-[(2-methyl-3-pyridyl)amino]pyridine-3-carbonitrile To a solution of 6-(cyclopenten-1-yl)-2-[(2-methyl-3-pyridyl)amino]pyridine-3-carbonitrile (130.0 mg, 0.470 mmol) in THF (26 mL) was added 10% Pd / C (0.26 mmol). After the mixture was stirred at 20 °C under a H balloon for 1 h, it was filtered and concentrated under reduced pressure to give 6-cyclopentyl-2-[(2-methyl-3-pyridyl)amino]pyridine-3-carbonitrile (150 mg, 100% yield) as a white solid. ([M+H] + 279.2)

[0277] Intermediate 57: 6-(3-azabicyclo[2.2.1]heptan-3-yl)-2-[(2-methylpyrazol-3-yl)amino]pyridine-3-carbonitrile TIFF0007749602000081.tif43170

[0278] Step 1: 6-(7-Azabicyclo[2.2.1]heptan-7-yl)-2-chloro-pyridine-3-carbonitrile To a solution of 2,6-dichloronicotinonitrile (800 mg, 4.62 mmol) in THF (50 mL) and ACN (50 mL) was added 7-azabicyclo[2.2.1]heptane hydrochloride (618 mg, 4.62 mmol) and N,N-diisopropylethylamine (2.42 mL, 13.87 mmol). After the reaction mixture was stirred at 30° C. for 16 h, it was concentrated in vacuo and purified by flash column chromatography to give 6-(7-azabicyclo[2.2.1]heptan-7-yl)-2-chloro-pyridine-3-carbonitrile (600 mg, 50%) as a yellow solid. 1 H NMR (DMSO-d6, 400 MHz) δ = 7.93 - 7.71 (m, 2H), 6.72 (br d, J = 8.8 Hz, 1H), 6.37 (br d, J = 8.8 Hz, 1H), 4.79 - 4.62 (m, 1H), 4.57 - 4.40 (m, 1H), 3.42 - 3.35 (m, 2H), 3.21 - 3.12 (m, 1H), 3.02 (br d, J = 9.6 Hz, 1H), 2.70 - 2.61 (m, 2H), 1.76 - 1.62 (m, 6H), 1.57 - 1.35 (m, 6H))

[0279] Step 2: 6-(3-azabicyclo[2.2.1]heptan-3-yl)-2-[(2-methylpyrazol-3-yl)amino]pyridine-3-carbonitrile Title compound ( 1H NMR (DMSO-d3, 400 MHz) δ = 7.38 (s, 1H), 7.31 (s, 1H), 6.31 (s, 1H), 6.23 (d, J = 8.1 Hz, 1H), 5.96 (d, J = 7.9 Hz, 1H), 4.57 (d, J = 1.7 Hz, 1H), 3.76 (q, J = 7.1 Hz, 3H), 3.32 - 3.23 (m, 1H), 3.08 (s, 1H), 2.63 (s, 1H), 1.74 - 1.57 (m, 4H), 1.42 (t, J = 7.1 Hz, 2H)) was prepared from 6-(7-azabicyclo[2.2.1]heptan-7-yl)-2-chloro-pyridine-3-carbonitrile by reaction with 1-methyl-1H-pyrazol-5-ylamine (CAS [1192-21-8]) using Pd(OAc) as catalyst and Xantphos as ligand at 100 °C (General Procedure B1).

[0280] Intermediate 58: 4-(2-fluoropropan-2-yl)-2-[(2-methylpyridin-3-yl)amino]benzonitrile TIFF0007749602000082.tif46170

[0281] Step 1: 2-Bromo-4-(2-hydroxypropan-2-yl)benzonitrile To a solution of 4-acetyl-2-bromobenzonitrile (50 mg, 223 μmol, CAS [93273-63-3]) in DCM (2 mL) was added methylmagnesium bromide solution (3 M in diethyl ether, 89 μL, 268 μmol) at 0° C. After 45 min, the reaction was diluted with saturated aqueous NH4Cl solution and extracted three times with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography to give 2-bromo-4-(2-hydroxypropan-2-yl)benzonitrile (37 mg, 68%) as a yellow viscous oil. ([GCMS:M] + 239.0)

[0282] Step 2: 2-Bromo-4-(2-fluoropropan-2-yl)benzonitrile To a solution of 2-bromo-4-(2-hydroxypropan-2-yl)benzonitrile (36 mg, 150 μmol) in DCM (1 mL) was added DAST (23.8 μL, 180 μmol) at −70° C. The ice bath was removed, and after 2 h the reaction was diluted with saturated aqueous NaHCO3 solution and extracted with DCM. The combined air layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography to give 2-bromo-4-(2-fluoropropan-2-yl)benzonitrile (20 mg, 54%) as a yellow viscous oil. ([GCMS:M] + 241.0)

[0283] Step 3: 4-(2-fluoropropan-2-yl)-2-[(2-methylpyridin-3-yl)amino]benzonitrile Title compound ([M+H] + 270.2) was prepared from 2-bromo-4-(2-fluoroprop-2-yl)benzonitrile by reaction with 3-amino-2-methylpyridine (CAS[3430-10-2]) at 100 °C using Pd2(dba)3 as catalyst and Xantphos as ligand (General Procedure I1).

[0284] Intermediate 59: 2-Fluoro-6-((2-methylpyridin-3-yl)amino]-4-(trifluoromethyl)benzonitrile TIFF0007749602000083.tif48170

[0285] Title compound ([M+H] + 296.2) was prepared from 2,6-difluoro-4-(trifluoromethyl)benzonitrile (CAS[1803828-56-9]) by reaction with 3-amino-2-methylpyridine (CAS[3430-10-2]) using NMP as the solvent and KOtBu as the base at room temperature (General Procedure I2).

[0286] Intermediate 60: 6-Cyclopropyl-2-((4-fluoro-2-methoxypyridin-3-yl)amino)nicotinonitrile TIFF0007749602000084.tif45170

[0287] Step 1: tert-butyl (4-fluoro-2-methoxypyridin-3-yl)carbamate To a solution of tert-butyl (2-methoxypyridin-3-yl)carbamate (500 mg, 2.23 mmol) and TMEDA (518 mg, 4.46 mmol) in dry THF (20 mL) at -35 °C, nBuLi (1.6 M in hexanes, 5.57 mL, 8.92 mmol) was added dropwise via syringe. After reaching -20 °C, the mixture was stirred at -20 °C for 2 h, cooled again to -35 °C, and N-fluorobenzenesulfonimide solution (1 M in THF, 2.45 mmol) was added. The resulting reaction mixture was allowed to reach -20 °C, quenched with saturated aqueous NH4Cl, and extracted with EtOAc. The crude product was purified by flash column chromatography to give tert-butyl (4-fluoro-2-methoxypyridin-3-yl)carbamate (232 mg, 43%) as a colorless oil. ([M+H] + 243.2).

[0288] Step 2: 4-Fluoro-2-methoxypyridin-3-amine tert-Butyl (4-fluoro-2-methoxypyridin-3-yl)carbamate (230 mg, 949 μmol) was dissolved in HCl (4 M in dioxane, 13 mL, 52.2 mmol) and stirred at room temperature for 20 hours, then quenched with saturated aqueous NaHCO and diluted with EtOAc. The layers were separated, and the organic phase was dried over NaSO, filtered, and concentrated in vacuo to give the crude title product (130 mg, 91%). 1 H NMR (CDCl3, 300 MHz) δ 7.52 (dd, 1H, J=5.7, 8.0 Hz), 6.65 (dd, 1H, J=5.7, 9.4 Hz), 4.00 (s, 3H), 3.6-3.8 (m, 2H)).

[0289] Step 3: 6-cyclopropyl-2-((4-fluoro-2-methoxypyridin-3-yl)amino)nicotinonitrile Title compound ([M+H] + 285.2) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) by reaction with 4-fluoro-2-methoxypyridin-3-amine hydrochloride using Pd(OAc)2 as catalyst and Xantphos as ligand (General Procedure B1).

[0290] Intermediate 61: 6-Cyclopropyl-2-[(2-ethylpyrazol-3-yl)amino]pyridine-3-carbonitrile TIFF0007749602000085.tif43170

[0291] Title compound ([M+H] + 254.3) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS[1198475-35-2]) by reaction with 5-amino-1-ethylpyrazole (CAS[3528-58-3]) using Pd(OAc)2 as catalyst and Xantphos as ligand (General Procedure B1).

[0292] Intermediate 62: 6-chloro-2-(o-tolylamino)nicotinonitrile TIFF0007749602000086.tif49170

[0293] Step 1: 6-chloro-2-(o-tolylamino)nicotinamide 2,6-Dichloronicotinamide (1.03 g, 5.39 mmol), o-toluidine (867 mg, 8.09 mmol), and DIPEA (4.71 mL, 27 mmol) were dissolved in NMP (10 mL) and heated to 140° C. for 100 h. The crude mixture was quenched with water and extracted with EtOAc. The layers were separated, and the organic phase was dried over NaSO, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography to afford 1.00 g (68%) of o-chloro-2-(o-tolylamino)nicotinamide as a white solid. ([M+H] + 262.2)

[0294] Step 2: 6-chloro-2-(o-tolylamino)nicotinonitrile To a solution of 6-chloro-2-(o-tolylamino)nicotinamide (19 mg, 74.5 μmol) and pyridine (48.2 μL, 596 μmol) in acetonitrile (1 mL) was added POCl (28 μL, 298 μmol) at 0° C., and the reaction mixture was stirred at 50° C. for 45 min. The reaction mixture was quenched with water, basified to pH 10 using 1 M NaOH, and extracted with EtOAc. The layers were separated, and the organic phase was dried over NaSO, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography to give 6-chloro-2-(o-tolylamino)nicotinonitrile (14 mg, 73%) as a white solid. ([M+H] + 244.2)

[0295] Intermediate 63: 6-Cyclopropyl-2-((2,3-dihydrobenzofuran-7-yl)amino)nicotinonitrile TIFF0007749602000087.tif46170

[0296] Title compound ([M+H] +278.2) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS[1198475-35-2]) by reaction with 2,3-dihydrobenzofuran-7-amine (CAS[13414-56-7]) using Pd(OAc)2 as catalyst and Xantphos as ligand (General Procedure B1).

[0297] Intermediate 64: 2-((2-chlorophenyl)amino)-6-cyclopropylnicotinonitrile TIFF0007749602000088.tif46170

[0298] Title compound ([M+H] + 270.1) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS[1198475-35-2]) by reaction with 2-chloroaniline (CAS[95-51-2]) using Pd2(dba)3 as catalyst and Xantphos as ligand (General Procedure B1).

[0299] Intermediate 65: 5-chloro-2-((3-cyano-2-methoxyphenyl)amino)-6-cyclopropylnicotinonitrile TIFF0007749602000089.tif52170

[0300] Step 1: 2-Amino-6-cyclopropylnicotinonitrile Title compound ([M+H] + 160.1) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) using general procedure D.

[0301] Step 2: 2-amino-5-chloro-6-cyclopropylnicotinonitrile Title compound ([M+H] + 194.0) was prepared from 2-amino-6-cyclopropylnicotinonitrile and NCS in MeCN at 80° C. (General procedure E).

[0302] Step 3: 5-chloro-2-((3-cyano-2-methoxyphenyl)amino)-6-cyclopropylnicotinonitrile Title compound ([M+H] + 325.2) was prepared from 2-amino-5-chloro-6-cyclopropylnicotinonitrile by reaction with 3-bromo-2-methoxybenzonitrile (CAS [874472-98-7]) using Pd2(dba)3 as catalyst and Xantphos as ligand (General Procedure F).

[0303] Intermediate 66: 5-chloro-6-cyclopropyl-2-((2-methoxypyridin-3-yl)amino)nicotinonitrile TIFF0007749602000090.tif45170

[0304] Step 1: 2-Amino-6-cyclopropylnicotinonitrile Title compound ([M+H] + 160.1) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) using general procedure D.

[0305] Step 2: 2-amino-5-chloro-6-cyclopropylnicotinonitrile Title compound ([M+H] + 194.0) was prepared from 2-amino-6-cyclopropylnicotinonitrile and NCS in MeCN at 80° C. (General procedure E).

[0306] Step 3: 5-chloro-6-cyclopropyl-2-((2-methoxypyridin-3-yl)amino)nicotinonitrile Title compound ([M+H] + 301.2) was prepared from 2-amino-5-chloro-6-cyclopropylnicotinonitrile by reaction with 3-bromo-2-methoxypyridine (CAS [13472-59-8]) using Pd2(dba)3 as catalyst and Xantphos as ligand (General Procedure F).

[0307] Intermediate 67: 6-Cyclopropyl-2-(4-fluoro-2-methylanilino)pyridine-3-carbonitrile TIFF0007749602000091.tif55170

[0308] Title compound ([M+H] + 268.2) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS[1198475-35-2]) by reaction with 4-fluoro-2-methylaniline (CAS[452-71-1]) using Pd2(dba)3 as catalyst and Xantphos as ligand (General Procedure B1).

[0309] Intermediate 68: 6-Cyclopropyl-2-((3-ethoxyphenyl)amino)nicotinonitrile TIFF0007749602000092.tif47170

[0310] Title compound ([M+H] + 264.2) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS[1198475-35-2]) by reaction with 3-ethylaniline (CAS[587-02-0]) using Pd(OAc)2 as catalyst and Xantphos as ligand (General Procedure B1).

[0311] Intermediate 69: 6-Cyclopropyl-2-(m-tolylamino)nicotinonitrile TIFF0007749602000093.tif46170

[0312] Title compound ([M+H] + 250.2) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS[1198475-35-2]) by reaction with 3-methylaniline (CAS[108-44-1]) using Pd(OAc)2 as catalyst and Xantphos as ligand (General Procedure B1).

[0313] Intermediate 70: 6-Cyclopropyl-2-((3,5-difluorophenyl)amino)nicotinonitrile TIFF0007749602000094.tif46170

[0314] Title compound ([M+H] + 272.2) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS[1198475-35-2]) by reaction with 3,5-difluoroaniline (CAS[372-39-4]) using Pd(OAc)2 as catalyst and Xantphos as ligand (General Procedure B1).

[0315] Intermediate 71: 6-Cyclopropyl-2-((3-methoxyphenyl)amino)nicotinonitrile TIFF0007749602000095.tif46170

[0316] Title compound ([M+H] + 266.2) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS[1198475-35-2]) by reaction with m-anisidine (CAS[536-90-3]) using Pd(OAc)2 as catalyst and xantphos as ligand (General Procedure B1).

[0317] Intermediate 72: 6-Cyclopropyl-2-((6-methoxypyridin-2-yl)amino)nicotinonitrile TIFF0007749602000096.tif47170

[0318] Title compound ([M+H] + 267.2) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS[1198475-35-2]) by reaction with 2-amino-6-methoxypyridine (CAS[17920-35-3]) using Pd(OAc)2 as catalyst and Xantphos as ligand (General Procedure B1).

[0319] Intermediate 73: 6-Cyclopropyl-2-(2,3-difluoroanilino)pyridine-3-carbonitrile TIFF0007749602000097.tif47170

[0320] Title compound ([M+H] + 272.2) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS[1198475-35-2]) by reaction with 2,3-difluoroaniline (CAS[4519-40-8]) using Pd2(dba)3 as catalyst and Xantphos as ligand (General Procedure B1).

[0321] Intermediate 74: 6-Cyclopropyl-2-(phenylamino)nicotinonitrile TIFF0007749602000098.tif45170

[0322] Title compound ([M+H] + 236.3) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS[1198475-35-2]) by reaction with aniline (CAS[62-53-3]) using Pd(OAc)2 as catalyst and Xantphos as ligand (General Procedure B1).

[0323] Intermediate 75: 6-Cyclopropyl-2-(1-oxazol-5-ylethylamino)pyridine-3-carbonitrile TIFF0007749602000099.tif46170

[0324] Step 1: (R)-2-methyl-N-((R)-1-(oxazol-5-yl)ethyl)propane-2-sulfinamide To a solution of 1-(oxazol-5-yl)ethan-1-one (150 mg, 1.35 mmol, CAS [1263378-07-9]) in THF (3 mL) was added (R)-2-methylpropane-2-sulfinamide (180 mg, 1.49 mmol), followed by titanium ethoxide (1.15 g, 4.05 mmol). The resulting reaction mixture was heated to 60 °C for 2 h, after which it was cooled to -15 °C. NaBH (61.3 mg, 1.62 mmol) was added at -15 °C, and the reaction mixture was stirred at this temperature for 3 h. 1N The reaction was quenched with HCl to approximately pH 5 and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and evaporated to dryness. The crude product was purified by flash column chromatography to give (R)-2-methyl-N-((R)-1-(oxazol-5-yl)ethyl)propane-2-sulfinamide (156 mg, 53%) as a pale yellow oil. ([M+H] + 217.2)

[0325] Step 2: (R)-1-(oxazol-5-yl)ethan-1-amine hydrochloride (R)-2-Methyl-N-((R)-1-(oxazol-5-yl)ethyl)propane-2-sulfinamide (150 mg, 693 μmol) was dissolved in MeOH (3 mL) and HCl (4 M in dioxane, 347 μL, 1.39 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated to dryness, the crude product was suspended in EtO, and the organic layer was removed. The residual solid was dried under vacuum to give (R)-1-(oxazol-5-yl)ethan-1-amine hydrochloride (84 mg, 81%) as a yellow gum. ([M+H] + 113.1)

[0326] Step: 6-cyclopropyl-2-(1-oxazol-5-ylethylamino)pyridine-3-carbonitrile Title compound ([M+H] +255.2) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) by reaction with (R)-1-(oxazol-5-yl)ethan-1-amine hydrochloride using Pd(OAc) as catalyst and Xantphos as ligand (General Procedure B1).

[0327] Intermediate 76: 3-((2-cyano-5-(trifluoromethyl)phenyl)amino)-2-methylbenzonitrile TIFF0007749602000100.tif51170

[0328] Title compound ([M+H] + 300.2) was prepared from 2-bromo-4-(trifluoromethyl)benzonitrile (CAS[35764-15-9]) by reaction with 3-amino-2-methylbenzonitrile (CAS[69022-35-1]) using Pd2(dba)3 as catalyst and Xantphos as ligand (General Procedure I1).

[0329] Intermediate 77: 2-((3-cyano-2-methylphenyl)amino)-6-(trifluoromethyl)nicotinonitrile TIFF0007749602000101.tif51170

[0330] Title compound ([M+H] + 301.2) was prepared from 2-chloro-6-(trifluoromethyl)nicotinonitrile (CAS[386704-06-9]) by reaction with 3-amino-2-methylbenzonitrile (CAS[69022-35-1]) using Pd2(dba)3 as catalyst and Xantphos as ligand (General Procedure B1).

[0331] Intermediate 78: 6-Cyclopropyl-2-((2,6-difluorophenyl)amino)nicotinonitrile TIFF0007749602000102.tif45170

[0332] Title compound ([M+H] + 272.2) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS[1198475-35-2]) by reaction with 2,6-difluoroaniline (CAS[5509-65-9]) using Pd(OAc)2 as catalyst and xphos as ligand (General Procedure B1).

[0333] Intermediate 79: 6-Cyclopropyl-2-((2-fluorophenyl)amino)nicotinonitrile TIFF0007749602000103.tif45170

[0334] Title compound ([M+H] + 254.1) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS[1198475-35-2]) by reaction with 2-fluoroaniline (CAS[348-54-9]) using Pd(OAc)2 as catalyst and xphos as ligand (General Procedure B1).

[0335] Intermediate 80: 6-Cyclopropyl-2-((3-fluorophenyl)amino)nicotinonitrile TIFF0007749602000104.tif47170

[0336] Title compound ([M+H] + 254.1) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS[1198475-35-2]) by reaction with 3-fluoroaniline (CAS[372-19-0]) using Pd(OAc)2 as catalyst and xphos as ligand (General Procedure B1).

[0337] Intermediate 81: 6-Cyclopropyl-2-[1-(oxetan-3-yl)ethylamino]pyridine-3-carbonitrile TIFF0007749602000105.tif45170

[0338] Title compound ([M+H] +244.2) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS[1198475-35-2]) by reaction with 1-(oxetan-3-yl)ethan-1-amine (CAS[1544892-89-8]) using NMP as solvent and DIPEA as base at 135°C / microwave (General Procedure B2).

[0339] Intermediate 82: 6-Cyclopropyl-2-((1-(pyrimidin-2-yl)ethyl)amino)nicotinonitrile TIFF0007749602000106.tif46170

[0340] Title compound ([M+H] + 265.5) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS[1198475-35-2]) by reaction with 1-(pyridin-2-yl)ethan-1-amine (CAS[40154-81-2]) using NMP as the solvent and TEA as the base at 135° C. (General Procedure B2).

[0341] Intermediate 83: 2-[(2-methyl-3-pyridyl)amino]-4-(2,2,2-trifluoroethyl)benzonitrile TIFF0007749602000107.tif47170

[0342] Step 1: 2-Bromo-4-(2,2,2-trifluoroethyl)benzonitrile To a solution of 2-bromo-4-(bromomethyl)benzonitrile (1.0 g, 3.64 mmol) in NMP (15 mL) was added 2,2-difluoro-2-(fluorosulfonyl)methyl acetate (1.4 g, 7.27 mmol) and copper(I) iodide (0.02 g, 0.730 mmol). The reaction mixture was purged with nitrogen three times and stirred at 80 °C under a nitrogen atmosphere for 16 h. The resulting mixture was cooled, diluted with saturated aqueous NH4Cl solution, and extracted with DCM. The combined organic layers were washed with brine and dried over Na2SO4. The solution was concentrated and purified by flash column chromatography to give 2-bromo-4-(2,2,2-trifluoroethyl)benzonitrile (580 mg, 49%) as a white solid. ([M+H] + 264.0)

[0343] Step 2: 2-[(2-methyl-3-pyridyl)amino]-4-(2,2,2-trifluoroethyl)benzonitrile Title compound ([M+H] + 292.0) was prepared from 2-bromo-4-(2,2,2-trifluoroethyl)benzonitrile by reaction with 3-amino-2-methylpyridine (CAS [3430-10-2]) using Pd(OAc) as catalyst and Xantphos as ligand (General Procedure B1).

[0344] Intermediate 84: 6-Cyclopropyl-2-((tetrahydrofuran-2H-pyran-4-yl)amino)nicotinonitrile TIFF0007749602000108.tif46170

[0345] Title compound ([M+H] + 244.2) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS[1198475-35-2]) by reaction with tetrahydro-2H-pyran-4-amine (CAS[38041-19-9]) using DMA as solvent and DIPEA as base at 150°C / microwave (General Procedure B2).

[0346] Intermediate 85: 2-((2-chloropyridin-3-yl)amino)-6-cyclopropylnicotinonitrile TIFF0007749602000109.tif46170

[0347] Step 1: 2-Amino-6-cyclopropylnicotinonitrile Title compound ([M+H] + 160.1) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) using general procedure D.

[0348] Step 2: 2-((2-chloropyridin-3-yl)amino)-6-cyclopropylnicotinonitrile Title compound ([M+H] + 271.1) was prepared from 2-amino-6-cyclopropylnicotinonitrile by reaction with 2-chloro-3-iodopyridine (CAS [78607-36-0]) using Pd2(dba)3 as catalyst and Xantphos as ligand (General Procedure B1).

[0349] Intermediate 86: 4-Cyclopropyl-2-[(2-methylpyridin-3-yl)amino]benzonitrile TIFF0007749602000110.tif45170

[0350] Title compound ([M+H] + 250.2) was prepared from 2-bromo-4-cyclopropylbenzonitrile (CAS[1237130-18-5]) by reaction with 3-amino-2-methylpyridine (CAS[3430-10-2]) at 120 °C using Pd(OAc)2 as catalyst, DPPF as ligand, and KOtBu as base in toluene (General Procedure I1).

[0351] Intermediate 87: 2-chloro-6-((2-methylpyridin-3-yl)amino]-4-(trifluoromethyl)benzonitrile TIFF0007749602000111.tif50170

[0352] Title compound ([M+H] + 312.1) was prepared from 2,6-dichloro-4-(trifluoromethyl)benzonitrile (CAS[157021-61-9]) by reaction with 3-amino-2-methylpyridine (CAS[3430-10-2]) using Pd2(dba)3 as catalyst and Xantphos as ligand (General Procedure I1).

[0353] Intermediate 88: 6-Cyclopropyl-2-(4-oxaspiro[2.5]octan-8-ylamino)pyridine-3-carbonitrile TIFF0007749602000112.tif46170

[0354] Step 1: Methyl 1-(allyloxy)cyclopropane-1-carboxylate To a solution of methyl 1-hydroxycyclopropane-1-carboxylate (10 g, 86.1 mmol) in THF (220 mL) was added sodium hydride (60% dispersion in mineral oil, 4.13 g, 103 mmol) portionwise over 30 min at 0 °C. The resulting yellow reaction mixture was stirred at 0 °C for 15 min, after which a solution of allyl bromide (9.69 mL, 112 mmol) in THF (50 mL) was added over 30 min. The reaction mixture was stirred overnight at room temperature. It was cooled in an ice bath and quenched with saturated NH Cl, followed by the addition of water and extraction with t-BME. The combined organic layers were dried over Na SO , filtered, and concentrated in vacuo at 20 °C / 100 mbar. The crude product was purified by vacuum distillation (short Vigreux column) to give methyl 1-(allyloxy)cyclopropane-1-carboxylate (6.25 g, 44%, bp: 79-82 °C / 12 mbar) as a colorless oil. ([M+H] + 157.1)

[0355] Step 2: 1-(allyloxy)-N-methoxy-N-methylcyclopropane-1-carboxamide To a suspension of N,O-dimethylhydroxyamine hydrochloride (6.56 g, 67.2 mmol) in DCM (63 mL) at 0 °C, AlMe3 (2 M in toluene, 33.6 mL, 67.2 mmol) was added over 45 min, maintaining the temperature below 5 °C. The resulting reaction mixture was stirred at 0 °C for 1 h, and then a solution of methyl 1-(allyloxy)cyclopropane-1-carboxylate (5.25 g, 33.6 mmol) in DCM (32 mL) was added over 30 min. The reaction solution was stirred overnight at room temperature, cooled in an ice bath, and carefully quenched with water (60 mL). HCl (4 M in water, approximately 50 mL) was added and the reaction was stirred for 20 min. The reaction was diluted with DCM. After extraction with DCM, the organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo at 20 °C. The crude product was purified by column chromatography to give 1-(allyloxy)-N-methoxy-N-methylcyclopropane-1-carboxamide (2.81 g, 45%) as a colorless oil. ([M+H] + 186.1)

[0356] Step 3: 1-(1-(allyloxy)cyclopropyl)prop-2-en-1-one To a solution of 1-(allyloxy)-N-methoxy-N-methylcyclopropane-1-carboxamide (3.11 g, 16.8 mmol) in THF (60 mL) at −75° C. was added vinylmagnesium bromide (1 M in THF, 35.3 mL, 35.3 mmol) over 15 min. The resulting yellow reaction mixture was stirred at −75° C. for 1 h and slowly warmed to 0° C. over 90 min. The reaction was cooled back to −75° C. and quenched with 4 N aqueous HCl, followed by the addition of water (100 mL). The reaction was repeatedly extracted with tBME, and the combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated in vacuo at 20° C. to afford 1-(1-(allyloxy)cyclopropyl)prop-2-en-1-one (2.43 g, 91%) as a yellow oil. ([M+H] + 153.2)

[0357] Step 4: 4-oxaspiro[2.5]oct-6-en-8-one To a solution of 1-(1-(allyloxy)cyclopropyl)prop-2-en-1-one (2.7 g, 17.7 mmol) in DCM (324 mL) was added Zhan Catalyst-1B (130 mg, 177 μmol), and the resulting pale greenish solution was stirred for 3 hours, after which it was concentrated in vacuo at 20° C. The crude product was purified by flash column chromatography to afford 4-oxaspiro[2.5]oct-6-en-8-one (1.85 g, 83%) as a colorless oil. ([M+H] + 125.1)

[0358] Step 5: (E)-4-Oxaspiro[2.5]octan-8-one oxime Step A: 4-Oxaspiro[2.5]oct-6-en-8-one (520 mg, 4.19 mmol) was combined with 10% Pd / C (25 mg, 23.5 μmol) in MeOH (25 mL) under a H atmosphere (balloon) at 20–25°C for 30 min. Upon completion, the reaction was filtered through Decalite. Step B: Hydroxyamine·HCl (582 mg, 8.38 mmol) and KOAc (1.64 g, 16.8 mmol) were added to the reaction mixture obtained in Step A and heated at 70°C for 1 h. The reaction mixture was concentrated in vacuo, and the product was isolated after extraction from water using EtOAc. The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo to afford (E)-4-oxaspiro[2.5]octan-8-one oxime (550 mg, 84%) as a colorless oil that solidified upon standing. ([M+H] + 142.1)

[0359] Step 6: 4-oxaspiro[2.5]octan-8-amine hydrochloride (E)-4-Oxaspiro[2.5]octan-8-one oxime (50 mg, 354 μmol) and Raney nickel (200 mg, 354 μmol) were combined in 7M NH3 / MeOH under a H2 atmosphere (balloon) at 25 °C. The reaction mixture was stirred for 75 minutes, after which the catalyst was removed by filtration. The filtrate was evaporated in vacuo, and the residue was dissolved in HCl (4 M in dioxane, 0.8 mL) and subsequently evaporated in vacuo. The white solid was suspended in MeCN / Et2O, filtered off, and washed with Et2O. The filter cake was dried in vacuo at 45 °C to give 4-oxaspiro[2.5]octan-8-amine hydrochloride (37 mg, 61%) as a white solid. ([M-NH4] + 111.1).

[0360] Step 7: 6-cyclopropyl-2-(4-oxaspiro[2.5]octan-8-ylamino)pyridine-3-carbonitrile Title compound ([M+H] + 270.3) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) by reaction with 4-oxaspiro[2.5]octan-8-amine hydrochloride using NMP as solvent and TEA as base at 210 °C (General Procedure B2).

[0361] Intermediate 89: 6-Cyclopropyl-2-[[rac(2S,3S)-2-methyltetrahydrofuran-3-yl]amino]pyridine-3-carbonitrile TIFF0007749602000113.tif45170

[0362] Step 1: (cis)-N-benzyl-2-methyltetrahydrofuran-3-amine To 2-methyldihydrofuran-3(2H)-one (200 mg, 193 μL, 2 mmol, CAS [3188-00-9]) and benzylamine (235 mg, 240 μL, 2.2 mmol) in DCM (5 mL) was added acetic acid (144 mg, 137 μL, 2.4 mmol) and sodium triacetoxyborohydride (635 mg, 3 mmol) at 0° C. After the reaction mixture was stirred at room temperature for 1 h, it was diluted with 1 M aqueous NaOH. The mixture was extracted twice with DCM, dried over NaSO, and concentrated under reduced pressure. The crude product was purified by flash column chromatography to give (cis)-N-benzyl-2-methyltetrahydrofuran-3-amine (320 mg, 75%) as a yellow oil. ([M+H] + 192.2)

[0363] Step 2: cis-2-methyloxolan-3-amine To (cis)-N-benzyl-2-methyltetrahydrofuran-3-amine (100 mg, 523 μmol) in THF (2 mL) was added acetic acid (59.9 μL, 1.05 mmol) and 10% Pd / C (111 mg, 105 μmol). H2 was bubbled through the solution for 5 min and stirred under a hydrogen atmosphere (balloon) for 2 h. The reaction mixture was filtered through Decalite and concentrated in vacuo to give crude cis-2-methyloxolan-3-amine. 1 H NMR (DMSO-d6, 300 MHz) δ3.8-3.9 (m, 1H), 3.7-3.8 (m, 1H), 3.53 (br d, 1H, J=6.0 Hz), 3.3-3.4 (m, 1H), 2.08 (s, 2H), 1.6-1.7 (m, 1H), 1.0-1.1 (m, 3H))

[0364] Step 3: 6-Cyclopropyl-2-[[(2SR,3SR)-2-methyltetrahydrofuran-3-yl]amino]pyridine-3-carbonitrile Title compound ([M+H] +244.2) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) by reaction with cis-2-methyloxolan-3-amine using DMSO as solvent and DIPEA as base at 120° C. (General Procedure B2).

[0365] Intermediate 90: 6-(7-azabicyclo[2.2.1]heptan-7-yl)-2-[(4-methylthiazol-5-yl)amino]pyridine-3-carbonitrile TIFF0007749602000114.tif45170

[0366] Step 1: 6-(7-Azabicyclo[2.2.1]heptan-7-yl)-2-chloro-pyridine-3-carbonitrile Title compound ([M+H] + 234.2) was prepared from 2,6-dichloronicotinonitrile (CAS [40381-90-6]) and 7-azabicyclo[2.2.1]heptane hydrochloride (CAS [27514-07-4]) using DIPEA as a base in THF / ACN at room temperature (General Procedure A2).

[0367] Step 2: tert-Butyl N-(4-methylthiazol-5-yl)carbamate To a solution of 4-methylthiazole-5-carboxylic acid (600 mg, 4.19 mmol) in tBuOH (15 mL) was added TEA (2.34 mL, 16.76 mmol) and diphenylphosphoryl azide (1.73 g, 6.29 mmol). The reaction mixture was stirred at 20° C. for 15 minutes and then heated to 80° C. for 2 hours. The reaction mixture was poured into saturated aqueous NaHCO solution (30 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated in vacuo to give crude tert-butyl N-(4-methylthiazol-5-yl)carbamate (400 mg, 44%) as a yellow solid. ([M+H] + 215.1)

[0368] Step 3: 4-Methylthiazol-5-amine hydrochloride A mixture of tert-butyl N-(4-methylthiazol-5-yl)carbamate (400.0 mg, 1.87 mmol) and HCl (4 M in dioxane, 2.0 mL, 8 mmol) in DCM (5 mL) was stirred at 25° C. for 12 h, after which it was concentrated in vacuo to give crude 4-methylthiazol-5-amine hydrochloride (200 mg, 71%) as a yellow solid. ([M+H] + 115.1)

[0369] Step 4: 6-(7-azabicyclo[2.2.1]heptan-7-yl)-2-[(4-methylthiazol-5-yl)amino]pyridine-3-carbonitrile Title compound ([M+H] + 312.1) was prepared from 6-(7-azabicyclo[2.2.1]heptan-7-yl)-2-chloro-pyridine-3-carbonitrile by reaction with 4-methylthiazol-5-amine hydrochloride using Pd(OAc)2 as catalyst and Xantphos as ligand (General Procedure B1). [Example]

[0370] TIFF0007749602000115.tif255170TIFF0007749602000116.tif217170TIFF0007749602000117.tif22 5170TIFF0007749602000118.tif227170TIFF0007749602000119.tif227170TIFF0007749602000120.t if215170TIFF0007749602000121.tif221170TIFF0007749602000122.tif228170TIFF00077496020001 23.tif222170TIFF0007749602000124.tif225170TIFF0007749602000125.tif223170TIFF00077496020 00126.tif217170TIFF0007749602000127.tif218170TIFF0007749602000128.tif218170TIFF0007749 602000129.tif218170TIFF0007749602000130.tif217170TIFF0007749602000131.tif232170TIFF000 7749602000132.tif220170TIFF0007749602000133.tif225170TIFF0007749602000134.tif224170TIF F0007749602000135.tif217170TIFF0007749602000136.tif217170TIFF0007749602000137.tif111170

[0371] Example 91: 4-amino-7-(difluoromethoxy)-1-(2-methylphenyl)pyrido[2,3-d]pyrimidin-2-one TIFF0007749602000138.tif48170

[0372] Step 1: 4-amino-7-((4-methoxybenzyl)oxy)-1-(o-tolyl)pyrido[2,3-d]pyrimidin-2(1H)-one To a solution of 4-methoxybenzyl alcohol (59 μL, 474 μmol) in NMP (1 mL) was added sodium hydride (33 mg, 60% dispersion in mineral oil, 837 μmol) at 0° C., and the reaction mixture was stirred for 15 minutes. 4-Amino-7-chloro-1-(o-tolyl)pyrido[2,3-d]pyrimidin-2(1H)-one (80 mg, 279 μmol) (Example 62) was added, and the mixture was heated to 150° C. until LCMS showed complete conversion. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography to give 4-amino-7((4-methoxybenzyl)oxy)-1-(o-tolyl)pyrido[2,3-d]pyrimidin-2(1H)-one (100 mg, 83%). ([M+H] + 389.2)

[0373] Step 2: 4-amino-7-hydroxy-1-(o-tolyl)pyrido[2,3-d]pyrimidin-2(1H)-one To a solution of 4-amino-7-((4-methoxybenzyl)oxy)-1-(o-tolyl)pyrido[2,3-d]pyrimidin-2(1H)-one (670 mg, 1.55 mmol) in DCM (10 mL) was added TFA (957 μL, 12.4 mmol). The resulting solution was stirred at room temperature for 2.5 h, after which it was quenched with water. The aqueous layer was washed with DCM and evaporated to dryness. The crude product was purified by reverse-phase preparative HPLC to give 4-amino-7-hydroxy-1-(o-tolyl)pyrido[2,3-d]pyrimidin-2(1H)-one as a white solid (400 mg, 96%). ([M+H] + 269.2)

[0374] Step 3: 4-amino-7-(difluoromethoxy)-1-(2-methylphenyl)pyrido[2,3-d]pyrimidin-2-one To a solution of 4-amino-7-hydroxy-1-(o-tolyl)pyrido[2,3-d]pyrimidin-2(1H)-one (14 mg, 51.1 μmol) in NMP (2 mL) was added sodium chlorodifluoroacetate (156 mg, 102 μmol) and K2CO3 (21 mg, 153 μmol). The mixture was heated to 80 °C for 25 min, after which it was quenched with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography to give 4-amino-7-(difluoromethoxy)-1-(2-methylphenyl)pyrido[2,3-d]pyrimidin-2-one (8 mg, 49%). ([M+H] + 319.1)

[0375] Example 92: 1-amino-4-(2-methoxyphenyl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one TIFF0007749602000139.tif49170

[0376] Step 1: 2-(2-methoxyphenyl)-2-(4-trifluoromethyl)pyridin-2-yl)acetonitrile To a solution of 2-chloro-4-(trifluoromethyl)pyridine (200 mg, 1.1 mmol) and 2-(2-methoxyphenyl)acetonitrile (162 mg, 1.1 mmol) in DMF (4 mL) was added NaH (60% dispersion in mineral oil, 88 mg, 2.2 mmol), and the reaction was stirred at room temperature for 1 h before it was quenched with saturated NH4Cl solution. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and evaporated to give a crude yellow oil. The compound was purified by flash column chromatography to give 2-(2-methoxyphenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile as a light brown oil (221 mg, 69%). ([M+H] + 293.2)

[0377] Step 2: 2-(2-methoxyphenyl)-2-(4-trifluoromethyl)pyridin-2-yl)acetamide To a solution of 2-(2-methoxyphenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile (50 mg, 0.17 mmol) in AcOH (0.7 mL) was added 95% H2SO4 (0.3 mL), and the mixture was stirred at 40 °C for 2 days. The reaction mixture was cooled to room temperature and poured onto ice, followed by extraction with EtOAc. The organic layer was washed with saturated NaHCO3 solution and brine, dried over Na2SO4, and concentrated. Purification by flash column chromatography afforded 2-(2-methoxyphenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (41 mg, 77%) as a white solid. ([M+H] + 311.2)

[0378] Step 3: Sodium 4-(2-methoxyphenyl)-3-oxo-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidine-1-thiolate To a mixture of 2-(2-methoxyphenyl)-2-(4-trifluoromethyl)pyridin-2-yl)acetamide (100 mg, 0.32 mmol) in EtOH (0.5 mL) was added sodium ethoxide (0.96 mL, 21% in EtOH, 2.58 mmol), followed by the dropwise addition of thiophosgene (50 μL, 0.65 mmol) while maintaining the temperature below 40 °C. The mixture was stirred in a sealed tube at 85 °C for 2 h, after which it was cooled to room temperature and quenched with approximately 3 mL of water. The resulting precipitate was filtered, washed with water, and dried in vacuo to give sodium 4-(2-methoxyphenyl)-3-oxo-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidine-1-thiolate (85 mg, 64%) as a yellow solid. ([M+H] + 353.2)

[0379] Step 4: 4-(2-methoxyphenyl)-1-(methylthio)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one To a solution of sodium 4-(2-methoxyphenyl)-3-oxo-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidine-1-thiolate (80 mg, 0.21 mmol) in EtOH (2 mL) was added iodomethane (15 μL, 0.24 mmol). The reaction was stirred at room temperature for 7 h. An additional portion of iodomethane (approximately 10 μL) was added, and stirring at room temperature was continued for 16 h. The reaction mixture was evaporated, and the residue was diluted with EtOAc / water. The organic layer was washed with brine, dried over NaSO, and concentrated. Purification by flash column chromatography afforded 4-(2-methoxyphenyl)-1-(methylthio)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (58 mg, 72%) as a yellow foam. ([M+H] + 367.2)

[0380] Step 5: 1-amino-4-(2-methoxyphenyl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one To a mixture of 4-(2-methoxyphenyl)-1-(methylthio)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (51 mg, 0.14 mmol) and ammonium hydroxide solution (1.5 mL, 9.24 mmol) was added THF (0.5 mL). The reaction was stirred at room temperature for 3 days, after which it was concentrated. Purification by flash column chromatography afforded 1-amino-4-(2-methoxyphenyl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (23 mg, 49%) as a yellow solid ([M+H] + 336.3).

[0381] Example 93: 4-amino-1-(2-methylpyridin-3-yl)-7-(tetrahydrofuran-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one TIFF0007749602000140.tif49170

[0382] 4-Amino-7-(4,5-dihydrofuran-3-yl)-1-(2-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (20 mg, 62 μmol) (Example 41) and Pd / C (7.0 mg, 62 μmol) were stirred under a hydrogen atmosphere at room temperature for 16 hours. The reaction mixture was filtered and concentrated in vacuo. Purification by flash column chromatography afforded 4-amino-1-(2-methylpyridin-3-yl)-7-(tetrahydrofuran-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (8 mg, 37%) as a white solid. ([M+H] + 322.3)

[0383] Example 94: 4-amino-7-cyclopropyl-2-oxo-1-(o-tolyl)-1,2-dihydropyrido[2,3-d]pyrimidine-5-carboxamide TIFF0007749602000141.tif53170

[0384] Step 1: Ethyl 3-cyano-6-cyclopropyl-2-hydroxyisonicotinate To a suspension of KOtBu (734 mg, 6.54 mmol) in THF (5 mL) was added a mixture of diethyl oxalate (806 μL, 5.94 mmol) and 1-cyclopropylethan-1-one (589 μL, 5.94 mmol) dropwise over 10 min. The reaction mixture was stirred at 0 °C for 40 min, quenched with dilute aqueous HCl, and diluted with water. It was extracted with DCM, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was added to a solution of 2-cyanoacetamide (500 mg, 5.94 mmol) and sodium methoxide (321 mg, 5.94 mmol) in MeOH (5 mL) and heated to 65 °C. After 90 min, the reaction mixture was cooled to room temperature, acidified with 6 M HCl, extracted with EtOAc, dried over Na2SO4, and concentrated in vacuo. Purification by flash column chromatography gave ethyl 3-cyano-6-cyclopropyl-2-hydroxyisonicotinate (540 mg, 27%) as a light brown solid. ([M+H] + 233.2)

[0385] Step 2: Ethyl 2-chloro-3-cyano-6-cyclopropyl isonicotinate Ethyl 3-cyano-6-cyclopropyl-2-hydroxyisonicotinate (60 mg, 258 μmol) was dissolved in POCl (300 μL, 3.22 mmol), and the reaction mixture was heated to 100° C. for 2.5 h. POCl was removed in vacuo to give crude 2-chloro-3-cyano-6-cyclopropylisonicotinate (22 mg, 32%) as a white solid. ([M+H] + 251.2)

[0386] Step 3: Ethyl 3-cyano-6-cyclopropyl-2-(o-tolylamino)isonicotinate Pd(OAc) (2 mg, 8.0 μmol) was added to a degassed solution of ethyl 2-chloro-3-cyano-6-cyclopropyl isonicotinate (20 mg, 79.8 μmol), o-toluidine (13 μL, 120 μmol), xphos (6 mg, 12 μmol), and CsCO (78 mg, 239 μmol), and the resulting reaction mixture was heated to 100 °C. After 2 h, it was cooled to room temperature, filtered through Decalite®, and concentrated in vacuo. The crude product was purified using flash column chromatography to afford 3-cyano-6-cyclopropyl-2-(o-tolylamino)isonicotinate (8 mg, 31%) as a yellow solid. ([M+H] + 322.3)

[0387] Step 4: 4-amino-7-cyclopropyl-2-oxo-1-(o-tolyl)-1,2-dihydropyrido[2,3-d]pyrimidine-5-carboxamide To a solution of ethyl 3-cyano-6-cyclopropyl-2-(o-tolylamino)isonicotinate (8 mg, 25 μmol) in DCM (0.5 mL) was added trichloroacetyl isocyanate (6 μL, 50 μmol), and the reaction mixture was stirred at room temperature until the starting material disappeared. After the addition of ammonia (7 M in MeOH, 1 mL, 7 mmol), the reaction was stirred until LCMS showed complete conversion of the product. The crude product was purified by reverse-phase preparative HPLC to give 4-amino-7-cyclopropyl-2-oxo-1-(o-tolyl)-1,2-dihydropyrido[2,3-d]pyrimidine-5-carboxamide (5 mg, 57%) as a white solid. ([M+H] + 336.1)

[0388] Example 95: 4-amino-7-cyclopropyl-2-oxo-1-(o-tolyl)-1,2-dihydropyrido[2,3-d]pyrimidine-5-carbonitrile TIFF0007749602000142.tif56170

[0389] To a solution of 4-amino-7-cyclopropyl-2-oxo-1-(o-tolyl)-1,2-dihydropyrido[2,3-d]pyrimidine-5-carboxamide (23 mg, 68 μmol) (Example 94) and TEA (33 μL, 239 μmol) in DCM (0.5 mL) was added trifluoroacetic anhydride (15 μL, 102 μmol) at 0° C., and the reaction mixture was stirred at room temperature. Three additional portions of TEA (33 μL, 239 μmol) and trifluoroacetic anhydride (15 μL, 102 μmol) were added every 30 min to give fully converted product. The orange solution was adsorbed onto silica and purified by flash column chromatography to give 4-amino-7-cyclopropyl-2-oxo-1-(o-tolyl)-1,2-dihydropyrido[2,3-d]pyrimidine-5-carbonitrile (7 mg, 31%) as a white solid. ([M+H] + 318.3)

[0390] Example 96: 4-amino-7-cyclopropyl-1-(o-tolyl)pyrimido[4,5-d]pyrimidin-2(1H)-one TIFF0007749602000143.tif49170

[0391] Step 1: 2-Cyclopropyl-4-hydroxypyrimidine-5-carbonitrile To a solution of cyclopropanecarboximidamide hydrochloride (200 mg, 1.58 mmol) and ethyl (E)-2-cyano-3-ethoxyacrylate (272 mg, 1.58 mmol) in EtOH (3.5 mL) was added KOtBu (442 mg, 3.94 mmol) at 0 °C, and the suspension was stirred at 0 °C for 10 min and refluxed for 2 h. The mixture was poured into water and acidified to pH 3 using 25% aqueous HCl, followed by extraction with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give crude 2-cyclopropyl-4-hydroxypyrimidine-5-carbonitrile (196.5 mg, 77%) as a pale yellow solid. ([M+H] + 162.1)

[0392] Step 2: 4-chloro-2-cyclopropylpyrimidine-5-carbonitrile 2-Cyclopropyl-4-hydroxypyrimidine-5-carbonitrile (196 mg, 1.22 mmol) was combined with phosphorus oxychloride (1.42 mL, 15.2 mmol) to give an orange suspension. The reaction mixture was stirred at 110° C. for 1 h. The mixture was cooled to room temperature, added dropwise to a well-stirred mixture of ice / water / EtOAc, and washed with saturated aqueous NaHCO. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed once with saturated aqueous NaHCO. The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo to give crude 4-chloro-2-cyclopropylpyrimidine-5-carbonitrile (122 mg, 56%). ([M+H] + 180.1)

[0393] Step 3: 2-Cyclopropyl-4-(o-tolylamino)pyrimidine-5-carbonitrile To a degassed solution of 4-chloro-2-cyclopropylpyrimidine-5-carbonitrile (122 mg, 679 μmol), o-toluidine (108 μL, 1.02 mmol), and CsCO (664 mg, 2.04 mmol) in dioxane (2.5 mL), 2-chloro-2-cyclopropylpyrimidine-5-carbonitrile (49 mg, 102 μmol) and Pd(OAc) (15 mg, 68 μmol) were added, and the reaction mixture was stirred at 80 °C overnight. The reaction mixture was diluted with EtOAc and washed three times with water. The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo. Purification by flash column chromatography afforded 2-cyclopropyl-4-(o-tolylamino)pyrimidine-5-carbonitrile (50 mg, 29%) as an off-white solid. ([M+H] + 251.3)

[0394] Step 4: 4-amino-7-cyclopropyl-1-(o-tolyl)pyrimido[4,5-d]pyrimidin-2(1H)-one To a solution of 2-cyclopropyl-4-(o-tolylamino)pyrimidine-5-carbonitrile (50 mg, 200 μmol) in DCE (1 mL) was added trichloroacetyl isocyanate (52 μL, 439 μmol), and the reaction mixture was stirred at 80° C. After concentration, ammonia (7 M in MeOH, 6.67 mL, 46.7 mmol) was added, the reaction was stirred for 1 h, and the reaction was concentrated to dryness. Purification by flash column chromatography, followed by suspension in EtOAc and filtration afforded 4-amino-7-cyclopropyl-1-(o-tolyl)pyrimido[4,5-d]pyrimidin-2(1H)-one (19 mg, 31%) as a white solid. ([M+H] + 294.3)

[0395] Example 97: 4-amino-7-cyclopropyl-1-(2-oxopiperidin-4-yl)pyrido[2,3-d]pyrimidin-2(1H)-one TIFF0007749602000144.tif55170

[0396] Step 1: 6-cyclopropyl-2-((2-oxopiperidin-4-yl)amino)nicotinonitrile To a solution of 2-chloro-6-cyclopropylnicotinonitrile (200 mg, 1.12 mmol) in DMSO (4 mL) was added DIPEA (978 μL, 5.6 mmol) and 4-aminopiperidin-2-one TFA salt (509 mg, 2.24 mmol). After the reaction mixture was heated to 120° C. for 48 hours, it was diluted with water and extracted twice with EtOAc. The organic layer was dried over Na SO , filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography to give 6-cyclopropyl-2-((2-oxopiperidin-4-yl)amino)nicotinonitrile (192 mg, 55%) as an off-white solid. ([M+H] + 257.2)

[0397] Step 2: 6-cyclopropyl-2-((1-(4-methoxybenzyl)-2-oxopiperidin-4-yl)amino)nicotinonitrile To a solution of 6-cyclopropyl-2-((2-oxopiperidin-4-yl)amino)nicotinonitrile (50 mg, 195 μmol) in THF (1 mL) was added 4-methoxybenzyl bromide (34 μL, 234 μmol) and KOtBu (43.8 mg, 390 μmol). The reaction mixture was stirred at room temperature. 4-Methoxybenzyl bromide (34 μL, 234 μmol) was added once more after 2 h, and the reaction mixture was stirred for an additional 7 h. The reaction mixture was quenched with water and extracted twice with DCM. The organic layer was dried over NaSO, filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography to afford 6-cyclopropyl-2-((1-(4-methoxybenzyl)-2-oxopiperidin-4-yl)amino)nicotinonitrile (33 mg, 36%) as a yellow oil. ([M+H] + 377.4)

[0398] Step 3: 4-amino-7-cyclopropyl-1-(1-(4-methoxybenzyl)-2-oxopiperidin-4-yl)pyrido[2,3-d]pyrimidin-2(1H)-one To a solution of 6-cyclopropyl-2-((1-(4-methoxybenzyl)-2-oxopiperidin-4-yl)amino)nicotinonitrile (47 mg, 125 μmol) in DCM (1.5 mL) was added trichloroacetyl isocyanate (33 μL, 275 μmol), and the reaction mixture was stirred at room temperature until the starting material disappeared. After the addition of ammonia (7 M in MeOH, 4 mL, 28 mmol), the reaction was stirred until LCMS showed complete conversion of the product. The crude product was purified by flash column chromatography to give 4-amino-7-cyclopropyl-1-(1-(4-methoxybenzyl)-2-oxopiperidin-4-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (27 mg, 48%) as a white solid. ([M+H] + 420.4)

[0399] Step 4: 4-amino-7-cyclopropyl-1-(2-oxopiperidin-4-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-7-cyclopropyl-1-(1-(4-methoxybenzyl)-2-oxopiperidin-4-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (27 mg, 64 μmol) was dissolved in TFA (2 mL, 26 mmol). After the reaction mixture was stirred at 75° C. for 67 hours, it was concentrated in vacuo and purified by reverse-phase HPLC to give 4-amino-7-cyclopropyl-1-(2-oxopiperidin-4-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (9 mg, 46%) as a white solid. ([M+H] + 300.2)

[0400] Example 98: 7-Cyclopropyl-1-(2-methylpyridin-3-yl)quinazoline-2,4-dione TIFF0007749602000145.tif49170

[0401] 4-Amino-7-cyclopropyl-1-(2-methylpyridin-3-yl)quinazolin-2(1H)-one (55 mg, 188 μmol) (Example 86) was suspended in KOH (2M aqueous, 941 μL, 1.88 mmol) and heated to 110° C. After 4 h, the reaction mixture was cooled to room temperature, diluted with water, and extracted three times with EtOAc. The combined organic layers were dried over magnesium sulfate, filtered, and evaporated in vacuo. The crude product was purified by flash column chromatography to give 4-amino-7-cyclopropyl-1-(1-(4-methoxybenzyl)-2-oxopiperidin-4-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (25 mg, 43%) as a white solid. ([M+H] + 294.3)

[0402] Example 99: 7-Cyclopropyl-1-(2-methylphenyl)pyrido[2,3-d]pyrimidine-2,4-dione TIFF0007749602000146.tif49170

[0403] Step 1: Methyl 2-chloro-6-cyclopropylpyridine-3-carboxylate To a solution of methyl 6-bromo-2-chloronicotinate (700 mg, 2.65 mmol) in degassed dioxane (12 mL) was added K2CO3 (734 mg, 5.31 mmol), cyclopropylboronic acid (1.14 g, 13.3 mmol), and Pd(dppf)2Cl2·CHCl2 (217 mg, 265 μmol). The reaction mixture was heated in a microwave at 80 °C for 1 h, after which it was poured into water and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and evaporated. The crude product was purified by flash column chromatography to give the title compound (498 mg, 87%) as a yellow crystalline solid. ([M+H] + 212.1)

[0404] Step 2: 2-chloro-6-cyclopropylpyridine-3-carboxylic acid To a solution of methyl 2-chloro-6-cyclopropylnicotinate (489 mg, 2.31 mmol) in THF (5 mL) and MeOH (5 mL) was added LiOH (1 M in water, 4.62 mL, 4.62 mmol). The reaction mixture was stirred at room temperature overnight, and then the volatiles were removed in vacuo. The residue was diluted with water, acidified with 1 M HCl, and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and evaporated to give the title compound (470 mg, 100%) as a white solid. ([M+H] + 198.1)

[0405] Step 3: 2-chloro-6-cyclopropylpyridine-3-carboxamide To a solution of 2-chloro-6-cyclopropylnicotinic acid (220 mg, 1.11 mmol) in DMF (2 mL) was added CDI (271 mg, 1.67 mmol). After heating the reaction to 50° C. for 2.5 hours, ammonia (25% aqueous solution, 1.21 g, 1.33 mL, 17.8 mmol) was added at room temperature and the reaction was allowed to stir for 3 days. The reaction was diluted with water and extracted three times with EtOAc. The combined organic layers were dried over magnesium sulfate, filtered, and evaporated in vacuo. The crude product was purified by flash column chromatography to give the desired compound (165 mg, 74%) as a white solid. ([M+H] + 197.2)

[0406] Step 4: 6-Cyclopropyl-2-(2-methylanilino)pyridine-3-carboxamide A solution of 2-chloro-6-cyclopropylnicotinamide (79 mg, 402 μmol) and o-toluidine (42.9 μL, 402 μmol) in AcOH (0.5 mL) was heated to 120° C. overnight. The reaction was cooled to room temperature, basified with 2N NaOH, and extracted three times with EtOAc. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered, and evaporated to dryness. The crude product was purified by flash column chromatography to give 6-cyclopropyl-2-(2-methylanilino)pyridine-3-carboxamide (50 mg, 46%) as a pale yellow solid. ([M+H] + 268.2)

[0407] Step 5: 7-Cyclopropyl-1-(2-methylphenyl)pyrido[2,3-d]pyrimidine-2,4-dione A pale yellow solution of 6-cyclopropyl-2-(2-methylanilino)pyridine-3-carboxamide (47 mg, 176 μmol), CDI (43 mg, 264 μmol), and DBU (53 μL, 352 μmol) in THF (1 mL) was heated to 70 °C for 1 h, after which it was cooled to room temperature, diluted with water, and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and evaporated to dryness. The crude product was purified by flash column chromatography to give 7-cyclopropyl-1-(2-methylphenyl)pyrido[2,3-d]pyrimidine-2,4-dione (33 mg, 63%) as a white solid. ([M+H] + 294.2)

[0408] Example 100: 7-Cyclopropyl-1-(2-methylphenyl)quinazoline-2,4-dione TIFF0007749602000147.tif49170

[0409] 4-Amino-7-cyclopropyl-1-(o-tolyl)quinazolin-2(1H)-one (60 mg, 206 μmol) (Example 8) was suspended in KOH (2 M in water, 1.03 mL, 2.06 mmol) and heated to 110° C. for 4 hours, after which it was cooled to room temperature, diluted with water, and extracted three times with EtOAc. The combined organic layers were dried over magnesium sulfate, filtered, and evaporated to dryness to give the title compound (56 mg, 90%) as a white solid. ([M+H] + 293.2)

[0410] Example 101: 7-Cyclopropyl-1-(2-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4-dione TIFF0007749602000148.tif48170

[0411] To a mixture of Example 7 (20 mg, 680 μmol) in THF (1 mL) was added tert-butyl nitrite (17 μL, 136 μmol). After stirring the reaction at 60° C. for 2 h, additional tert-butyl nitrite (17 μL, 136 μmol) was added and the mixture was stirred at 60° C. for an additional 5 h. The reaction was cooled to room temperature and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and evaporated in vacuo. The compound was purified by flash chromatography to give 7-cyclopropyl-1-(2-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4-dione (14 mg, 70%) as a white solid. ([M+H] + 295.1)

[0412] Example 102: 4-amino-5-methoxy-1-(2-methylpyridin-3-yl)-7-(trifluoromethyl)quinazolin-2(1H)-one TIFF0007749602000149.tif52170

[0413] 4-Amino-5-fluoro-1-(2-methylpyridin-3-yl)-7-(trifluoromethyl)quinazolin-2(1H)-one (61 mg, 180 μmol) (Example 59) and sodium methoxide (15 mg, 270 μmol) were stirred in MeOH (3 mL) at room temperature for 48 hours. The solvent was evaporated and the crude product was purified by flash column chromatography to give 4-amino-5-methoxy-1-(2-methylpyridin-3-yl)-7-(trifluoromethyl)quinazolin-2(1H)-one (42 mg, 63%) as a white solid. ([M+H] + 351.2)

[0414] Example 103 and Example 104: (+)-4-Amino-7-cyclopropyl-1-(3-fluoro-2-methylphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one and (-)-4-Amino-7-cyclopropyl-1-(3-fluoro-2-methylphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one TIFF0007749602000150.tif52170

[0415] Step 1: 6-cyclopropyl-2-((3-fluoro-2-methylphenyl)amino)nicotinonitrile Title compound ([M+H] + 268.3) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS[1198475-35-2]) by reaction with 3-fluoro-2-methylaniline (CAS[443-86-7]) using Pd(OAc)2 as catalyst and Xantphos as ligand (General Procedure B1).

[0416] Step 2: 4-amino-7-cyclopropyl-1-(3-fluoro-2-methylphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one To a solution of 6-cyclopropyl-2-((3-fluoro-2-methylphenyl)amino)nicotinonitrile (57 mg, 213 μmol) in DCE (3 mL) was added trichloroacetyl isocyanate (56 μL, 469 μmol), and the reaction mixture was stirred at room temperature until the starting material disappeared. After the addition of ammonia (7 M in MeOH, 3.81 mL, 26.6 mmol), the reaction was stirred until LCMS showed complete conversion of the product. The crude product was purified by flash column chromatography to give 4-amino-7-cyclopropyl-1-(3-fluoro-2-methylphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one (61 mg, 91%) as a white solid. ([M+H] + 311.2)

[0417] Step 3: (+)-4-amino-7-cyclopropyl-1-(3-fluoro-2-methylphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one and (-)-4-amino-7-cyclopropyl-1-(3-fluoro-2-methylphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-Amino-7-cyclopropyl-1-(3-fluoro-2-methylphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one was separated by reverse-phase chiral preparative HPLC to give (+)-4-amino-7-cyclopropyl-1-(3-fluoro-2-methylphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one as a white solid and (-)-4-amino-7-cyclopropyl-1-(3-fluoro-2-methylphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one as a white solid. ([M+H] + 420.4) and ([M+H] + 311.2)

[0418] Example 105: 3-(4-amino-6-chloro-7-isopropyl-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)-2-methoxybenzonitrile TIFF0007749602000151.tif55170

[0419] Step 1: 2-amino-6-isopropylnicotinonitrile Title compound ([M+H] + 162.2) was prepared from 2-chloro-6-isopropylnicotinonitrile (CAS [108244-44-6]) using general procedure D.

[0420] Step 2: 2-amino-5-chloro-6-isopropylnicotinonitrile To a solution of 2-amino-6-isopropylnicotinonitrile (130 mg, 806 μmol) in CHCl (5 mL) was added NCS (118 mg, 887 μmol), and the reaction was stirred at 60 °C in the dark for 6 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed twice with water, and the combined organic layers were dried and evaporated to dryness to give the crude product (180 mg, 114%) as an orange solid. ([M+H] + 196.1)

[0421] Step 3: 5-chloro-2-((3-cyano-2-methoxyphenyl)amino)-6-isopropylnicotinonitrile 2-Amino-5-chloro-6-isopropylnicotinonitrile (90 mg, 460 μmol), 3-bromo-2-methoxybenzonitrile (127 mg, 598 μmol), Xantphos (26.6 mg, 46 μmol), and CsCO (450 mg, 1.38 mmol) were mixed in dioxane (3 mL) and degassed under argon. Pd(OAc) (5.16 mg, 23 μmol) was added, and the mixture was stirred at 90 °C overnight. The next day, Xantphos (27 mg, 46 μmol) and Pd(OAc) (5.2 mg, 23 μmol) were added again, and the reaction was stirred at 90 °C for an additional 3 h. The crude product was purified by flash column chromatography to give 5-chloro-2-((3-cyano-2-methoxyphenyl)amino)-6-isopropylnicotinonitrile (75 mg, 50%) as a yellow solid. ([M+H] + 327.2)

[0422] Step 4: 3-(4-amino-6-chloro-7-isopropyl-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)-2-methoxybenzonitrile 5-Chloro-2-((3-cyano-2-methoxyphenyl)amino)-6-isopropylnicotinonitrile (70 mg, 214 μmol) was dissolved in DCM (1 mL) and trichloroacetyl isocyanate (121 mg, 76.1 μL, 643 μmol) was added. The mixture was stirred at room temperature overnight, after which additional trichloroacetyl isocyanate (121 mg, 76.1 μL, 643 μmol) was added and stirred at room temperature. After 3 h, ammonia (7 M in MeOH, 5 mL, 35 mmol) was added and stirred at room temperature overnight. The reaction mixture was evaporated and the residue was purified by flash column chromatography to give 3-(4-amino-6-chloro-7-isopropyl-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)-2-methoxybenzonitrile (76 mg, 96%) as a white solid. ([M+H] + 370.2)

[0423] Example 106: 4-amino-7-cyclopropyl-1-(3-fluoro-2-methylphenyl)quinazolin-2-one TIFF0007749602000152.tif37170

[0424] Step 1: 4-Cyclopropyl-2-((3-fluoro-2-methylphenyl)amino)benzonitrile Title compound ([M+H] + 267.2) was prepared from 2-chloro-4-cyclopropylbenzonitrile (Angew. Chem. 2018, 12573) by reaction with 3-fluoro-2-methylaniline (CAS[443-86-7]) using Pd(OAc)2 as catalyst and X-phos as ligand (General Procedure B1).

[0425] Step 2: 4-amino-7-cyclopropyl-1-(3-fluoro-2-methylphenyl)quinazolin-2-one To a solution of 4-cyclopropyl-2-((3-fluoro-2-methylphenyl)amino)benzonitrile (76 mg, 284 μmol) in DCM (3 mL) was added trichloroacetyl isocyanate (75 μL, 625 μmol), and the reaction mixture was stirred at room temperature until the starting material disappeared. After the addition of ammonia (7 M in MeOH, 6.1 mL, 42.6 mmol), the reaction was stirred until LCMS showed complete conversion of the product. The crude product was purified by flash column chromatography to give 4-amino-7-cyclopropyl-1-(3-fluoro-2-methylphenyl)quinazolin-2-one (70 mg, 80%) as a white solid. ([M+H] + 308.2)

[0426] Example 107: 4-amino-7-cyclopropyl-1-(1,4-dioxepan-6-yl)pyrido[2,3-d]pyrimidin-2-one TIFF0007749602000153.tif37170

[0427] Step 1: 6-Cyclopropyl-2-(1,4-dioxepan-6-ylamino)pyridine-3-carbonitrile Title compound ([M+H] + 260.2) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) by reaction with 1,4-dioxepan-6-amine (EP1958666 A1) using Pd(OAc)2 as catalyst and Xantphos as ligand (General Procedure B1).

[0428] Step 2: 4-amino-7-cyclopropyl-1-(1,4-dioxepan-6-yl)pyrido[2,3-d]pyrimidin-2-one To a solution of 6-cyclopropyl-2-(1,4-dioxepan-6-ylamino)pyridine-3-carbonitrile (15 mg, 60 μmol) in DCM (1 mL) was added trichloroacetyl isocyanate (35 μL, 290 μmol), and the reaction mixture was stirred at room temperature until the starting material disappeared. After the addition of ammonia (7 M in MeOH, 1.0 mL, 0.06 mmol), the reaction was stirred until LCMS showed complete conversion of the product. The crude product was purified by flash column chromatography to give 4-amino-7-cyclopropyl-1-(1,4-dioxepan-6-yl)pyrido[2,3-d]pyrimidin-2-one (9 mg, 78%) as a white solid. ([M+H] + 303.1)

[0429] Example 108: 4-amino-7-cyclopropyl-1-(6-(difluoromethoxy)pyridin-2-yl)pyrido[2,3-d]pyrimidin-2(1H)-one TIFF0007749602000154.tif43170

[0430] Step 1: 6-cyclopropyl-2-((6-(difluoromethoxy)pyridin-2-yl)amino)nicotinonitrile Title compound ([M+H] + 303.1) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS[1198475-35-2]) by reaction with 6-(difluoromethoxy)pyridin-2-amine (CAS[1131007-43-6]) using Pd(OAc)2 as catalyst and Xantphos as ligand (General Procedure B1).

[0431] Step 2: 4-amino-7-cyclopropyl-1-(6-(difluoromethoxy)pyridin-2-yl)pyrido[2,3-d]pyrimidin-2(1H)-one To a solution of 6-cyclopropyl-2-((6-(difluoromethoxy)pyridin-2-yl)amino)nicotinonitrile (87 mg, 210 μmol) in DCE (2 mL) was added trichloroacetyl isocyanate (62 μL, 525 μmol), and the reaction mixture was stirred at room temperature until the starting material disappeared. The reaction was concentrated to dryness, redissolved by the addition of ammonia (7 M in MeOH, 12 mL, 84 mmol), and the reaction was stirred until LCMS showed complete conversion of the product. Evaporation of methanol and trituration with ethyl acetate afforded 4-amino-7-cyclopropyl-1-(6-(difluoromethoxy)pyridin-2-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (35 mg, 48%) as a white solid. ([M+H] + 346.2)

[0432] Example 109: 4-amino-1-(2-chloro-3-pyridyl)-7-(trifluoromethoxy)quinazolin-2-one TIFF0007749602000155.tif35170

[0433] Step 1: 2-[(2-chloro-3-pyridyl)amino]-4-(trifluoromethoxy)benzonitrile Title compound ([M+H] + 313.8) was prepared from 2-bromo-4-(trifluoromethoxy)benzonitrile (CAS[1214334-83-4]) by reaction with 3-amino-2-chloro-pyridine (CAS[6298-19-7]) using Pd(OAc)2 as catalyst and Xantphos as ligand (General Procedure B1).

[0434] Step 2: 4-amino-1-(2-chloro-3-pyridyl)-7-(trifluoromethoxy)quinazolin-2-one To a solution of 2-[(2-chloro-3-pyridyl)amino]-4-(trifluoromethoxy)benzonitrile (100 mg, 320 μmol) in DCM (5 mL) was added trichloroacetyl isocyanate (187 μL, 1.5 mmol), and the reaction mixture was stirred at room temperature until the starting material disappeared. Ammonia (7 M in MeOH, 5 mL, 35 mmol) was added, and the reaction was stirred until LCMS showed complete conversion of the product. The crude product was purified by flash column chromatography to give 4-amino-1-(2-chloro-3-pyridyl)-7-(trifluoromethoxy)quinazolin-2-one (33 mg, 26%) as a white solid. ([M+H] + 357.1)

[0435] Example 110: 4-Amino-7-cyclopropyl-1-[2-(trifluoromethoxy)phenyl]pyrido[2,3-d]pyrimidin-2-one TIFF0007749602000156.tif33170

[0436] Step 1: 6-Cyclopropyl-2-[2-(trifluoromethoxy)anilino]pyridine-3-carbonitrile Title compound ([M+H] + 320.0) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS[1198475-35-2]) by reaction with 2-(trifluoromethoxy)aniline (CAS[175205-77-3]) using Pd(OAc)2 as catalyst and Xantphos as ligand (General Procedure B1).

[0437] Step 2: 4-amino-7-cyclopropyl-1-[2-(trifluoromethoxy)phenyl]pyrido[2,3-d]pyrimidin-2-one Title compound ([M+H] + 363.0) was prepared from 6-cyclopropyl-2-[2-(trifluoromethoxy)anilino]pyridine-3-carbonitrile using general procedure C.

[0438] Example 111: 4-(2-chlorophenyl)-6-cyclopropyl-1-imino-pyrido[1,2-c]pyrimidin-3-one TIFF0007749602000157.tif35170

[0439] Step 1: (4-bromo-2-pyridyl)-(2-chlorophenyl)methanol To a solution of 2,4-dibromopyridine (500 mg, 2.11 mmol) in toluene (25 mL), n-BuLi / (1.6 M in hexane, 1.01 mL, 2.53 mmol) was added dropwise at −78° C. The reaction mixture was stirred for 1 h, after which 2-chlorobenzaldehyde (326 mg, 2.32 mmol) was added, and the mixture was stirred for an additional 1 h. The reaction mixture was then poured into saturated NH4Cl and extracted with ethyl acetate. The combined extracts were washed with brine and concentrated. Purification by flash column chromatography afforded the product (4-bromo-2-pyridyl)-(2-chlorophenyl)methanol (500 mg, 71%) as a yellow oil. ([M+H] + 298.0)

[0440] Step 2: (4-Bromo-2-pyridyl)-(2-chlorophenyl)methanone To a solution of (4-bromo-2-pyridyl)-(2-chlorophenyl)methanol (500 mg, 1.67 mmol) in chloroform (20 mL), MnO (1455 mg, 16.75 mmol) was added at 25° C., and the reaction mixture was stirred at 50° C. for 2 hours. The mixture was filtered through Celite® and concentrated. Purification by flash column chromatography afforded the product (4-bromo-2-pyridyl)-(2-chlorophenyl)methanone (450 mg, 91%) as a yellow oil. ([M+H] + 295.9)

[0441] Step 3: (2-chlorophenyl)-(4-cyclopropyl-2-pyridyl)methanone A mixture of (4-bromo-2-pyridyl)-(2-chlorophenyl)methanone (400 mg, 1.35 mmol), potassium cyclopropyltrifluoroborate (399 mg, 2.7 mmol), K2CO3 (558 mg, 4.05 mmol), and Pd(dppf)Cl2 (40.0 mg, 0.130 mmol) in 1,4-dioxane (4 mL) and water (1 mL) was stirred at 80 °C under an inert atmosphere for 12 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography to give the product (2-chlorophenyl)-(4-cyclopropyl-2-pyridyl)methanone (300 mg, 69%) as a yellow oil. ([M+H] + 258.1)

[0442] Step 4: 2-(2-chlorophenyl)-2-(4-cyclopropyl-2-pyridyl)acetonitrile To an ice-cold solution of (2-chlorophenyl)-(4-cyclopropyl-2-pyridyl)methanone (500 mg, 191 mmol) and Tosmic (568 mg, 2.9 mmol) in DME (10 mL) was added potassium tert-butyrate (1 M in tBuOH, 4.85 mL, 4.85 mmol), and the reaction was then heated to 50° C. for 12 h before being quenched by the addition of water. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried (NaSO), and concentrated. The product was purified by flash column chromatography to give 2-(2-chlorophenyl)-2-(4-cyclopropyl-2-pyridyl)acetonitrile as a pale yellow oil (500 mg, 67%). ([M+H] + 269.1)

[0443] Step 5: 2-(2-chlorophenyl)-2-(4-cyclopropyl-2-pyridyl)acetamide To a solution of 2-(2-chlorophenyl)-2-(4-cyclopropyl-2-pyridyl)acetonitrile (450 mg, 1.67 mmol) in AcOH (15 mL) was added 95% H2SO4 (5 mL), and the mixture was stirred at 40 °C for 2 days. The reaction mixture was cooled to room temperature and poured onto ice, followed by extraction with EtOAc. The organic layer was washed with saturated NaHCO3 solution and brine, dried (Na2SO4), and concentrated. Purification by flash column chromatography afforded 2-(2-chlorophenyl)-2-(4-cyclopropyl-2-pyridyl)acetamide (400 mg, 83%) as a yellow solid. ([M+H] + 287.1)

[0444] Step 6: 4-(2-chlorophenyl)-6-cyclopropyl-1-thioxo-pyrido[1,2-c]pyrimidin-3-one To a mixture of 2-(2-chlorophenyl)-2-(4-cyclopropyl-2-pyridyl)acetamide (400 mg, 1.39 mmol) in EtOH (2.5 mL) was added sodium ethoxide (4.2 mL, 21% in EtOH, 11.6 mmol), followed by the dropwise addition of thiophosgene (215 μL, 2.79 mmol) while maintaining the temperature below 40 °C. The mixture was stirred in a sealed tube at 85 °C for 2 h, after which it was cooled to room temperature and quenched with approximately 3 mL of water. The mixture was extracted with ethyl acetate, and the combined washings were washed with brine and concentrated. Purification by flash column chromatography afforded 4-(2-chlorophenyl)-6-cyclopropyl-1-thioxo-pyrido[1,2-c]pyrimidin-3-one (250 mg, 44%) as a yellow solid. ([M+H] + 329.0)

[0445] Step 7: 4-(2-chlorophenyl)-6-cyclopropyl-1-methylsulfanyl-pyrido[1,2-c]pyrimidin-3-one To a solution of 4-(2-chlorophenyl)-6-cyclopropyl-1-thioxo-pyrido[1,2-c]pyrimidin-3-one (200 mg, 0.61 mmol) in DMF (2 mL) was added potassium carbonate (168 mg, 1.22 mmol) in iodomethane (45 μL, 0.73 mmol). The reaction was stirred at room temperature for 7 h. The reaction mixture was evaporated, and the residue was diluted with EtOAc / water. The organic layer was washed with brine, dried (NaSO), and concentrated. Purification by flash column chromatography afforded 4-(2-chlorophenyl)-6-cyclopropyl-1-methylsulfanyl-pyrido[1,2-c]pyrimidin-3-one 4-(2-methoxyphenyl)-1-(methylthio)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one (100 mg, 43%) as a yellow oil. ([M+H] + 343.0)

[0446] Step 8: 1-amino-4-(2-methoxyphenyl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one To a mixture of 4-(2-chlorophenyl)-6-cyclopropyl-1-methylsulfanyl-pyrido[1,2-c]pyrimidin-3-one (90 mg, 0.260 mmol) and ammonium hydroxide solution (1.5 mL, 9.24 mmol) was added THF (0.5 mL). The reaction was heated to 50° C. for 48 h, after which it was concentrated. Purification by flash column chromatography afforded 4-(2-chlorophenyl)-6-cyclopropyl-1-imino-pyrido[1,2-c]pyrimidin-3-one (8 mg, 9%) as a yellow solid (([M+H] + 312.2).

[0447] Example 112: 4-amino-7-cyclopropyl-1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)pyrido[2,3-d]pyrimidin-2-one TIFF0007749602000158.tif35170

[0448] Step 1: 6-Cyclopropyl-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-ylamino)pyridine-3-carbonitrile Title compound ([M+H] + 266.1) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS[1198475-35-2]) by reaction with 6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-amine hydrochloride (CAS[272438-86-5]) using Pd(OAc)2 as catalyst and Xantphos as ligand (General Procedure B1).

[0449] Step 2: 4-amino-7-cyclopropyl-1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)pyrido[2,3-d]pyrimidin-2-one Title compound ([M+H] + 309.2) was prepared from 6-cyclopropyl-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-ylamino)pyridine-3-carbonitrile using general procedure C.

[0450] Example 113: 4-amino-7-cyclopropyl-6-(difluoromethoxy)-1-(o-tolyl)pyrido[2,3-d]pyrimidin-2-one TIFF0007749602000159.tif37170

[0451] Step 1: 2-Amino-5-bromo-6-cyclopropyl-pyridine-3-carbonitrile To a solution of 2-amino-6-cyclopropyl-pyridine-3-carbonitrile (1000 mg, 6.28 mmol) in chloroform (20 mL) was added N-bromosuccinimide (1173 mg, 6.6 mmol). The mixture was stirred at 20 °C in the dark for 16 h, after which it was concentrated. Purification by flash column chromatography afforded 2-amino-5-bromo-6-cyclopropyl-pyridine-3-carbonitrile (1.4 g, 93% yield) as a yellow solid. ([M+H] + 238.0)

[0452] Step 2: 2-[bis[(4-methoxyphenyl)methyl]-5-bromo-6-cyclopropyl-pyridine-3-carbonitrile A mixture of 2-amino-5-bromo-6-cyclopropyl-pyridine-3-carbonitrile (200 mg, 0.84 mmol) in THF (10 mL) was cooled to 0 °C. NaH (141.13 mg, 3.53 mmol, 4.2 equiv) was added and the mixture was stirred for 0.5 h, after which 4-methoxybenzyl chloride (0.46 mL, 3.36 mmol) was added and the mixture was stirred at room temperature for 12 h. The reaction was quenched by adding saturated NH4Cl, extracted with ethyl acetate, and concentrated. Purification by flash column chromatography afforded 2-[bis[(4-methoxyphenyl)methyl]-5-bromo-6-cyclopropyl-pyridine-3-carbonitrile (300 mg, 75%) as a pale yellow gum ([M+H] + 480.2).

[0453] Step 3: 2-[bis[(4-methoxyphenyl)methyl]amino]-6-cyclopropyl-5-hydroxy-pyridine-3-carbonitrile A mixture of 2-[bis[(4-methoxyphenyl)methyl]-5-bromo-6-cyclopropyl-pyridine-3-carbonitrile (300 mg, 0.63 mmol), potassium hydroxide (105 mg, 1.88 mmol, 3), t-BuBretPhos Pd G3 (107 mg, 0.13 mmol), and t-BuBretPhos (61 mg, 0.13 mmol) in 1,4-dioxane (3 mL) and water (0.30 mL) was stirred at 80 °C for 2 h. The reaction was then diluted with water, extracted with ethyl acetate, and the combined organic layers were washed with brine and concentrated. Purification by flash column chromatography afforded 2-[bis[(4-methoxyphenyl)methyl]amino]-6-cyclopropyl-5-hydroxy-pyridine-3-carbonitrile (260 mg, 70%) as an orange oil. ([M+H] + 416.3)

[0454] Step 4: 2-[bis[(4-methoxyphenyl)methyl]amino]-6-cyclopropyl-5-(difluoromethoxy)pyridine-3-carbonitrile A mixture of 2-[bis[(4-methoxyphenyl)methyl]amino]-6-cyclopropyl-5-hydroxy-pyridine-3-carbonitrile (270 mg, 0.45 mmol), sodium chlorodifluoroacetate (138 mg, 0.91 mmol), and cesium carbonate (444 mg, 1.36 mmol) in DMF (2 mL) was stirred at 80° C. for 2 h. The reaction was then diluted with water, extracted with ethyl acetate, and the combined organic layers were washed with brine and concentrated. Purification by flash column chromatography afforded 2-[bis[(4-methoxyphenyl)methyl]amino]-6-cyclopropyl-5-(difluoromethoxy)pyridine-3-carbonitrile (180 mg, 85%) as a yellow oil. ([M+H] + 466.3)

[0455] Step 5: 2-Amino-6-cyclopropyl-5-(difluoromethoxy)pyridine-3-carbonitrile To 2-[bis[(4-methoxyphenyl)methyl]amino]-6-cyclopropyl-5-(difluoromethoxy)pyridine-3-carbonitrile (160 mg, 0.34 mmol) was added TFA (3.0 mL, 0.34 mmol) at room temperature, and the reaction was stirred for 1 hour before being quenched by the addition of saturated sodium bicarbonate solution. It was then extracted with ethyl acetate, concentrated, and the residue purified by flash column chromatography to give 2-amino-6-cyclopropyl-5-(difluoromethoxy)pyridine-3-carbonitrile (70 mg, 90%) as a colorless oil. ([M+H] + 226.2)

[0456] Step 6: 6-Cyclopropyl-5-(difluoromethoxy)-2-(2-methylanilino)pyridine-3-carbonitrile Title compound ([M+H] +316.2) was prepared from 2-amino-6-cyclopropyl-5-(difluoromethoxy)pyridine-3-carbonitrile by reaction with 2-bromotoluene using Pd(OAc)2 as catalyst and Xantphos as ligand (General Procedure B1).

[0457] Step 7: 4-amino-7-cyclopropyl-6-(difluoromethoxy)-1-(o-tolyl)pyrido[2,3-d]pyrimidin-2-one Title compound ([M+H] + 359.2) was prepared from 6-cyclopropyl-5-(difluoromethoxy)-2-(2-methylanilino)pyridine-3-carbonitrile using general procedure C.

[0458] Examples 114 and 115: (+)-4-amino-1-(2-chlorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2(1H)-one and (-)-4-amino-1-(2-chlorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2(1H)-one TIFF0007749602000160.tif35170

[0459] Step 1: 2-((2-chlorophenyl)amino)-6-cyclopropylnicotinonitrile Title compound ([M+H] + 270.1) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS[1198475-35-2]) by reaction with 2-chloroaniline (CAS[95-51-2]) using Pd(OAc)2 as catalyst and Xantphos as ligand (General Procedure B1).

[0460] Step 2: (+)-4-amino-1-(2-chlorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2(1H)-one and (-)-4-amino-1-(2-chlorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2(1H)-one Title compound ([M+H] +313.1) was prepared from 2-((2-chlorophenyl)amino)-6-cyclopropylnicotinonitrile using general procedure C and subsequently separated using chiral HPLC.

[0461] Examples 116 and 117: (+)-4-amino-1-(2-chloro-3-fluorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2(1H)-one and (-)-4-amino-1-(2-chloro-3-fluorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2(1H)-one TIFF0007749602000161.tif36170

[0462] Step 1: 2-((2-chloro-3-fluorophenyl)amino)-6-cyclopropylnicotinonitrile Title compound ([M+H] + 288.1) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS[1198475-35-2]) by reaction with 2-chloro-3-fluoroaniline (CAS[21397-08-0]) using Pd(OAc)2 as catalyst and Xantphos as ligand (General Procedure B1).

[0463] Step 2: (+)-4-amino-1-(2-chloro-3-fluorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2(1H)-one and (-)-4-amino-1-(2-chloro-3-fluorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2(1H)-one Title compound ([M+H] + 331.1 & 331.1) were prepared from 2-((2-chloro-3-fluorophenyl)amino)-6-cyclopropylnicotinonitrile using general procedure C and subsequently separated using chiral HPLC.

[0464] Examples 118 and 119: 4-amino-7-cyclopropyl-1-((2R,3S)-2-methyltetrahydro-2H-pyran-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (Example 118) and 4-amino-7-cyclopropyl-1-((2S,3R)-2-methyltetrahydro-2H-pyran-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (Example 119) TIFF0007749602000162.tif34170

[0465] Step 1: 2-Methyldihydro-2H-pyran-3(4H)-one To a solution of 2-methyl-2H-pyran-3(6H)-one (WO2010 / 96338 A1) (6.45 g, 57.5 mmol) in MeOH (250 mL) was added 10% palladium on activated carbon (317 mg, 298 μmol) and the reaction was stirred under a hydrogen (balloon) atmosphere for 1 h. The reaction was filtered through Celite® and concentrated. Vacuum distillation (BP: 42-43, 10 mbar) through a short Vigreux column afforded the title compound (4.75 g, 65%) as a colorless liquid. ([M+H] + 115.1)

[0466] Step 2: (2RS,3RS)-2-methyltetrahydro-2H-pyran-3-ol To a cooled (-78°C) solution of 2-methyldihydro-2H-pyran-3(4H)-one (1.00 g, 8.76 mmol) in dry THF (25 mL) was added 1 M L-selectride® in THF (20 mL, 20 mmol) dropwise over 30 min, and the mixture was stirred for an additional 3 h, during which time the reaction was allowed to reach -10°C, after which ethanol (2.4 mL, 41.1 mmol) was added dropwise, followed by water (6 mL, 333 mmol), and finally 1 M NaOH in water (6 mL, 6 mmol). The temperature was then raised to 0°C, and 36% HO (6 mL, 70.5 mmol) was added while maintaining the temperature below 10°C, after which the mixture was stirred for an additional 1 h at room temperature. The reaction was filtered through Celite® and washed with ethyl acetate. The filtrate was washed with saturated NaHCO3 and 10% sodium thiosulfate solution. All aqueous layers were re-extracted with DCM:MeOH (9:1), and the organic layers were combined, dried (Na2SO4), and concentrated. The residue was subjected to flash column chromatography to give the title compound (0.74 g, 72%) as a colorless oil. 1H NMR (300 MHz, chloroform-d) δ ppm 1.18 - 1.23 (m, 3H), 1.35 - 1.45 (m, 1H), 1.61 - 1.73 (m, 1H), 1.81 - 2.01 (m, 3H), 3.43 - 3.59 (m, 3H), 3.91 - 4.00 (m, 1H).

[0467] Step 3: (2RS,3RS)-2-methyltetrahydro-2H-pyran-3-yl 4-methylbenzenesulfonate To a solution of (2RS,2RS)-2-methyltetrahydro-2H-pyran-3-ol (730 mg, 6.28 mmol) in dry DCM (25 mL) was added DABCO (1.41 g, 12.6 mmol). The solution was cooled in an ice bath, toluenesulfonyl chloride (1.8 g, 9.43 mmol) was added, the ice bath was removed, and the mixture was stirred at room temperature for 20 minutes. The reaction was concentrated, and the residue was purified by flash column chromatography to give the title compound (1.37 g, 80%) as a white solid. 1H NMR (300 MHz, chloroform-d) δ ppm 1.04 (d, J = 6.45 Hz, 3H) 1.31 - 1.41 (m, 1H) 1.62 - 1.74 (m, 1H) 1.83 - 1.99 (m, 1H) 2.05 - 2.16 (m, 1H) 2.45 (s, 3H) 3.40 - 3.54 (m, 2H) 3.91 - 3.99 (m, 1H) 4.50 (br s, 1H) 7.30 - 7.36 (m, 2H) 7.79 - 7.84 (m, 2H)

[0468] Step 4: (2RS,3SR)-2-methyltetrahydro-2H-pyran-3-amine acetate To a solution of (2RS,3RS)-2-methyltetrahydro-2H-pyran-3-yl 4-methylbenzenesulfonate (1.37 g, 5.07 mmol) in dry DMF (8 mL) was added sodium azide (1.65 g, 25.3 mmol), and the suspension was heated to 65 °C for 94 h. The reaction was diluted with water and extracted with diethyl ether. The combined organic extracts were washed with water, dried (NaSO), filtered, and 30 mL of methanol was added to the filtrate, which was then carefully concentrated (p > 250 mbar, water bath 25 °C) to remove the diethyl ether. Acetic acid (1.45 mL, 25.3 mmol) was then added to the methanol solution, followed by 10% palladium on charcoal (132 mg, 124 μmol). The reaction was placed under a hydrogen (balloon) atmosphere, and the mixture was stirred for 3 h. The reaction was then filtered through Celite® and concentrated. The residue was suspended in diethyl ether, sonicated, and filtered to give the title compound (176 mg, 16%) as an off-white solid. ([M+H] + 116.1)

[0469] Step 5: 6-Cyclopropyl-2-(((2RS,3SR)-2-methyltetrahydro-2H-pyran-3-yl)amino)nicotinonitrile Title compound ([M+H] + 258.2) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) by reaction with (2SR,3RS)-2-methyltetrahydro-2H-pyran-3-amine acetate in NMP at 150°C using DIPEA as a base (General Procedure B2).

[0470] Step 6: 4-amino-7-cyclopropyl-1-((2R,3S)-2-methyltetrahydro-2H-pyran-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one and 4-amino-7-cyclopropyl-1-((2S,3R)-2-methyltetrahydro-2H-pyran-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one Title compound ([M+H] +301.2 & 301.2) were prepared from 6-cyclopropyl-2-(((2RS,3SR)-2-methyltetrahydro-2H-pyran-3-yl)amino)nicotinonitrile using general procedure C and subsequently separated using chiral HPLC.

[0471] Example 120: 4-amino-1-(benzo[d]thiazol-7-yl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2(1H)-one TIFF0007749602000163.tif34170

[0472] Step 1: 2-(benzo[d]thiazol-7-ylamino)-6-cyclopropylnicotinonitrile Title compound ([M+H] + 293.1) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS[1198475-35-2]) by reaction with 6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-amine hydrochloride (CAS[272438-86-5]) using Pd2(dba)3 as catalyst and tBuXphos as ligand (General Procedure B1).

[0473] Step 2: 4-amino-1-(benzo[d]thiazol-7-yl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2(1H)-one Title compound ([M+H] + 336.1) was prepared from 2-((benzo[d]thiazol-7-ylamino)-6-cyclopropylnicotinonitrile using general procedure C.

[0474] Example 121: 4-amino-7-cyclopropyl-1-[(2SR,3SR)-2-methyltetrahydropyran-3-yl]pyrido[2,3-d]pyrimidin-2-one TIFF0007749602000164.tif51170

[0475] Step 1: (2SR,3SR)-N-benzyl-2-methyltetrahydro-2H-pyran-3-amine To a solution of 2-methyldihydro-2H-pyran-3(4H)-one (Example 118, Step 1) (500 mg, 4.38 mmol) and sodium triacetoxyborohydride (1.39 g, 6.57 mmol) in dry DCM (14 mL) was added phenylmethanamine (526 μL, 4.82 mmol) and acetic acid (301 μL, 5.26 mmol) at 0° C. The reaction was allowed to reach room temperature and stirred for 1 h, after which it was diluted with DCM, washed with 1N NaOH solution, dried (NaSO), and concentrated. The residue was purified by flash column chromatography to afford the title compound (736 mg, 65%) as a colorless oil. ([M+H] + 116.1)

[0476] Step 1: (2SR,3SR)-2-methyltetrahydro-2H-pyran-3-amine acetate To a solution of (2SR,3SR)-N-benzyl-2-methyltetrahydro-2H-pyran-3-amine (730 mg, 3.56 mmol) in dry THF (14 mL) and acetic acid (407 μL, 7.11 mmol), 10% palladium on activated carbon (378 mg, 356 μmol) was added and the reaction was placed under an atmosphere of hydrogen (balloon) and stirred for 24 hours. The reaction was filtered through Celite®, washed with MeOH, and concentrated to give the title compound (628 mg, 75%) as an off-white solid. ([M+H] + 116.1)

[0477] Step 1: 6-cyclopropyl-2-(((2SR,3SR)-2-methyltetrahydro-2H-pyran-3-yl)amino)nicotinonitrile Title compound ([M+H] + 258.2) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) by reaction with (2SR,3SR)-2-methyltetrahydro-2H-pyran-3-amine acetate using Pd2(dba)3 as catalyst and tBuXphos as ligand (General Procedure B1).

[0478] Step 2: 4-amino-1-(benzo[d]thiazol-7-yl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2(1H)-one Title compound ([M+H] + 301.2) was prepared from 6-cyclopropyl-2-(((2SR,3SR)-2-methyltetrahydro-2H-pyran-3-yl)amino)nicotinonitrile using general procedure C.

[0479] Example 122: 4-amino-7-(difluoromethoxy)-1-(3-fluoro-2-methylphenyl)quinazolin-2(1H)-one TIFF0007749602000165.tif36170

[0480] Step 1: 4-(difluoromethoxy)-2-((3-fluoro-2-methylphenyl)amino)benzonitrile Title compound ([M+H] + 293.1) was prepared from 2-bromo-4-(trifluoromethoxy)benzonitrile (CAS [1214334-83-4]) by reaction with 3-fluoro-2-methylaniline using Pd(OAc)2 as catalyst and Xantphos as ligand (General Procedure B1).

[0481] Step 2: 4-amino-7-(difluoromethoxy)-1-(3-fluoro-2-methylphenyl)quinazolin-2(1H)-one Title compound ([M+H] + 336.2) was prepared from 4-(difluoromethoxyl)-2-((3-fluoro-2-methylphenyl)amino)benzonitrile using general procedure C.

[0482] Example 123: 4-amino-7-cyclopropyl-1-(3-hydroxy-2-methylphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one TIFF0007749602000166.tif35170

[0483] Step 1: 2-((3-((tert-butyldimethylsilyl)oxy)-2-methylphenyl)amino)-6-cyclopropylnicotinonitrile Title compound ([M+H] + 380.6) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) by reaction with 3-((tert-butyldimethylsilyl)oxy)-2-methylaniline using Pd(OAc) as catalyst and Xantphos as ligand (General Procedure B1).

[0484] Step 2: 4-amino-1-(3-((tert-butyldimethylsilyl)oxy)-2-methylphenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2(1H)-one Title compound ([M+H] + 423.8) was prepared from 2-((3-((tert-butyldimethylsilyldimethylsilyl)oxy)-2-methylphenyl)amino)-6-cyclopropylnicotinonitrile using general procedure C.

[0485] Step 3: 4-amino-7-cyclopropyl-1-(3-hydroxy-2-methylphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one To a suspension of 4-amino-1-(3-((tert-butyldimethylsilyl)oxy)-2-methylphenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2(1H)-one (47 mg, 111 μmol) in 4 M HCl in dioxane (1 mL) was added MeOH (0.5 mL) and the reaction was stirred at room temperature for 4 h. 1 mL of water was then added and the mixture was stirred for 30 min before the title product (22 mg, 64%) was isolated as a white solid by filtration. ([M+H] + 309.2)

[0486] Examples 124 and 125: (R)-4-amino-7-cyclopropyl-1-(oxepan-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one and (S)-4-amino-7-cyclopropyl-1-(oxepan-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one TIFF0007749602000167.tif37170

[0487] Step 3: (E / Z)-Oxepan-3-one oxime To a solution of 6,7-dihydrooxepin-3(2H)-one (1.35 g, 12 mmol, CAS: 497063-30-6) in MeOH (50 mL) was added 10% palladium on activated carbon (100 mg, 94 μmol), the reaction was placed under a hydrogen (balloon) atmosphere, and the mixture was stirred for 30 minutes. The reaction was then filtered through Celite®, washed with methanol, and the filtrate was partially concentrated (p>100 mbar, 20° C.). Hydroxylamine hydrochloride (1.67 g, 24.1 mmol) and potassium acetate (4.73 g, 48.2 mmol) were then added, and the reaction was heated to 70° C. for 1 hour. After that, the reaction was concentrated to dryness and then partitioned between water and ethyl acetate. The layers were separated, and the aqueous fraction was re-extracted with ethyl acetate. The combined organic layers were washed with brine and concentrated. The residue was subjected to flash column chromatography to give the title compound (1.21 g, 74%) as a colorless oil. ([M+H] + 130.0)

[0488] Step 4: Oxepan-3-amine hydrochloride To a solution of oxepan-3-one oxime (1.21 g, 9.37 mmol) in 7 M ammonia in methanol (150 mL) was added Raney®-Nickel (6.2 g, 9.37 mmol), and the mixture was stirred under an atmosphere of hydrogen (balloon) for 90 minutes. The reaction was then filtered through Celite® and concentrated. Purification by flash column chromatography, followed by precipitation from diethyl ether (acidified by the addition of 4 N HCl in dioxane), afforded the title compound (1.05 g, 76%) as a white solid. ([M+H] + 116.1)

[0489] Step 5: 6-Cyclopropyl-2-(oxepan-3-ylamino)nicotinonitrile Title compound ([M+H] + 258.2) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) by reaction with oxepan-3-amine hydrochloride using DIPEA as a base in NMP at 150° C. (General Procedure B2).

[0490] Step 6: (R)-4-amino-7-cyclopropyl-1-(oxepan-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one and (S)-4-amino-7-cyclopropyl-1-(oxepan-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one Title compound ([M+H] + 301.2 & 301.2) were prepared from 6-cyclopropyl-2-(oxepan-3-ylamino)nicotinonitrile using general procedure C and subsequently separated using chiral HPLC.

[0491] Example 126: 3-(4-amino-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)-2-fluorobenzonitrile TIFF0007749602000168.tif34170

[0492] Step 1: 2-((3-cyano-2-fluorophenyl)amino)-6-cyclopropylnicotinonitrile Title compound ([M+H] + 279.1) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) by reaction with 3-amino-2-fluorobenzonitrile using Pd(OAc)2 as catalyst and Xantphos as ligand (General Procedure B1).

[0493] Step 2: 3-(4-amino-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)-2-fluorobenzonitrile Title compound ([M+H] + 322.1) was prepared from 2-((3-cyano-2-fluorophenyl)amino)-6-cyclopropylnicotinonitrile using general procedure C.

[0494] Example 127: 4-amino-7-cyclopropyl-1-(2-fluoro-3-methylphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one TIFF0007749602000169.tif35170

[0495] Step 1: 6-cyclopropyl-2-((2-fluoro-3-methylphenyl)amino)nicotinonitrile Title compound ([M+H] + 268.2) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) by reaction with 2-fluoro-3-methylaniline using Pd(OAc)2 as catalyst and Xantphos as ligand (General Procedure B1).

[0496] Step 2: 4-amino-7-cyclopropyl-1-(2-fluoro-3-methylphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one Title compound ([M+H] +311.1) was prepared from 6-cyclopropyl-2-((2-fluoro-3-methylphenyl)amino)nicotinonitrile using general procedure C.

[0497] Example 128: 4-amino-7-cyclopropyl-1-(2,3-dichlorophenyl)pyrido[2,3-d]pyrimidin-2(1H)-one TIFF0007749602000170.tif32170

[0498] Step 1: 6-cyclopropyl-2-((2,3-dichlorophenyl)amino)nicotinonitrile Title compound ([M+H] + 304.0) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) by reaction with 2,3-dichloroaniline using Pd(OAc)2 as catalyst and Xantphos as ligand (General Procedure B1).

[0499] Step 2: 4-amino-7-cyclopropyl-1-(2,3-dichlorophenyl)pyrido[2,3-d]pyrimidin-2(1H)-one Title compound ([M+H] + 347.1) was prepared from 6-cyclopropyl-2-((2,3-dichlorophenyl)amino)nicotinonitrile using general procedure C.

[0500] Example 129: 4-amino-1-(3-chloro-2-methylphenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2-one TIFF0007749602000171.tif32170

[0501] Step 1: 2-((3-chloro-2-methylphenyl)amino)-6-cyclopropylnicotinonitrile Title compound ([M+H] +284.1) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) by reaction with 3-chloro-2-methylaniline using Pd(OAc)2 as catalyst and Xantphos as ligand (General Procedure B1).

[0502] Step 2: 4-amino-1-(3-chloro-2-methylphenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2-one Title compound ([M+H] + 327.1) was prepared from 2-((3-chloro-2-methylphenyl)amino)-6-cyclopropylnicotinonitrile using general procedure C.

[0503] Example 130: 4-amino-1-(2-chloro-3-methylphenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2-one TIFF0007749602000172.tif32170

[0504] Step 1: 2-((2-chloro-3-methylphenyl)amino)-6-cyclopropylnicotinonitrile Title compound ([M+H] + 284.1) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) by reaction with 2-chloro-3-methylaniline using Pd(OAc)2 as catalyst and Xantphos as ligand (General Procedure B1).

[0505] Step 2: 4-amino-1-(2-chloro-3-methylphenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2-one Title compound ([M+H] + 327.1) was prepared from 2-((2-chloro-3-methylphenyl)amino)-6-cyclopropylnicotinonitrile using general procedure C.

[0506] Example 131: 4-amino-7-cyclopropyl-1-(3-(fluoromethyl)-2-methylphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one TIFF0007749602000173.tif36170

[0507] Step 1: 6-cyclopropyl-2-((3-(fluoromethyl)-2-methylphenyl)amino)nicotinonitrile Title compound ([M+H] + 282.3) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) by reaction with 3-(fluoromethyl)-2-methylaniline using Pd(OAc) as catalyst and Xantphos as ligand (General Procedure B1).

[0508] Step 2: 4-amino-7-cyclopropyl-1-(3-(fluoromethyl)-2-methylphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one Title compound ([M+H] + 325.1) was prepared from 6-cyclopropyl-2-((3-(fluoromethyl)-2-methylphenyl)amino)nicotinonitrile using general procedure C.

[0509] Example 132: 4-amino-7-cyclopropyl-1-[2-(trifluoromethyl)phenyl]pyrido[2,3-d]pyrimidin-2(1H)-one TIFF0007749602000174.tif34170

[0510] Step 1: 6-Cyclopropyl-2-((2-(trifluoromethyl)phenyl)amino)nicotinonitrile Title compound ([M+H] +304.1) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS[1198475-35-2]) by reaction with 2-(trifluoromethyl)aniline (CAS[88-17-5]) using Pd2(dba)3 as catalyst and Xphos as ligand (General Procedure B1).

[0511] Step 2: 4-amino-7-cyclopropyl-1-(2-(trifluoromethyl)phenyl)pyrido[2,3-d]pyrimidin-2(1H)-one Title compound ([M+H] + 347.1) was prepared from 6-cyclopropyl-2-((2-(trifluoromethyl)phenyl)amino)nicotinonitrile using general procedure C.

[0512] Example 133: 4-amino-7-(difluoromethoxy)-1-(2-fluoro-3-methylphenyl)quinazolin-2(1H)-one TIFF0007749602000175.tif32170

[0513] Step 1: Bromo-4-(difluoromethoxy)benzonitrile To a solution of 2-bromo-4-hydroxybenzonitrile (30.2 g, 122 mmol) and cesium carbonate (119.3 g, 366 mmol) in DMF (302 mL) was added sodium 2-chloro-2,2-difluoroacetate (55.8 g, 366 mmol). The reaction mixture was heated to 80 °C for 2 h. The reaction mixture was then filtered, diluted with ethyl acetate, washed with water and brine, and concentrated. Purification by flash column chromatography afforded the title compound (6.0 g, 18%) as a white solid. H NMR (400 MHz, chloroform-d) δ = 7.72–7.65 (m, 1H), 7.51–7.45 (m, 1H), 7.24–7.14 (m, 1H), 6.81–6.39 (m, 1H).

[0514] Step 2: 4-(difluoromethoxy)-2-((2-fluoro-3-methylphenyl)amino)benzonitrile Title compound ([M+H] + 293.1) was prepared from 2-bromo-4-(difluoromethoxy)benzonitrile by reaction with 2-fluoro-3-methylaniline using Pd(OAc)2 as catalyst and Xantphos as ligand (General Procedure B1).

[0515] Step 3: 4-amino-7-(difluoromethoxy)-1-(2-fluoro-3-methylphenyl)quinazolin-2(1H)-one Title compound ([M+H] + 336.1) was prepared from 4-(difluoromethoxy)-2-((2-fluoro-3-methylphenyl)amino)benzonitrile using general procedure C.

[0516] Example 134: 4-amino-7-(difluoromethoxy)-1-(m-tolyl)quinazolin-2(1H)-one TIFF0007749602000176.tif32170

[0517] Step 1: 4-(Difluoromethoxy)-2-(m-tolylamino)benzonitrile Title compound ([M+H] + 275.1) was prepared from 2-bromo-4-(difluoromethoxy)benzonitrile (Example 133, Step 1) by reaction with m-toluidine using Pd(OAc) as catalyst and xantphos as ligand (General Procedure B1).

[0518] Step 2: 4-amino-7-(difluoromethoxy)-1-(m-tolyl)quinazolin-2(1H)-one Title compound ([M+H] + 318.1) was prepared from 4-(difluoromethoxy)-2-(m-tolylamino)benzonitrile using general procedure C.

[0519] Examples 135 and 136: (+)-4-amino-1-(2-chloropyridin-3-yl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2(1H)-one and (-)-4-amino-1-(2-chloropyridin-3-yl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2(1H)-one TIFF0007749602000177.tif33170

[0520] Step 1: 2-((2-chloropyridin-3-yl)amino)-6-cyclopropylnicotinonitrile Title compound ([M+H] + 271.1) was prepared from 2-amino-6-cyclopropylnicotinonitrile (CAS [1249836-67-6]) by reaction with 2-chloro-3-iodopyridine using Pd2(dba)3 as catalyst and Xantphos as ligand (General Procedure B1).

[0521] Step 2: (+)-4-amino-1-(2-chloropyridin-3-yl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2(1H)-one and (-)-4-amino-1-(2-chloropyridin-3-yl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2(1H)-one Title compound ([M+H] + 314.2 & 314.2) were prepared from 6-2-((2-chloropyridin-3-yl)amino)-6-cyclopropylnicotinonitrile using general procedure C and subsequently separated using chiral HPLC.

[0522] Example 137: 4-amino-1-(2-chloropyridin-3-yl)-7-(difluoromethoxy)quinazolin-2(1H)-one TIFF0007749602000178.tif32170

[0523] Step 1: 2-((2-chloropyridin-3-yl)amino)-4-(difluoromethoxy)benzonitrile Title compound ([M+H] +296.1) was prepared from 2-bromo-4-(difluoromethoxy)benzonitrile (CAS [1261818-72-7]) by reaction with 2-chloropyridin-3-amine using Pd2(dba)3 as catalyst and Xantphos as ligand (General Procedure B1).

[0524] Step 2: 4-amino-1-(2-chloropyridin-3-yl)-7-(difluoromethoxy)quinazolin-2(1H)-one Title compound ([M+H] + 339.1) was prepared from 2-((2-chloropyridin-3-yl)amino)-4-(difluoromethoxy)benzonitrile using general procedure C.

[0525] Example 138: 4-amino-7-cyclopropyl-1-(2,3-dimethylphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one TIFF0007749602000179.tif31170

[0526] Step 1: 6-cyclopropyl-2-((2,3-dimethylphenyl)amino)nicotinonitrile Title compound ([M+H] + 264.3) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) by reaction with 2,3-dimethylaniline using Pd2(dba)3 as catalyst and Xantphos as ligand (General Procedure B1).

[0527] Step 2: 4-amino-7-cyclopropyl-1-(2,3-dimethylphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one Title compound ([M+H] + 307.2) was prepared from 6-cyclopropyl-2-((2,3-dimethylphenyl)amino)nicotinonitrile using general procedure C.

[0528] Example 139: 4-amino-7-cyclopropyl-1-(1H-indazol-4-yl)pyrido[2,3-d]pyrimidin-2(1H)-one TIFF0007749602000180.tif34170

[0529] Step 1: tert-butyl-4-((3-cyano-6-cyclopropylpyridin-2-yl)amino)-1H-indazole-1-carboxylate Title compound ([M+H] + 264.3) was prepared from 2-amino-6-cyclopropylnicotinonitrile (CAS [1249836-67-6]) by reaction with 4-bromo-1H-indazole-1-carboxylate using Pd2(dba)3 as catalyst and Xphos as ligand (General Procedure B1).

[0530] Step 2: 4-amino-7-cyclopropyl-1-(1H-indazol-4-yl)pyrido[2,3-d]pyrimidin-2(1H)-one Title compound ([M+H] + 319.1) was prepared from tert-butyl 4-((3-cyano-6-cyclopropylpyridin-2-yl)amino)-1H-indazole-1-carboxylate using general procedure C.

[0531] Example 140: 4-amino-7-cyclopropyl-1-(1H-indazol-4-yl)pyrido[2,3-d]pyrimidin-2(1H)-one TIFF0007749602000181.tif33170

[0532] Step 1: tert-butyl-4-((3-cyano-6-cyclopropylpyridin-2-yl)amino)-1H-benzo[d]imidazole-1-carboxylate Title compound ([M+H] +376.2) was prepared from 2-amino-6-cyclopropylnicotinonitrile (CAS [1249836-67-6]) by reaction with tert-butyl 4-bromo-1H-benzo[d]imidazole-1-carboxylate (WO2018 / 132372 A1) using Pd2(dba)3 as catalyst and Xphos as ligand (General Procedure B1).

[0533] Step 2: 4-amino-7-cyclopropyl-1-(1H-indazol-4-yl)pyrido[2,3-d]pyrimidin-2(1H)-one Title compound ([M+H] + 317.2) was prepared from tert-butyl 4-((3-cyano-6-cyclopropylpyridin-2-yl)amino)-1H-indazole-1-carboxylate using general procedure C.

[0534] Example 141: 4-amino-7-cyclopropyl-1-[(8R)-4-oxaspiro[2.5]octan-8-yl]pyrido[2,3-d]pyrimidin-2-one TIFF0007749602000182.tif32170

[0535] Step 1: Methyl 1-(allyloxy)cyclopropane-1-carboxylate To an ice-cooled solution of 1-hydroxycyclopropane-1-carboxylate (10 g, 86.1 mmol) in dry THF (220 mL) was added sodium hydride, 60% dispersion in mineral oil (4.13 g, 103 mmol). The mixture was stirred for 15 min, after which allyl bromide (9.69 mL, 112 mmol) dissolved in dry THF (50 mL) was added over 30 min. The mixture was allowed to warm to room temperature and stirred for 16 h. The reaction was quenched by the addition of saturated aqueous ammonium chloride, extracted with TBME, and the combined organic extracts were dried (NaSO) and concentrated. Distillation (BP 79-82 °C, 12 mmbar) afforded the title compound (6.25 g, 44.1% yield) as a pale yellow oil. ([M+H] + 157.1)

[0536] Step 2: 1-(allyloxy)-N-methoxy-N-methylcyclopropane-1-carboxamide To an ice-cold suspension of N,O-dimethylhydroxyamine hydrochloride (1.25 g, 12.8 mmol) in dry DCM (12 mL) was added 2 M trimethylaluminum in toluene (6.4 mL, 12.8 mmol), and the mixture was stirred for 1 h, followed by the addition of a solution of methyl 1-(allyloxy)cyclopropane-1-carboxylate (1 g, 6.4 mmol) in dry DCM (6 mL) over 10 min. The ice bath was removed, and the reaction was stirred at room temperature for 16 h. The reaction was then cooled to 0 °C and quenched by the careful addition of water followed by 4 N aqueous HCl, and extracted with DCM. The combined organic extracts were dried (Na SO ) and concentrated. The residue was subjected to flash column chromatography to afford the title compound (768 mg, 65%) as a colorless oil. ([M+H] + 186.1)

[0537] Step 3: 1-(1-(allyloxy)cyclopropyl)prop-2-en-1-one To a solution of 1-(allyloxy)-N-methoxy-N-methylcyclopropane-1-carboxamide (463 mg, 2.5 mmol) in dry THF (8 mL) at −78° C., 1 M vinylmagnesium bromide in THF (2.75 mL, 2.75 mmol) was added over 10 minutes, and the mixture was stirred for 1 hour. A second portion of 1 M vinylmagnesium bromide in THF (2.75 mL, 2.75 mmol) was added, and the reaction was warmed to 0° C. over 30 minutes. After cooling the reaction to −78° C. again, 4 N aqueous HCl (10 mL) was added and the temperature was allowed to rise to room temperature. The mixture was diluted with water and extracted with TBME, and the combined organic extracts were dried (NaSO) and concentrated to give the title compound (357 mg, 89%) as a yellow oil.

[0538] 1H NMR (300 MHz, Chloroform-d) δ ppm 1.21 - 1.28 (m, 2 H) 1.34 - 1.41 (m, 2 H) 4.04 (dt, J =5.44, 1.51 Hz, 2 H) 5.15 - 5.36 (m, 2 H) 5.74 (dd, J =10.38, 1.91 Hz, 1 H) 5.92 (ddt, J =17.33, 10.58, 5.39, 5.39 Hz, 1 H) 6.40 (dd, J =17.33, 2.01 Hz, 1 H) 7.02 (dd, J =17.23, 10.38 Hz, 1 H)

[0539] Step 4: 4-oxaspiro[2.5]oct-6-en-8-one To a solution of 1-(1-(allyloxy)cyclopropyl)prop-2-en-1-one (2.7 g, 17.7 mmol) in DCM (324 mL) was added Zhan Catalyst-1B (130 mg, 177 μmol), and the mixture was stirred at room temperature for 3 hours. The reaction was concentrated, and the residue was purified by flash column chromatography to give the title compound (1.9 g, 83%) as a colorless oil. ([M+H] + 125.0)

[0540] Step 5: 4-oxaspiro[2.5]octan-8-one To a solution of 4-oxaspiro[2.5]oct-6-en-8-one (302 mg, 2.43 mmol) in THF (7 mL) was added 10% palladium on activated carbon (12 mg, 11.3 μmol), the mixture was placed under an atmosphere of hydrogen (balloon), and the mixture was stirred for 40 minutes. It was then filtered through Celite® and concentrated to give the title compound (296 mg, 96%) as a colorless oil. ([M+H] + 127.1)

[0541] Step 6: (S,Z)-2-methyl-N-(4-oxaspiro[2.5]octan-8-ylidene)propane-2-sulfinamide To a solution of TiOEt (496 μL, 2.35 mmol) in THF (2 mL) was added 4-oxaspiro[2.5]octan-8-one (148 mg, 1.17 mmol) in THF (2 mL), followed by (S)-(−)-2-methyl-2-propanesulfinamide (174 mg, 1.41 mmol), and the mixture was heated at 45° C. for 68 h. The reaction was diluted with ethyl acetate, and brine was added, resulting in a thick suspension that was then filtered through Celite®. The mixture was extracted with ethyl acetate, and the combined organic extracts were dried (NaSO) and concentrated. The residue was subjected to flash column chromatography to afford the title compound (120 mg, 44%) as a yellow oil. ([M+H] + 230.2)

[0542] Step 7: (S)-2-methyl-N-((R)-4-oxaspiro[2.5]octan-8-yl)propane-2-sulfinamide To a solution of (S,Z)-2-methyl-N-(4-oxaspiro[2.5]octan-8-ylidene)propane-2-sulfinamide (120 mg, 523 μmol) in THF (2.0 mL) was added water (41 μL) and cooled to −50° C., followed by the addition of sodium borohydride (59.4 mg, 1.57 mmol). The mixture was allowed to warm to 15° C. over 3 hours. The reaction was quenched by the addition of methanol (0.5 mL), water (2 mL), and 10% sodium carbonate solution (2 mL) and stirred for 30 minutes. The reaction was extracted with ethyl acetate, and the combined organic extracts were dried (NaSO) and concentrated. The residue was subjected to flash column chromatography to afford the title compound (65 mg, 54%) as a white solid. ([M+H] + 232.1)

[0543] Step 8: (R)-4-oxaspiro[2.5]octan-8-amine hydrochloride To a solution of (S)-2-methyl-N-((R)-4-oxaspiro[2.5]octan-8-yl)propane-2-sulfinamide (60 mg, 0.3 mmol) in dioxane (2 mL) was added 4 M HCl in dioxane (195 μL, 778 μmol) and the mixture was stirred at room temperature for 16 h. The reaction was evaporated to dryness, suspended in diethyl ether, and filtered to give the title compound (38 mg, 89%) as a white solid. ([M+H] + 111.1)

[0544] Step 9: 6-Cyclopropyl-2-((2,3-dimethylphenyl)amino)nicotinonitrile Title compound ([M+H] + 270.2) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) by reaction with (R)-4-oxaspiro[2.5]octan-8-amine hydrochloride using Pd2(dba)3 as catalyst and tBuXphos as ligand (General Procedure B1).

[0545] Step 10: 4-amino-7-cyclopropyl-1-[(8R)-4-oxaspiro[2.5]octan-8-yl]pyrido[2,3-d]pyrimidin-2-one Title compound ([M+H] + 313.1) was prepared from (R)-2-((4-oxaspiro[2.5]octan-8-yl)amino)-6-cyclopropylnicotinonitrile using general procedure C.

[0546] Example 142: 4-amino-7-cyclopropyl-1-[(8S)-4-oxaspiro[2.5]octan-8-yl]pyrido[2,3-d]pyrimidin-2-one TIFF0007749602000183.tif32170

[0547] Step 1: (S)-2-((4-oxaspiro[2.5]octan-8-yl)amino)-6-cyclopropylnicotinonitrile Title compound ([M+H] +270.2) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) by reaction with (S)-4-oxaspiro[2.5]octan-8-amine hydrochloride (prepared in a similar manner as in Example 141, but using (R)-(−)-2-methyl-2-propanesulfinamide in step 6) using Pd(dba) as catalyst and tBuXphos as ligand (General Procedure B1).

[0548] Step 2: 4-amino-7-cyclopropyl-1-[(8R)-4-oxaspiro[2.5]octan-8-yl]pyrido[2,3-d]pyrimidin-2-one Title compound ([M+H] + 313.1) was prepared from (S)-2-((4-oxaspiro[2.5]octan-8-yl)amino)-6-cyclopropylnicotinonitrile using general procedure C.

[0549] Example 143: 3-(4-amino-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)-2-chlorobenzonitrile TIFF0007749602000184.tif33170

[0550] Step 1: 3-Amino-2-chlorobenzonitrile To 2-chloro-3-nitrobenzonitrile (0.5 g, 2.74 mmol), iron powder (3.09 g, 54.8 mmol), and ammonium chloride (3.66 g, 68.5 mmol) was added EtOH (29 mL) and water (12 mL). The reaction was stirred at 70° C. for 3 h. The reaction was filtered through Decalite®, washed with DCM, MeOH, and EtOAc, and the filtrate was evaporated to dryness. After suspension in DCM, the filtrate was concentrated to give the title compound (426 mg, 102%) as an off-white solid. ([M+H] + 153.0)

[0551] Step 2: 2-((2-chloro-3-cyanophenyl)amino)-6-cyclopropylnicotinonitrile Title compound ([M+H] + 295.1) was prepared from 2-amino-6-cyclopropylnicotinonitrile (CAS [1249836-67-6]) by reaction with 3-amino-2-chlorobenzonitrile using Pd2(dba)3 as catalyst and Xantphos as ligand (General Procedure B1).

[0552] Step 3: 3-(4-amino-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)-2-chlorobenzonitrile Title compound ([M+H] + 338.2) was prepared from 2-((2-((2-chloro-3-cyanophenyl)amino)-6-cyclopropylnicotinonitrile using general procedure C.

[0553] Example 144: 4-amino-7-(difluoromethoxy)-1-(o-tolyl)quinazolin-2(1H)-one TIFF0007749602000185.tif32170

[0554] Step 1: 4-(Difluoromethoxy)-2-(o-tolylamino)benzonitrile Title compound ([M+H] + 275.2) was prepared from 2-bromo-4-(difluoromethoxy)benzonitrile (CAS [1261818-72-7]) by reaction with o-toluidine using Pd2(dba)3 as catalyst and xantphos as ligand (General Procedure B1).

[0555] Step 2: 4-amino-1-(2-chloropyridin-3-yl)-7-(difluoromethoxy)quinazolin-2(1H)-one Title compound ([M+H] + 318.2) was prepared from 4-(difluoromethoxy)-2-(o-tolylamino)benzonitrile using general procedure C.

[0556] Examples 145 and 146: (+)-3-(4-amino-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)-2-methylbenzonitrile and (-)-3-(4-amino-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)-2-methylbenzonitrile TIFF0007749602000186.tif33170

[0557] Step 1: 2-((3-cyano-2-methylphenyl)amino)-6-cyclopropylnicotinonitrile Title compound ([M+H] + 275.3) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS[1198475-35-2]) by reaction with 3-amino-2-methylbenzonitrile (CAS[69022-35-1]) using Pd(OAc)2 as catalyst and Xphos as ligand (General Procedure B1).

[0558] Step 2: (+)-3-(4-amino-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)-2-methylbenzonitrile and (-)-3-(4-amino-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)-2-methylbenzonitrile Title compound ([M+H] + 318.2 & 318.2) were prepared from 2-((3-cyano-2-methylphenyl)amino)-6-cyclopropylnicotinonitrile using general procedure C and subsequently separated using chiral HPLC.

[0559] Example 147: 4-amino-7-cyclopropyl-1-(3,4-difluorophenyl)pyrido[2,3-d]pyrimidin-2(1H)-one TIFF0007749602000187.tif37170

[0560] Step 1: 6-cyclopropyl-2-((3,4-difluorophenyl)amino)nicotinonitrile Title compound ([M+H] + 272.1) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) by reaction with 3,4-difluoroaniline using Pd2(dba)3 as catalyst and Xantphos as ligand (General Procedure B1).

[0561] Step 2: 4-amino-7-cyclopropyl-1-(3,4-difluorophenyl)pyrido[2,3-d]pyrimidin-2(1H)-one Title compound ([M+H] + 315.1) was prepared from 6-cyclopropyl-2-((3,4-difluorophenyl)amino)nicotinonitrile using general procedure C.

[0562] Example 148: 4-amino-1-(benzo[d]oxazol-4-yl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2(1H)-one TIFF0007749602000188.tif33170

[0563] Step 1: 2-(benzo[d]oxazol-4-ylamino)-6-cyclopropylnicotinonitrile Title compound ([M+H] + 277.2) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) by reaction with benzo[d]oxazol-4-amine using Pd2(dba)3 as catalyst and tBuXphos as ligand (General Procedure B1).

[0564] Step 2: 4-amino-7-cyclopropyl-1-(3,4-difluorophenyl)pyrido[2,3-d]pyrimidin-2(1H)-one Title compound ([M+H] + 320.1) was prepared from 2-((benzo[d]oxazol-4-ylamino)-6-cyclopropylnicotinonitrile using general procedure C.

[0565] Example 149: 1-amino-4-(2-chlorophenyl)-6-(trifluoromethyl)pyrido[1,2-c]pyrimidin-3-one TIFF0007749602000189.tif32170

[0566] Step 1: 2-(2-chlorophenyl)-2-[4-(trifluoromethyl)-2-pyridyl]acetonitrile To a solution of 2-chloro-4-(trifluoromethyl)pyridine (3.35 g, 18.4 mmol) and 2-chlorobenzyl cyanide (2.00 g, 13.1 mmol) in DMF (50 mL) was added NaH (1.47 g, 36.9 mmol), and the reaction mixture was stirred for 20 minutes. The reaction mixture was poured into water and extracted with ethyl acetate, and the combined extracts were washed with brine and concentrated. Purification by preparative TLC afforded the title compound (3.00 g, 69% yield) as a yellow oil. ([M+H] + 297.1)

[0567] Step 2: 2-(2-chlorophenyl)-2-[4-(trifluoromethyl)-2-pyridyl]acetamide To a solution of 2-(2-chlorophenyl)-2-[4-(trifluoromethyl)-2-pyridyl]acetonitrile (2.0 g, 6.74 mmol) in AcOH (15 mL) was added 95% H2SO4 (5 mL), and the mixture was stirred at 40 °C for 2 days. The reaction mixture was cooled to room temperature and poured onto ice, followed by extraction with EtOAc. The organic layer was washed with saturated NaHCO3 solution and brine, dried over Na2SO4, and concentrated. Trituration from hexane afforded the title compound (1500 mg, 69%) as a yellow solid. ([M+H] + 315.1)

[0568] Step 3: 4-(2-chlorophenyl)-1-thioxo-6-(trifluoromethyl)pyrido[1,2-c]pyrimidin-3-one To a mixture of 2-(2-chlorophenyl)-2-[4-(trifluoromethyl)-2-pyridyl]acetamide (500 mg, 1.59 mmol) in EtOH (2.5 mL) was added sodium ethoxide (4.6 mL, 21% in EtOH, 12.7 mmol), followed by the dropwise addition of thiophosgene (245 μL, 3.18 mmol) while maintaining the temperature below 40° C. The mixture was stirred in a sealed tube at 85° C. for 2 h, after which it was cooled to room temperature and quenched with approximately 3 mL of water. The mixture was extracted with ethyl acetate, and the combined washings were washed with brine and concentrated. Purification by flash column chromatography afforded the title compound (400 mg, 64%) as a yellow solid. ([M+H] + 357.0)

[0569] Step 4: 4-(2-chlorophenyl)-1-methylsulfanyl-6-(trifluoromethyl)pyrido[1,2-c]pyrimidin-3-one To a solution of 4-(2-chlorophenyl)-1-thioxo-6-(trifluoromethyl)pyrido[1,2-c]pyrimidin-3-one (250 mg, 0.70 mmol) in DMF (5 mL) was added potassium carbonate (193 mg, 1.40 mmol) and iodomethane (51 μL, 0.84 mmol). The reaction was stirred at room temperature for 7 h. The reaction mixture was evaporated and the residue was diluted with EtOAc / water. The organic layer was washed with brine, dried over NaSO, and concentrated. Purification by flash column chromatography afforded the title compound (150 mg, 55%) as a yellow solid. ([M+H] + 371.0)

[0570] Step 5: 1-amino-4-(2-chlorophenyl)-6-(trifluoromethyl)pyrido[1,2-c]pyrimidin-3-one To a mixture of 4-(2-chlorophenyl)-1-methylsulfanyl-6-(trifluoromethyl)pyrido[1,2-c]pyrimidin-3-one (100 mg, 0.270 mmol) and ammonium hydroxide solution (1.5 mL, 0.270 mmol) was added THF (1 mL). The reaction was stirred at room temperature for 48 hours, after which it was concentrated. Purification by reverse-phase preparative HPLC afforded the title product (65 mg, 68%) as a yellow solid.

[0571] Example 150: 4-amino-7-(difluoromethoxy)-1-(4-oxaspiro[2.5]octan-8-yl)quinazolin-2(1H)-one TIFF0007749602000190.tif32170

[0572] Step 1: 2-((4-oxaspiro[2.5]octan-8-yl)amino)-4-(difluoromethoxy)benzonitrile Title compound ([M+H] + 295.1) was prepared from 2-bromo-4-(difluoromethoxy)benzonitrile (CAS [1261818-72-7]) by reaction with 4-oxaspiro[2.5]octan-8-amine hydrochloride using Pd2(dba)3 as catalyst and Xantphos as ligand (General Procedure B1).

[0573] Step 2: 4-amino-7-(difluoromethoxy)-1-(4-oxaspiro[2.5]octan-8-yl)quinazolin-2(1H)-one Title compound ([M+H] + 338.2) was prepared from 2-((4-oxaspiro[2.5]octan-8-yl)amino)-4-(difluoromethoxy)benzonitrile using general procedure C.

[0574] Example 151: 3-(4-amino-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)benzonitrile TIFF0007749602000191.tif33170

[0575] Step 1: 2-((3-cyanophenyl)amino)-6-cyclopropylnicotinonitrile Title compound ([M+H] + 261.1) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) by reaction with 3-aminobenzonitrile using Pd2(dba)3 as catalyst and Xantphos as ligand (General Procedure B1).

[0576] Step 2: 3-(4-amino-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)benzonitrile Title compound ([M+H] + 304.1) was prepared from 2-((3-cyanophenyl)amino)-6-cyclopropylnicotinonitrile using general procedure C.

[0577] Example 152: 4-amino-1-(3-chlorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2(1H)-one TIFF0007749602000192.tif33170

[0578] Step 1: 2-((3-chlorophenyl)amino)-6-cyclopropylnicotinonitrile Title compound ([M+H] + 270.1) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) by reaction with 3-chloroaniline using Pd(OAc)2 as catalyst and Xantphos as ligand (General Procedure B1).

[0579] Step 2: 4-amino-1-(3-chlorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2(1H)-one Title compound ([M+H] + 313.1) was prepared from 2-((3-chlorophenyl)amino)-6-cyclopropylnicotinonitrile using general procedure C.

[0580] Example 153: 4-amino-7-(ethylamino)-1-(o-tolyl)quinazolin-2-one TIFF0007749602000193.tif37170

[0581] Step 1: 2-Bromo-4-(ethylamino)benzonitrile To a solution of 2-bromo-4-fluorobenzonitrile (700 mg, 3.5 mmol) in DMF (7 mL) was added ethylamine hydrochloride (571 mg, 7 mmol) and K2CO3 (967 mg, 7 mmol), and the reaction mixture was heated to 90 °C for 6 h. The reaction was diluted with ethyl acetate, washed with water and brine, and concentrated. Purification by flash column chromatography afforded the title compound (850 mg, 75%) as a yellow solid. ([M+H] + 225.1)

[0582] Step 2: tert-butyl N-(3-bromo-4-cyano-phenyl)-N-ethyl-carbamate To a solution of 2-bromo-4-(ethylamino)benzonitrile (750 mg, 2.70 mmol) and di-t-butyl dicarbonate (1163 mg, 5.33 mmol) in DCM (15 mL) was added triethylamine (1.11 mL, 8 mmol) and DMAP (65.13 mg, 0.530 mmol). After the reaction mixture was stirred at room temperature for 12 h, it was concentrated and the residue was purified by flash column chromatography to give the title compound (700 mg, 81%) as a yellow oil. ([M+H-tBu] + 269.1)

[0583] Step 3: tert-butyl N-[4-cyano-3-(2-methylanilino)phenyl]-N-ethyl-carbamate Title compound ([M+H] +296.1) was prepared from tert-butyl N-(3-bromo-4-cyano-phenyl)-N-ethyl-carbamate by reaction with o-toluidine using Pd(OAc)2 as catalyst and Xantphos as ligand (General Procedure B1).

[0584] Step 4: tert-butyl N-(4-amino-1-(o-tolyl)-2-oxo-quinazolin-7-yl]-N-ethyl-carbamate Title compound ([M+H] + 395.3) was prepared from tert-butyl N-[4-cyano-3-(2-methylanilino)phenyl]-N-ethyl-carbamate using general procedure C.

[0585] Step 5: 4-amino-7-(ethylamino)-1-(o-tolyl)quinazolin-2-one To a solution of tert-butyl N-[4-amino-1-(o-tolyl)-2-oxo-quinazolin-7-yl]-N-ethyl-carbamate (350 mg, 0.89 mmol) in DCM (5 mL) was added TFA (3.0 mL, 0.89 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction was quenched by adding saturated sodium bicarbonate solution, extracted with DCM, and the combined organic extracts were concentrated. Purification by reverse-phase preparative HPLC afforded the title compound (51 mg, 19%) as a white solid. ([M+H] + 295.2)

[0586] Example 154: 4-amino-7-cyclopropyl-1-(2,5-difluorophenyl)pyrido[2,3-d]pyrimidin-2(1H)-one TIFF0007749602000194.tif33170

[0587] Step 1: 6-cyclopropyl-2-((2,5-difluorophenyl)amino)nicotinonitrile Title compound ([M+H] +272.2) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) by reaction with 2,5-difluoroaniline using Pd(OAc)2 as catalyst and Xantphos as ligand (General Procedure B1).

[0588] Step 2: 4-amino-7-cyclopropyl-1-(2,5-difluorophenyl)pyrido[2,3-d]pyrimidin-2(1H)-one Title compound ([M+H] + 315.2) was prepared from 6-cyclopropyl-2-((2,5-difluorophenyl)amino)nicotinonitrile using general procedure C.

[0589] Example 155: 4-amino-1-(2-chloro-4-fluorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2(1H)-one TIFF0007749602000195.tif37170

[0590] Step 1: 2-((2-chloro-4-fluorophenyl)amino)-6-cyclopropylnicotinonitrile Title compound ([M+H] + 288.1) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) by reaction with 2-chloro-4-fluoroaniline using Pd(OAc)2 as catalyst and Xantphos as ligand (General Procedure B1).

[0591] Step 2: 4-amino-1-(2-chloro-4-fluorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2(1H)-one Title compound ([M+H] + 331.0) was prepared from 6-cyclopropyl-2-((2,5-difluorophenyl)amino)nicotinonitrile using general procedure C.

[0592] Example 156: 4-amino-1-(2-chloro-5-fluorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2-one TIFF0007749602000196.tif33170

[0593] Step 1: 2-((2-chloro-5-fluorophenyl)amino)-6-cyclopropylnicotinonitrile Title compound ([M+H] + 288.0) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) by reaction with 2-chloro-5-fluoroaniline using Pd(OAc)2 as catalyst and Xantphos as ligand (General Procedure B1).

[0594] Step 2: 4-amino-1-(2-chloro-5-fluorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2-one Title compound ([M+H] + 331.0) was prepared from 2-((2-chloro-5-fluorophenyl)amino)-6-cyclopropylnicotinonitrile using general procedure C.

[0595] Example 157: 4-amino-7-cyclopropyl-1-(2,3-dihydro-1H-indol-4-yl)pyrido[2,3-d]pyrimidin-2-one TIFF0007749602000197.tif33170

[0596] Step 1: tert-butyl-4-((3-cyano-6-cyclopropylpyridin-2-yl)amino)indoline-1-carboxylate Title compound ([M+H] +377.2) was prepared from tert-butyl-4-aminoindoline-1-carboxylate (US2010 / 36123 A1) by reaction with 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) using Pd(OAc) as catalyst and Xantphos as ligand (General Procedure B1).

[0597] Step 2: 4-amino-7-cyclopropyl-1-(2,3-dihydro-1H-indol-4-yl)pyrido[2,3-d]pyrimidin-2-one Similar to Example 153, tert-butyl-4-((3-cyano-6-cyclopropylpyridin-2-yl)amino)indoline-1-carboxylate was first converted to tert-butyl-4-(4-amino-7-cyclopropyl-2-oxo-pyrido[2,3-d]pyrimidin-1-yl)indoline-1-carboxylate using general procedure C, and the crude material was deprotected using TFA in DCM to give the title compound. ([M+H] + 320.1)

[0598] Example 158: 3-[4-amino-2-oxo-7-(trifluoromethoxy)quinazolin-1-yl]-2-methylbenzonitrile TIFF0007749602000198.tif34170

[0599] Step 1: 3-((2-cyano-5-(trifluoromethoxy)phenyl)amino)-2-methylbenzonitrile Title compound ([M+H] + 316.1) was prepared from 2-amino-4-(trifluoromethoxy)benzonitrile (CAS[1260847-67-3]) by reaction with 3-chloro-2-methylbenzonitrile (CAS[54454-12-5]) using Pd(OAc)2 as catalyst and Xantphos as ligand (General Procedure B1).

[0600] Step 2: 3-[4-amino-2-oxo-7-(trifluoromethoxy)quinazolin-1-yl]-2-methylbenzonitrile Title compound ([M+H] + 361.1) was prepared from 6-cyclopropyl-2-((2,5-difluorophenyl)amino)nicotinonitrile using general procedure C.

[0601] Example 159: 4-amino-1-(3-fluoro-2-methylphenyl)-7-(trifluoromethoxy)quinazolin-2-one TIFF0007749602000199.tif33170

[0602] Step 1: 2-((3-fluoro-2-methylphenyl)amino)-4-(trifluoromethoxy)benzonitrile Title compound ([M+H] + 311.1) was prepared from 2-bromo-4-(trifluoromethoxy)benzonitrile (CAS[1214334-83-4]) by reaction with 3-fluoro-2-methylaniline (CAS[54454-12-5]) using Pd(OAc)2 as catalyst and Xantphos as ligand (General Procedure B1).

[0603] Step 2: 4-amino-1-(3-fluoro-2-methylphenyl)-7-(trifluoromethoxy)quinazolin-2-one Title compound ([M+H] + 354.1) was prepared from 6-cyclopropyl-2-((2,5-difluorophenyl)amino)nicotinonitrile using general procedure C.

[0604] Example 160: 4-amino-1-(2,3-dihydro-1-benzofuran-4-yl)-7-(trifluoromethoxy)quinazolin-2-one TIFF0007749602000200.tif32170

[0605] Step 1: 2-((2,3-dihydrobenzofuran-4-yl)amino)-4-(trifluoromethoxy)benzonitrile Title compound ([M+H] + 321.0) was prepared from 2-bromo-4-(trifluoromethoxy)benzonitrile (CAS[1214334-83-4]) by reaction with 2,3-dihydrobenzofuran-4-amine (CAS[61090-37-7]) using Pd(OAc)2 as catalyst and Xantphos as ligand (General Procedure B1).

[0606] Step 2: 4-amino-1-(3-fluoro-2-methylphenyl)-7-(trifluoromethoxy)quinazolin-2-one Title compound ([M+H] + 364.2) was prepared from 2-((2,3-dihydrobenzofuran-4-yl)amino)-4-(trifluoromethoxy)benzonitrile using general procedure C.

[0607] Example 161: 4-amino-1-(3-chloro-2-fluorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2-one TIFF0007749602000201.tif33170

[0608] Step 1: 2-((3-chloro-2-fluorophenyl)amino)-6-cyclopropylnicotinonitrile Title compound ([M+H] + 288.1) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS[1198475-35-2]) by reaction with 2-chloro-5-fluoroaniline (CAS[2106-04-9]) using Pd(OAc)2 as catalyst and Xantphos as ligand (General Procedure B1).

[0609] Step 2: 4-amino-1-(3-chloro-2-fluorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2-one Title compound ([M+H] +331.0) was prepared from 4-amino-1-(3-chloro-2-fluorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2-one using general procedure C.

[0610] Example 162: 4-amino-1-(2,3-dihydrobenzofuran-4-yl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one TIFF0007749602000202.tif32170

[0611] Step 1: 2-((2,3-dihydrobenzofuran-4-yl)amino)-6-(trifluoromethyl)nicotinonitrile Title compound ([M+H] + 306.1) was prepared from 2-chloro-6-(trifluoromethyl)nicotinonitrile (CAS [1249836-67-6]) by reaction with 2,3-dihydrobenzofuran-4-amine using Pd(OAc) as catalyst and Xantphos as ligand (General Procedure B1).

[0612] Step 2: 4-amino-1-(2,3-dihydrobenzofuran-4-yl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one Title compound ([M+H] + 349.1) was prepared from 2-((2,3-dihydrobenzofuran-4-yl)amino)-6-(trifluoromethyl)nicotinonitrile using general procedure C.

[0613] Example 163: 4-amino-7-cyclopropyl-1-[6-(trifluoromethoxy)pyridin-2-yl]pyrido[2,3-d]pyrimidin-2-one TIFF0007749602000203.tif39170

[0614] Step 1: 6-Cyclopropyl-2-((6-(trifluoromethoxy)pyridin-2-yl)amino)nicotinonitrile Title compound ([M+H]+ 321.1) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (CAS[1198475-35-2]) by reaction with 6-(trifluoromethoxy)pyridin-2-amine (CAS[1131007-45-8]) using Pd(OAc)2 as catalyst and Xantphos as ligand (General Procedure B1).

[0615] Step 2: 4-amino-7-cyclopropyl-1-[6-(trifluoromethoxy)pyridin-2-yl]pyrido[2,3-d]pyrimidin-2-one Title compound ([M+H] + 364.1) was prepared from 6-cyclopropyl-2-((6-(trifluoromethoxy)pyridin-2-yl)amino)nicotinonitrile using general procedure C.

[0616] Example 164: 4-amino-7-cyclopropyl-1-(1H-indol-4-yl)pyrido[2,3-d]pyrimidin-2-one TIFF0007749602000204.tif33170

[0617] Step 1: tert-butyl-4-((3-cyano-6-cyclopropylpyridin-2-yl)amino)-1H-indole-1-carboxylate Title compound ([M+H] + 375.2) was prepared from tert-butyl-4-amino-1H-indole-1-carboxylate (US2009 / 227575A1) by reaction with 2-chloro-6-cyclopropylnicotinonitrile (CAS [1198475-35-2]) using Pd(OAc) as catalyst and Xantphos as ligand (General Procedure B1).

[0618] Step 2: 4-amino-7-cyclopropyl-1-(2,3-dihydro-1H-indol-4-yl)pyrido[2,3-d]pyrimidin-2-one Similar to Example 153, tert-butyl-4-((3-cyano-6-cyclopropylpyridin-2-yl)amino)-1H-indole-1-carboxylate was first converted to tert-butyl-4-(4-amino-7-cyclopropyl-2-oxo-pyrido[2,3-d]pyrimidin-1-yl)indole-1-carboxylate using general procedure C, and the crude material was deprotected using TFA in DCM to give the title compound. ([M+H] + 318.1)

[0619] Example 165: 4-amino-1-(3-fluoro-2-methylphenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one TIFF0007749602000205.tif31170

[0620] Step 1: 2-((3-fluoro-2-methylphenyl)amino)-6-(trifluoromethyl)nicotinonitrile Title compound ([M+H] + 296.1) was prepared from 2-chloro-6-(trifluoromethyl)nicotinonitrile (CAS [1249836-67-6]) by reaction with 3-fluoro-2-methylaniline using Pd(OAc) as catalyst and Xantphos as ligand (General Procedure B1).

[0621] Step 2: 4-amino-1-(3-fluoro-2-methylphenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one Title compound ([M+H] + 339.1) was prepared from 2-((3-fluoro-2-methylphenyl)amino)-6-(trifluoromethyl)nicotinonitrile using general procedure C.

Claims

1. Formula I': [In the formula, X １ is either N or CH, X ３ is N or CR ３ Either R １ are 2,3-dihydrobenzofuranyl, 2-hydroxycyclopentyl, 3-hydroxycyclopentyl, 1-(tetrahydrofuran-2-yl)ethyl, 1-tetrahydrofuran-3-yl-ethyl, 1-pyridin-2-yl-ethyl, oxepan-3-yl, 1,4-dioxepan-6-yl, dihydro-1H-indol-4-yl, 1-(oxetan-3-yl)ethyl, 1-(oxazol-5-yl)ethyl, indazol-4-yl, oxaspiro[2.5]octanyl, 4-methyloxazol-5-yl, phenyl, 2-methoxyphenyl, 3-methylphenyl, 3-fluoro-2-methoxyphenyl, 2-methylbenzonitrile, 2-methoxybenzonitrile, 2-ethoxybenzonitrile, 3-chlorophenyl, 4-fluoro-2-methylphenyl, 3-fluoro-2-methylphenyl, 3-fluorophenyl, 2-fluorophenyl, 2,6-difluorophenyl, 2,3-dimethylphenyl, 2,3-difluorophenyl, 2-fluoro-3-methylphenyl, 3-methoxyphenyl, 3,5-difluorophenyl, 3 , 4-difluorophenyl, 2-trifluoromethyl-phenyl, 3-(fluoromethyl)-2-methylphenyl, 3-ethylphenyl, 3-chloro-2-fluorophenyl, 2-chloro-5-fluorophenyl, 2-chloro-4-fluorophenyl, 2,3-dichlorophenyl, benzo[d]oxazol-4-yl, benzo[d]imidazolyl, benzo[d]thiazol-7-yl, 2-oxopiperidin-4-yl, 2-methylpyrazol-3-yl, 1-ethyl-1H-pyrazol-5-yl, picolinonitrile , 2-methoxypyridin-3-yl, 2-(trifluoromethyl)pyridin-3-yl, 4-methylpyridin-3-yl, 4-fluoro-2-methoxypyridin-3-yl, indolyl, 2-chloropyridin-3-yl, 6-methoxypyridin-2-yl, 4-methylpyrimidin-5-yl, trifluoromethoxypyridin-2-yl, dihydrobenzofuranyl, tetrahydrofuranyl, 4-methyltetrahydrofuran-3-yl, methyl-tetrahydro-2H-pyran-3-yl, 6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4-yl or 4-methylthiazol-5-yl, R ２ is hydrogen, amino, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, halo (C １ ~C ６ ) alkyl, halo (C １ ~C ６ ) alkoxy, one or more substituents R ２ａ (C ３ ~C ６ ) cycloalkyl, one or more substituents R ２ｂ (C ３ ~C ６ ) cycloalkyl-(C １ ~C ６ ) alkyl, one or more substituents R ２ｃ (C ３ ~C ６ ) cycloalkyl-(C １ ~C ６ ) alkoxy, one or more substituents R ２ｄ heterocycloalkyl optionally substituted with NR ２ｆ R ２ｇ or one or more substituents R ２ｅ phenyl optionally substituted with R ２ａ , R ２ｂ , R ２ｃ , R ２ｄ and R ２ｅ are each independently a halogen, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, halo (C １ ~C ６ ) alkyl and halo(C １ ~C ６ ) alkoxy; R ２ｆ and R ２ｇ are each independently hydrogen or (C １ ~C ６ ) alkyl; R ３ is hydrogen, halogen, cyano, amino, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, halo (C １ ~C ６ ) alkyl, halo (C １ ~C ６ ) alkoxy, one or more substituents R ３ａ (C ３ ~C ６ ) cycloalkyl, one or more substituents R ３ｂ (C ３ ~C ６ ) cycloalkyl-(C １ ~C ６ ) alkyl, one or more substituents R ３ｃ (C ３ ~C ６ ) cycloalkyl-(C １ ~C ６ ) alkoxy, one or more substituents R ３ｄ heterocycloalkyl optionally substituted with one or more substituents R ３ｅ phenyl optionally substituted with R ３ａ , R ３ｂ , R ３ｃ , R ３ｄ and R ３ｅ are each independently a halogen, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, halo (C １ ~C ６ ) alkyl and halo(C １ ~C ６ ) alkoxy; R ４ is hydrogen, cyano, halogen, amino, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, halo (C １ ~C ６ ) alkyl, halo (C １ ~C ６ ) alkoxy, (C １ ~C ６ ) alkoxy-(C １ ~C ６ ) alkyl, (C ３ ~C ６ ) cycloalkyl, (C ３ ~C ６ ) cycloalkyl-(C １ ~C ６ ) alkyl, one or more substituents R ４ａ (C ３ ~C ６ ) cycloalkyl, one or more substituents R ４ｂ (C ３ ~C ６ ) cycloalkyl-(C １ ~C ６ ) alkyl, one or more substituents R ４ｃ (C ３ ~C ６ ) cycloalkyl-(C １ ~C ６ ) alkoxy, one or more substituents R ４ｄ heterocycloalkyl optionally substituted with -CO ２ R ４ａ or -CONR ４ｂ R ４ｃ and R ４ａ , R ４ｂ , R ４ｃ and R ４ｄ are each independently hydrogen and (C １ ~C ６ ) alkyl] or a pharmaceutically acceptable salt thereof.

2. X ３ is CR ３ 2. The compound of claim 1, wherein:

3. X １ 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein:

4. R １ are 2,3-dihydrobenzofuranyl, 2-hydroxycyclopentyl, 3-hydroxycyclopentyl, 1-(tetrahydrofuran-2-yl)ethyl, 1-tetrahydrofuran-3-yl-ethyl, 1-pyridin-2-yl-ethyl, 1-(oxetan-3-yl)ethyl, 1-(oxazol-5-yl)ethyl, oxaspiro[2.5]octanyl, 4-methyloxazol-5-yl, 2-methoxy-phenyl, 3-methyl-phenyl, 3-fluoro-2-methoxyphenyl, 2-methylbenzonitrile, 2-methoxybenzonitrile, 2-ethoxybenzonitrile, 4-fluoro-2-methylphenyl, 3-fluorophenyl, 2-fluorophenyl, 2,6-difluorophenyl, 2,3-difluorophenyl, 3-methoxyphenyl 4. The compound of claim 1, wherein the aryl group is 2-(2-methyl-2-pyridin-3-yl), ...

5. R １ is 2,3-dihydrobenzofuranyl, oxaspiro[2.5]octanyl, oxepan-3-yl, 3-methyl-phenyl, 2-methyl-phenyl, 2-methylbenzonitrile, 2-chlorophenyl, phenyl, 2-methylpyridin-3-yl, 4-methylpyridin-3-yl, 2-chloropyridin-3-yl, methyl-tetrahydro-2H-pyran-3-yl, or 4-methylpyrimidin-5-yl, or a pharmaceutically acceptable salt thereof.

6. R １ is 2,3-dihydrobenzofuranyl, oxaspiro[2.5]octanyl, 3-methyl-phenyl, 2-methyl-phenyl, 2-methylbenzonitrile, 2-chlorophenyl, phenyl, 2-methylpyridin-3-yl, 4-methylpyridin-3-yl, 2-chloropyridin-3-yl, or 4-methylpyrimidin-5-yl, or a pharmaceutically acceptable salt thereof.

7. R ２ is hydrogen, amino, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, halo (C １ ~C ６ ) alkyl, halo (C １ ~C ６ ) alkoxy, one or more substituents R ２ａ (C ３ ~C ６ ) cycloalkyl, one or more substituents R ２ｂ (C ３ ~C ６ ) cycloalkyl-(C １ ~C ６ ) alkyl, one or more substituents R ２ｃ (C ３ ~C ６ ) cycloalkyl-(C １ ~C ６ ) alkoxy, one or more substituents R ２ｄ heterocycloalkyl optionally substituted with one or more substituents R ２ｅ phenyl optionally substituted with R ２ａ , R ２ｂ , R ２ｃ , R ２ｄ and R ２ｅ are each independently a halogen, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, halo (C １ ~C ６ ) alkyl and halo(C １ ~C ６ 7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

8. R ２ However, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, halo (C １ ~C ６ ) alkyl, halo (C １ ~C ６ ) alkoxy, one R ２ａ (C ３ ~C ６ ) cycloalkyl, (C ３ ~C ６ ) cycloalkyl-(C １ ~C ６ ) alkoxy or one or two R ２ｄ 8. The compound of claim 1, wherein R is a heterocycloalkyl optionally substituted with R, or phenyl, or a pharmaceutically acceptable salt thereof.

9. R ２ However, (C １ ~C ３ ) alkyl, (C １ ~C ３ ) alkoxy, halo (C １ ~C ３ ) alkyl, halo (C １ ~C ３ ) alkoxy, one R ２ａ cyclopropyl optionally substituted with one R ２ａ cyclobutyl optionally substituted with one R ２ａ cyclopentyl optionally substituted with (C ３ ~C ６ ) cycloalkyl-(C １ ~C ３ ) alkoxy, 4,5-dihydrofuran-3-yl, 7-azabicyclo[2.2.1]heptan-7-yl, 3-azabicyclo[2.2.1]heptan-3-yl, tetrahydrofuranyl, tetrahydropyranyl, or one or two R ２ｄ 9. The compound of claim 1, wherein R is azetidinyl optionally substituted with R, or phenyl, or a pharmaceutically acceptable salt thereof.

10. R ２ However, (C １ ~C ３ ) alkyl, (C １ ~C ３ ) alkoxy, halo (C １ ~C ３ ) alkyl, halo (C １ ~C ３ ) alkoxy; halogen or (C １ ~C ３ cyclopropyl, cyclobutyl, or cyclopentyl optionally substituted by one or two (C ) alkyl; cyclopropyloxy, 4,5-dihydrofuran-3-yl, 7-azabicyclo[2.2.1]heptan-7-yl, 3-azabicyclo[2.2.1]heptan-3-yl, tetrahydrofuranyl, tetrahydropyranyl, or one or two (C １ ~C ３ 10. The compound of claim 1, wherein R is 1 or 2; R is 2 or 3; R is 3 or 4; R is 4 or 5; R is 5 or 6; R is 6 or 7; R is 7 or 8; R is 8 or 9; R is 9 or 10; R is 10 or 11; R is 11 or 12; R is 13 or 14; R is 15 or 16; R is 16 or 17; R is 18 or 19; R is 20 or 21; R is 22 or 23; R is 24 or 25; R is 26 or 27; R is 28 or 29; R is 29 or 30; R is 29 or 30; R is 29 or 31; R is 29 or 32; R is 29 or 33; R is 29 or 34;

11. R ２ But, Halo (C １ ~C ３ ) alkyl, halo (C １ ~C ３ ) alkoxy, or halogen or (C １ ~C ３ 11. The compound of claim 1, wherein R is 1 or 2; and R is 2 or 3.

12. The compound of claim 1, wherein R is 1 or 2; and R is 2 or 3; and R is 3 or 4; and R is 4 or 5; and R is 5 or 6; and R is 6 or 7; and R is 7 or 8; and R is 8 or 9; and

12. R ２ 12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein is trifluoromethyl, difluoromethoxy, trifluoromethoxy, or cyclopropyl.

13. R ２ａ , R ２ｂ , R ２ｃ , R ２ｄ and R ２ｅ are each independently a halogen and (C １ ~C ６ 12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein:

14. R ２ａ , R ２ｂ , R ２ｃ , R ２ｄ and R ２ｅ are each independently a halogen and (C １ ~C ３ 14. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein:

15. R ２ａ , R ２ｂ , R ２ｃ , R ２ｄ and R ２ｅ 15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein each is independently selected from chloro, fluoro, and methyl.

16. R ２ｆ and R ２ｇ are each independently hydrogen or (C １ ~C ３ 12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein:

17. R ３ 16. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein is hydrogen, halogen, or cyano.

18. R ３ 18. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein is hydrogen, chloro, fluoro, or cyano.

19. R ３ 19. The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

20. R ３ａ , R ３ｂ , R ３ｃ , R ３ｄ and R ３ｅ are each independently a halogen and (C １ ~C 3 16. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein:

21. R ４ is hydrogen, cyano, halogen, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy or —CONR ４ｂ R ４ｃ 20. The compound of any one of claims 1 to 19, wherein:

22. R ４ is hydrogen, cyano, chloro, fluoro or (C １ ~C ３ 22. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein:

23. R ４ 23. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

24. R ４ｂ or R ４ｃ 22. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

25. 4-amino-7-cyclopropyl-1-(o-tolyl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-7-cyclopropyl-1-(2-methoxyphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-7-(tert-butyl)-1-(o-tolyl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-1-(2-methoxyphenyl)-7-phenylpyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-7-(3,3-difluoroazetidin-1-yl)-1-(o-tolyl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-7-cyclopropyl-1-(tetrahydrofuran-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-7-cyclopropyl-1-(2-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-7-cyclopropyl-1-(2-oxopiperidin-4-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-7-cyclopropyl-1-((cis)-2-methyltetrahydrofuran-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-7-cyclopropyl-1-(o-tolyl)pyrido[4,3-d]pyrimidin-2(1H)-one 4-amino-7-cyclopropyl-1-(2-methylpyridin-3-yl)quinazolin-2-one 4-amino-7-cyclopropyl-1-(2-methylphenyl)quinazolin-2-one 7-cyclopropyl-1-(2-methylphenyl)quinazoline-2,4-dione 4-amino-7-cyclopropyl-1-(o-tolyl)pyrimido[4,5-d]pyrimidin-2(1H)-one 7-cyclopropyl-1-(2-methylpyridin-3-yl)quinazoline-2,4-dione 4-amino-7-cyclopropyl-1-(2-methoxypyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-7-cyclopropyl-6-fluoro-1-(2-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 7-cyclopropyl-1-(2-methylphenyl)pyrido[2,3-d]pyrimidine-2,4-dione 3-(4-amino-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)picolinonitrile 4-amino-7-cyclopropyl-1-(oxan-3-yl)pyrido[2,3-d]pyrimidin-2-one 4-amino-7-cyclopropyl-1-[1-(oxolan-3-yl)ethyl]pyrido[2,3-d]pyrimidin-2-one 4-amino-7-cyclopropyl-1-(3-fluoro-2-methoxyphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one 3-(4-amino-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)-2-methylbenzonitrile 4-amino-1-(2-methylpyridin-3-yl)-7-propan-2-ylpyrido[2,3-d]pyrimidin-2-one 4-amino-7-cyclopropyl-1-(2,3-dihydrobenzofuran-4-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-6-chloro-7-cyclopropyl-1-(2-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 3-(4-amino-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)-2-methoxybenzonitrile 3-(4-amino-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)-2-ethoxybenzonitrile 4-amino-7-cyclopropyl-1-(1-(tetrahydrofuran-2-yl)ethyl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-1-(2-methylpyridin-3-yl)-7-(oxetan-3-yl)quinazolin-2(1H)-one 7-cyclopropyl-1-(2-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4-dione 4-amino-7-((1RS,2RS)-2-methylcyclopropyl)-1-(2-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-7-cyclopentyl-1-(2-methyl-3-pyridyl)pyrido[2,3-d]pyrimidin-2-one 4-amino-7-cyclopropyl-1-((1SR,2RS)-2-hydroxycyclopentyl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-2-cyclopentyl-7-(o-tolyl)pyrazolo[3,4-d]pyrimidin-6-one; Formic acid 4-amino-7-cyclopentyl-1-(4-methylpyrimidin-5-yl)pyrido[2,3-d]pyrimidin-2-one 4-amino-7-cyclopropyl-1-(3-fluoro-2-methylphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-7-cyclopropyl-1-[(3R)-oxan-3-yl]pyrido[2,3-d]pyrimidin-2-one 4-amino-7-cyclopropyl-1-[(3S)-oxan-3-yl]pyrido[2,3-d]pyrimidin-2-one 4-amino-7-cyclopropyl-1-(4-methyltetrahydrofuran-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-7-cyclopropyl-2-oxo-1-(o-tolyl)-1,2-dihydropyrido[2,3-d]pyrimidine-5-carboxamide 4-amino-1-(2-methoxy-3-pyridyl)-7-tetrahydropyran-2-yl-pyrido[2,3-d]pyrimidin-2-one 4-amino-7-[(1S,4R)-3-azabicyclo[2.2.1]heptan-3-yl]-1-(2-methylpyrazol-3-yl)pyrido[2,3-d]pyrimidin-2-one; Formic acid 4-amino-7-cyclopropyl-1-[rac-(2R,3S)-2-methyloxolan-3-yl]pyrido[2,3-d]pyrimidin-2-one 4-amino-7-cyclobutyl-1-(2-methyl-3-pyridyl)pyrido[2,3-d]pyrimidin-2-one; Formic acid 4-amino-7-cyclopropyloxy-1-(2-methylpyridin-3-yl)quinazolin-2-one 4-amino-7-(7-azabicyclo[2.2.1]heptan-7-yl)-1-(4-methylthiazol-5-yl)pyrido[2,3-d]pyrimidin-2-one; Formic acid 4-amino-7-cyclopropyl-1-(3-hydroxycyclopentyl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-7-(difluoromethoxy)-1-(2-methylpyridin-3-yl)quinazolin-2(1H)-one 4-amino-7-(difluoromethyl)-1-(2-methylpyridin-3-yl)quinazolin-2(1H)-one 4-amino-7-[(1R,2S)-2-fluorocyclopropyl]-1-(2-methyl-3-pyridyl)pyrido[2,3-d]pyrimidin-2-one 4-amino-7-cyclopropyl-1-(2-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile 3-(4-amino-7-isopropyl-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)-2-methoxybenzonitrile 4-amino-7-cyclopropyl-2-oxo-1-(o-tolyl)-1,2-dihydropyrido[2,3-d]pyrimidine-5-carbonitrile 4-amino-7-methoxy-1-(2-methylpyridin-3-yl)quinazolin-2(1H)-one 4-amino-1-(2-methylpyridin-3-yl)-7-(trifluoromethoxy)quinazolin-2(1H)-one 4-amino-7-(4,5-dihydrofuran-3-yl)-1-(2-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-1-(2-methylpyridin-3-yl)-7-(tetrahydrofuran-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-7-cyclopropyl-1-(2-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2-one 4-amino-7-cyclopropyl-1-(2-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2-one 4-amino-7-cyclopropyl-1-(4-methylthiazol-5-yl)pyrido[2,3-d]pyrimidin-2-one 4-amino-7-cyclopropyl-1-(4-methylpyrimidin-5-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-7-cyclopropyl-1-(2-(trifluoromethyl)pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-7-cyclopropyl-1-(2-methylpyrazol-3-yl)pyrido[2,3-d]pyrimidin-2-one 4-amino-7-cyclopropyl-1-(2,3-dihydrobenzofuran-4-yl)quinazolin-2(1H)-one (R)-4-amino-1-(tetrahydro-2H-pyran-3-yl)-7-(trifluoromethyl)quinazolin-2(1H)-one 4-amino-7-cyclopropyl-1-(4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-7-ethyl-1-(2-methylpyridin-3-yl)quinazolin-2(1H)-one 4-amino-7-[(1S,2R)-2-fluorocyclopropyl]-1-[(3R)-tetrahydropyran-3-yl]pyrido[2,3-d]pyrimidin-2-one 4-amino-7-cyclopropyl-1-(4-methyloxazol-5-yl)pyrido[2,3-d]pyrimidin-2-one 3-(4-amino-6-chloro-7-isopropyl-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)-2-methoxybenzonitrile 4-amino-7-cyclopropyl-1-((R)-1-((S)-tetrahydrofuran-3-yl)ethyl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-7-cyclopropyl-1-((R)-1-((R)-tetrahydrofuran-3-yl)ethyl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-7-(2-fluoropropan-2-yl)-1-(2-methylpyridin-3-yl)quinazolin-2-one 4-amino-5-methoxy-1-(2-methylpyridin-3-yl)-7-(trifluoromethyl)quinazolin-2(1H)-one 4-amino-7-cyclopropyl-1-(4-fluoro-2-methoxypyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-5-fluoro-1-(2-methylpyridin-3-yl)-7-(trifluoromethyl)quinazolin-2(1H)-one 4-amino-7-cyclopropyl-1-(1-ethyl-1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-7-chloro-1-(o-tolyl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-7-cyclopropyl-1-(2,3-dihydrobenzofuran-7-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 1-amino-4-(2-methoxyphenyl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one 4-amino-1-(2-chlorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2-one 4-amino-7-cyclopropyl-1-[(1R)-1-[(3S)-oxolan-3-yl]ethyl]pyrido[2,3-d]pyrimidin-2-one 4-amino-7-cyclopropyl-1-[(1R)-1-[(3R)-oxolan-3-yl]ethyl]pyrido[2,3-d]pyrimidin-2-one 3-(4-amino-6-chloro-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)-2-methoxybenzonitrile 4-amino-7-cyclopropyl-1-(4-oxaspiro[2.5]octan-8-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-6-chloro-7-cyclopropyl-1-(2-methoxypyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-7-cyclopropyl-1-(4-fluoro-2-methylphenyl)pyrido[2,3-d]pyrimidin-2-one 4-amino-7-cyclopropyl-1-(3-ethylphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-7-cyclopropyl-1-(m-tolyl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-7-cyclopropyl-1-(3,5-difluorophenyl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-7-cyclopropyl-1-(6-methoxypyridin-2-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-7-cyclopropyl-1-(3-methoxyphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-7-cyclopropyl-1-(2,3-difluorophenyl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-7-cyclopropyl-1-phenylpyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-7-cyclopropyl-1-(1-(oxazol-5-yl)ethyl)pyrido[2,3-d]pyrimidin-2(1H)-one 3-(4-amino-2-oxo-7-(trifluoromethyl)quinazolin-1(2H)-yl)-2-methylbenzonitrile 3-(4-amino-2-oxo-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-1(2H)-yl)-2-methylbenzonitrile 4-amino-7-cyclopropyl-1-(2,6-difluorophenyl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-7-cyclopropyl-1-(2-fluorophenyl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-7-cyclopropyl-1-(3-fluorophenyl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-7-cyclopropyl-1-[1-(oxetan-3-yl)ethyl]pyrido[2,3-d]pyrimidin-2-one 4-amino-7-(difluoromethoxy)-1-(2-methylphenyl)pyrido[2,3-d]pyrimidin-2-one 4-amino-7-cyclopropyl-1-(1-pyridin-2-ylethyl)pyrido[2,3-d]pyrimidin-2-one 4-amino-1-(2-methyl-3-pyridyl)-7-(2,2,2-trifluoroethyl)quinazolin-2-one hydrochloride 4-amino-7-cyclopropyl-1-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-1-(2-chloropyridin-3-yl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-2-cyclopentyl-7-(2-methyl-3-pyridyl)pyrazolo[3,4-d]pyrimidin-6-one 4-amino-5-chloro-1-(2-methylpyridin-3-yl)-7-(trifluoromethyl)quinazolin-2(1H)-one 4-amino-1-(3-fluoro-2-methylphenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-7-cyclopropyl-1-(1H-indol-4-yl)pyrido[2,3-d]pyrimidin-2-one 4-amino-7-cyclopropyl-1-[6-(trifluoromethoxy)pyridin-2-yl]pyrido[2,3-d]pyrimidin-2-one 4-amino-1-(2,3-dihydrobenzofuran-4-yl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-1-(3-chloro-2-fluorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2-one 4-amino-1-(2,3-dihydro-1-benzofuran-4-yl)-7-(trifluoromethoxy)quinazolin-2-one 4-amino-1-(3-fluoro-2-methylphenyl)-7-(trifluoromethoxy)quinazolin-2-one 3-[4-amino-2-oxo-7-(trifluoromethoxy)quinazolin-1-yl]-2-methylbenzonitrile 4-amino-7-cyclopropyl-1-(2,3-dihydro-1H-indol-4-yl)pyrido[2,3-d]pyrimidin-2-one 4-amino-1-(2-chloro-5-fluorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2-one 4-amino-1-(2-chloro-4-fluorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-7-cyclopropyl-1-(2,5-difluorophenyl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-7-(ethylamino)-1-(o-tolyl)quinazolin-2-one 4-amino-1-(3-chlorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2(1H)-one 3-(4-amino-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)benzonitrile 4-amino-7-(difluoromethoxy)-1-(4-oxaspiro[2.5]octan-8-yl)quinazolin-2(1H)-one 1-amino-4-(2-chlorophenyl)-6-(trifluoromethyl)pyrido[1,2-c]pyrimidin-3-one 4-amino-1-(benzo[d]oxazol-4-yl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-7-cyclopropyl-1-(3,4-difluorophenyl)pyrido[2,3-d]pyrimidin-2(1H)-one 3-(4-amino-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)-2-methylbenzonitrile 3-(4-amino-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)-2-methylbenzonitrile 4-amino-7-(difluoromethoxy)-1-(o-tolyl)quinazolin-2(1H)-one 3-(4-amino-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)-2-chlorobenzonitrile 4-amino-7-cyclopropyl-1-[(8S)-4-oxaspiro[2.5]octan-8-yl]pyrido[2,3-d]pyrimidin-2-one 4-amino-7-cyclopropyl-1-[(8R)-4-oxaspiro[2.5]octan-8-yl]pyrido[2,3-d]pyrimidin-2-one 4-amino-1-(1H-benzo[d]imidazol-4-yl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-7-cyclopropyl-1-(1H-indazol-4-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-7-cyclopropyl-1-(2,3-dimethylphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-1-(2-chloropyridin-3-yl)-7-(difluoromethoxy)quinazolin-2(1H)-one 4-amino-1-(2-chloropyridin-3-yl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-1-(2-chloropyridin-3-yl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-7-(difluoromethoxy)-1-(m-tolyl)quinazolin-2(1H)-one 4-amino-7-(difluoromethoxy)-1-(2-fluoro-3-methylphenyl)quinazolin-2(1H)-one 4-amino-7-cyclopropyl-1-(2-(trifluoromethyl)phenyl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-7-cyclopropyl-1-(3-(fluoromethyl)-2-methylphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-1-(2-chloro-3-methylphenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2-one 4-amino-1-(3-chloro-2-methylphenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2-one 4-amino-7-cyclopropyl-1-(2,3-dichlorophenyl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-7-cyclopropyl-1-(2-fluoro-3-methylphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one 3-(4-amino-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)-2-fluorobenzonitrile (S)-4-amino-7-cyclopropyl-1-(oxepan-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (R)-4-amino-7-cyclopropyl-1-(oxepan-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-7-cyclopropyl-1-(3-hydroxy-2-methylphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-7-(difluoromethoxy)-1-(3-fluoro-2-methylphenyl)quinazolin-2(1H)-one 4-amino-7-cyclopropyl-1-[rac(2S,3S)-2-methyltetrahydropyran-3-yl]pyrido[2,3-d]pyrimidin-2-one 4-amino-1-(benzo[d]thiazol-7-yl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-7-cyclopropyl-1-((2S,3R)-2-methyltetrahydro-2H-pyran-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-7-cyclopropyl-1-((2R,3S)-2-methyltetrahydro-2H-pyran-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (-)-4-amino-1-(2-chloro-3-fluorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2(1H)-one (+)-4-amino-1-(2-chloro-3-fluorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2(1H)-one (-)-4-amino-1-(2-chlorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2(1H)-one (+)-4-amino-1-(2-chlorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-7-cyclopropyl-6-(difluoromethoxy)-1-(o-tolyl)pyrido[2,3-d]pyrimidin-2-one 4-amino-7-cyclopropyl-1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)pyrido[2,3-d]pyrimidin-2-one; formic acid 4-(2-chlorophenyl)-6-cyclopropyl-1-imino-pyrido[1,2-c]pyrimidin-3-one; Formic acid 4-amino-7-cyclopropyl-1-[2-(trifluoromethoxy)phenyl]pyrido[2,3-d]pyrimidin-2-one 4-amino-1-(2-chloro-3-pyridyl)-7-(trifluoromethoxy)quinazolin-2-one 4-amino-7-cyclopropyl-1-(6-(difluoromethoxy)pyridin-2-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-7-cyclopropyl-1-(1,4-dioxepan-6-yl)pyrido[2,3-d]pyrimidin-2-one 4-amino-7-cyclopropyl-1-(3-fluoro-2-methylphenyl)quinazolin-2-one 1. A compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

26. 4-amino-7-cyclopropyl-1-(o-tolyl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-7-cyclopropyl-1-(2-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 3-(4-amino-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)-2-methylbenzonitrile 4-amino-7-cyclopropyl-1-(2,3-dihydrobenzofuran-4-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-7-cyclopropyl-1-(3-fluoro-2-methylphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-7-cyclopropyl-1-(oxan-3-yl)pyrido[2,3-d]pyrimidin-2-one 4-amino-7-(difluoromethoxy)-1-(2-methylpyridin-3-yl)quinazolin-2(1H)-one 4-amino-1-(2-methylpyridin-3-yl)-7-(trifluoromethoxy)quinazolin-2(1H)-one 4-amino-7-cyclopropyl-1-(2,3-dihydrobenzofuran-4-yl)quinazolin-2(1H)-one 4-amino-7-cyclopropyl-1-(2,3-dihydrobenzofuran-7-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-1-(2-chlorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2-one 4-amino-7-cyclopropyl-1-(4-oxaspiro[2.5]octan-8-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-1-(2-chloropyridin-3-yl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-7-(difluoromethoxy)-1-(2-methylphenyl)pyrido[2,3-d]pyrimidin-2-one 3-(4-amino-2-oxo-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-1(2H)-yl)-2-methylbenzonitrile 4-amino-7-cyclopropyl-1-(m-tolyl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-7-cyclopropyl-1-[(8S)-4-oxaspiro[2.5]octan-8-yl]pyrido[2,3-d]pyrimidin-2-one 4-amino-7-cyclopropyl-1-[(8R)-4-oxaspiro[2.5]octan-8-yl]pyrido[2,3-d]pyrimidin-2-one (R)-4-amino-7-cyclopropyl-1-(oxepan-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-7-cyclopropyl-1-((2S,3R)-2-methyltetrahydro-2H-pyran-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 1. A compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

27. 27. A pharmaceutical composition comprising a compound of any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

28. A pharmaceutical composition for treating, preventing and / or delaying the progression of lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, esophageal cancer, glioblastoma multiforme, and mesothelioma, comprising a compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof.

29. A pharmaceutical for the treatment, prevention and / or delay of progression of lung adenocarcinoma, lung squamous cell carcinoma, pancreatic adenocarcinoma, glioblastoma multiforme, and head and neck squamous cell carcinoma, comprising a compound described in any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof.

30. 27. Use of a compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment, prevention and / or delay of progression of lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, esophageal carcinoma, glioblastoma multiforme, and mesothelioma.

31. 30. Use of a compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment, prevention and / or delay of progression of lung adenocarcinoma, lung squamous cell carcinoma, pancreatic adenocarcinoma, glioblastoma multiforme, and head and neck squamous cell carcinoma.

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