UA79518C2 - Process for preparation of phosphodiesterase-4 inhibitors - Google Patents

Abstract

In one aspect, the present invention is directed to a one pot method of preparing intermediates of Formula (V), which are useful in making inhibitors of phosphodiesterase-4: The present invention is also directed to a method of preparing phosphodiesterase inhibitors comprising the Formula (IX, IXa).

Description

Description of the invention

This invention relates to a method of obtaining phosphodiesterase-4 inhibitors. In particular, this invention 2 relates to a method of obtaining compounds that are biaryl-substituted 1,8-naphthyridine-(1H)-ones.

Hormones are compounds that affect cellular activity in various ways. In many ways, hormones are messengers to initiate certain cellular responses and activities. However, many of the effects caused by hormones are not the result of the hormone itself. Instead, the hormone first binds to the receptor, thereby triggering the release of a second compound that continues to influence cellular activity. In 70 such a scenario, the hormone is known as the primary messenger, and the second compound is called the second messenger. Cyclic adenosine monophosphate (adenosine 35'- cyclic monophosphate, "CAMP" or "cyclic

AMP") is known as a second messenger for hormones including epinephrine, glucagon, calcitonin, corticotropin, lipotropin, luteinizing hormone, norepinephrine, parathyroid hormone, thyroid-stimulating hormone, and vasopressin. Thus, cAMP mediates the cellular response to hormones. Cyclic AMP also 12 mediates the cellular response to various neurotransmitters.

Phosphodiesterases ("PDEs") are a family of enzymes involved in the metabolism of 3", 5-cyclic nucleotides, converting them into b-nucleoside monophosphates, thereby limiting the activity of CMF as a second messenger. A certain phosphodiesterase, phosphodiesterase-4 ("PDE4" , also known as "PDE-IM"), which has high affinity and specificity for CAMP, an IM-type PDE, is of particular interest as a potential target for the development of new anti-asthmatic and anti-inflammatory compounds. PDE4 is known to exist as at least four isozymes, each of which is encoded by a separate gene. All four known PDE4 gene products are thought to play different roles in allergic and/or inflammatory responses. Thus, it is thought that inhibition of PDE4, especially the specific isoforms of PDEAY that cause adverse reactions, may have beneficial effects on symptoms of allergy and inflammation. It would be desirable to obtain new compounds and compositions that inhibit the activity of PDE4. c

The main problem with the use of PDE4 inhibitors is the side effect in the form of vomiting, which is observed when taking several variants of the compounds, (as described in S. Vygposhki ei ai., ("Vygpoiyi"), App. Ker.

Il Med. Spet., 33: 91-109 (1998). In V. Nidpez ei ai., Vg. U. RIaptasoi., 118:1183-1191 (1996); Mu. Reitu her aI. Seyi Viospet. Viorpuvz., 29: 113-132 (1998); 5.8. SpPgiziepzep ei aiYi.,, U. Med. Spet., 41:821-835 (1998) and

Undesirable effects of varying degrees of severity caused by various compounds are described above. As (described in so

M.O. Noiziau ei aiYi., Aim. Ip RIaptasoi!., 44:225-342 (1998) and O. Zripa ei aYi., Aim. Ip РНаптасой., 44:33–89 "pd (1998)), there is great interest, and numerous studies of therapeutic PDE4 inhibitors are being conducted.

In the publication |international application UMO 9422852)| described quinolines as PDE4 inhibitors. In the publication of the international application UUO 99077041, derivatives of 1-aryl-1,8-naphthyridin-4-one are described as PDEYA4 inhibitors. Gee!

In IA-N. Sook ei ai.,, 9. Spet. boss, 413-417 (1943)| gamma-pyridylquinolines are described. Other quinoline compounds 3o (described in Keii Mapabe ei ai., 9. Ogd. Spet., 58 (24): 6692-6700 (1993); Keii tapabre ei ai.,, 9. At. Spet. 5os, in 115 ( 12):5324-5325 (1993) and Kei Maparbe et al., U. At. Spect. os., 114 (17):6940-6941 (1992)|.

Compounds that include ring systems have been described by various researchers as effective in various therapies and other applications. For example, |in the publication of the international application UUO 98/25883)| described "ketobenzamides as calpain inhibitors, in the publication (European patent EP 811610 and US patents C

MoMmo 5679712, 5693672 and 5747541) described substituted benzoylguanidine blockers of sodium channels, |in the US patent Mo5736297| ring systems used as a photosensitive composition are described.

Із» У (патентах США МоМо5491147, 5608070, 5622977, 5739144, 5776958, 5780477, 5786354, 5798373, 5849770, 5859034, 5866593, 5891896 і публікації міжнародної заявки УУО 95/35283) описані інгібітори ФДЕЯ4, які являють собою похідні тризаміщеного арилу або гетероарилфенілу . In US patent Mo5580888) PDEYA4 inhibitors are described, which are styryl derivatives. U.S. Patent Mo5550137 describes PDE4 inhibitors that are 7 phenylaminocarbonyl derivatives. U.S. Patent Mo5340827 describes PDE4 inhibitors that are (se) phenoxycarboxamide compounds. U.S. Patent Mo5780478 describes PDE4 inhibitors that are derivatives tetrasubstituted phenyl. In the publication |international application UMO 96/00215) derivatives of substituted oxime, which are used as PDE4 inhibitors, are described. PDEYA4 inhibitors are described in US patent No. 5633257, which are -kp 70 compounds of cyclo(alkyl and alkenyl)phenyl-alkenyl(aryl and heteroaryl)y.

In one aspect, the present invention relates to a one-reactor method for obtaining intermediate compounds of the formula U, which are used in the preparation of phosphodiesterase-4 inhibitors: - 866665"-u

F) name) 60

IN

65 In another aspect, the present invention relates to a method of preparing compounds of formula IX and formula IXa, which are phosphodiesterase-4 inhibitors:

and

Sha

AND I

Phosphodiesterase-4 inhibitors have been shown to be useful in the treatment of mammals, for example, for asthma, 7/5 chronic bronchitis, chronic obstructive pulmonary disease (COPD), eosinophilic granuloma, psoriasis and other benign or malignant proliferative skin diseases, endotoxic shock (Her pov associated conditions such as laminitis and colic in horses), septic shock, ulcerative colitis,

Crohn's disease, reperfusion injury of the myocardium and brain, inflammatory arthritis, osteoporosis, chronic glomerulonephritis, atopic dermatitis, urticaria, respiratory distress syndrome in adults, 2nd respiratory distress syndrome in children, chronic obstructive pulmonary disease in animals, non-diabetes, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, arterial restenosis, atherosclerosis, neurogenic inflammation, pain, cough, rheumatoid arthritis, ankylosing spondylitis, transplant rejection and graft-versus-host disease, gastric acid hypersecretion caused by bacteria, fungi, or viruses, sepsis, or septic shock, inflammatory and cytokine-mediated chronic tissue degeneration, osteoarthritis, cancer, cachexia, loss of muscle tissue, depression, memory impairment, monopolar depression, acute and chronic neurodegenerative diseases with i) inflammatory phenomena, Parkinson's disease, Alzheimer's disease, damage to Mr other brain, head injuries, multiple sclerosis, tumor growth and cancerous invasion of normal tissues.

In one variant, the preparation of compounds of the formula IX can begin with the preparation of the intermediate compound of the formula sozozoU. "-

IN

IF) (o) - -

I.Y and? where - OV! is an acceptable departure group, such as described in standard texts such as: |Rgoiesiime Sgoirv - 45 |ip Ogdapis Zupipevziv, 2pa eyyiop, Bu Tpeodoga MU. Sgeepe apa Reyeg OM. Umivi (1991) and Rgoiesiipd OSgoir, author

Rpiyir y, Kosiepeki (1994)). For example, BC! may be optionally C/alkyl, aryl, heteroaryl, where (Ce) substituents are selected from the group including aryl, C. dalalkyl;

BZ is C1 alkyl, aryl or heteroaryl, optionally mono-, di-, tri- or tetrasubstituted halogen, 1 1-8

B(OH)», OSH, aryl, heteroaryl, alkyl, alkyl, alkoxy, ketone, alcohol, triflate, mesylate, amide, ether, ketone, acetal, phosphate, stanna, silyl, B(OK)", where E is Su. alkyl or aryl; "which includes:

Stage A: interaction, in a non-nucleophilic solvent, of compounds of formula I:

It's her name) " 60

And and. . b5 where

B2 is each independently C alkyl, optionally mono- or disubstituted C alkyl, such as methyl or ethyl, or aryl, such as phenyl or heteroaryl; with the compound of formula I in the presence of a base: se» 1 And where

B" is bromine or chlorine, giving a compound of formula PI

PI with o

Shsh with i

Stage B: interaction, in a non-nucleophilic solvent, of the compound of formula III with the amino compound of formula II --

IS)

IM pe-nn, F "tu m. in the presence of a base to obtain a compound of the formula M.

The definition of a non-nucleophilic solvent in stage B is the same as that given above for stage A. Also, the definition of a base in stage B is the same as that described above for stage A. with c At stage Amolar ratio of the base to the compound of the formula | can vary from about 12:1 to about 3:1. A ratio of 8:1 is usually used. A ratio below 3:11 can cause ;" trimerization of aminoacrylate to obtain 1,3,5-tricarboxybenzene. molar ratio of the compound of the formula

The ratio of I to the compound of formula II can vary from 1:1 to 1:3, usually it is about 1:1.5. Interaction on stage

And it can be carried out at a temperature from 25 to 10090; usually use an interval from 40 to about 602C, and continue the reaction to almost complete completion within 2 to 18 hours; usually from 6 to 12 hours. Interaction at stage B is carried out as described above. In this variant, there is a sub-variant in which: 1 B is optionally C 4 alkyl, aryl, heteroaryl, where the substituents are selected from the group consisting of C 50 aryl, C alkyl;

K is methyl, ethyl or phenyl; co BZ is C 1 alkyl, aryl or heteroaryl, optionally mono-, di-, tri- or tetra-substituted halogen,

B(OH)», С-CH, aryl, heteroaryl;

This option has a sub-option in which: 25 V! is methyl or ethyl;

HF) B2 is methyl;

GI VZ is a phenyl substituted with a halogen, в(Он», с- CH.

In this variant, there is a sub-variant in which: the non-nucleophilic solvent is chosen from dimethylformamide, because dimethylacetamide, tetrahydrofuran, ethyl acetate, acetonitrile, toluene, benzene, dioxane, methylene chloride.

In the above sub-variant there is a sub-variant in which the non-nucleophilic solvent is acetonitrile.

In this variant, there is a sub-variant in which the base is selected from sodium or potassium carbonate, triethylamine, diethylamine and Hoenig's base.

In this variant, there is a sub-variant in which the basis is chosen from sodium carbonate or triethylamine. 65 In this variant, there is a sub-variant in which the molar ratio of the compound of the formula IM to the compound of the formula I is from about 2:1 to 1:2.

In the sub-variant indicated above, there is a sub-variant in which the molar ratio of the compound of formula IM to the compound of formula III is about 1:1.

In this variant, there is a sub-variant in which the molar ratio of the base to the compound of formula IM is at least 1:1.

In the sub-variant indicated above, there is a sub-variant in which the molar ratio of the base to the compound of the formula IM is about 1:1.

In this variant, there is a sub-variant in which the interaction is carried out at a temperature from about 20 to 10020.

In the above sub-option, there is a sub-option in which the reaction is carried out at a temperature of from about 40 to 7/0 about 5090.

In the second version, the method of obtaining the compound of formula M is presented

IN

5 then where c 29 -OV is an acceptable leaving group; Go)

BZ is C1 alkyl, aryl or heteroaryl, optionally mono-, di-, tri- or tetra-substituted halogen,

B(OH)», C-CH (alkyne), aryl, heteroaryl, C. alkyl, alkoxy, ketone, alcohol, triflate, mesylate, amide, ester, ketone, acetal, phosphate, stanna, silyl, B(OK )", where K is co

C-alkyl or aryl; which includes: --

Stage A: interaction, in a non-nucleophilic solvent, of compounds of formula I:

HER (22) 5 0-7 t and "

I - s I « «NI p». where and B2 are each independently C alkyl, optionally mono- or disubstituted C alkyl, such as methyl or co ethyl, or aryl or heteroaryl; with the compound of formula I in the presence of a base: 1 ! -l 70

IR e) ko s 60 de

B is bromine or chlorine, giving a compound of the formula IP! b5

PI and

I tein and 18 Stage B: interaction, in a non-nucleophilic solvent, of the compound of the formula III with the amino compound of the formula IM

And IM

-nn, and in the presence of a base to obtain a compound of the formula U. In this variant, there is a sub-variant in which:

B is optionally C 4 alkyl, aryl, heteroaryl, where the substituents are selected from the group consisting of aryl, C. alkyl;

VI is methyl, ethyl or phenyl; with

BZ is C1 alkyl, aryl or heteroaryl, optionally mono-, di-, tri- or tetrasubstituted halogen, o

B(OH)», С-CH, aryl, heteroaryl;

This second option has a sub-option in which:

B" is chlorine.

In this second option, there is a sub-option in which: co

From V! is methyl or ethyl; --

B2 is methyl; yu

BZ is phenyl substituted with a halogen, B(OH)»,-С--CH.

In this second variant, there is a sub-variant in which: the non-nucleophilic solvent is selected from F dimethylformamide, dimethylacetamide, tetrahydrofuran, ethyl acetate, acetonitrile, toluene, benzene, dioxane, methylene chloride.

In the above sub-variant there is a sub-variant in which the non-nucleophilic solvent is acetonitrile.

In this second variant, there is a sub-variant in which the base is chosen from sodium or potassium carbonate, triethylamine, diethylamine and Hennig's base.

In this variant, there is a sub-variant in which the basis is chosen from sodium carbonate or triethylamine. - c In this second variant, there is a sub-variant of stage A, in which the molar ratio of the base in the compound of formula h is from about 12:1 to about 3:1. ," In the sub-variant indicated above, there is a sub-variant of stage A, in which the molar ratio of the base in the compound of the formula I! is from about 8:1 to about 3:1.

In this second variant, there is a sub-variant of stage A, in which the molar ratio of the compound of the formula | to -i compound of formula II is from about 1:1 to 1:3. c In this second embodiment, there is a sub-variant of stage A, in which the reaction is carried out at a temperature of from about 25 to about 10096, o In this second embodiment, there is a sub-variant of stage A, in which the reaction is carried out at a temperature of from about 40 -l 20 to about 6090.

In this second variant, there is a sub-variant of stage B, in which the molar ratio of the compound of formula IM to the compound of formula III is from about 2:1 to 1:2.

In the above-mentioned sub-variant, there is a sub-variant of stage B, in which the molar ratio of the compound of the formula IM to the compound of the formula I is about 1:1. oo In this second variant, there is a sub-variant of stage B, in which the molar ratio of the base to the compound of the formula

Gee! MI is about 1:1 or more.

In the sub-variant indicated above, there is a sub-variant of stage B, in which the molar ratio of the base to the compound of formula IM is about 1:1.

In this second variant, there is a sub-variant of stage B, in which the reaction is carried out at a temperature of about 20 60 to 10090.

In the sub-variant indicated above, there is a sub-variant of stage B, in which the reaction is carried out at a temperature of about

AO to 5090.

In this second variant, there is a sub-variant in which the interaction at stage A and the interaction at stage B are carried out in the same reactor without purification or isolation of the product of stage A before proceeding to stage B. In another variant, the present invention relates to a method for producing a phosphodiesterase-4 inhibitor formulas IX and Xa: what includes them

Stage C: interaction, in solvent A, of compounds of the formula Ma

Y T Toma with Fr

M so with -

IS) where -OV! is an acceptable outgroup as described in standard texts such as: |Rgoiesiime Sgoire (is) ip Ogdapis Zupipevziz, 2pj eaiiop, Bu Tpeodoga MU. Sgeepe apa Reieg S.M. MUtsiv (1991) and Rgoiesiipd Ogotsirv, Bu ich-

Rpiir 9. Kosiepeki (1994)).

For example, V! may optionally be C alkyl, aryl, heteroaryl, where the substituents are selected from the group including aryl, C alkyl; with the compound of the formula MII or MPa "shi c;" "No. -AND

MI M se) in the presence of a palladium catalyst and a phosphine ligand, in an amine base, to obtain a compound of the formula MIII or MPa. - 50

IR e)

Ф) име) 60 or 65 The preferred compound of formula Ma, formula MI! and MPa, respectively, are the following compounds:

. 70, her or th

For the purposes of this invention, solvent A is selected from the group consisting of dimethylaminoacetamide, 7/5 dimethylformamide, acetonitrile, DMSO, methylacetamide, ethers or mixtures thereof. For the purposes of the present invention, the phosphine ligand is selected from the group consisting of P(Ci-alkyl)z, such as P(tert-butyl)z, P(SU)»z and

P(tert-butyl)"(biphenyl). For the purposes of this invention, the palladium catalyst includes Fu catalyst (e.g., P(tert-butyl)z3--Ra-P(tert-butyl)z, IRasi(alkyl))", Rao(dba)z and (P(tert- butyl)zRavg|" (catalyst

Johnson-Mattei). For the purposes of this invention, the amine base is a hindered amine base, such as 2o tert-amylamine, tert-butylamine, isopropylamine, or diisopropylamine.

At the stage, the molar ratio of the compound of formula Ma to the compound of formula MIII or MIIIa can vary widely, but is optimally from about 1:1.5 to 1.51, usually about 1:1. As a rule of thumb, at least 1 imolar base equivalent of a compound of formula Ma plus 1 imolar base equivalent of a compound of formula MI or Miia is desirable. Decreasing this ratio sch ov DECREASES the output. Thus, in the reaction presented above, the ratio of the amine base to the compound of the formula Ma can be 1.211 or more, but usually it is from 2:1 to 3.5:1. The molar ratio of palladium to the compound o of the formula M is from 0.05:1 to 0.10:1. If, for example, (Rasi(allyl))" is used, which contains two moles of palladium per mole of catalyst, the ratio will be from 0.025:1 to 0.05:1. The molar ratio of phosphine ligand to palladium is usually from 3:1 to 5:1, often about 4:1. The reaction can be carried out at a temperature from 25 to 1252C, usually at a temperature from 40 to 702C, and continues until the reaction is almost complete. The presence of oxygen is minimized by blowing the reaction vessel with nitrogen gas before adding reagents. yu

The product from stage C is cooled to a temperature from 0 to about 59C. Then 3-6 volumes of antisolvent per volume of solvent are added to the product from stage C to precipitate the compound of formula MI! or Mina. For Fr

For the purposes of this invention, an antisolvent is defined as a non-reactive solvent in which a compound of the formula rch-

MI or MPa precipitates.

The suspension containing the precipitated compound of formula MIII or MIPa is filtered or centrifuged. The precipitate on the filter or in the centrifuge containing the compound of formula III or MPa is resuspended or directly washed with isobutanol or isopropanol to remove residual palladium. For example, a filter cake containing a compound of the formula MI or MPa can be washed (e.g., on a filter press) with 40 to 60 volumes of isobutanol per unit weight of dry compound of the formula MI! or MPa. Alternatively, residual palladium can be removed by redissolving the compound of formula "" in a C.v.alkanol solvent (such as methanol, ethanol, or propanol) and treating the slurry containing the compound of formula IIX or IX with activated carbon such as Juagso 0-60 or Esovogr. The suspension is then filtered to remove activated carbon. It is obviously convenient to increase the solubility of the product in the -I alkanol solvent by heating the alkanol (e.g., to a temperature of 25 to 7022) either before or after contact with the product. Usually, the suspension is held in the warm state for 1 to 6 hours and filtered while still warm. 1 Functionally, the complete conversion achieved in stage C is the same as in a typical Sonogashira coupling reaction of Shu 50. As such, stage C is an efficient one-step method the combination of an alkyne with an aryl halide On the other hand, stage C differs from the Sonogashira combination reaction in several

IR e) in important directions. For example, the Sonogashira coupling reaction usually requires the use of a copper, zinc, magnesium, or zirconium reagent in addition to a palladium catalyst. Copper is predominant.

However, the authors of this invention found that when combined according to Sanagashira (Zopodazpiga, Kip Meya!I-Sa(azugei Stov8-Socriipud Keasiiope; Oiedegis, E apa 5(apo, R. edv; UMieu-MSN; UUeippeiit, Segtapu, 1998, section Spet.

Ipi Ed. 1998, 37, Mo24, p. 3387-3388; MuUoMe, 9. bipdeg, K., Mapd, V. apa VispmaiYid, 5., U. At. Spent 5os, about 1999, 121, p. 9550-9561.) of compounds of formula Ma and formula MII, at least 1095 dimer of compound ime) of formula Ma is formed in the product.

In Negtapp, hey! (Eig. U. Speth 2000, 3679-3681| it is described that if the palladium catalyst is chosen correctly, the need to use copper is eliminated. Two such catalysts are P(Su) z-Ra-P(SU)»z and

P(tert-butyl)z3-Ra-P(tert-butyl)z (Fu catalyst). Such catalysts require special treatment.

In contrast, the catalysts of this invention are obtained by reacting a stable palladium source (such as (Ra(allyl)CI|») with a stable commercially available prepackaged ligand (such as 1095 wt. tri-(tert-butyl)phosphine in hexane) Moreover, due to the preparation of the ips catalyst, the present invention 65 provides an appropriate ligand/palladium ratio not normally available using commercial products.

Stage 0: interaction, in solvent B, of a compound of formula MI with cyclopropylamine, optionally in the presence of a phosphite or other catalyst.

For the purposes of this invention, solvent B is defined as including an alkanol solvent such as Sudalkanol solvents methanol, ethanol, propanols and butanols, and trifluoroethanol, or mixtures thereof. Acetonitrile can also be used. For the purposes of this invention, the catalyst includes butyl phosphite (BIC) pyridine-M-oxides, trialkyl orthoacetate, zinc chloride, magnesium chloride, magnesium triflate, scandium triflate, lanthanum triflate, ytterbium triflate, titanocene dichloride or zirconocene dichloride. It should be noted that for the purposes of this invention, the term "catalyst" means a reagent that accelerates a reaction, even when present in 70 greater than classical "catalytic" amounts.

The molar ratio of cyclopropylamine to the compound of formula MIII or MPa is usually greater than 1:21, often 1.111 or greater. Decreasing the specified ratio reduces output. The ratio of catalyst to compound of formula MI or MPa is usually from 0.025:1 to 0.075:1, often around 0.05:1 or possibly from 0.101 to 1:11 or more. When using magnesium chloride, a typical ratio of catalyst to compound 7/5 of Formula MII or MPa is 0.9:1 to 1:1.5. The reaction can be carried out at a temperature of from 40 to about 602C, usually at a temperature of 55-602C, and it is carried out until the reaction is practically complete.

The presence of oxygen is minimized by purging the reaction vessel with nitrogen gas before adding the reagents. To obtain optimal results, it is desirable to conduct stage O at Kt equal to or below zOObch/million.

The product from stage O is cooled to a temperature from 0 to about 302C, usually to room temperature.

Then the solvent is replaced by an antisolvent (antisolvent B), for example, by evaporating the solvent followed by the addition of an excess of antisolvent. For the purposes of this invention, antisolvent B is defined as the solvent in the reaction product (in this case, the compound of formula IX), 3-6 volumes of antisolvent per volume of solvent are added to the product from stage C to precipitate the compound of formula III or MPa. For the purposes of this invention, an antisolvent is defined as a non-reactive solvent in which a compound of formula o is precipitated

MI or Misha.

To remove impurities, the suspension containing the precipitated compound of formula MI or MiIPa is washed with a solvent such as water, acetonitrile, isopropyl acetate, ethyl acetate, tetrahydrofuran, ethanol, propanols, and butanols. Then the solvent is removed, for example, by filtration and vacuum drying. The filtered compound (se) of the formula MIII or MЩa can be mixed with a transformation solvent, such as dry ethanol, methanol, trifluoroethanol, M-methylpyrrolidinone, methyl-tert-butyl ether or their mixtures, optionally heated and - kept at a temperature of 40 to 502C, until, at least, 95956 compounds of the formula MI or MSa take the desired form. The conversion solvent is then removed, for example, by filtration or F centrifugation, and the resulting product is dried under vacuum. The required amount of conversion solvent should be sufficient to suspend or dissolve the compound of the formula MI! or MPa. -

The term "aryl", unless otherwise specified, includes multi-ring systems as well as single-ring systems such as, for example, phenyl or naphthyl.

The term "hetero", unless otherwise specified, includes one or more OO, 5 or M atoms. For example, heterocycloalkyl and heteroaryl include ring systems that contain one or more O, C, or M atoms in the ring, including mixtures of these atoms. Heteroatoms replace carbon atoms in the ring. Thus, for example, - c heterocycloSbalkyl is a 5-membered ring containing from 5 to 0 carbon atoms. " Examples of heteroaryl include, for example, pyridinyl, hyaolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl, " pyrazinyl, quinoxalinyl, furyl, benzofuryl, dibenzofuryl, thienyl, benzothienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl , benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl. -i Compounds described above may include one or more centers of asymmetry and thus may have c diastereomers and optical isomers. This invention includes all these possible diastereomers, as well as their racemic mixtures, their practically pure separated enantiomers, all possible geometric isomers and their salts. 1 Implementation of this invention is illustrated by examples of phosphodiesterase-4 inhibitors that can be obtained using this invention.

Dosage from about 0.001mg/kg to about 14Omg/kg of body weight per day is used in the treatment of such

IR e) conditions such as asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), eosinophilic granuloma, psoriasis and other benign or malignant proliferative skin diseases, endotoxic shock (and related conditions such as equine laminitis and colic ), septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, inflammatory arthritis, osteoporosis, chronic glomerulonephritis, o atonic dermatitis, urticaria, respiratory distress syndrome in adults, respiratory distress syndrome in children, chronic obstructive pulmonary disease in animals, diabetes mellitus, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, arterial restenosis, atherosclerosis, neurogenic inflammation, pain, cough, rheumatoid arthritis, ankylosing spondylitis, transplant rejection and graft-versus-host disease, hypersecretion stomach acid, caused by bacteria, fungi or viruses, sepsis or septic shock, inflammatory and cytokinesis chronic tissue degeneration, osteoarthritis, cancer, cachexia, loss of muscle tissue, depression, memory impairment, monopolar depression, acute and chronic neurodegenerative diseases with inflammatory phenomena, Parkinson's disease, Alzheimer's disease, spinal cord damage, head injury, diffuse sclerosis, tumor growth, and cancerous invasion of normal tissues that respond 65 to PDEIA4 inhibition, or, alternatively, from 0.05 mg to about 7 g per patient per day. For example, inflammation can be effectively treated by administering about 0.01mg to 5Omg of a compound per kilogram of body weight per day, or,

alternatively, from about 0.5 mg to about 2.5 g per patient per day. It is further understood that the PDE4 inhibitory compounds according to the present invention can be administered in a prophylactically effective amount for the prevention of the conditions indicated above.

The amount of active ingredient that can be combined with the carrier to obtain standard dosage forms varies depending on the patient to be treated and the method of administration. For example, formulations for oral human administration may contain from about 0.5 mg to about 5 g of active agent combined with a suitable and convenient amount of carrier, which can vary from about 5 to about 9595 of the total weight of the composition. Standard dosage forms usually contain from about 0.01mg to about 1000mg/o of the active ingredient, usually 0.01, 0.05mg, 0.25mg, mg, 5mg, 25mg, B5Omg, 100mg, 20Omg, ZOOmg, 40Omg,

BoOOmg, bOOmg, 80Omg or 100Omg.

It will be understood that the particular dosage level for a particular patient will depend on such factors as age, body weight, general health, sex, diet, time of administration, route of administration, rate of elimination, drug combination and severity of the particular disease to be treated.

The following examples are intended to illustrate some preferred embodiments of the present invention and are not intended to limit the present invention.

The compounds according to this invention can be prepared by the following methods. Substituents are the same as in formula I unless otherwise indicated.

Preparation of the intermediate compound of the formula M

I | N z z ; ' as ii oi KYY

Mon | | about (ee) iynyy. y h-- and y. Ge) s i - r «Ж « m i ! p s zn - a and -.

DAY Schi -I o U s Naphthyridone 1 - 50 juice Stage 1: Ethyl 1-(3-bromophenyl)-1,4-dihydro|1,8)naphthyridin-4-one-3-carboxylate

A mixture of ethyl-2-chloronicotinoyl acetate (commercially available or obtained according to the method, (described in ..

Nei Spet., 30, 855, 1993)| (Eq.), triethylamine (4 eq.) and ethyl 3,3-dimethylaminoacrylate (1.eq.) in acetonitrile (0.5 m) are refluxed for 3 hours, cooled to a temperature of 40-502C and added 3-bromaniline (Tech.). The reaction mixture is refluxed overnight, cooled to room temperature, diluted with water (2 volumes). The product is isolated by filtration and washed with water, ether or acetonitrile-water (1:1).

"IN NMR (Acetone-dv) 5 1.32 (t, ZH), 4.29 (sq., 2H), 7.54-7.63 (m, 2H), 7.69 (dd, 1H), 7.78 (dd, 1H), 7.93 (s, 1H), 8.66-8.71 (m, ЗН).

Naphthyridone 2

Ethyl 1-(3-acetylenylphenyl)-1,4-dihydro|1,8Inaphthyridin-4-one-3-carboxylate

According to the method of obtaining naphthiridone 1, but replacing 3-acetylenylaniline with 3-bromoaniline, the naphthiridone 2 specified in the title is obtained. (sq., 2H), 7.42-7.46 (m, 2H), 7.53-7.59 (m, 2H), 7.67 (dt, 1H), 8.64 (dd, 1H) , 8.86 (c, 1H), 8.83 (dd, 1H).

Naphthyridone Z c o c "-

Ethyl 1-(3-cyanophenyl)-1,4-dihydro|1,8|Inaphthyridin-4-one-3-carboxylate

According to the method of obtaining naphthiridone 1, but replacing 3-cyanosaniline with 3-bromoaniline, naphthiridone 3 indicated in the title is obtained. b"

TN NMR (0M5O-yv) 5 1.27 (t, ЗН), 4.23 (q., 2Н), 7.57 (dd, 1Н), 7.80 (t, 1Н), 7.96-8 .04 (m, 2H), 8.20 M (t, 1H), 8.61 (dd, 1H), 8.86 (dd, 1H), 8.70 (s, 1H).

Ethyl 1-(4-bromophenyl)-1,4-dihydro|1,8|naphthyridin-4-one-3-carboxylate

According to the method of preparation of naphthiridone 1, but replacing 3-bromoaniline with 4-bromoaniline, the naphthiridone 4 indicated in the title is obtained. c TN NMR (0M5O-yv) 5 1.26 (t, 3H), 4.22 (q., 2H) .

Naphthyridone 5

F) ime) 60 v5 Ethyl 1-(2-bromophenyl)-1,4-dihydro|1,8|naphthyridin-4-one-3-carboxylate

According to the method of obtaining naphthiridone 1, but replacing 2-bromoaniline with 3-bromoaniline, naphthiridone 5 indicated in the title is obtained.

TN NMR (0ОМ5О-yv) 5 1.26 (t, ЗН), 4.23 (sq., 2Н), 7.53-7.62 (m, ЗН), 7.75 (dd, 1Н), 7 .78 (dd, 1H), 8.61 (s, 1H), 8.63 (dd, 1H), 8.68 (dd, 1H).

Naphthyridone 6 70 suq

Ethyl 1-(2-tert-butylphenyl)-1,4-dihydro|1,8Inaphthyridin-4-one-3-carboxylate

According to the method of obtaining naphthiridone 1, but replacing 1-bromo-2-tert-butylphenylaniline with 3-bromoaniline, naphthiridone 6 indicated in the title is obtained.

TN NMR (0M5O-yv) 5 1.08 (s, 9H), 1.25 (t, ЗН), 4.22 (q., 2H), 7.30-7.40 (m, 2H), 7 ,50-7.56 (m, 2H), 7.73 (dd, 1H), 8.59 (s, 1H), 8.62 (dd, 1H), 8.70 (dd, 1H).

Naphthyridone 7 c o c "-

Ethyl 1-(3-phenylboronic acid)-1,4-dihydro|!1,8|Inaphthyridin-4-one-3-carboxylate

According to the method of obtaining naphthiridone 1, but replacing 3-bromoaniline with 3-aminophenylboronic acid, Ge"), naphthiridone 7 specified in the title is obtained.

IN nMR (0M5O-y6) 5 1.26 (t, ЗН), 4.22 (sq., 2Н), 7.56 (coincidence of triplets, 2Н), 7.60 (d, 1Н), 7.87 ( c, 1H), - 7.94 (d, 1H), 8.24 (c, 2H, exchangeable), 8.61 (d, 1H), 8.62 (c, 1H), 8.68 (d, 1H).

PDE-4 inhibitor compounds

The following are examples of PDE-4 inhibitor compounds that can be obtained by the methods described below. It should be noted that the numbers ? formulas that are used in schemes 1-12 and descriptions of these schemes should not be mixed with numbers of formulas that are used elsewhere in the application description. The compounds in examples 1-13 are obtained using naphthiridone 1. ;" Scheme 1

In the first method described in scheme 1 below, an appropriately substituted ethyl-2-chloronicotinoyl acetate derivative of formula II is reacted with 1.5 equivalents of triethylorthoformate and 5 equivalents of acetic anhydride at a temperature of 1302C, and after removal of volatile components, crude 2-chloronicotinoyl acrylate of formula I immediately react with 1.2 equivalents of an appropriately substituted haloarylamine of formula IM, such as, for example, 3-bromoaniline, in a halogenated hydrocarbon solvent such as methylene chloride at a temperature of 02C to room temperature. After the required time for this reaction, which varies from 2 to 24 hours, the resulting 3-arylaminoacrylate of formula M is obtained by evaporation of the solvent and further purified by chromatography on silica gel or crystallization from an acceptable solvent.

Alternatively, the compound of formula M can be used in the next step without further purification.

Cyclization of a compound of formula M to 1-haloaryl-1,4-dihydro(1,8)naphthyridine-4-one carboxylate of formula MI is carried out by treatment with a small excess of a strong base such as an alkali metal hydride, for example sodium hydride, in a suitable solvent such as as tetrahydrofuran, at an initial temperature of 02С, heating to

IF) at room temperature if necessary to complete the process. The product of formula M! isolated in crude form by dilution with a large volume of water followed by filtration or extraction into a suitable organic solvent such as diethyl ether, ethyl acetate or a halogenated hydrocarbon solvent such as chloroform or methylene chloride. The product can be further purified by silica gel chromatography, crystallization, or prolonged stirring in an acceptable solvent followed by filtration.

The product of formula MI thus obtained can be hydrolyzed to the corresponding carboxylic acid derivative under basic conditions, using an aqueous solution of an alkaline base, such as alkaline carbonate or, preferably, sodium or potassium hydroxide, with an organic cosolvent, such as tetrahydrofuran or primary, secondary or a tertiary alkanol, such as methanol or ethanol, or a mixture thereof, at temperatures from room temperature to reflux, for a suitable period of time.

The resulting carboxylic acid is isolated in a crude form followed by acidification using an aqueous solution of an inorganic acid such as hydrochloric, sulfuric or similar acids and filtration or extraction into a suitable organic solvent such as diethyl ether, ethyl acetate or a halogenated hydrocarbon solvent such as chloroform or methylene chloride. Further, the product can be purified by silica gel chromatography, crystallization, or prolonged stirring in a suitable solvent followed by filtration.

Then the carboxylic acid is converted into the corresponding analogue of the primary, secondary or tertiary amide of the formula MI! by any general technique well known to one skilled in the art of organic chemistry, preferably 7/0 By primary conversion to the mixed anhydride by treatment with a small excess, for example 1.25 equivalents, of the appropriate alkyl chloroformate, such as ethyl or isobutyl chloroformate, in the presence of a larger excess , for example, 2.5 equivalents, of a tertiary organic amine such as triethylamine or

M,M-diisopropylethylamine, in an organic solvent, such as tetrahydrofuran, at a low temperature, preferably 09C, for 30 minutes to 3 hours. An excess, usually 5 or more 7/5 equivalents, of the corresponding primary or secondary amine or aqueous ammonium hydroxide solution is then added, and the resulting reaction mixture is kept at a temperature of 02C to room temperature for an appropriate period of time, usually 1-24 hours.

The desired amide of formula MI is then isolated in crude form by precipitation with water and filtration or extraction into a suitable organic solvent such as diethyl ether, ethyl acetate or a halogenated 20 hydrocarbon solvent such as chloroform or methylene chloride. Further, the product can be purified by silica gel chromatography, crystallization, or prolonged stirring in a suitable solvent followed by filtration. If the amide group is 2,6-dichloropyridin-4-yl, another technique is used in which the 4-amino-3,5-dichloropyridine anion is formed at low temperature, preferably at 02C, using a strong alkaline hydride such as sodium hydride , in a solvent such as tetrahydrofuran, and is subjected to Ge reaction with carboxylic acid chloride (after hydrolysis of the ester of the formula MI) obtained by a suitable known technique, usually from oxalyl chloride activated by a catalytic amount

of M,M-dimethylformamide in a solvent such as tetrahydrofuran.

Amides of the general formula MYI are converted into products of the formula | by interaction with an appropriately substituted aryl or heteroaryl of boronic acid or boronic ether of the formula MI in the presence of a catalyst c based on a transition metal such as trans-dibrombis(triphenylphosphine)palladium (I) or

I1,1-bis(diphenylphosphino)ferrocene|dichloropalladium (I), in a suitable solvent or a mixture of solvents, - preferably, a 1:1 mixture of toluene and ethanol, in the presence of an excess of an aqueous solution of an alkaline base, such as sodium carbonate, at a suitable temperature , preferably from 50 to 1002С, for an appropriate period of time, from 0.5 to 48 hours.

The resulting reaction product is then isolated in crude form by precipitation with water and filtration or by extraction into a suitable organic solvent such as diethyl ether, ethyl acetate or a halogenated hydrocarbon solvent such as chloroform or methylene chloride. The product can be further purified by silica gel chromatography, crystallization, or prolonged stirring in a suitable solvent followed by filtration.

Compounds of the formula | can also be obtained by the interaction of compounds of the formula MI with an appropriately substituted aryl- or heteroaryltributylstannane of the formula IX using a catalyst based on a transition metal, such as trans-dibrombis(triphenylphosphine) palladium (I) or "I1,1-bis( diphenylphosphino)ferrocene|dichloropalladium (I), in the presence of copper (I) compounds, such as copper iodide, in a suitable solvent, such as M,M-dimethylformamide, at a temperature of 50 to 1002 for 2 to 24 hours. Isolation of the reaction product is carried out as described above. - Alternatively, an ester of formula MI can be converted to an ester of formula X by reaction with an appropriately substituted boronic acid or boronic ether, or with an appropriately substituted stannane derivative, under the conditions described above, and the ester can be hydrolyzed and converted to an amide 1 of the formula I. -l 20 Boric acids of the formula MI or the corresponding boric ether are usually obtained from commercial sources. If necessary, they can be easily obtained from the corresponding halides by metalation with n-butyllithium followed by interaction with trialkylborate, or using classical transition metal-catalyzed coupling techniques using diborpinacone ether. Stannanes of formula IX are obtained from the corresponding halides, first by metallation using n-butyllithium, then by adding tributyltin chloride.

F) ime) 60 b5 still more

More. In g. - th day g 4 In 'th 70 t -: I . . sh iy" g che In shchi Ge.

Owen ra

And.

You shchi vt ley : i chi "i

Y ' ay E I Pk y " i rl-tyar. z dinvnnyy Z ; "y yan pr o y h : I щ Y sha de hi 7 y le pishi Sho i int --z " і-

In NN. - The first and second. ! that t Artek zba 8 s I pnrotszhh ts : y. and" From page 45. - E c In an alternative method for the preparation of compounds of formula I shown in Scheme 2 below, the amide of formula MII can be converted to the corresponding boronic ether of formula XI by treatment with an excess of diborpinacone ester 1 in the presence of an inorganic salt such as potassium acetate in the presence of a catalyst based on a transient shu 50 metal such as trans-dibrombis(triphenylphosphine)palladium (I) or

I1,1-bis(diphenylphosphino)ferrocene|dichloropalladium (I), in a solvent such as M,M-dimethylformamide, at

IR e) temperature from 50 to 1002 for 1 to 48 hours. The borate of formula XI may be isolated by precipitation with water and filtration or by extraction into a suitable organic solvent such as diethyl ether, ethyl acetate or a halogenated hydrocarbon solvent such as chloroform or methylene chloride. The resulting product can be further purified by chromatography on silica gel, crystallization or prolonged stirring in a suitable solvent followed by filtration.

Alternatively, the borate of formula XI can be used directly in the reaction medium without isolation and reacted with a small excess of an appropriately substituted aryl or heteroaryl halide of formula XI in the presence of a transition metal catalyst such as 60 0 (1,1-bisbidiphenylphosphino) ferrocene|dichloropalladium (II), in a suitable solvent or a mixture of solvents, preferably a 1:1 mixture of toluene and ethanol, in the presence of an excess of an aqueous solution of an alkaline base, such as sodium carbonate, at a suitable temperature, preferably from 50 to 1002С, for a suitable period time from 0.5 to 48 hours.

The reaction product of the formula | then isolated in crude form by precipitation with water and filtration or extraction into a suitable organic solvent such as diethyl ether, ethyl acetate or a halogenated hydrocarbon solvent such as chloroform or methylene chloride. The resulting product can be further purified by silica gel chromatography, crystallization, or prolonged stirring in a suitable solvent followed by filtration. " t. t E . r goo--y seMschi : -y Her SHHI shi" od y chi ru y y nochte " teku A

Ksh G-Ya ' those: y . и " » i. ee an daeylaik" is ШІ шря ee и o

In the third method used for the synthesis of compounds of formula I according to this invention (Scheme 3), the intermediate nicotinyl acrylate of formula III is subjected to reaction with an appropriately obtained diaryl- or heteroarylamine of formula XIII under the conditions described above, to obtain a compound of formula XIM, which cyclized - by interaction with a strong base, such as sodium hydride, as described above, to obtain an ester of formula X, which is converted into a compound of formula I by hydrolysis and amide formation, as described above. yuyu n m. . and ry. in school "! i shi

Their drinkable -SHSH What: In so ayb'ayuv t

From sh sht niy -I cha y se) y : p V pi more

IR e) manifestations of the plates from x in Diaryl- or heteroarylarylamine derivatives of formula XII! are obtained as shown in Scheme 4. An appropriately substituted anilinboronic acid of the formula XM is subjected to coupling with an appropriately substituted aryl or heteroaryl halide of the formula XIII in the presence of a catalyst based on a transition metal as described above, to obtain compounds of the formula XIII used in scheme 3. b5 six days

IS ; y y shi y y y y

Bromopyridine intermediates substituted in the 2-position by carbon-based nucleophiles of the formula HMI, in which KZ is selected from K2 groups having a carbon-carbon bond with pyridine, are obtained as shown in Scheme 5. Bromopyridine intermediates are obtained from dihalides of the formula HMI treatment with an appropriate solution of the Grignard reagent, in the presence of a catalyst based on a transition metal, such as 20. (1,1-bis(idiphenylphosphino)ferrocenedichloro-nickel (I), in a solvent such as tetrahydrofuran, at a temperature from -102С to room temperature, and the resulting reaction mixture is processed according to well-known techniques to obtain the desired product.

Sinai school

S Remokh » o chi kinny " so z o Metalizzhna te «-niy km o (22)

Halopyridine intermediate compounds of the formula HMIII, in which the substituent in position 2 is an oxy group ОВ У, are obtained from dihalides of the formula HMI by substitution with the corresponding alkaline alkoxide, as shown in scheme 6. -

The reaction is carried out in a solvent such as M,M-dimethylformamide at a temperature from 0 oC to room temperature, and, upon completion of the reaction, the products are isolated and purified by classical methods. - - mon - and? more

Kona KON -I so EL yaChChY. sl If intermediate compounds of formulas XIX or XX, in which the substituent in position 2 is a sulfide, sulfoxide, or sulfone, are required, they are obtained as described in Scheme 7. The corresponding dihalopyridine of the formula HMI is reacted with - the corresponding tisalkyoxide, which is usually obtained from the corresponding thiol or disulfide under the action of a strong base such as alkaline hydride or n-butyllithium in a solvent such as M,M-dimethylformamide or diethyl ether at a temperature of -7892C to room temperature. At the end of the reaction, the products of formula XIX are isolated and purified by classical methods. The products obtained in this way can be oxidized to the corresponding sulfoxides or sulfones of formula XX by treatment with an oxidizing agent such as oxone or an organic peroxyacid.

F, In scheme 7, VZ is H or S. valkyl. name) 60 b5 shk Yaiov both parlastililis p shE 15 Psh paz xx

Preparation of haloacylpyridine intermediate compounds of formula XXIII, presented in Scheme 8, requires treatment of halopyridine ether of formula XXII with a solution of the corresponding Grignard reagent, in a solvent such as diethyl ether, at a temperature from 02С to room temperature. If the reaction is carried out for a longer period of time or under reflux, a halopyridine carbinol of formula XXIII is obtained. In the diagrams, 819 B is C. alkyl and KZ is methyl or ethyl.

Sk sch 25

With (8) so 30 kl yuyu (22) shk them

Ach Moi « ' - s eh

I.Y." Scheme 9 shows an alternative method of synthesis of certain halopyridine carbinols of formula XXI. If 2,5-dibromopyridine is treated with n-butyllithium in toluene at a temperature of -78 °C with the subsequent addition of the appropriate ketone or aldehyde, followed by quenching of the reaction at a temperature of -782 °C, a carbinol is obtained - formula XXIII, in which the carbinol group occupies position 2 of the pyridine ring . If the metallation step is carried out in diethyl ether, the same process gives an intermediate compound of formula XXIII, in which the carbinol group occupies the 5-position of the pyridine ring. 1 "I Kvmae so Tu pni, vashchn

Y "o, (F) . xx still Sho y-yi ti ni bo vtsotm b5

B and VU can be the same or different, or B", or EZ can be hydrogen.

Scheme 10 shows methods of synthesis of compounds of formula I, in which EC? is substituted phenyl or heteroaryl.

The intermediate compound of the formula I, in which B 2 is a halogen, is reacted with an appropriately substituted boric acid or boric ether of the formula MI! or tributylstannane of formula IX using one of the methods described above to give the desired compound. y but Ach shk y y y y

Various further transformations of previously obtained compounds of the formula | are presented in Scheme 11. If the aryl group is a pyridine or quinoline group, the compound can be oxidized to the corresponding nitrogen oxide by treatment with a suitable oxidizing agent, such as m-chloroperoxybenzoic acid or magnesium monoperoxyphthalate, under conditions commonly used. If one or more of the substituents of the Ag group is a ketone, the compound is converted to an oxime analog by treatment with hydroxylamine in pyridine as a solvent.

The sulfide substituent is easily oxidized to the corresponding sulfoxide or sulfone when an appropriate amount of an oxidizing agent such as oxone or an organic peroxyacid is used.

Conversion of 2-benzyloxypyridine to the corresponding 2-pyridone is carried out by treatment with trifluoroacetic acid in a solvent such as methylene chloride at room temperature or with slight heating. The removal of the tert-butoxycarbonyl protecting group from the piperazine ring is carried out by reaction with trifluoroacetic acid in a solvent such as 1,2-dichloroethane at reflux temperature. In examples where the Ar substituent is a hydroxymethyl group, it can be converted to a similar halomethyl group using tetrahalomethane in the presence of a trisubstituted phosphine such as triphenylphosphine or diphos in a solvent such as methylene chloride. The halide can be replaced by (o) the corresponding sodium salt of sulfinic acid to give an alkyl- or arylsulfonylmethyl analogue. m yu nn Ya. z ; and he would 2

I.Y "» g. -K, eh -i 4 oi ne -i

Shsh ili se) p tA -l 70

IR e) sc. "ory, " " zinnshchinrfny- o y

Conversion of a 1-hydroxy-1-methylalkyl derivative, such as the compound of formula XXIM in Scheme 12, into where 1,2-dihydroxyalkyl analogs of formula XXM! is carried out first by dehydration using an acid catalyst, for example, heating in aqueous sulfuric acid, to obtain the intermediate 1-alkylvinyl compound 60 of the formula XXU, which is converted into the desired diol of the formula XXMI by dihydroxylation, using, for example, an oxidizing agent such as 4-methylmorpholine M-oxide (MMO) in the presence of a catalytic amount of potassium osmate dihydrate. b5

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Examples

Examples of this invention, presented in the following table, refer to formula (I)

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Beat Kk 17 O- and I

AND

Ka izn vno . 5! How Tv what i: so; | I Ж ИЙ aa 1 in | them | yes yes and I V Univ. oo t d. Y Li DN shchi shchi y: kv tya p slyni pisnnnntsa klin palsilstya shk t i sit: PN ss sin H pnya h- sity sich Bin ti pen 1 Z7Z 70 Example 1 with M-Isopropyl-1-IZ-( 3-acetylphenyl)phenyl/|-1,4-dihydro/1,8)naphthyridin-4-one-3-carboxamide;» y y y t i ; s ka cherries 1 l - - i z » s so She y (y dya 59 Stage 1: Ethyl-3-(3Z-bromoaniline)-2-(2-chloronicotinoyl)acrylate

GF) A mixture of ethyl 2-chloronicotinoyl acetate (41.1g, 180.5mmol), triethyl orthoformate (40.12g, 271mmol) and acetic anhydride (92.05g, 902.5mmol) is heated at a temperature of 1309C for 2.5 hours. Volatile components are distilled off, and the residue is co-evaporated twice with xylene. The oily residue is dissolved in methylene chloride (250 ml) and 3-bromoaniline (37.25 g, 216.6 mmol) is slowly added. The resulting solution is stirred at 60 room temperature for 18 hours and the solvent is evaporated. The obtained crude compound is used as is in the next step.

Stage 2: Ethyl 1-(3-bromophenyl)-1,4-dihydro|1,8|Inaphthyridin-4-one-3-carboxylate

The crude compound from stage 1 is dissolved in tetrahydrofuran (500 ml), the solution is cooled to a temperature of 02C and sodium hydride is added in portions (in the form of 6095 dispersion in oil, 94 g, 235 mmol). After stirring at a temperature of 02C for 1 hour, allow the mixture to warm to room temperature.

After 2 hours, water (40 Oml) is added to the suspension, and the insoluble solid is filtered and washed abundantly with water. When dry, the solid was stirred in ether (15 mL) at room temperature for 24 hours and filtered to give the title compound as a creamy solid.

TN NMR (Acetone-dv) 5 1.32 (t, ЗН), 4.29 (q, 2Н), 7.54-7.63 (m, 2Н), 7.69 (dd, 1Н), 7, 78 (dd, 1H), 7.93 (s, 1H), 8.66-8.71 (m, ЗН).

Stage 3: 1-(3-Bromophenyl)-1,4-dihydro|1,8Inaphthyridin-4-one-3-carboxylic acid

A suspension of ethyl 1-(3-bromophenyl)-1,4-dihydro!1,8|)naphthyridin-4-one-3-carboxylate from stage 2 (52.5g, 140./7mmol) in a mixture of tetrahydrofuran (400ml) , methanol (40O0ml) and IM aqueous sodium hydroxide (280ml) 70 are heated at a temperature of about 502C with stirring for 20 minutes. After cooling, the mixture is diluted with water (300ml) and 1M aqueous HCl (325ml) is added. After stirring for 45 minutes, the precipitate is filtered, washed well with water and dried to give the title acid as a creamy solid.

TN NMR (Acetone-dv) 5 7.65 (t, 1H), 7.76 (m, 2H), 7.84 (d, 1H), 7.99 (s, 1H), 8.87 (m, 2H), 9.01 (s, 1H).

Step 4: M-Isopropyl-1-(3-bromophenyl)-1,4-dihydro/1,8)naphthyridine-4-one-3-carboxamide

To a suspension of 1-(3-bromophenyl)-1,4-dihydro(1,8)naphthyridin-4-one-3-carboxylic acid from stage C (26.3 g, 7 mmol) and triethylamine (23.2 g, 230 mmol) in isobutyl chloroformate (18.85g, 138mmol) is added to tetrahydrofuran (1000O0ml) at a temperature of 09C. After stirring at 02C for 2 hours, isopropylamine (23g, 3900mmol) was added and the mixture was allowed to warm to room temperature and stirred overnight. The mixture is then partitioned between ethyl acetate and water, the organic phase, dried and evaporated to a solid, which is stirred in ether at room temperature for 3 hours and filtered to give

M-isopropyl-1-(3-bromophenyl)-1,4-dihydro|1,8|-naphthyridin-4-one-3-carboxamide as a white solid.

TN nMR (Acetone-dv) 5 1.25 (d, 6H), 4.17 (m, 1H), 7.59-7.63 (m, 2H), 7.70 (d, 1H), 7, 80 (d, 1H), 7.94 (s, 1H), 8.73 (m, 1H), 8.78 (d, 1H), 8.85 (s, 1H), 9.61 (ush., MN). high school

Stage 5: M-Isopropyl-1-I3-3-Acetylphenyl)phenyl|-1,4-dihydro|1,8)naphthyridine-4-one-3-carboxamide (o)

A mixture of M-isopropyl-1-(3-bromophenyl)-1,4-dihydro|!1,8)|naphthyridin-4-one-3-carboxamide from the stage of 4,3-acetylphenylboronic acid (1.2 equiv.), trans -dibrombis(triphenylphosphine)palladium (II) (0O,O5eq.), toluene (bml/mmol), ethanol (2ml/mmol) and 2M aqueous sodium carbonate (equiv.) are refluxed at room temperature for 1 hour in an atmosphere nitrogen The mixture is diluted with ethyl acetate and the organic phase is washed with water and saturated salt solution, dried and evaporated. The crude product is subjected to chromatography on silica gel, eluting with a gradient of 20-4090 ether in methylene chloride Kk) to obtain the product

M-isopropyl-1-3-(3-acetylphenyl)phenyl/|-1,4-dihydro|1,8|inaphthyridin-4-one-3-carboxamide as a solid. (at)

TN nMR (SOCI8) 5 1.29 (d, 6H), 2.65 (s, ЗН), 4.28 (m, 1H), 7.47 (m, 2H), 7.55 (t, 1H) , 7.65 (m, 2H), them 7.80 (m, 2H), 7.95 (dd, 1H), 8.19 (ush.s, 1H), 8.70 (dd, 1H), 8 .81 (dd, 1H), 9.05 (s, 1H), 9.65 ((ush, МН).

Example 2

M-(2,6-Dichloropyridin-4-yl)-1-I3-3-acetylphenyl)(phenyl)-1,4-dihydro|(1,8|-naphthyridin-4-one-3-carboxamide " - s. ;» -I se) 1 - 50 so Stage 1: Anion of 4-amino-3,5-dichloropyridine

A suspension of sodium hydride in the form of a bObo dispersion in oil (3bOmg, Ummol) in tetrahydrofuran (15 ml) is cooled to a temperature of 02С. A solution of 4-amino-3,5-dichloropyridine (978 mg, mmol) in tetrahydrofuran (15 mL) was added slowly. The resulting mixture is kept at a temperature of 02C for 2.5 hours.

GF! Stage 2: Chloroanhydride of 1-(3-bromophenyl)-1,4-dihydro|!1,8|Inaphthyridin-4-one-3-carboxylic acid

A suspension of 1-(3-bromophenyl)-1,4-dihydro|!1,8|Inaphthyridin-4-one-3-carboxylic acid from step C of example 17 (6b9Omg, 2mmol) in tetrahydrofuran (12ml) is cooled to a temperature of 02С and add oxalyl chloride (381 mg,

Zmmol) followed by the addition of 2 drops of M,M-dimethylformamide. Then the resulting mixture is stirred at 60 room temperature for 1 hour, then refluxed for 45 minutes and cooled to room temperature.

Step 3: M-(2,6-Dichloropyridin-4-yl)-1-(3-bromophenyl)-1,4-dihydro/(1,8|-naphthyridin-4-one-3-carboxamide

The mixture from stage 2 in the form of a brown suspension is added through a syringe to the cold suspension from stage 1.

The resulting mixture was stirred at room temperature for 18 hours, quenched with an aqueous saturated solution of ammonium chloride, and partitioned between ethyl acetate and water. After evaporation of the organic phase, the crude product is triturated with ether (BOml) and filtered to obtain

IM-(2,6-dichloropyridin-4-yl)-1-(3-bromophenyl)-1,4-dihydro|1,8I-naphthyridin-4-one-3-carboxamide as a beige solid.

TN NMR (Acetone-dv) 5 7.61-7.70 (m, 2H), 7.76 (d, 1H), 7.81 (d, 1H), 8.00 (s, 1H), 8, 62 (s, 2H), 8.80 (ush.s, 1H), 8.86 (d, 1H), 8.99 (s, 1H) 12.1 (ush., MN).

Stage A:

IM-(2,6-Dichloropyridin-4-yl)-1-I3-"3-acetylphenyl)phenyl|-1,4-dihydro-I1,8)naphthyridin-4-one-3-carboxamide

According to the method of stage 5 of example 1, but replacing 70... -carboxamide from stage Z

M-isopropyl-1-(3-bromophenyl)-1,4-dihydro|!1,8|Inaphthyridin-4-one-3-carboxamide, obtain

M-(2,6-dichloropyridin-4-yl)-1-3-(3-acetylphenyl)phenyl/|-1,4-dihydro/1,8)naphthyridin-4-one-3-carboxamide as a solid .

TN nMR (SOCI8) 5 2.65 (s, ЗН), 7.47 (d, 1Н), 7.50-7.60 (m, 2Н), 7.70 (m, 2Н), 7.82 ( d, 2H), 7.98 (d, 1H), 8.20 (s, 1H), 8.55 (s, 2H), 8.75 (ush.s, 1H), 8.92 (dd, 1H ), 9.14 (s, 1H) 12.08 (ush., MN).

Example C

M-isopropyl-1-3-(4-n-propylphenyl)phenyl)-1,4-dihydro/(1,8)naphthyridine-4-one-3-carboxamide

I s o s «- iv)

According to the method of stage 5 of example 1, but replacing 4-n-propylphenylboronic acid with 3-acetylphenylboronic acid, the title compound is obtained as a white solid. 325 "IN NMR (Acetone-dv) 5 0.93 (t, ЗН), 1.24 (d, 6Н), 1.65 (m, 2Н), 2.62 (t, 2Н), 4.18 ( m, 1H), 7.31 (d, 2H), - 7.58-7.61 (m, 2H), 7.68-7.72 (m, ЗН), 7.87 (d, 1H), 7.95 (s, 1H), 8.72 (m, 1H), 8.78 (dd, 1H), 8.92 (s, 1H), 9.66 (ush., MH).

Example 4

M-Isopropyl-1-3-(4-acetylphenyl)phenyl/|-1,4-dihydro/1,8)naphthyridin-4-one-3-carboxamide « shi c z -I se) 1 - 50

IR e)

According to the method of stage 5 of example 1, but replacing 3-acetylphenylboronic acid with 4-acetylphenylboronic acid, the title compound is obtained as a solid. "YAN NMR (Acetone-dv) 5 1.25 (5, 6Н), 2.61 (s, ЗН), 4.17 (m, 1Н), 7.59 (m, 1Н), 7.70 (d , 1H), 7.76 (t, 1H),

F) 7.92 (d, 2H), 7.97 (d, 1H), 8.07-8.10 (m, ZH), 8.72 (ush.s, 1H), 8.78 (dd, 1H), 8.92 (c, 1H) 9.65 (ear, MN). Example 5

M-isopropyl-1-|3-(2-methylphenyl)phenyl)-1,4-dihydro/1,8)naphthyridin-4-one-3-carboxamide 60 b5

According to the method of stage 5 of example 1, but replacing 2-methylphenylboronic acid with 3-acetylphenylboronic acid, the title compound is obtained as a solid.

TN NMR (Acetone-dv) 5 1.24 (d, 6H), 2.35 (s, ЗН), 4.17 (m, 1), 7.27-7.34 (m, 4H), 7, 56-7.60 (m, 2H), 7.65 (m, 2H), 7.70 (t, 1H), 8.74 (m, 1H), 8.78 (dd, 1H), 8.92 (c, 1H) 9.64 (early, MN).

Example 6

M-Isopropyl-M-methyl-1-3-(4-acetylphenyl)phenyl/|-1,4-dihydro/1,8)naphthyridin-4-one-3-carboxamide c (8) c «- . iv)

Step 1: M-Isopropyl-M-methyl-1-(3-bromophenyl)-1,4-dihydro|1,8|Inaphthyridin-4-one-3-carboxamide (22)

According to the method of example 1, stage 4, but replacing M-isopropyl-M-methylamine with isopropylamine, they obtain

M-isopropyl-M-methyl-1-(3-bromophenyl)-1,4-dihydro|!1,8|Inaphthyridin-4-one-3-carboxamide as a yellow solid.

TN NMR (Acetone-dv) (exists as two amide rotamers) b 1.18 (m, 6H), 2.85 (s, ЗН), 4.05 (m, 0.5 H), « 4.84 (m, 0.5 N), 7.49-7.64 (m, ЗН), 7.72 (d, 1Н), 7.86 (s, 1Н), 8.14 (s, 1Н), 8 .65 (d, 2H).

Stage 2: M-Isopropyl-M-methyl-1-(3-(4-acetylphenyl)phenyl)-1,4-dihydro|1,8|-naphthyridin-4-one-3-carboxamide 8 s According to the method of the stage 5 of example 1, but also replacing M-isopropyl-M-methyl-1-(3-bromophenyl)-1,4-dihydro|!1,8|Inaphthyridin-4-one-3-carboxamide from stage 1 "" M- isopropyl-1-(3-bromophenyl)-1,4-dihydro|!1,8|Inaphthyridin-4-one-3-carboxamide, and replacing 4-acetylphenylboronic acid with 3-acetylphenylboronic acid gives

M-isopropyl-M-methyl-1-I3-4-acetylphenyl)phenyl/|-1,4-dihydro/1,8|-naphthyridin-4-one-3-carboxamide as a white solid. c TN NMR (SOCI") (exists in the form of two amide rotamers) 5 1.23 (m, 6Н), 2.62 (с, ЗН), 4.00 (m, 0.5 Н), 4.92 ( m, 0.5 H), 7.38-7.55 (m, 2H), 7.63-7.77 (m, 5H), 8.03 (d, 2H), 8.14 (s, 0 .5 H), 8.21 (s, 0.5 H), 8.65 (m, 1 1H), 8.75-8.80 (m, 1H). shu 720 Example 7

M-isopropyl-1-3-(pyridin-3-yl)phenyl-1,4-dihydro|1,8|inaphthyridin-4-one-3-carboxamide

IR e) with Ken

F) name) 60

According to the method of stage 5 of example 1, but replacing pyridine-3-boronic acid 1,3-propanediol cyclic b5 ether with 3-acetylphenylboronic acid, and replacing (1,1"-bisyidiphenylphosphino)ferrocene|dichloropalladium (II) trans-dibrombis(triphenylphosphine) palladium (II), the title compound is obtained as a beige solid.

TN NMR (Acetone-dv) 5 1.24 (d, 6H), 4.17 (m, 1H), 7.48 (m, 71H), 7.60 (m, 1H), 7.71 (dd, 1H), 7.78 (t, 1H), 7.95 (dd, 1H), 8.05 (ush.s, 1H), 8.15 (m, 1H), 8.60 (m, 1H), 8.72 (m, 1H), 8.78 (dd, 1H), 8.92 (s, 1H), 8.99 (ush.s, 1H), 9.65 (ush., MH).

Example 8

M-isopropyl-1-3-(indol-5-yl)phenyl-1,4-dihydro|!1,8|inaphthyridin-4-one-3-carboxamide

According to the method of stage 5 of example 1, but replacing 9-acetylphenylboronic acid with 5-indolylboronic acid, the title compound is obtained as a whitish solid.

TN NMR (DMSO-yv) 5 1.20 (d, 6H), 4.10 (m, 1H), 6.47 (s, 1H), 7.38 (ush.s, 1H), 7.46- 7.52 (m, ZN), 7.59-7.66 (m, 2H), 7.87-7.93 (m, ZN), 8.72-8.81 (m, ZN), 9, 67 (ush., MN), 11.2 (ush., MN). Gee!

Example 9 Fr

M-tert-Butyl-1-3-4-acetylphenyl)phenyl/|-1,4-dihydro|!1,8|Inaphthyridin-4-one-3-carboxamide c «-

IS) (22) and - "shi c Stage 1: M-tert-Butyl-1-(3-bromophenyl)-1,4-dihydro(1,8)naphthyridin-4-one-3-carboxamide :z" By by the method of example 1, stage 4, but replacing isopropylamine with tert-butylamine, we get

N-tert-butyl-1-(3-bromophenyl)-1,4-dihydro|(1,8|-naphthyridine-4-one-3-carboxamide) as a yellow solid.

TN NMR (Acetone-dv) 5 1.44 (s, 9H), 7.58-7.62 (m, 2H), 7.70 (dd, 1H), 7.78 (dd, 1H), 7, 93 (ush.s, 1H), -I 8.72 (m, 1H), 8.77 (dd, 1H), 8.81 (s, 1H) 9.73 (ush., MN).

Stage 2: M-tert-Butyl-1-|3-(4-acetylphenyl)phenyl)-1,4-dihydro/(1,8|-naphthyridin-4-one-3-carboxamide) According to the method of stage 5 of example 1, but replacing with N-tert-butyl-1-(3-bromophenyl)-1,4-dihydro/1,8)naphthyridin-4-one-3-carboxamide from stage 1

M-isopropyl-1-(3-bromophenyl)-1,4-dihydro|!1,8|Inaphthyridin-4-one-3-carboxamide, and replacing 4-acetylphenylboronic acid with 3-acetylphenylboronic acid is obtained with M-tert- butyl-1-I3-4-acetylphenyl)phenyl|-1,4-dihydro|!1,8|naphthyridin-4-one-3-carboxamide with a yield of 9395 in the form of a white solid.

TN o NMR (Acetone-dbv) 5 1.45 (s, 9H), 2.61 (s, ЗН), 7.59 (m, 1), 7.69-7.72 (m, 1), 7 .77 (t, МН), 58 7.92-7.99 (m, ЗН), 8.07-8.11 (m, ЗН), 8.72 (m, 1Н), 8.78 (dd, 1H), 8.91 (c, 1H), 9.79 (ear, MH).

Example 10 o M-(2,6-Dichloropyridin-4-yl)-1-3-(pyridin-3-yl)phenyl/|-1,4-dihydro|1,8|-naphthyridin-4-one-3 -carboxamide ime) 60 b5

:

According to the method of stage 4 of example 2, but replacing |1,1-bisidiphenylphosphino)ferrocene|dichloropalladium (II) with trans-dibromobis-(triphenylphosphine)palladium (I) and replacing pyridine-3-boronic acid with 1,3-propanediol cyclic ether З- acetylphenylboronic acid, the title compound is obtained as a transparent solid.

TN NMR (Acetone-dv) 6 7.48 (m, 1H), 7.68 (m, 1H), 7.77-7.82 (m, 2H), 7.98 (m, 1H), 8, 12-8.17 (m, 2H), 8.61 (m, 1H), 8.62 (s, 2H), 8.80 (m, 1H), 8.88 (dd, 1H), 8.99 (ush.s, 1H), 9.06 (s, 1H), 12.2 (ush., MH).

Example 11

M-Isopropyl-1-(3-I4-(4-tertbutyloxycarbonylpiperazin-1-yl)phenyl|phenyl)-1,4-dihydro/(1,8|naphthyridin-4-one-3-carboxamide) "-

IS) (22) m. shi s :z» Stage 1: 4-tert-Butyloxycarbonyl-1-(3-bromophenyl)piperazine

A catalytic amount of 4-dimethylaminopyridine (4.54g, 37.159mmol) -1 followed by the addition of triethylamine (155 ml, 1114.77 mmol) and di-tert-butyl dicarbonate (121.65 g, 557.385 mmol, dissolved in a minimal amount of acetonitrile), and the resulting reaction mixture was heated to se) room temperature and stirred for 5.5 hours. The reaction mixture is filtered, ethyl acetate is added, and the organic phase is washed with 10956 aqueous citric acid, water (2x) and saturated salt solution, then dried and evaporated to obtain the crude product 4-tert-butyloxycarbonyl-1-(3-bromophenyl)piperazine, which is used as such at the next stage. co Stage 2: 3-(4-tert-Butyloxycarbonylpiperazin-1-yl)-phenylboronic acid

To //4-tert-butyloxycarbonyl-1-(3-bromophenyl)piperazine from stage (1 (118.30g, 346b,mmol) in tetrahydrofuran/toluene (1/1, 1.5l) at a temperature of -782C in a nitrogen atmosphere n-butyllithium (2.5M, 16Oml, 398.9mmol) was added dropwise, and the resulting reaction mixture was stirred at a temperature of -782C for 20 minutes.

Triisopropylborate (96.1 ml, 416.0 mmol) is added dropwise, and the reaction mixture is heated to 02C and (F, stirred for 2 hours. Aqueous saturated ammonium chloride (40Oml), water (1O0Oml) and 1 equivalent of H3PO, (2Oml ), and the mixture is stirred for 15 minutes, then concentrated to a volume of approximately 200 ml (at this stage the mixture becomes bluish and a precipitate forms). The mixture is slowly diluted with heptane (800 ml) as the resulting suspension is stirred overnight. The suspension is filtered, the solid is washed with heptane and dried to obtain the boric acid indicated in the title.

Stage C:

M-Isopropyl-1-(3-(4-(4-tertbutyloxycarbonylpiperazin-1-yl)phenyl|-phenyl)-1,4-dihydro|!1,8|Inaphthyridin-4-one-3-car boxamide 65 Per by the method of stage 5 of example 1, but replacing |1,1-bisidiphenylphosphino)ferrocene|dichloropalladium (II) with trans-dibromobis-(triphenylphosphine)palladium (I) and replacing 3-acetylphenylboronic acid with boric acid from stage 2, 4-tert-butyloxycarbonyl- 1-(3-bromophenyl)piperazine derivative as a solid. "YAN iNMR (SOSIz) 5 1.30 (d, 6H), 1.49 (s, 9H), 3.18 (m, 4H), 3.58 (m, 4H), 4.29 (m, 1 ), 6.98 (d, 2H), 7.32 (d, 71H), 7.45 (m, 1H), 7.53 (d, 2H), 7.55-7.62 (m, 2H) , 7.72 (d, 1H), 8.70 (m, 1H), 8.82 (d, 1H), 9.07 (s, 1H), 9.68 (ush., MH).

Example 12

M-Isopropyl-1-3-(quinoline-3-iluphenyl/|-1,4-dihydro/1,8|naphthyridin-4-one-carboxamide

According to the method of stage 5 of example 1, but substituting 3-quinolinboronic acid for 3-acetyl phenylboronic acid, the title compound is obtained as a solid.

TN nMR (SOCI3) 5 1.29 (d, 6H), 4.29 (m, 1H), 7.49 (m, 2H), 7.61 (t, 1H), 7.70-7.78 ( m, ZN), 7.86-7.92 (m, 2H), 8.14 (d, 1H), 8.36 (s, 1H), 8.71 (m, 1H), 8.84 (dd , 1H), 9.10 (c, 1H), 9.19 (c, 1H) 9.67 (ush., MH). Ha

Example 13 Fr

M-Isopropyl-1-3-(pyrimidin-5-yl)phenyl|-1,4-dihydro|1,8Inaphthyridin-4-one-carboxamide and c «-

IS) (22) m. « shi c According to the method of stage 5 of example 1, but replacing 3-acetylphenylboronic acid with 5-pyrimidineboronic acid, . the title compound is obtained as a solid. "» TN NMR (SOCI3) 5 1.28 (d, 6H), 4.27 (m, 1H), 7.48 (dd, 1H), 7.52 (m, 1H), 7.65 (s, 1H), 7.74 (m, 2H), 8.68 (m, 1H), 8.72 (d, 1H), 8.98 (s, 2H), 9.03 (s, 1H), 9, 22 (c, 1H) 9.62 (ear, MN).

Example 14 - and M-Cyclopropyl-1-(Z-«(pyridin-Z3-yl)uphenyl/|-1,4-dihydro|1,8Inaphthyridin-4-one-3-carboxamide se) 1 - 50' 42)

AND

F) yuyu ' 60 Stage 1: M-Cyclopropyl-1-(3-bromophenyl)-1,4-dihydro|1,8|Inaphthyridin-4-one-3-carboxamide

According to the method of example 1, stage 4, but replacing cyclopropylamine with isopropylamine, we get

M-cyclopropyl-1-(3-bromophenyl)-1,4-dihydro|1,8|-naphthyridin-4-one-3-carboxamide as a fluffy solid.

TN nMR (Acetone-dv) 5 0.59 (m, 2H), 0.80 (m, 2H), 2.96 (m, 1H), 7.59-7.68 (m, 2H), 7, 72 (dd, 1H), 7.82 bo (dd, 1H), 7.97 (s, 1H), 8.72-8.81 (m, 2H), 8.89 (s, 1H) 9.70 (Us., MN).

Step 2: M-Cyclopropyl-|(Z-(pyridin-3-yl)phenyl|-1,4-dihydro|1,81-naphthyridin-4-one-3-carboxamide

According to the method of example 7, but replacing

M-cyclopropyl-i-(3-bromophenyl)-1,4-dihydro|!1,8|Inaphthyridin-4-one-3-carboxamide from stage 1

M-isopropyl-1-(3-bromophenyl)-1,4-dihydro|!1,8|Inaphthyridin-4-one-3-carboxamide, obtain

M-Cyclopropyl-1-3-(pyridin-3-yl)phenyl/|-1,4-dihydro|!1,8|inaphthyridin-4-one-3-carboxamide as a cream solid.

TN nMR (DMSO-in) 5 0.57 (m, 2H), 0.78 (m, 2H), 2.91 (m, 1H), 7.52 (m, 1H), 7.63-7, 69 (m, 2H), 7.74 (t, 1H), 7.97 (d, 1H), 8.07 (sh.s, 1H), 8.17 (d, 7H), 8.61 (m , 71H), 8.73 (dd, 1H), 8.79 (m, 1H), 8.85 (s, 1H), 70 8.99 (ush.s, 1H), 9.74 (ush, MH ).

Example 15

M-Isopropyl-1-3-(5-methylthiopyridin-3-yl)uphenyl/|-1,4-dihydro|1,8|-naphthyridin-4-one-3-carboxamide c

According to the method of stage 5 of example 1, but replacing 3-acetylphenylboronic (8) acid with 5-methylthiopyridine-3-boronic acid, and replacing (1,1-bisbidiphenylphosphino)ferrocene|dichloropalladium (I) with trans-dibromobis-(triphenylphosphine)palladium (II) ) obtain the title compound in the form of a solid substance. c zo TN nMR (SOCI8) 6 1.33 (d, 6H), 2.60 (s, ЗН), 4.33 (m, 1), 7.48-7.54 (m, 2H), 7, 66 (m, 1H), 7.73 (t, 1H), 7.78-7.81 (m, 2H), 8.55 (s, 1H), 8.66 (s, 1H), 8.74 (m, 1H), 8.87 (d, 1H), 9.09 (s, 1H), 9.69 (ush., MH). -

Example 16

M-Cyclopropyl-1-3-(4-hydroxymethylphenyl)phenyl)-1,4-dihydro/(1,8-naphthyridin-4-one-3-carboxamide) that According to the method of stage 2 of example 14, but replacing the 1,3-propanediol cyclic ether with 4-hydroxymethylphenylboronic acid of pyridine-3-boronic acid, the compound specified in the title is obtained as a solid. , 2H), 0.89 (m, 2H), 1.88 (t, 1H), 3.03 (m, 1H), 4.78 (d, 2H), 7.43 (d, 1H), s 7.46-7.52 (m, ZN), 7.61-7.69 (m, 4H), 7.80 (d, 1H), 8.73 (m, 1H), 8.83 (dd, 1H), 9.10 (c, 1H), 9.82 (ush, MH).

Example 17 - M-Cyclopropyl-1-3-(pyridin-4-yl)phenyl)-1,4-dihydro(1,8)naphthyridin-4-one-3-carboxamide

IR e)

F) name) 60

According to the method of stage 5 of example 1, but replacing 65 | M-cyclopropyl-1-(3-bromophenyl)-1,4-dihydro|1,8)inaphthyridin-4-one-3-carboxamide

M-isopropyl-1-(3-bromophenyl)-1,4-dihydro|!1,8|Inaphthyridin-4-one-3-carboxamide, and replacing 3-acetylphenylboronic acid with /4-pyridineboronic acid gives the title compound in in the form of a white solid.

TN nMR (DMSO-in) 5 0.57 (m, 2H), 0.77 (m, 2H), 2.90 (m, 1H), 7.64 (m, 1H), 7.72-7, 89 (m, 4H), 8.03 (d, 1H), 8.13 (s, 1H), 8.66-8.78 (m, 4H), 8.84 (s, 1H) 9.72 ( ear., MN).

Example 18

M-Cyclopropyl-1-3-(4-ethylthiophenyl)phenyl|-1,4-dihydro|1,8Inaphthyridin-4-one-3-carboxamide

According to the method of stage 2 of example 14, but replacing the 1,3-propanediol cyclic ether with 4-ethylthiobenzeneboronic acid of pyridine-3-boronic acid, the title compound is obtained as a solid.

TN nMR (SOCI3) 5 0.72 (m, 2H), 0.90 (m, 2H), 1.48 (t, ЗН), 3.03 (m, ЗН), 7.42 (d, ЗН) , 7.50 (m, 1H), 7.57 (d, 2H), 7.64 (s, 1H), 7.68 (t, 1H), 7.78 (d, 1H), 8.75 ( m, 1H), 8.85 (d, 1H), 9.10 (s, 1H), 9.83 (ear, MH).

Example 19 se

M-Cyclopropyl-1-3-(3-thienyl)phenyl)-1,4-dihydro/1,8)naphthyridin-4-one-3-carboxamide

IS) and (22) m.

According to the method of stage 2 of example 14, but replacing 3-thiophenboric acid of pyridine-3-boronic acid with 1,3-propanediol cyclic ether, the title compound is obtained as a solid. From TN NMR (Acetone-dv) 5 0.60 (m, 2H), 0.79 (m, 1H), 2.96 (m, 1H), 7.57-7.72 (m, 5H), 7.92-7.98 (m, 2H), s 8.05 (s, 1H), 8.74 (s, 1H), 8.78 (d, 1H), 8.93 (s, 1H) 9 ,74 (Us., MN). Example 20

M-Cyclopropyl-1-|3-(4-sulfamoylphenyl)phenyl]-1,4-dihydro|1,8|Inaphthyridin-4-one-3-carboxamide ! - se) 1 - 50

IR e)

F) name)

Stage 1: Pinacone ester of 4-sulfamoylbenzeneboronic acid 60 A mixture of 4-bromobenzenesulfonamide, diborpinacone ether (1.1 eq.), potassium acetate (3.eq. and

I1,1-bisbidiphenylphosphino)ferrocene|dichloropalladium (I) (0.0 equiv.) in M,M-dimethylformamide (4 ml/mmol) is heated at a temperature of 8593 for 18 hours. After quenching with a saturated aqueous solution of ammonium chloride, the mixture was partitioned between ethyl acetate and water, and the product from the organic phase was subjected to chromatography on silica gel, eluting with a 1:1 mixture of ethyl acetate and hexane to give 4-sulfamoylbenzeneboronic acid 65 Ppinacone ether as a solid.

Step 2: M-Cyclopropyl-1-3-(4-sulfamoylphenyl)phenyl)-1,4-dihydro[1,8]-naphthyridine-4-one-3-carboxamide

A mixture of M-cyclopropyl-1-(3-bromophenyl)-1,4-dihydro|1,8|Inaphthyridin-4-one-3-carboxamide, borate from stage 1 (1.2 equiv.) palladium acetate (0.Eq. ), triphenylphosphine (0.3 bEq.) and 2M aqueous sodium carbonate (3.Eq.) in n-propanol (TOml/mmol) are stirred at a temperature of 8523 for 1 hour. After cooling, the mixture is quenched with a saturated aqueous solution of ammonium chloride and distributed between ethyl acetate and water, and the product from the organic phase is subjected to chromatography on silica gel eluting with a 1:5:4 mixture of ethanol, ethyl acetate and methylene chloride Kk! receiving

M-cyclopropyl-1-|I3--4-sulfamoylphenyl)phenyl!/-1,4-dihydro/1,8Inaphthyridin-4-one-3-carboxamide as a solid. 70 TN NMR (Acetone-dv) 5 0.62 (m, 2H), 0.82 (m, 2H), 2.98 (m, 1H), 6.66 (ush., MH"), 7.64 (m, 1H), 7.74 (m, 1H), 7.80 (t, 1H), 7.97-8.05 (m, 5H), 8.10 (m, 1H), 8.76 ( m, 1H), 8.81 (dd, 1H), 8.97 (s, 1H), 9.77 (ush., MH).

Example 21

M-Isopropyl-1-3-(3-ethoxyphenyl)phenyl/|-1,4-dihydro|!1,8|Inaphthyridin-4-one-3-carboxamide c o

Stage 1: Ethyl 1-3-(3-ethoxyphenyl)phenyl/|-1,4-dihydro|!1,8|inaphthyridin-4-one-3-carboxylate

According to the method of stage 5 of example 1, but replacing 1-(3-bromophenyl)-1,4-dihydro/(1,8)|naphthyridin-4-one-3-carboxylate from stage 2 of example 1

M-isopropyl-1-(3-bromophenyl)-1,4-dihydro|!1,8|Inaphthyridin-4-one-3-carboxamide, and replacing 3-ethoxybenzeneboronic acid with 3-acetylbenzeneboronic acid gives the compound ethylyl 1- 13-(3-ethoxyphenyl)phenyl|-1,4-dihydro|1,8-inaphthyridin-4-one-3-carboxylate as a solid.

Stage 2: 1-I3-(3-Ethoxyphenyl)phenyl)-1,4-dihydro/1,8)naphthyridin-4-one-3-carboxylic acid IC o)

According to the method of stage C of example 1, but replacing ethyl b 1-I3-(3-ethoxyphenyl)phenylc|-1,4-dihydro|1,8|Inaphthyridin-4-one-3-carboxylate from stage 1 ethyl 1-( 3-bromophenyl)-1,4-dihydro|!1,8|Inaphthyridin-4-one-3-carboxylate, the compound 1-13-(3-ethoxyphenyl)phenyl|-1,4-dihydro|1 is obtained, 8Inaphthyridin-4-one-3-carboxylic acid, which is used at the next stage without purification.

Stage 3: M-Isopropyl-1-3-(3-ethoxyphenyl)phenyl)-1,4-dihydro(1,8)naphthyridine-4-one-3-carboxamide

A mixture of 1-I3-(3-ethoxyphenyl)phenyl|-1,4-dihydro (|1,8)) naphthyridin-4-one-3-carboxylic acid from step 2 and thionyl chloride (4 eq.) in tetrahydrofuran (1LOml/mmol ) is boiled under reflux for 45 - s minutes, then evaporated. The residue is dissolved in the same volume of tetrahydrofuran, isopropylamine (eq.) is added, and the mixture is stirred at room temperature for 18 hours. After quenching with a saturated aqueous solution of ammonium chloride, the resulting mixture was partitioned between ethyl acetate and water, and the product from the organic phase was subjected to chromatography on silica gel, eluting with 1095 ether in methylene chloride to give

M-isopropyl-1-3-(3-ethoxyphenyl)phenyl/|-1,4-dihydro/1,8|inaphthyridin-4-one-3-carboxamide in the form of a solid substance. co TN NMR (SOCI3) 5 1.29 (d, 6H), 1.42 (t, ЗН), 4.08 (q., 2H), 4.28 (m, 1H), 6.91 (d, 1H), 7.12 (s, 1H), 7.18 (dD, 7), 7.34 (t, 71H), 7.40 (d, 1H), 7.46 (m, 1H), 7, 60-7.65 (m, 2H), 7.75 (d, 1H), 8.71 (ush.s, 1H), o 8.82 (dd, 1H), 9.08 (s, 1H), 9.70 (Ush., MN). -- 70 Example 22 with M-Isopropyl-1-3-(4-methylthiophene)phenyl)-1,4-dihydro(1,8)naphthyridin-4-one-3-carboxamide

F) name) 60 b5

Stage 1: Ethyl 1-3-4-methylthiophenyl)phenyl/|-1,4-dihydro|!1,8|naphthyridine-4-one-3-carboxylate

According to the method of stage 5 of example 1, but replacing 1-(3-bromophenyl)-1,4-dihydro/(1,8)|naphthyridin-4-one-3-carboxylate from stage 2 of example 1

M-isopropyl-1-(3-bromophenyl)-1,4-dihydro|1,8|Inaphthyridin-4-one-3-carboxamide, and replacing 3-acetylbenzeneboronic acid with 4-methylthiobenzeneboronic acid gives the compound ethyl 1-(3- -4-methylthiophenyl)phenyl/|-1,4-dihydro|1,8|Inaphthyridin-4-one-3-carboxylate as a solid.

Stage 2: 1-I3-(4-Methylthiophenyl)phenyl|-1,4-dihydro|1,8Inaphthyridin-4-one-3-carboxylic acid

According to the method of stage C of example 1, but replacing ethyl 70 with 1-(3--4-methylthiophenyl)phenyl/|-1,4-dihydro|!1,8|Inaphthyridin-4-one-3-carboxylate from stage 1 ethyl 1 -(3-bromophenyl)-1,4-dihydro|1,8|naphthyridin-4-one-3-carboxylate, the compound 1-(3--4-methylthiophenyl)phenyl/|-1,4-dihydro|! 1,8|Inaphthyridin-4-one-3-carboxylic acid as a solid.

Step 3: M-Isopropyl-1-(3-(4-methylthiophenyl)phenyl/)-1,4-dihydro/(1,8|-naphthyridin-4-one-3-carboxamide

According to the method of stage C of example 21, but replacing 1-(3--4-methylthiophenyl)phenyl/|-1,4-dihydro|!1,8|Inaphthyridin-4-one-3-carboxylic acid with 1-I3-(З -ethoxyphenyl)phenylic|-1,4-dihydro|!1,8|Inaphthyridin-4-one-3-carboxylic acid is obtained

M-isopropyl-1-3-(4-methylthiophenyl)phenyl)-1,4-dihydro|1,8|inaphthyridin-4-one-33-carboxamide as a white solid.

TN NMR (Acetone-dv) 5 1.24 (d, 6H), 2.52 (s, ЗН), 4.18 (m, 1H), 7.37 (d, 2H), 7.58-7, 62 (m, 2H), 7.69-7.73 (m, ЗН), 7.87 (d, 1H), 7.96 (s, 1H), 8.72 (m, 1H), 8.78 (dd, 1H), 8.91 (s, 1H), 9.65 (ush., MN).

Example 23

M-Isopropyl-1-3-(3-acetyl-4-hydroxyphenyl)phenyl/|-1,4-dihydro|1,8|-naphthyridin-4-one-3-carboxamide c o c ' i "-

IS) (22) and -

A mixture of 5-bromo-2'-hydroxyacetophenone, diborpinacone ether (1.2 eq.), potassium acetate (Zeq.) and

I1,1-bisbidiphenylphosphino)ferrocene|dichloropalladium (I) (0.0 equiv.) in M,M-dimethylformamide (T1Oml/mmol) is stirred at a temperature of 809C for 3 hours and cooled. Add solution "

M-isopropyl-1-(3-bromophenyl)-1,4-dihydro|!1,8|Inaphthyridin-4-one-3-carboxamide from example 1, stage 4 (0.75 eq.) in M,M-dimethylformamide (7 ml/mmol), (|1,1-bis(idiphenylphosphino)ferrocene|-dichloropalladium (II) (0.O05 beq.) and 2M - s of aqueous sodium carbonate (8.beq.), The resulting mixture is stirred at a temperature of 802С for 2.5 hours. The cooled mixture was partitioned between ethyl acetate and water, and the product from the organic phase was chromatographed on silica gel eluting with ethyl acetate in hexane to give the title compound as a pale yellow solid. Acetone-dv) 5 1.24 (d, 6H), 2.75 (s, ЗН), 4.19 (m, 1H), 7.06 (d, 1H), 7.59-7.63 (m , 2H), 7.72 (t,

She 1H), 7.92 (d, 1H), 7.97 (d, 1H), 8.02 (s, 1H), 8.33 (s, 1H), 8.73 (m, 1H), 8 .78 (dd, 1H), 8.90 (s, 1H), 9.65 (uip., MH).

Te) Example 24, sl M-isopropyl-1-3-(5-carboethoxypyridin-3-yl)phenyl)-1,4-dihydro[(1,8|-naphthyridin-4-one-3-carboxamide) - 50 so

F) yuyu. . 60

According to the method of example 23, but replacing

M-isopropyl-1-(3-bromophenyl)-1,4-dihydro|!1,8|Inaphthyridin-4-one-3-carboxamide 5'-bromo-2-hydroxyacetophenone, replacing M-isopropyl-1-5-bromonicotinate -(3-bromophenyl)-1,4-dihydro|1,8|Inaphthyridin-4-one-3-carboxamide, in5 the title compound is obtained as a beige solid.

TN NMR (SOCI3) 5 1.29 (d, 6H), 1.40 (t, ЗН), 4.28 (m, 1H), 4.42 (q., 2H), 7.45-7.51 (m, 2H), 7.68 (s,

1H)U, 7.71 (t, 7H), 7.80 (d, 1H), 8.49 (s, 1H), 8.59 (m, 1H), 8.82 (d, 71H), 9 .03 (s, 1H), 9.07 (s, 1H), 9.23 (s, 1H) 9.64 (ush., MH).

Example 25

M-isopropyl-1-(3-N5-(1-hydroxy-1-methylethyl)pyridin-3-yl|-phenyl)-1,4-dihydro/(1,8)naphthyridin-4-one-3-carbox amd, 11111111

Stage 1: 3-Bromo-5-(1-hydroxy-1-methylethyl)pyridine

To a solution of ethyl 5-bromonicotinate (1.02g, 44mmol) in diethyl ether (15ml) at a temperature of -302C, add 3M solution of methylmagnesium bromide (4ml, 12mmol) in ether. The resulting suspension is then refluxed for 2 hours, then cooled and quenched with an excess of 0.5M aqueous monobasic sodium phosphate and partitioned between ether and water. The product from the organic phase was chromatographed on silica gel, eluting with a 2:1:2 mixture of ether, pentane, and ammonium-saturated methylene chloride, to give the compound 3-bromo-5-(1-hydroxy-1-methylethyl)pyridine as a yellow oil. Gee)

Stage 2:

M-isopropyl-1-13-15-(1-hydroxy-1-methylethyl)pyridin-3-yl|-phenyl)-1,4-dihydro/1,8)naphthyridin-4-one-3-carboxamide

According to the method of example 24, but substituting 3-bromo-5-(1-hydroxy-1-methylethyl)pyridine from stage 1 of ethyl 5-bromonicotinate, the title compound is obtained in the form of a yellow foam. so "YAN YMR (SOSI8) 5 1.28 (d, 6H), 1.62 (s, 6H), 2.52 (ush.s, 1H), 4.25 (m, 1H), 7.41- 7.48 (m, 2H), 7.60-7.68 "-- (m, 2H), 7.75 (d, 1H), 8.05 (s, 1H), 8.67-8.71 (m, ZN), 8.80 (dd, 1H), 9.03 (s, 1H) 9.66 (ush., MN).

Example 26 Fr

M-isopropyl-1-13-16-(2-methylpropyl)pyridin-3-yl|-phenyl)-1,4-dihydro|1,8|-naphthyridin-4-one-3-carboxamide Ge) and - « - with ;" -I (Se) Stage 1: 5-Bromo-2-(2-methylpropyl)pyridine sl To a solution of 2,5-dibromopyridine (4.5g, 19mmol) in tetrahydrofuran (BOml) is added

1,1-bisbidiphenylphosphino)ferrocene|dichloronickel (II) (10 mg, 0.1 μmol) and the resulting mixture is cooled to a temperature of -10C. A 2M solution of isobutylmagnesium bromide in ether (12.4 mL, 24.7 mmol) is slowly added, and the mixture is stirred at a temperature from -10 to 102 for 3.5 hours. After quenching with saturated aqueous ammonium chloride solution, the mixture is partitioned between ether and water, and the product from the organic phase is chromatographed on silica gel, eluting with 1095 ether in pentane to give / compound 5-bromo-2-(2-methylpropyl)pyridine as a volatile oil

Stage 2: (F) M-isopropyl-1-(3-16-(2-methylpropyl)pyridin-3-ylphenyl)-1,4-dihydro/1,8)naphthyridin-4-one-3-carboxamide by the method of example 24, but replacing ethyl 5-bromonicotinate with 5-bromo-2-(2-methylpropyl)-pyridine from stage 1, the compound is obtained as M-isopropyl-1-13-16-(2-methylpropyl)pyridin-3-ylphenyl )-1,4-dihydro/1,8)naphthyridine-4-one-3-carboxamide. as a white solid.

TN NMR (SOCI3) 5 0.92 (d, 6H), 1.28 (d, 6H), 2.10 (m, 1H), 2.69 (d, 2H), 4.28 (m, 1H) , 7.19 (d, 1H), 7.40-7.47 (m, 2H), 7.60 (s, 1H), 7.64 (t, 1H), 7.73 (d, 1H), 7.79 (dd, 1H), 8.68 (m, 1), 8.77-8.83 (m, 2H), 9.05 (s, 1H), 9.66 (ush., MH). 65 Example 27

M-Isopropyl-1-3-(5-acetylpyridin-3-yl)phenyl/|-1,4-dihydro/1,8)naphthyridin-4-one-3-carboxamide

:

Stage 1: 3-Acetyl-5-bromopyridine 19 To a solution of ethyl 5-bromonicotinate (3.9g, 16.9mmol) in ether (HOml) at a temperature of 09C, add a 3M solution of methylmagnesium bromide (16g, 0ml, 50.8mmol). The resulting thick suspension is slowly heated to room temperature, and after 1.5 hours it is slowly poured into an excess of 1M aqueous monobasic sodium phosphate.

The mixture is partitioned between ether and water, and the product from the organic phase is chromatographed on silica gel, eluting with a 1:1:2 mixture of ether, pentane, and saturated ammonium methylene chloride, to give the compound

C-acetyl-5-bromopyridine. This technique also gives 3-bromo-5-(1-hydroxy-1-methylethyl)pyridine, described in Example 25.

Step 2: M-isopropyl-1-I(3--5-acetylpyridin-3-yl)phenyl|-1,4-dihydro|1,81-naphthyridin-4-one-3-carboxamide

According to the method of example 23, but replacing ethyl 5-bromonicotinate with 3-acetyl-5-bromopyridine from stage 17, compound 29 M-isopropyl-1-3-(5-acetylpyridin-3-yl)phenyl/|-1,4 -dihydro|1,8|Inaphthyridin-4-one-3-carboxamide in the form of a white Ge) solid. NMR (SOCI5) 5 1.29 (d, 6H), 2.69 (s, ЗН), 4.28 (m, 1H), 7.48 (dd, 1H), 7.51 (d, 1H ), 7.69 (s, 1H), 7.72 (t, 1H), 7.80 (d, 1H), 8.42 (s, 1H), 8.69 (m, 1H), 8.82 (d, 1H), 9.05 (s, 2H), 9.17 (s, 1H), 9.63 (ush., MH).

Example 28

M-isopropyl-1-[3-(b-methylpyridin-3-yl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide --

I iv) (22) and - - p

AND"

Stage 1: 5-Bromo-2-methylpyridine -I According to the method of stage 1 of example 26, but replacing methylmagnesium chloride with isobutylmagnesium bromide, the compound 5-bromo-2-methylpyridine is obtained as a solid. is, Stage 2: M-isopropyl-1-3-(b-methylpyridin-3-yl)phenyl/|-1,4-dihydro|1,8|-naphthyridin-4-one-3-carboxamide "sl According to the method Example 24, but replacing ethyl 5-bromonicotinate with 5-bromo-2-methylpyridine from stage 1, 5o gives the compound M-isopropyl-1-(3-(b-methylpyridin-3-yl)uphenyl/-1,4-dihydro/ 1,8|naphthyridin-4-one-Z-carboxamide - in the form of a solid substance. co TN nNMR (SOCI8) 5 1.32 (d, 6H), 2.63 (m, ЗН), 4.30 (m, 1H), 7.25 (d, 1H), 7.45-7.51 (m, 2H), 7.63 (s, 1H), 7.69 (t, 71H), 7.77 (d, 1H ), 7.82 (dd, 1H), 7.82 (dd, 1H), 8.72 (m, 1H), 8.78 (s, 1H), 8.85 (d, 1H), 9.08 (c, 1H), 9.68 (early, MN).

Example 29 o M-Cyclopropyl-1-3-(1-oxidopyrimidin-5-yl)phenyl)-1,4-dihydro/(1,8|-naphthyridin-4-one-3-carboxamide) 60 b5

Stage 1: 5-Bromo-1-oxidopyrimidine

To 5-bromopyrimidine (2.05g, 12.9mmol) in methylene chloride (25ml) was added m-chloroperoxybenzoic acid (purity about 70905, 3.17g, 12.9mmol), and the resulting mixture was stirred at room temperature for 5 days. Calcium hydroxide (1 g) is added and after 10 minutes the mixture is filtered through celite. The product of evaporation of the filtrate is subjected to chromatography on silica gel eluting with ethyl acetate to obtain the compound 5-bromo-1-oxidopyrimidine in the form of a white solid.

Stage 2:

M-Cyclopropyl-1-3-(1-oxidopyrimidinyl-5-yl)phenyl)-1,4-dihydro-(1,8|inaphthyridin-4-one-3-carboxamide

According to the method of example 24, but replacing ethyl 5-bromonicotinate with 5-bromo-1-oxidopyrimidine from stage 1, and replacing M-cyclopropyl-1-(33-bromophenyl)-1,4-dihydro|1,8|Inaphthyridine-4- on-3-carboxamide

M-isopropyl-1-(3-bromophenyl)-1,4-dihydro|!1,8|Inaphthyridin-4-one-3-carboxamide gives compound SM

M-cyclopropyl-1-13-(1-oxidopyrimidinyl-5-iluphenyl)-1,4-dihydro|!1,8|Inaphthyridin-4-one-3-carboxamide in the form of a white solid.

TN NMR (SOCI3) 5 0.66 (m, 2H), 0.84 (m, 2H), 2.97 (m, 1H), 7.48 (m, 1), 7.58 (d, 1H) , 7.65 (s, 1H), 7.71 (d, l1H), 7.77 (t, 1H), 8.46 (s, 1H), 8.60 (s, 1H), 8.68 ( ush.s, 1H), 8.81 (dd, 71H), 8.98 (s, 1H), 9.02 (s, 1H), 9.72 (ush, MH). co

Example 30 "- 1-(3-I(6-(1-Hydroxy-1-methylethyl)-1-oxidopyridin-3-yl|-phenyl)-1,4-dihydro-(1,8)naphthyridine-4- on-3-carboxamide

IS) (22) ! - " : - with : ;" - Stage 1: 5-Bromo-2-(1-hydroxy-1-methylethyl)pyridine

Gee! To a suspension of 2,5-dibromopyridine in toluene (12 ml/mmol), cooled to a temperature of -782C, n-butyllithium 2.5M in hexane (1.05 eq.) is added, and the resulting mixture is stirred in the cold for 2.5 hours. Acetone (2 eq.) is added and stirring is continued for 1.5 hours. After quenching with a saturated aqueous solution of 20% ammonium chloride, the mixture is heated to room temperature and partitioned between ethyl acetate and water. The product from the organic phase was subjected to chromatography on silica gel, eluting with 2095 ethyl acetate in hexane to give the compound 5-bromo-2-(1-hydroxy-1-methylethyl)pyridine as a syrup.

Stage 2: 5-Bromo-2-(1-hydroxy-1-methylethyl)pyridine M-oxide

To a solution of 5-bromo-2-(1-hydroxy-1-methylethyl)pyridine from stage 1 in methylene chloride (bml/mmol) at room temperature is added m-chloroperoxybenzoic acid 70965 (1.1 eq.), and the resulting mixture is stirred

HF) at room temperature for 18 hours. An excess of calcium hydroxide is added and after 5 minutes the mixture is filtered through a layer of celite. The crude product of evaporation of the filtrate is subjected to chromatography on di-silica gel, eluting with 809 ethyl acetate in hexane Kk) to obtain the compound 5-bromo-2-(1-hydroxy-1-methylethyl)pyridine M-oxide in the form of a white solid. 60 Stage 3: 1-(3-Bromophenyl)-1,4-dihydro|1,8|Inaphthyridin-4-one-3-carboxamide

According to the method of stage 4 of example 1, but replacing 2895 with aqueous ammonium hydroxide isopropylamine, the compound 1-(3-bromophenyl)-1,4-dihydro|!1,8|Inaphthyridin-4-one-3-carboxamide is obtained as a solid.

Stage A: 1-43-16-(1-Hydroxy-1-methylethyl)-1-oxidopyridin-3-yl|-phenyl)-1,4-dihydro/1,8)naphthyridin-4-one-3-carboxamide by the method of example 24, but replacing 5-bromo-2-(1-hydroxy-1-methylethyl)pyridine with M-oxide from step 2 above ethyl b5B-bromonicotinate, and replacing 1-(3-bromophenyl)-1,4-dihydro/ 1,8Inaphthyridin-4-one-3-carboxamide

M-isopropyl-1-(3-bromophenyl)-1,4-dihydro|1,8)naphthyridin-4-one-3-carboxamide gives the compound 1-43-I(6-(1-hydroxy-1-methylethyl) -1-oxidopyridin-3-yl|-phenyl)-1,4-dihydro|1,8)naphthyridin-4-one-3-carboxamide

In the form of a solid substance. "YAN NMR (SOSIz) 5 1.76 (s, 6H), 5.83 (us., IN, MH), 7.50 (d, 1H), 7.55 (m, 1H), 7.57- 7.62 (m, 2H), 7.65 (m, 2H), 7.72-7.78 (m, 2H), 8.55 (s, 1H, OH), 8.75 (m, 1H) , 8.90 (dd, 1H), 9.08 (s, 1H), 9.52 (ear, 1H, MH).

Example 31

M-isopropyl-1-(3-(4-(pyridin-3-yl)uphenyl|phenyl)-1,4-dihydro|!1,8)|Inaphthyridin-4-one-3-carboxamide

Stage 1: p

M-Isopropyl-1-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl|-1,4-dihydro|1,8|Inaphthyridin-4-one -3-carboxamide (o)

A mixture of M-isopropyl-1-(3-bromophenyl)-1,4-dihydro|1,8|Inaphthyridin-4-one-3-carboxamide from step 4 of example 1, diborpinacone ether (1.Eq.), potassium acetate ( 3.Beq.) and (1,1-bis(idiphenylphosphino)ferrocene|dichloropalladium (II) (0.05 eq.) in M,M-dimethylformamide (bml/mmol) are stirred at a temperature of 8593 for 18 hours. diborpinacone ether (0.4 eq.) and palladium catalyst (0.05 eq.), and heating and stirring continued for another 24 h. After cooling, the mixture was partitioned between ethyl acetate and water, and the crude product from the organic phase was chromatographed on silica gel, eluting with 1:1 mixture of ethyl acetate and hexane

Then the product is stirred in hexane at room temperature for several hours, and filtered to obtain the compound Me.

Z M-isopropyl-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,4-dihydro/1,8|naphthyridine-4- on-Z-carbox h-amide as a white solid.

Stage 2: 3--4-Bromophenyl)pyridine

A mixture of pyridine-3Z-boronic acid, 1,3-propanediol cyclic ether, 4-bromoiodobenzene (1, Teq.),

I1,1-bisbidiphenylphosphino)ferrocene|dichloropalladium (I) (0.00 beq.) and 2M aqueous sodium carbonate (beq.) in

MM-dimethylformamide (2ml/mmol) is stirred at a temperature of 859С for 4 hours. After quenching with a saturated aqueous solution of ammonium chloride, the mixture is partitioned between ethyl acetate and water, and the crude product from the organic phase is subjected to chromatography on silica gel, eluting with a 1:9 mixture of ethyl acetate and hexane to give the compound 3-(4-bromophenyl)pyridine in in the form of a solid substance.

Step 3: M-isopropyl-1-73-(4-(pyridin-3-yl)phenyl|phenyl/1,4-dihydro/(1,8|-naphthyridin-4-one-3-carboxamide

A mixture of borate from stage 1, 3-(4-bromophenyl)pyridine from stage 2 (1.5 eq.), -I 1,1-bisbidiphenylphosphino)ferrocene|dichloropalladium (I) (0.00 eq.) and 2M aqueous sodium carbonate ( bekw.) in

M,M-dimethylformamide (7 ml/mmol) is stirred at a temperature of 859C for 1 hour. After cooling, the mixture is partitioned between ethyl acetate and water. The crude product from the organic phase was subjected to chromatography on silica gel, eluting with a 7:3 mixture of ethyl acetate and methylene chloride to obtain the compound s.sub.M-isopropyl-1-13-14-(pyridin-3-yl)uphenyl|phenyl)-1,4-dihydro |1,8|Inaphthyridin-4-one-3-carboxamide in the form of a solid substance.

IR e) TN nMR (SOSIz) 5 1.30 (d, 6H), 4.25 (m, 1H), 7.35 (m, 1H), 7.39-7.48 (m, 2H), 7 ,60-7.75 (m, 6H), 7.80 (d, 1H), 7.90 (d, 1H), 8.58 (d, 1H), 8.70 (m, 1H), 8, 82 (d, 1H), 8.88 (s, 1H), 9.08 (s, 1H), 9.68 (ush., MN).

Example 32

M-Cyclopropyl-1-(3-(5-methylsulfonylpyridin-3-yl)phenyl|/|-1,4-dihydro/1,8H1-naphthyridin-4-one-3-carboxamide

F) name) 60 b5 and

Stage 1:

M-Cyclopropyl-1-I3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,4-dihydro/1,8|naphthyridin-4-one-3 -carb 75 oxamide

According to the method of stage 1 of example 31, but substituting

M-cyclopropyl-1-(3-bromophenyl)-1,4-dihydro|1,8|Inaphthyridin-4-one-3Z-carboxamide from stage 71 of example 14

M-isopropyl-1-(3-bromophenyl)-1,4-dihydro|1,8|Inaphthyridin-4-one-3-carboxamide, the compound is obtained

M-cyclopropyl-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl/|-1,4-dihydro/!1,8|naphthyridine-4 -on-3-carbo xamide as a white solid.

Stage 2: 3-Bromo-5-methylsulfonylpyridine

n-butyllithium 1.6M in hexanes (8.bml, 13.7mmol) was added to 3,5-dibromopyridine (2.96g, 12.5mmol) in diethyl ether (7/Oml) at a temperature of -789С0, and the resulting mixture was stirred in the cold for 3 hours.

Dimethyl disulfide (1.12 mL, 12.5 mmol) was added and the mixture was warmed to room temperature, then partitioned between ether and water. To the crude product of the evaporation of the organic phase, add He) tetrahydrofuran (8Oml), methanol (2Oml), oxon (17g) and a sufficient amount of saturated aqueous sodium bicarbonate to obtain a slightly basic medium. After stirring for 4 hours at room temperature, an excess of 1M aqueous sodium metabisulfite, organic solvents are added, and the residue is partitioned between ethyl acetate and water. The crude product from the organic phase is stirred in a small volume of ethyl acetate filtered to obtain the compound 3-bromo-5-methylsulfonylpyridine as a solid. "--

Stage C:

M-Cyclopropyl-1-|3-(5-methylsulfonylpyridin-3-yl)phenyl|-1,4-dihydro|1,8|Inaphthyridin-4-one-3-carboxamide o

According to the method of stage C of example C1, but replacing with 3-bromo-5-methylsulfonylpyridine from stage 2 above du 3-(4-bromophenyl)pyridine, and replacing

M-cyclopropyl-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl/|-1,4-dihydro/!1,8|naphthyridine-4 -one-3-carbo-xamide from stage 1

M-isopropyl-1-I3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,4-dihydro-(1,8|Inaphthyridine-4- on-3-carboxamide, the compound "Sh

M-cyclopropyl-1-3-"-5-methylsulfonylpyridin-3-yl)phenyl-1,4-dihydro|1,8|inaphthyridin-4-one-3-carboxamide. In the form of a solid substance. in TN nMR ( SOSI5) 5 0.71 (m, 2H), 0.90 (m, 2H), 3.03 (m, 1H), 3.21 (s, ЗН), 7.53 (m, 1H), 7, 60 (d, 1H), :z» 7.74 (s, 1H), 7.80 (t, 1H), 7.86 (d, 71H), 8.45 (m, 1H), 8.74 ( m, 1H), 8.86 (d, 1H), 9.09 (s, 1H), 9.20 (d, 2H), 9.78 (ush., MH).

Example 33 -1 no M-Cyclopropyl-1-13-I(4-(1-hydroxy-1-methylethyl)-1-oxidopyridin-2-ylIfenyl-1,4-dihydro/1,8|Inaphthyridin-4-one -

Z-carboxamide se) 1 - 50

IR e)

F) name) 60

Stage 1: Methyl 2-bromisonicotinate

To a solution of 2-bromisonicotinic acid |Spet. RIagt. ViiYi., 38:2446 (1990)|) (2.0 g) in tetrahydrofuran (100 ml) add an excess of ethereal diazomethane, and the resulting mixture is stirred at room temperature 65 for 1 hour. The mixture is evaporated, and the product is subjected to chromatography on silica gel, eluting with a 1:3 mixture of ethyl acetate and hexane to give the methyl ester of 2-bromisonicotinic acid as a colorless liquid.

Stage 2: 2-Bromo-4-(1-hydroxy-1-methylethyl)pyridine

According to the method of stage 17 of example 25, but replacing methyl 2-bromoisonicotinate from stage 1 with ethyl 5-bromonicotinate, the compound 2-bromo-4-(1-hydroxy-1-methylethyl)pyridine is obtained as a white solid.

Stage 3: 2-Bromo-4-(1-hydroxy-1-methylethyl)pyridine-M-oxide

According to the method of stage 2 of example 30, but replacing 5-bromo-2-(1-hydroxy-1-methylethyl)pyridine with 2-bromo-4-(1-hydroxy-1-methylethyl)pyridine from stage 2, the compound 2-bromo is obtained -4-(1-hydroxy-1-methylethyl)pyridine-M-oxide as a white solid. 70 Stage A:

M-Cyclopropyl-1-13-I4-(1-hydroxy-1-methylethyl)-1-oxidopyridin-2-yl|Ifenyl)-1,4-dihydro/1,8|Inaphthyridin-4-one-3-k arboxamide

According to the method of the stage From example 32, but. replacing 2-bromo-4-(1-hydroxy-1-methylethyl)pyridine-M-oxide from stage C with 3-bromo-5-methylsulfonylpyridine, compound 75 is obtained. M-cyclopropyl-1-13-I4-(1-hydroxy -1-methylethyl)-1-oxidopyridin-2-ylphenyl)-1,4-dihydro/1,8|inaphthyridin-4-one-3-k arboxamide as a beige solid.

TN nMR (DMSO-iv) 5 0.57 (m, 2H), 0.79 (m, 2H), 1.45 (s, 6H), 2.90 (m, 1H), 5.35 (s, 1H, OH), 7.48 (m, 1H), 7.64 (m, 1H), 7.72 (m, ЗН), 8.11 (m, 2H), 8.30 (d, 1H), 8.72 (dd, 1H), 8.78 (m, 1H), 8.82 (s, 1H), 9.72 (ush., MH).

Example 34

M-Cyclopropyl-1-(3-15-(1-hydroxy-1-methylethyl)pyridin-2-yl|Ifenyl)-1,4-dihydro|1,8|Inaphthyridin-4-one-3-carboxamide with o s "-

IS) (22)

Stage 1: 2-Bromo-5-(1-hydroxy-1-methylethyl)pyridine -

A solution of 2,5-dibromopyridine in diethyl ether (bml/mmol) is cooled to a temperature of -782C and n-butyllithium 2.5M in hexanes (1.05 eq.) is slowly added. After 2 hours of standing in the cold, acetone (1.eq.) is added and stirring is continued for 1 hour. The resulting mixture is quenched with a saturated aqueous solution of ammonium chloride, heated to room temperature and partitioned between ether and water. The crude product from the organic phase is triturated with 1:11 ether texane and filtered to obtain the compound with 2-bromo-5-(1-hydroxy-1-methylethyl)pyridine as a solid. :z" Stage 2:

M-Cyclopropyl-1-13-I5-(1-hydroxy-1-methylethyl)pyridin-2-ylIfenyl)-1,4-dihydro|1,8Inaphthyridin-4-one-3-carboxami d -1 15 By the method of stage From example 32, but replacing 2-bromo-5-(1-hydroxy-1-methylethyl)pyridine from stage 1

3-bromo-5-methylsulfonylpyridine, the compound (Ce) M-cyclopropyl-1-3-(5-(1-hydroxy-1-methylethyl)pyridin-2-ylphenyl)-1,4-dihydro/1,8) is obtained naphthyridin-4-one-3-carboxami salt in the form of a solid substance. "YAN NMR (SOSI8) 5 0.71 (m, 2H), 0.90 (m, 2H), 1.68 (s, 6H), 1.85 (s, IN, OH), 3.04 (m , 1H), 7.45-7.52 (m, - 2H), 7.71 (t, 1H), 7.79 (d, 1H), 7.95 (dd, 1H), 8.16 (s , 1H), 8.20 (d, 1H), 8.72 (m, 1H), 8.80-8.87 (m, 2H), c 9.12 (s, 1H), 9.82 (ush ., MN).

Example 35

M-Cyclopropyl-1-(3-I3-(1-hydroxy-1-methylethyl)pyridin-4-ylIfenyl)-1,4-dihydro|1,8|Inaphthyridin-4-one-3-carboxamide

F) name) 60 b5

Stage 1: 4-Bromo-2-(1-hydroxy-1-methylethyl)pyridine

According to the method of stages 1-2 of example 33, but replacing with 4-bromopicolinic acid |A!yvi. U. Spet. 24:390 t (1971)) 2-bromisonicotinic acid in stage 1, the compound 4-bromo-2-(1-hydroxy-1-methylethyl)pyridine is obtained as a white solid.

Stage 2:

M-Cyclopropyl-1-13-I3-(1-hydroxy-1-methylethyl)pyridin-4-yl|-phenyl)-1,4-dihydro|!1,8|Inaphthyridin-4-one-3-carboxamide

According to the method of stage C of example 32, but replacing 4-bromo-2-(1-hydroxy-1-methylethyl)pyridine from stage 1

C-bromo-5-methylsulfonylpyridine, the compound is obtained

M-cyclopropyl-1-3-(3-(1-hydroxy-1-methylethyl)tridin-4-yl|phenyl)-1,4-dihydro|!1,8|Inaphthyridin-4-one-3-carboxamide in as a beige solid. NMR NMR (DMSO-yv) 5 0.57 (m, 2H), 0.78 (m, 2H), 1.48 (s, 6H), 2.91 (m, 1H), 5.27 (s, IN, OH), 7.62-7.66 (m, 2H), 7.72 7.79 (m, 2H), 8.01 (m, 1H), 8.10 (s, 1H) , 8.58 (d, 1H), 8.73-8.79 (m, 2H), 8.84 (s, 1H), 9.73 (ush., MH). o

Example 36

Synthesis

M-cyclopropyl-1-(3-I3-(1-hydroxy-1-methylethyl)-1-oxidopyridin-4-yl|phenyl)-1,4-dihydro|/1,8|inaphthyridin-4-one-3 -k so z arboxamide and -

IS)

I (22) m. « shi s z Stage 1: 4-Bromo-2-(1-hydroxy-1-methylethyl)pyridine-M-oxide

According to the method of stage 2 of example 30, but replacing 4-bromo-2-(1-hydroxy-1-methylethyl)pyridine from stage 1 of example 35 with 5-bromo-2-(1-hydroxy-1-methylethyl)pyridine, the compound is obtained - And 4-bromo-2-(1-hydroxy-1-methylethyl)pyridine-M-oxide in the form of a white solid.

Stage 2: ise) M-cyclopropyl-1-1|3-I3-(1-hydroxy-1-methylethyl)-1-oxidopyridin-4-ylIfenyl)-1,4-dihydro/1,8|Inaphthyridine-4- on-3-k with arboxamide

According to the method of stage C of example 32, but replacing 4-bromo-2-(1-hydroxy-1-methylethyl)pyridine-M-oxide from stage 1 with 3-bromo-5-methylsulfonylpyridine, a compound with M-cyclopropyl-1- 73-I3-(1-hydroxy-1-methylethyl)-1-oxidopyridin-4-yl|phenyl)-1,4-dihydro|/1,8|Inaphthyridin-4-one-3-k arboxamide in the form of a beige solid substances NMR NMR (DMSO-yv) 5 0.57 (m, 2H), 0.78 (m, 2H), 1.62 (s, 6H), 2.90 (m, 1H), 6.99 (s , IN, OH), 7.65-7.84 (M, 4H), 7.94 (s, 1H), 8.03 (dd, 1H), 8.15 (s, 1H), 8.38 ( d, 1H), 8.73-8.78 (m, 2H), 8.83 (s, 1H), 9.73 (ush., MH).

Example 37 o M-Cyclopropyl-1-3-(6-isopropylsulfonylpyridin-3-yl)phenyl)-1,4-dihydro-/1,8)naphthyridin-4-one-3-carboxamide 60 b5

Step 1: 5-Bromo-2-isopropylthiopyridine 19 To a mixture of 2,5-dibromopyridine (2.077, 8.7 mmol) and 2-propanethiol (0.97 mL, 104 mmol) in

Sodium hydride, 60906 dispersion in oil (450mg, 11.3mmol) is added in portions to M,M-dimethylformamide (2O0ml) at a temperature of 09. The resulting mixture was stirred at room temperature for 1 hour, then partitioned between ether and water. The crude product from the organic phase was chromatographed on silica gel, eluting with 10905 ethyl acetate in hexane, to give the compound 5-bromo-2-isopropylthiopyridine as a solid.

Stage 2: 5-Bromo-2-isopropylsulfonylpyridine

To a solution of 5-bromo-2-isopropylthiopyridine from stage 1 (2.03g, 8.75mmol) in tetrahydrofuran (5Oml) and methanol (25ml) at a temperature of 09С, oxone (15.8g, 25.8mmol) is added, and then saturated aqueous bicarbonate of sodium (25 ml). The resulting mixture is stirred at room temperature for 6 hours. The mixture was quenched with aqueous sodium bicarbonate and partitioned between ethyl acetate and water. The crude product from the organic phase is subjected to chromatography on silica gel, eluting with 2095 ethyl acetate in hexane to give the compound 5-bromo-2-isopropylsulfonylpyridine as a white solid.

Stage C:

M-Cyclopropyl-1-3-(6-isopropylsulfonylpyridin-3-yl)phenyl1|-1,4-dihydro|!1,8|Inaphthyridin-4-one-3-carboxamide so

According to the method of stage C of example 32, but replacing 5-bromo-2-isopropylsulfonylpyridine from stage 2 h-

C-bromo-5-methylsulfonylpyridine, the compound is obtained

M-cyclopropyl-1-3-(b-isopropylsulfonylpyridin-3-yl)phenyl-1,4-dihydro|1,8|Inaphthyridin-4-one-3-carboxamide. In the form of a solid substance. Ge")

TN nMR (SOCI3) 5 0.70 (m, 2H), 0.89 (m, 2H), 1.39 (d, 6H), 3.00 (m, 1H), 3.82 (m, 1H) , 7.51 (m, 1H), m 7.60 (d, 1), 7.72 (s, 1H), 7.80 (t, 1H), 7.83 (d, 1H), 8.15 -8.24 (m, 2H), 8.72 (m, 1H), 8.86 (dd, 1H), 9.03 (s, 1H), 9.10 (s, 1H), 9.82 ( ear., MN).

Example 38

M-Cyclopropyl-1-3-(b-methoxytridin-3-yl)phenyl/|-1,4-dihydro|1,8|-naphthyridin-4-one-3-carboxamide « - с ;» -I se) 1 - 50

Stage 1: 5-Bromo-2-methoxypyridine co To a solution of 2,5-dibromopyridine (6.95g, 29mmol) in M,M-dimethylformamide (ml) add methanol (3.56bml) and 1M potassium tert-butoxide (32, Zml), and the resulting mixture is stirred at room temperature for 18 hours.

The resulting suspension is quenched with a saturated aqueous solution of ammonium chloride and partitioned between ethyl acetate and water. The crude product from the organic phase is subjected to chromatography on silica gel, eluting with a 1:9 mixture

HF) of ether and hexane to obtain the compound 5-bromo-2-methoxypyridine in the form of an oil.

Stage 2: M-Cyclopropyl-1-(3-(b-methoxypyridin-3-yl)phenyl/|-1,4-dihydro|1,8|-naphthyridin-4-one-3-carboxamide o By the method of stage C of example 32, but substituting 5-bromo-2-methoxypyridine from step 1

C-bromo-5-methylsulfonylpyridine is obtained; a compound of M-cyclopropyl-1-3-(b-methoxypyridin-3-yl)phenyl/|-1,4-dihydro|1,8|-naphthyridin-4-one-3-carboxamide as a solid.

TN NMR (SOCI3) 5 0.71 (m, 2H), 0.89 (m, 2H), 3.00 (m, 1H), 4.00 (s, ЗН), 6.85 (d, 1H) , 7.44 (d, 1H), 7.50 (m, 71H), 7.62 (s, 1H), 7.68 (t, 1H), 7.73 (d, 71H), 7.83 ( dd, 1H), 8.44 (s, 1H), 8.73 (m, 1H), 8.85 (dd, 1H), 9.10 (s, 1H), 9.82 (ush., MH) . b5

Example 39

M-Cyclopropyl-1-3-(b-methylpyridin-3-yl)phenyl/|-1,4-dihydro|1,8H1-naphthyridin-4-one-3-carboxamide

According to the method of stage C of example 32, but replacing 3-bromo-5-methylsulfonylpyridine with 5-bromo-2-methylpyridine from stage 1 of example 28, the title compound is obtained as a solid.

TN NMR (SOCI3) 5 0.72 (m, 2H), 0.90 (m, 2H), 2.65 (s, ЗН), 3.03 (m, 1H), 7.28 (d, 1H) , 7.45-7.53 (m, 2H), 7.66 (s, 1H), 7.72 (t, 1H), 7.80 (d, 1H), 7.84 (dd, 1H), 7.83 (m, 1H), 8.80 (s, 1H), 8.86 (dd, 1H), 9.11 (s, 1H), 9.82 (ush, MH).

Example 40

M-Cyclopropyl-1-13-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl|Ifenyl)-1,4-dihydro/(1,8|naphthyridin-4-one-3-carboxamide s - o s "-

IS) (22) m.

Stage 1: 5-Bromo-2-(2,2,2-trifluoroethoxy)pyridine

According to the method of stage 1 of example 38, but replacing 2,2,2-trifluoroethanol with methanol, when heated at a temperature of 702 for 18 hours, the compound 5-bromo-2-(2,2,2-trifluoroethoxy)pyridine is obtained in the form of oil. "

Stage 2:

M-Cyclopropyl-1-(3-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl|Phenyl)-1,4-dihydro|!1,8)Inaphthyridin-4-one-3-carboxamide - c According to the method of stage C of example 32, but replacing 5-bromo-2-(2,2,2-trifluoroethoxy)pyridine from stage 1 "with 3-bromo-5-methylsulfonylpyridine, the compound "M-cyclopropyl-1-( 3-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl|Iphenyl)-1,4-dihydro/(1,8|naphthyridin-4-one-3-carboxamide in the form of a solid substance. "YAN nNMR (SOCI3) 5 0.72 (m, 2H), 0.90 (m, 2H), 3.03 (m, 1), 4.85 (sq., 2H), 7.00 (d, 1H) , 7.43-7.53 (m, w- 2H), 7.62 (s, 1H), 7.69-7.78 (m, 2H), 7.92 (dd, 1H), 8.42 (c, 1H), 8.73 (m, 1H), 8.85 (dd, 1H), 9.10 (c, 1H), 9.80 (ush, MH). co Example 41

M-Cyclopropyl-1-3-(5-bromopyridin-3-yl)phenyl/|-1,4-dihydro/!1,8|inaphthyridin-4-one-3-carboxamide 1 - 50

IR e) and

F) name) 60

By the method of stage C of example 32, but replacing 3-bromo-5-methylsulfonylpyridine with 3,5-dibromopyridine, 65 gives the title compound as a white solid.

TN NMR (DMSO-iv) 5 0.58 (m, 2H), 0.79 (m, 2H), 2.90 (m, 1H), 7.65 (m, 1H), 7.71-7, 77 (m, 2H), 8.03 (d,

1H), 8.14 (s, 1H), 8.49 (s, 1H), 8.74 (sh.s, 1H), 8.79 (sh.s, 1H), 8.86 (s, 1H ), 9.01 (c, 1H), 9.73 (ush., MN).

Example 42

M-Cyclopropyl-1-3-(6-benzyloxypyridin-3-yl)phenyl|-1,4-dihydro|1,81-naphthyridin-4-one-3-carboxamide « 70 years

S e il, goes

Stage 1: 2-Benzyloxy-5-bromopyridine

A mixture of 2,5-dibromopyridine, benzyl alcohol (1.3 eq.), potassium hydroxide granules (2.4 eq.), and dibenzo-18-crown-b6 (0.0 eq.) in toluene (4 mol/mmol) was boiled with reflux with simultaneous azeotropic removal of water, within 3 hours. After evaporation of toluene, the resulting mixture is distributed between chloroform and water. The crude product from the organic phase is recrystallized from ether-hexane to give the compound 2-benzyloxy-5-bromopyridine as a solid. high school

Stage 2:

M-Cyclopropyl-1-3-(6-benzyloxypyridin-3-yl)phenyl|-1,4-dihydro-1,8)naphthyridin-4-one-3-carboxamide i)

According to the method of stage C of example 32, but replacing 2-benzyloxy-5-bromopyridine from stage 1

C-bromo-5-methylsulfonylpyridine, the compound is obtained

M-cyclopropyl-1-3-(b-benzyloxypyridin-3-yl)phenyl-1,4-dihydro|1,8|-naphthyridin-4-one-3-carboxamide as a white solid.

TN NMR (DMSO-iv) 5 0.57 (m, 2H), 0.79 (m, 2H), 2.91 (m, 1H), 5.42 (s, 2H), 7.00 (d, 1H), 7.32-7.48 (m, - 5H), 7.61-7.72 (m, ЗН), 7.90 (d, 1H), 7.99 (s, 1H), 8, 14 (d, 1H), 8.59 (s, 1H), 8.73-8.84 (m, ЗН), 9.73 (ush., МН). i am

Example 43 F

M-Cyclopropyl-1-(3-I(b-dicyclopropyl(hydroxy)methyl-1-okeidopyridine-3-ylphenyl)-1,4-dihydro/1,8|Inaphthyridin-4-one-3-carboxamide that - « shi c ;» -I se) i-th Stage 1: 5-Bromo-2-dicyclopropyl(hydroxy)methylpyridine-M-oxide -l 70 According to the method of stages 1 and 2 of example 30, but replacing dicyclopropyl ketone with acetone in stage 1 , the compound 5-bromo-2-dicyclopropyl(hydroxy)-methylpyridine-M-oxide is obtained as a solid.

Stage 2:

M-Cyclopropyl-1-(3-I(b-dicyclopropyl(hydroxy)methyl-1-oxidopyridin-3-ylphenyl)-1,4-dihydro|1,8)inaphthyridin-4-o n-3-carboxamide 25 For by the method of the stage From example 32, but replacing

HF) 5-bromo-2-dicyclopropyl(hydroxy)methylpyridine-M-oxide from stage 1 with 3-1-3-(b-dicyclopropyl(hydroxy)methyl-1-oxidopyridin-3-ylphenyl)-1,4-dihydro /(1,8|Y-naphthyridin-4-one-3-carbox of copper in the form of a white solid. in TN NMR (SOCI3) 5 0.52 (m, 4H), 0.70 (m, 4H), 0 .76 (m, 2H), 0.89 (m, 2H), 1.35 (m, 2H), 3.02 (m, 1H), 7.52 (m, 1H), 7.58 (m, 1H), 7.62 (dd, 1H), 7.68 (s, 1H), 7.73-7.80 (m, ZH), 8.15 (ush., IN, OH), 8.49 ( s, 1H), 8.72 (m, 1H), 8.85 (dd, 1H), 9.09 (s, 1H), 9.78 (ush., MH).

Example 44

M-Cyclopropyl-1-13-I5-(1-hydroxy-1-methylethyl)-1-oxidopyridin-2-yl|Ifenyl)-1,4-dihydro/1,8|Inaphthyridin-4-one 65 -3- carboxamide

"and I - and; 70 and:

I am E

Stage 1: 2-Bromo-5-(1-hydroxy-1-methylethyl)pyridine-M-oxide t According to the procedure of stage 2 of example 30, but replacing 2-bromo-5-(1-hydroxy-1-methylethyl)pyridine with stage 1 of example 34 5-bromo-2-(1-hydroxy-1-methylethyl)pyridine, the compound 2-bromo-5-(1-hydroxy-1-methylethyl)pyridine-M-oxide is obtained as a white solid.

Stage 2: M-Cyclopropyl-1-13-I5-(1-hydroxy-1-methylethyl)-1-oxidopyridin-2-yl|phenyl)-1,4-dihydro

P1,8Inaphthyridin-4-one-3-carboxamide

According to the method of stage C of example 32, but replacing 2-bromo-5-(1-hydroxy-1-methylethyl)pyridine-M-oxide from stage 1 with 3-bromo-5-methylsulfonylpyridine, the compound is obtained

M-cyclopropyl-1-73-I5-(1-hydroxy-1-methylethyl)-1-oxidopyridin-2-yl|phenyl)-1,4-dihydro|/1,8|Inaphthyridin-4-one-3- k arboxamide in the form of a solid substance. sc re "YAN NMR (SOCIz) 5 0.69 (m, 2H), 0.88 (m, 2H), 1.63 (s, 6H), 2.20 (s, IN, OH), 2.98 (m, 1H), 7.38-7.49 (m,

ЗН), 7.52 (d, 1Н), 7.70 (t, 1Н), 7.98-8.04 (m, 2Н), 8.50 (s, 1Н), 8.69 (m, 1Н ), 8.80 (dd, 1H), 9.08 (s, 1H), 9.75 (ush., MN). at

Example 45

Cyclopropyl-1-(3-16-(1-hydroxy-1-methylethyl)pyridin-3-ylphenyl/1,4-dihydro|!1,8|Inaphthyridin-4-one-3-carboxam "-

IS) (22) m. "shi s"; According to the method of stage C of example 32, but replacing 3-bromo-5-methylsulfonylpyridine with 5-bromo-2-(1-hydroxy-1-methylethyl)pyridine from stage 1 of example 30, the title compound is obtained as a solid. - "YAN NMR (SOSIz) 5 0.72 (m, 2H), 0.90 (m, 2H), 1.62 (s, 6H), 3.02 (m, 1H), 4.85 (s, IN, OH), 7.48-7.53 (m, se) ZN), 7.68 (s, 1H), 7.73 (t, 1H), 7.80 (d, 1H), 7.95 (dd, 1H), 8.72 (m, 1H), 8.81 (s, 1H), 8.86 (dd, 1H), 910 (s, 1H), 9.78 (ush., MH). 1

Example 46 - 70 M-Isobutyl-1-(3-(6-(1-hydroxy-1-methylethyl)pyridin-3-ylIfenyl)-1,4-dihydro-(1,8Inaphtyridin-4-one-3-carboxa)

IR e) m

F) name) 60 b5

Stage 1: 5-(3-Aminophenyl)-2-(1-hydroxy-1-methylethyl)pyridine

According to the method of stage 5 of example 1, but substituting 3-aminophenylboronic acid for 3-acetylphenylboronic acid, and replacing 5-bromo-2-(1-hydroxy-1-methylethyl)pyridine from stage 1 of example Zo

M-isopropyl-1-(3-bromophenyl)-1,4-dihydro|1,8|Inaphthyridin-4-one-3-carboxamide, compound 50 is obtained 5-(3-aminophenyl)-2-(1-hydroxy- 1-methylethyl)pyridine as a solid.

Stage 2: 1-(3-N6-(1-Hydroxy-1-methylethyl)pyridin-3-ylphenyl)yl,4-dihydro-(1,8-inaphthyridin-4-one-3-carboxylic acid)

According to the method of stages 1-3 of example 1, but replacing 5-(3-aminophenyl)-2-(1-hydroxy-1-methylethyl) pyridine

3-bromoaniline from stage 1 in the first stage, compound 70 is obtained 1-43-16-(1-hydroxy-1-methylethyl)pyridin-3-ylIfenyl)-1,4-dihydro/1,8|naphthyridin-4-one -3-carboxylic acid in the form of a solid substance.

Stage C:

M-Isobutyl-1-(3-(6-(1-hydroxy-1-methylethyl)pyridin-3-ylphenyl)-1,4-dihydro/1,8)naphthyridin-4-one-3-carboxamide

According to the method of stage 4 of example 1, but replacing 1-(3-bromophenyl)-1,4-dihydro(1,8)|naphthyridin-4-one-3-carboxylic acid with the acid from stage 2, and replacing isobutylamine with isopropylamine, the compound is obtained

M-isobutyl-1-(3-16-(1-hydroxy-1-methylethyl)pyridin-3-ylphenyl)-1,4-dihydro(1,8|naphthyridin-4-one-3-carboxamide) in the form of a cream solid substances

TN NMR (Acetone-dv) 5 0.98 (d, 6H), 1.53 (s, 6H), 1.88 (m, 1H), 3.26 (t, 2H), 4.66 (s, 1H, OH), 7.60 (m, 1H), 7.69 (d, 1H), 7.76-7.79 (m, 2H), 7.95 (d, 1H), 8.05 (s , 1H), 8.16 (dd, 1H), 8.73 (m, 1H), 8.79 (dd, 1H), 8.90 (s, 1H), 8.94 (s, 1H), 9 ,83 (Us, MN).

Example 47

M-Cyclopropyl-1-(5-bromo-3-I(6-(1-hydroxy-1-methylethyl)pyridin-3-yl|phenyl)-1,4-dihydro|!1,8|Inaphthyridin-4- on-3-carboxamide Ge o c "-

IS) (22)

And m.

Stage 1: 1-(3,5-Dibromophenyl)-1,4-dihydro|1,8|Inaphthyridin-4-one-3-carboxylic acid

According to the method of stages 1-3 of example 1, but replacing 3,5-dibromoaniline with 3-bromoaniline in stage 1, the compound 1-(3,5-dibromophenyl)-1,4-dihydro|!1,8|Inaphthyridine-4 is obtained -on-3-carboxylic acid in the form of a beige solid -about 70 substances. c Step 2: M-Cyclopropyl-1-(3,5-dibromophenyl)-1,4-dihydro| (3,5-dibromophenyl)-1,4-dihydro|1,8Inaphthyridin-4-one-3-carboxylic acid from stage 1 1-(3-bromophenyl)-1,4-dihydro|1,8|Inaphthyridin-4 -one-3-carboxylic acid, and replacing isopropylamine with /cyclopropylamine 75, the compound is obtained. M-cyclopropyl-1-(3,5-dibromophenyl)-1,4-dihydro|!1,8|Inaphthyridin-4-one-3-carboxamide as a solid. (Ce) Steel 3: 2-(1-Hydroxy-1-methylethyl)-5-tributylstannylpyridine c To a suspension of 2,5-dibromopyridine in toluene (bml/mmol) at a temperature of 782, n-butyllithium 2.5M in hexane is added (Teq .), and the resulting mixture is stirred in the cold for 2.5 hours. Acetone (Teq.) is added, and the mixture - 70 is heated to a temperature of -502C, where it turns into a brown solution. After cooling to -78 C, more n-butyllithium (Teq.) is added together with ether (2 ml/mmol). After stirring in the cold for another hour, tributyltin chloride (1.1 eq.) was added and the mixture was warmed to room temperature and stirred for 2 hours. The mixture was quenched with a saturated aqueous solution of ammonium chloride and partitioned between ethyl acetate and pv WATER. The crude product from the organic phase is subjected to chromatography on silica gel, eluting with a 1:9 mixture of ethyl acetate and hexane to obtain the compound 2-(1-hydroxy-1-methylethyl)-5-tributylstannylpyridine as a colorless liquid (F).

Ge Stage A:

M-Cyclopropyl-1-15-bromo-3-(6-(1-hydroxy-1-methylethyl)pyridin-3-yl|phenyl)-1,4-dihydro|!1,8|Inaphthyridin-4-one- 3-car in boxamide

A mixture of //M-cyclopropyl-1-(3,5-dibromophenyl)-1,4-dihydro|!1,8|Inaphthyridin-4-one-3-carboxamide from stage 2, 2-(1-hydroxy-1- methylethyl)-5-tributylstannylpyridine from stage C (1, Seq.),

I1,1-bisbidiphenylphosphino)ferrocene|dichloropalladium (I) (0.05 beq.) and copper iodide (0.05 beq.) in

M,M-dimethylformamide (1 bml/mmol) is stirred at a temperature of 859C for 5 hours. After 65 minutes of cooling, the resulting mixture is partitioned between ethyl acetate and water. The crude product from the organic phase is subjected to chromatography on silica gel eluting with a 1:6:3 mixture of ethanol, ethyl acetate and methylene chloride with -BO0-

obtaining the compound

M-cyclopropyl-1-(5-bromo-3-16-(1-hydroxy-1-methylethyl)pyridin-3-yl|Ifenyl)-1,4-dihydro|1,8Inaphtyridin-4-one-3-car boxamide in the form of a solid substance. "YAN NMR (SOSIz) 5 0.72 (m, 2H), 0.90 (m, 2H), 1.62 (s, 6H), 3.02 (m, 1H), 4.76 (s, IN , OH), 7.50-7.56 (m, 2H), 7.62 (s, 1H), 7.69 (s, 1H), 7.90-7.96 (m, 2H), 8, 74 (m, 1H), 8.79 (s, 1H), 8.86 (dd, 1H), 9.07 (s, 1H), 9.74 (ush., MH).

Example 48

M-Cyclopropyl-1-13-I6-(1-hydroxy-1-methylethyl)pyridin-2-yl|Ifenyl)-1,4-dihydro|1,8|Inaphthyridin-4-one-3-carboxamide

Stage 1: 2-(1-Hydroxy-1-methylethyl)-6-tributylstannylpyridine

According to the method of stage C of example 47, but replacing 2,6-dibromopyridine with 2,5-dibromopyridine, the compound 2-(1-hydroxy-1-methylethyl)-6-tributylstannylpyridine is obtained.

Stage 2: M-Cyclopropyl-1-13-I6-(1-hydroxy-1-methyl c ethyl)pyridin-2-yl|Ifenyl)-1,4-dihydro/1,8|naphthyridin-4-one-3 -carboxamide he)

According to the method of stage 4 of example 47, but replacing 2-(1-hydroxy-1-methylethyl)-b-tributylstannylpyridine from stage 1 with 2-(1-hydroxy-1-methylethyl)-5-tributylstannylpyridine, the compound is obtained

M-cyclopropyl-1-3-(6-(1-hydroxy-1-methylethyl)pyridin-2-ylphenyl)-1,4-dihydro/1,8)naphthyridin-4-one-3-carboxamide as a solid substances co "IN NMR (SOCI3) 5 0.72 (m, 2H), 0.90 (m, 2H), 1.61 (s, EN), 3.04 (m, 1H), 5.13 (s, IN, OH), 7.40 (d, 2H), «- 7.46-7.53 (m, 2H), 7.70-7.76 (m, 2H), 7.85 (t, 1H) , 8.13 (s, 1H), 8.22 (d, 1H), 8.73 (m, 1H), 8.87 (d, 1H), 9.12 (s, 1H), 9.83 ( ush, MN).

Example 49 Ge")

M-Isopropyl-1-3-(4-methylsulfonylphenyl)phenyl)-1,4-dihydro/(1,8-naphthyridin-4-one-3-carboxamide) a mixture of M-isopropyl-1-I3-(4-methylthiophenyl)phenyl)-1,4-dihydro(1,8|-naphthyridin-4-one-3-carboxamide - from tsu 50 of example 22 in tetrahydrofuran (24 ml/mmol) , methanol (12 mL/mmol) and water (12 mL/mmol) was added oxone (2.24 equiv) and the resulting mixture was stirred at room temperature for 2 hours. The mixture was quenched with saturated aqueous sodium bicarbonate solution and partitioned between ethyl acetate and water. Crude the product from the organic phase was subjected to chromatography on silica gel, eluting with 3095 ether in methylene chloride to give the title compound as a white solid. "IN NMR (Acetone-dv) 5 1.25 (d, 6H), 3.16 (s, ZH), 4.18 (m, 1H), 7.60 (m, 1H), 7.74 (d, 1H), 7.79 (t, 1Hn), o 7.99 (d, 1H), 8 .05 (s, 4H), 8.09 (s, 1H), 8.72 (m, 1H), 8.78 (dd, 1H), 8.93 (s, 1H), 9.64 (ush. , MN).

Example 50 ime) M-Cyclopropyl-1-3-(6-methylsulfonylpyridin-3-yl)phenyl|-1,4-dihydro|1,81-naphthyridin-4-one-3-carboxamide 60 b5 che

Stage 1: 5-Bromo-2-methylthiopyridine t A mixture of 2,5-dibromopyridine and sodium thiomethoxide (1.Eq.) in M,M-dimethylformamide (2ml/mmol) is stirred at room temperature for 20 minutes, then cooled to a temperature of 02С . After dilution with cold water, the precipitate is filtered to obtain the 5-bromo-2-methylthiopyridine compound as a solid.

Stage 2; M-Cyclopropyl-1-(3-(b-methylthiopyridin-3-yl)phenyl|-1,4-dihydro-/1,8)naphthyridin-4-one-3-carboxamide

According to the method of stage C of example 32, but replacing 5-bromo-2-methylthiopyridine from stage 1

C-bromo-5-methylsulfonylpyridine, the compound is obtained

M-cyclopropyl-1-3-(b-methylthiopyridin-3-yl)phenyl/|-1,4-dihydro|1,8|-naphthyridin-4-one-3-carboxamide as a solid.

Stage C: preparation of M-Cyclopropyl-1-|3-(b-methylsulfonylpyridin-3-yl)phenyl|-1,4-dihydro|1,8|Inaphthyridin-4-one-3-carboxamide

According to the method of example 49, but replacing (o)

M-cyclopropyl-1-3-[(b-methylthiopyridine-3-1H)phenyl-1,4-dihydro|!1,8|Inaphthyridin-4-one-33-carboxamide from stage 2

M-isopropyl-1-I3-(4-methylthiophenyl)phenyl)-1,4-dihydro(1,8|Inaphthyridin-4-one-3-carboxamide), the compound is obtained

M-cyclopropyl-1-3-[(b-methylsulfonylpyridin-3-yl)phenyl-1,4-dihydro|1,8|inaphthyridin-4-one-3-carboxamide. In the form of a solid substance.

TN nMR (SOCI3) 5 0.66 (m, 2H), 0.84 (m, 2H), 2.97 (m, 1H), 3.26 (s, ЗН), 7.48 (m, 1H) , 7.55 (d, 1); 68 (m, 1H), 8.81 (dd, 1H), 8.96 (s, 1H), 9.05 (s, 1H), 9.73 (ush., MH). yu

Example 51

M-isopropyl-1-3-(x-methylsulfonylpyridin-3-yl)phenyl/|-1,4-dihydro|1,8|-naphthyridin-4-one-3-carboxamide b» m. « shi c z - And According to the method of example 49, but replacing

M-isopropyl-1-3-(5-methylthiopyridin-3-yl)phenyl)-1,4-dihydro(1,8|inaphthyridin-4-one-3-carboxamide from example 15 is, M-isopropyl-1 -I3-(4-methylthiophenyl)phenyl/|-1,4-dihydro|1,8|-naphthyridin-4-one-3-carboxamide, obtain the compound indicated in the title in the form of a solid substance. m 20 TN NMR (SOCI3 ) 5 1.33 (d, 6H), 3.20 (s, ЗН), 4.31 (m, 1H), 7.52 (m, 1H), 7.60 (d, 1H), 7.73 (s, 1H), 7.79 (t, 1H), 7.86 (d, 1H), 8.48 (m, 1H), 8.73 (m, 1H), 8.88 (d, 1H) , 9.08 (c, 1H), 9.19 (d, 2H), 9.68 (ear, MH).

IR e) Example 52

M-Cyclopropyl-1-(3-(4-ethylsulfonylphenyl)phenyl-1,4-dihydro|1,8|-naphthyridin-4-one-3-carboxamide

F) name) 60 b5

According to the method of example 49, but replacing

M-cyclopropyl-1-I3-(4-ethylthiophenyl)phenyl/|-1,4-dihydro|1,8|Inaphthyridin-4-one-3-carboxamide from example 18

M-isopropyl-1-N3-(4-methylthiophenyl)phenyl)-1,4-dihydro|1,8|naphthyridin-4-one-3-carboxamide, the title compound is obtained as a solid.

TN nMR (SOCI3) 5 0.72 (m, 2H), 0.90 (m, 2H), 1.35 (t, 3H), 3.02 (m, 1H), 3.18 (q., 2H ), 7.48-7.56 (m, 2H), 7.70 (s, 1H), 7.75 (t, 1H), 7.84 (m, ЗН), 8.03 (d, 2H) , 8.73 (m, 1H), 8.85 (dd, 1H), 9.10 (s, 1H), 9.80 (ush., MH).

Example 53

M-Cyclopropyl-1-|13-(4-ethylsulfinylphenyl)phenyl|d|-1,4-dihydro|1,8|-naphthyridin-4-one-3-carboxamide c (8) co «-

IS) (22) m.

To a solution of /M-cyclopropyl-1-I3-(4-ethylthiophenyl)phenyl/|-1,4-dihydro|1,8|-naphthyridin-4-one-3-carboxamide from example 18 in a 1:1 mixture of methylene chloride and of methanol (Zuml/mmol) add, at a temperature of 09C, magnesium monoperoxyphthalate hexahydrate (MMRR, 0.5 molar equiv.), the resulting mixture is stirred in the cold for 2 hours. The mixture is quenched with saturated aqueous sodium bicarbonate and partitioned between methylene chloride and water. . The crude product from the organic phase is chromatographed on silica gel eluting with a 90:9:1 mixture of methylene chloride, ethanol and 2895 aqueous ammonium hydroxide to give the title compound as a solid.

TN nMR (SOCI3) 5 0.68 (m, 2H), 0.85 (m, 2H), 1.15 (m, ЗН), 2.80 (m, 1H), 2.94 (m, 1H) , 2.98 (m, 1H), and 7.45-7.50 (m, 2H), 7.65-7.73 (m, 4H), 7.76-7.82 (m, ЗН) , 8.71 (m, 1H), 8.83 (dd, 1H), 9.06 (s, 1H), 9.78 (ush., MH). with Example 54

M-Isopropyl-1-(3-I4-(1-oxymidoethyl)phenyl|phenyl)-1,4-dihydro|1,8|-naphthyridin-4-one-3-carboxamide 1 sh 20 .

IR e) I

AND

F) : her ai bo

To the solution // M-isopropyl-1-I3-(4-acetylphenyl)phenyl)-1,4-dihydro(1,8|-naphthyridin-4-one-Z-carboxamide - from example 4 in pyridine (11 ml/ mmol) at room temperature, add hydroxylamine hydrochloride (21 eq.), and the resulting mixture is stirred for 16 hours. The mixture is filtered through celite, and the filtrate is evaporated. The residue is dissolved in ethyl acetate, washed with saturated aqueous sodium carbonate solution and then with water, dried and evaporated. The residue is stirred in a small volume of acetone and filtered to obtain the title compound as a solid.

TN nMR (SOCI8) 5 1.29 (d, 6H), 2.27 (s, ЗН), 4.30 (m, 1H), 7.39 (d, 71H), 7.46 (m, 1) , 7.56 (d, 2H), 7.59-7.63 (m, 2H), 7.66 (d, 2H); 7.72 (d, 1H), 8.17 (s, 1H, OH), 8.69 (sh.s, 1H), 8.82 (d, 1H), 9.10 (s, 1H), 9 ,71 (Us, MN).

Example 55

M-Isopropyl-1-(3-(4-(4-piperazin-1-iluphenyl|phenyl)-1,4-dihydro|1,8|-naphthyridin-4-one-3-carboxamide

To the solution

M-isopropyl-1-13-I4-(4-tertbutyloxycarbonylpiperazin-1-yl)phenyl|phenyl)-1,4-dihydro|1,8Inaphthyridin-4-one-3-carb oxamide from example 11 in methylene chloride (TOml/ mmol) trifluoroacetic acid (bml/mmol) is added, and the resulting mixture is stirred at room temperature for 2 hours, then gently heated for 15 minutes. The mixture is evaporated and the crude product is subjected to chromatography on silica gel, eluting with a 9:0.9:0.1 mixture of methylene chloride, methanol and 2895 aqueous ammonium hydroxide, to obtain the title compound as a solid.

TN nMR (SOCI3) 5 1.29 (d, 6H), 2.99 (m, 4H), 3.16 (m, 4H), 4.25 (m, 1H), 6.94 (d, 2H) , 7.29 (d, 1H), 7.42 (m, 1H), 7.50 (d, 2H), 7.52-7.58 (m, 2H), 7.69 (d, 1H), 8.66 (m, 1H), 8.78 (dd, 1H), 9.04 (s, 1H), 9.69 (ush, MH).

Example 56 so

M-Cyclopropyl-1-3-(4-methylsulfonylmethylphenyl)phenyl)-1,4-dihydro/(1,8-naphthyridin-4-one-3-carboxamide)

IS) t y i - « 40 . shi s ;" " Stage 1: M-Cyclopropyl-1-3-(4-bromomethylphenyl)phenyl|-1,4-dihydro|1,81-naphthyridin-4-one-3-carboxamide

A mixture of /N-cyclopropyl-1-(3-(4-hydroxymethylphenyl)phenyl|-1,4-dihydro|1,81-naphthyridin-4-one-3-carboxamide from example 16, carbon tetrabromide (2 eq.), and diphos (0.6 molar equiv.) in methylene chloride (15 ml/mmol) - stirred at room temperature for 3 hours. The mixture was concentrated at room temperature and subjected to chromatography on silica gel, eluting with a 1:11 mixture of ethyl acetate and methylene chloride, to give compound M -cyclopropyl-1-3-(4-bromomethylphenyl)phenyl)|-1,4-dihydro|!1,8|naphthyridin-4-one-3-carboxamide. o Stage 2: show 970 M-Cyclopropyl-1-I3--4-methylsulfonylmethylphenyl)phenyl)-1,4-dihydro|1,8|Inaphthyridin-4-one-3-carboxamide

To a solution of M-cyclopropyl-1-3-(4-bromomethylphenyl)phenyl|-1,4-dihydro|1,8I-naphthyridin-4-one-3-carboxamide from step 1 in M,M-dimethylformamide (2Oml/ mmol) sodium salt of methanesulfinic acid (1.Eq.) is added, and the resulting mixture is stirred at room temperature for 18 hours. A saturated aqueous solution of ammonium chloride and ethyl acetate are added to the mixture, and the insoluble solid is filtered, washed well with 2% water, hexane, ether, and ethyl acetate to give the title compound as a solid.

HF) TN NMR (SOCI3) 5 0.72 (m, 2H), 0.89 (m, 2H), 2.85 (s, ЗН), 3.04 (m, 1H), 4.34 (s, 2H), 7.46-7.52 (m, yuyu 2H), 7.55 (d, 2H), 7.65-7.73 (m, 4H), 7.80 (d, 1H), 8, 76 (m, 1H), 8.85 (d, 1H), 9.12 (s, 1H), 9.82 (ush, MH).

Example 57

M-Cyclopropyl-1-I3-(1,6-dihydro-b-oxopyridin-3-yl)phenyl/|-1,4-dihydro|1,8|-naphthyridin-4-one-3-carboxamide 60 b5 - B4-

To a solution of M-cyclopropyl-1-3-(b-benzyloxypyridin-3-yl)phenyl-1,4-dihydro|1,8|inaphthyridin-4-one-3-carboxamide from example 42 in 1,2-dichloroethane (25 ml/mmol) add trifluoroacetic acid (1.5 ml/mmol), and the resulting mixture is stirred at 602 for 18 hours. Trifluoroacetic acid (0.75 ml/mmol) is added, and heating is continued for another 24 hours. The cooled mixture is diluted with methylene chloride and saturated aqueous sodium bicarbonate is added, which precipitates a solid substance that is filtered. The organic phase is collected from the filtrate and evaporated to a solid substance, which is combined with the previously filtered solid substance. This mixture was chromatographed on silica gel eluting with 10906 methanol in methylene chloride to give the title compound as a white fluffy solid.

TN NMR (DMSO-yv) 5 0.57 (m, 2H), 0.78 (m, 2H), 2.90 (m, 1H), 6.45 (d, 1H), 7.52 (m, 1H), 7.61-7.65 (m, sc dv 2H), 7.78 (d, 1H), 7.85 (s, 1H), 7.89-7.93 (m, 2H), 8 .74 (d, 1H), 8.78-8.81 (m, 2H), 9.73 (ush., MH), or MH" 11h/million.

Example 58 i)

M-Cyclopropyl-1-|((3-15-(6-(1-hydroxy-1-methylethyl)pyridin-3-yl|Ipyridine-3-iluphenyl|-1,4-dihydro|1,8)naphthyridine -4-one-3-carboxamide c «-

IC) (22) m. « shi c According to the method of stage 4 of example 47, but replacing " with M-cyclopropyl-1-3-(5-bromopyridin-3-yl)phenyl/|-1,4-dihydro|!1 ,8|Inaphthyridin-4-one-3-carboxamide from example 41 "M-cyclopropyl-1-(3,5-dibromophenyl)-1,4-dihydro|!1,8|Inaphthyridin-4-one-3-carboxamide , the title compound is obtained as a white solid. "YAN NMR (DMSO-yv) 5 0.58 (m, 2H), 0.79 (m, 2H), 2.91 (m, 1H), 5.30 (s, IN, OH), 7.65 (m, 1H), 7.71-7.79 w- (m, ЗН), 8.12 (d, 1H), 8.23-8.26 (m, 2H), 8.49 (s, 1H ), 8.75 (dd, 71Н), 8.80 (m, 1Н), 8.87 (s, 1Н), 8.97 (m,

Gee! 2H), 9.04 (c, 1H), 9.74 (ear, MH).

Example 59 o M-isopropyl-1-3-(1-oxidopyridin-3-yl)phenyl|-1,4-dihydro|!1,8|Inaphthyridin-4-one-3-carboxamide - 50

IR e)

F) name) 60

According to the method of stage 2 of example ZO, but replacing

M-isopropyl-1-3-(pyridin-3-yl)phenyl-1,4-dihydro|1,8|inaphthyridin-4-one-3-carboxamide from example 7 5-bromo-2-(1-hydroxy 1-methylethyl)pyridine, the title compound is obtained as a white solid. "YAN NMR (DMSO-yv) 5 1.21 (d, 6H), 4.10 (m, 1H), 7.51 (t, 1H), 7.64 (m, 1H), 7.71-7 .75 (m, ZN), 7.97 (m,

1H), 8.09 (s, 1H), 8.23 (d, 1H), 8.69-8.77 (m, ЗН), 8.84 (s, 1H), 9.66 (ush., MN).

Example 60

1M-(2,6-Dichloropyridin-4-yl)-1-I3-"1-oxidopyridin-3-yl)phenyl)-1,4-dihydro-(1,8|Inaphtyridin-4-one-3- carboxamide

According to the method of stage 2 of example ZO, but replacing

1M-(2,6-dichloropyridin-4-yl)-1-3-(pyridin-3-yl)phenyl)-1,4-dihydro|1,8|inaphthyridin-4-one-3-carboxamide from the example 10 5-bromo-2-(1-hydroxy-1-methylethyl)pyridine, the title compound is obtained as a white solid.

TN NMR (DMSO-yv) 5 7.51 (m, 1H), 7.69-7.78 (m, 4H), 7.99 (dd, 1H), 8.14 (s, 1H), 8, 24 (dd, 1H), 8.70 (s, 1H), 8.73 (s, 2H), 8.84 (m, 2H), 8.99 (s, 1H), 12.05 (ush., MN).

Example 61

M-Isopropyl-1-3-(5-carboethoxy-1-oxidopyridin-3-yl)phenyl/|-1,4-dihydro-1,8|inaphthyridin-4-one-3-carboxamide c o c "-

IS) (22) and -

According to the method of stage 2 of example ZO, but replacing

M-isopropyl-1-3-(5-carboethoxypyridin-3-yl)phenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide from example 24 5-bromo-2-( 1-hydroxy-1-methylethyl)pyridine, the title compound is obtained as a white solid. 2 s "YAN NMR (SOSIz) 5 1.28 (d, 6H), 1.40 (t, ЗН), 4.28 (m, 1H), 4.43 (q., 2H), 7.49 ( dd, 1H), 7.56 (m, 1H), is 7.68 (s, 1H), 7.73 (d, 2H), 8.04 (s, 1H), 8.60 (s, 1H) , 8.68 (dd, 1H), 8.77 (s, 1H), 8.82 (d, 1H), 9.01 (s, "» 1H), 9.61 (ush, MH).

Example 62

M-Isopropyl-1-13-(5-(1-hydroxy-1-methylethyl)-1-oxidopyridin-3-ylphenyl)-1,4-dihydro|1,8)naphthyridin-4-one-3-I - carboxamide Sho Y se) sl - - 50

IR e)

Ф) име) 60 According to the method of stage 2 of example ZO, but replacing

M-isopropyl-1-13-15-(1-hydroxy-1-methylethyl)pyridin-3-yl|-phenyl)-1,4-dihydro/1,8)naphthyridin-4-one-3-carboxamide with of example 25 5-bromo-2-(1-hydroxy-1-methyl ethyl)pyridine, the title compound is obtained as a white solid. "YAN YMR (SOSIz) 5 1.29 (d, 6H), 1.60 (s, 6H), 4.11 (ush.s, 1H), 4.23 (m, 1H), 7.42-7 .51 (m, 2H), 7.58 (s, bo 2H), 7.65 (m, 2H), 8.28 (s, 1H), 8.33 (s, 1H), 8.64 (m , 1H), 8.80 (d, 1H), 8.98 (s, 1H), 9.61 (ush., MN). -58v-

Example 63 1 Ivopropyl-1-(3-|(6-(2-methylpropyl)-1-oxidopyridin-3-yl|phenyl)-1,4-dihydro-(/1,8|naphthyridin-4-one-3 -carboxamide

IN

According to the method of stage 2 of example ZO, but replacing

M-isopropyl-1-13-16-(2-methylpropyl)pyridin-3-yl|-phenyl)-1,4-dihydro|1,8-inaphthyridin-4-one-33-carboxamide from example 26 5-bromo-2 -(1-hydroxy-1-methyl ethyl)pyridine, the title compound is obtained as a white 2o solid.

TN NMR (SOCI3) 5 0.98 (d, 6H), 1.29 (d, 6H), 2.29 (m, 1H), 2.32 (d, 2H), 4.26 (m, 1H) , 7.28 (d, 1H), 7.38 (d, 1H), 7.47-7.52 (m, 2H), 7.60 (c, 1H), 7.69 (m, 2H), 8.53 (s, 1H), 8.69 (m, 1H), 8.82 (dd, 1H), 9.03 (s, 1H), 9.62 (ush., MH).

Example 64 si

M-Isopropyl-1-(3-(b-methyl-1-oxidopyridine-3-iluphenyl)1-4-dihydro/1,8-naphthyridin-4-one-3-carboxamido and I

And (22) ' h- "

According to the method of stage 2 of example 30, but replacing it with M-isopropyl-1-3-(b-methylpyridin-3-yl)phenyl)-1,4-dihydro/1,8)naphthyridin-4-one-3- carboxamide from example 28 with 5-bromo-2-(1-hydroxy-1-methylethyl)pyridine, the title compound is obtained as a white solid.

TN nMR (SOCI8) 5 1.32 (d, 6H), 2.60 (s, ЗН), 4.30 (m, 1), 7.35-7.45 (m, 2H), 7.50 ( m, 2H), 7.62 (s, 1H), 7.72 (d, 2H), 8.58 (s, 1H), 8.72 (m, 1H), 8.85 (dd, 2H), 9.06 (c, 1H), 9.66 (ear, MN). - Example 65 with M-Cyclopropyl-1-3-(1-oxidopyridin-3-yl)phenyl|-1,4-dihydro|1,81-naphthyridin-4-one-3-carboxamide 1 - 50

IR e)

Ф) name) in According to the method of stage 2 of example ZO, but replacing

M-cyclopropyl-1-3-(pyridin-3-yl)uphenyl/|-1,4-dihydro/1,8|naphthyridin-4-one-3-carboxamide from example 14 5-bromo-2-(1- hydroxy-1-methylethyl)pyridine, the title compound is obtained as a white solid. "YAN NMR (DMSO-yv) 5 0.57 (m, 2H), 0.78 (m, 2H), 2.90 (m, 1H), 7.52 (t, 1H), 7.65 (m , 1H), 1.12-11 in (m, 65 ZN), 7.98 (m, 1H), 8.10 (s, 1H), 8.25 (d, 1H), 8.70-8, 79 (m, ZN), 8.85 (s, 1H), 9.72 (ush., MN).

Example 66

M-Cyclopropyl-1-13-16-(1-hydroxy-1-methylethyl)-1-oxidopyridin-3-ylphenyl)-1,4-dihydro/1,8|inaphthyridin-4-one-3-carboxamide

According to the method of stage 2 of example 29, but replacing M-oxide with 5-bromo-2-(1-hydroxy-1-methylethyl)pyridine from stage 2 of example 30 5-bromo-1-oxidopyrimidine, the title compound is obtained as a white solid substances

TN nMR (SOCI3) 5 0.66 (m, 2H), 0.85 (m, 2H), 1.70 (s, 6H), 2.97 (m, 1), 7.43-7.49 ( m, 2H), 7.52-7.56 (m, 2H), 7.61 (s, 2H), 7.71-7.74 (m, 2H), 8.49 (s, 1H), 8 .68 (m, 1H), 8.80 (d, 1H), 9.02 (s, 1H), 9.74 (ush., MH).

Example 67

M-Cyclopropyl-1 -I3-/1-oxidopyridine-4-iluphenyl/|-1"4-dihydro/1,8|-naphthyridin-4-one-3-carboxamide c o c "-

IS)

F m.

According to the method of stage 2 of example ZO, but replacing

M-cyclopropyl-1-3-(pyridin-4-yl)phenyl/|-1,4-dihydro/1,8|naphthyridin-4-one-3-carboxamide from example 17 « 5-bromo-2-(1 -hydroxy-1-methylethyl)pyridine, the title compound is obtained as a white solid. - with TN NMR (DMSO-ydv) 5 0.57 (m, 2H), 0.79 (m, 2H), 2.92 (m, 1H), 7.62-7.70 (m, 2H), 7.75 (t, 1H), 7.88 (d, with 2H), 8.03 (d, 1H), 8.15 (c, 1H), 8.30 (d, 2H), 8.75 ( d, 1H), 8.80 (m, 1H), 8.86 (s, 1H), 9.73 (ush., MH). " Example 68

M-Cyclopropyl-1-3-(5-bromo-1-oxidopyridin-3-yl)phenyl)-1,4-dihydro/1,8)naphthyridin-4-one-3-carboxamide -I se) 1 - l 70 and so '

AND

IF) And name) According to the method of stage 2 of example ZO, but replacing

M-cyclopropyl-1-3-(5-bromopyridin-3-yl)phenyl/|-1,4-dihydro|!1,8|inaphthyridin-4-one-3-carboxamide from example 41 60 0 5-bromo- 2-(1-hydroxy-1-methylethyl)pyridine, the title compound is obtained as a light yellow solid.

TN NMR (DMSO-iv) 5 0.56 (m, 2H), 0.78 (m, 2H), 2.91 (m, 1H), 7.65 (m, 1H), 7.71-7, 74 (m, 2H), 8.02-8.06 (m, 2H), 8.15 (s, 1H), 8.60 (s, 1H), 8.73-8.79 (m, ЗН) , 8.86 (c, 1H), 9.73 (ear, MN).

Example 69 bo M-Cyclopropyl-1-|(3-15-(6-(1-hydroxy-1-methylethyl)-1-oxidopyridin-3Z-yl|pyridin-3-iluphenyl)|-1,4-dihydro| 1

»8Inaphthyridin-4-one-3-carboxamide

According to the method of stage 2 of example 30, but replacing t M-cyclopropyl-1-((3-15-16-(1-hydroxy-1-methylethyl)pyridin-3-yl|Ipyridin-3-iluphenyl/|-1,4 -dihydro/1,8|Inaphthyridine with -4-one-33-carboxamide from example 58 5-bromo-2-(1-hydroxy-1-methylethyl)pyridine, and using 1.eq of m-chloroperoxybenzoic acid, obtain indicated in the title compound as a white solid.

TN nMR (DMSO-in) 5 0.57 (m, 2H), 0.78 (m, 2H), 2.91 (m, 1H), 6.94 (z, IN, OH), 7.65 ( m, 1H), 7.71-7.79 h (mM, ЗН), 7.97 (dd, 1H), 8.13 (d, 1H), 8.25 (s, 1H), 8.55 ( s, 1H), 8.74 (dd, 1H), 8.80 (m, 1H), 8.87 (s, 1H), 8.91 (s, 1H), 9.00 (s, 1H), 9.09 (c, 1H), 9.73 (ush, MN).

Example 70

M-Cyclopropyl-1-|(3-15-(6-(1-hydroxy-1-methylethyl)pyridin-3-yl|-1-oxidopyridin-3-yl phenyl|-1,4-dihydro|1,8 |Inaphthyridin-4-one-3-carboxamide with 25 in y - | o what in wai: zo and Chia. SHY - "A le with in I b 35 I, ! -

And.

According to the method of example 69, the title compound is also obtained as a white solid. NMR (DMSO-yv) 5 0.57 (m, 2H), 0.79 (m, 2H), 2.92 (m, 1H), 5.32 (s, 1H, OH), 7, 65 (m, 1H), 7.72-7.80 - in s (m, ЗН), 8.08-8.17 (m, 2H), 8.27 (m, 2H), 8.70-8 .82 (m, 4H), 8.88 (s, 1H), 8.98 (s, 1H), 9.73 (ush., MH).

Example 71 a M-Cyclopropyl-1-|(3-15-(6-(1-hydroxy-1-methylethyl)-1-oxidopyridin-3-yl|-1-oxidopyridin-3-ylphenyl|-1,4- dihydro|1,8Inaphthyridin-4-one-3-carboxamide

AND

-I se) 1 - 50

IR e)

F) name)

According to the method of example 69, the title compound is also obtained in the form of a white solid. 1H), 6.85 (ush.s, IN, OH), 7.65 (m, MH), 7.70-7.80 (m, ЗН), 7.96 (d, 1H), 8.13 (m, 2H), 8.29 (s, 1H), 8.71-8.84 (m, 4H), 8.89 (s, 1H), 8.92 (s, 1H), 9.73 ( ear., MN).

Example 72

M-Isopropyl-1-3-(1-oxydoquinolin-3-yl)phenyl-1,4-dihydro|1,8|Inaphthyridin-4-one-3-carboxamide b5

According to the method of stage 2 of example ZO, but replacing

M-isopropyl-1-|3-(quinolin-3-yl)phenyl/|-1,4-dihydro|1,8|naphthyridin-4-one-3-carboxamide from example 12 5-bromo-2-(1 -hydroxy-1-methylethyl)pyridine, the title compound is obtained as a solid.

TN NMR (SOCI3) 5 1.30 (d, 6H), 4.28 (m, 1H), 7.49 (dd, 1H), 7.54 (d, 1H), 7.66-7.85 ( m, 5H), 7.92 (m, 2H), 8.69-8.75 (m, 2H), 8.84 (d, 1H), 8.86 (s, 1H), 9.08 (s , 1H), 9.64 (early, MN).

Example 73

M-Isobutyl-1-3-(6-(1-hydroxy-1-methylethyl)-1-oxidopyridin-3-ylIfenyl/|-1,4-dihydro/(1,8|naphthyridin-4-one-3- carboxamide

And with (8) ' (he) "- . iv) (22) ' m.

To the mixture "

M-isobutyl-1-(3-16-(1-hydroxy-1-methylethyl)pyridin-3-ylphenyl)-1,4-dihydro(1,8|naphthyridin-4-one-3-carboxamide) of example 46 in 13:11 methylene chloride/methanol (33 mL/mmol) at room temperature is added magnesium monoperoxyphthalate hexahydrate (MMPP, 1.1 molar equiv.), and the resulting mixture is stirred at room temperature for 24 hours. The mixture is filtered through a pad of Celite, and the filtrate washed with aqueous sodium carbonate, then water, and dried. The crude product was chromatographed on silica gel eluting with 895 ethanol in ethyl acetate, and the resulting solid was stirred at room temperature in ether for several hours and filtered to give the title compound as a light pink solid." NMR (Acetone-dv) 5 0.98 (d, 6H), 1.61 (s, 6H), 1.88 (m, 1H), 3.26 (t, 2H), 7 .52 (c, 1H, OH), 7.61 (m, i-o 1), 7.66 (d, 1H), 7.77-7.82 (m, 2H), 7.88 (d, 1H), 7.99 (d, 1H), 8.12 (s, 1H), 8.68 (s, 1H), 8.73 (m, tn), 1 8.80 (dd, 1H), 8 .93 (c, 1H), 9.81 (ush, MN). tsu Example 74

M-cyclopropyl-1-3-(b-methyl-1-oxidopyridin-3-yl)phenyl|-1,4-dihydro|1,8|-naphthyridin-4-one-3-carboxamide

IR e)

F) ime) 60 bo According to the method of example 73, but replacing

M-cyclopropyl-1-3-[(b-methylpyridin-3-yl)phenyl]-1,4-dihydro|!1,8-naphthyridin-4-one-3-carboxamide from example 39

M-isobutyl-1-(3-I6-(1-hydroxy-1-methylethyl)pyridin-3-ylIfenyl)-1,4-dihydro|1,8|Inaphthyridin-4-one-3-carboxamide, obtain indicated in title compound in the form of a solid substance.

TN nMR (SOCI3) 5 0.72 (m, 2H), 0.91 (m, 2H), 2.61 (s, ЗН), 3.02 (m, 1), 7.38 (d, 1H) , 7.45 (dd, 1H), 7.49-7.58 (m, 2H), 7.66 (s, 1H), 7.75 (m, 2H), 8.61 (s, 1H), 8.72 (m, 1H), 8.87 (dd, 1H), 9.08 (s, 1H), 9.78 (ush., MH).

Example 75

M-Cyclopropyl-1-3-(β6-methylsulfonyl-1-oxidopyridin-3-yl)phenyl|-1,4-dihydro|1,8|inaphthyridin-4-one-3-carboxamide

To the suspension of

M-cyclopropyl-1-(3-(b-methylsulfonylpyridin-3-yl)uphenyl/|-1,4-dihydro/1,8-naphthyridin-4-one-3-carboxamide from example 51 in methylene chloride (30 ml/mmol) add urea-hydrogen peroxide (8 eq.) and the resulting mixture is cooled to a temperature of 02. Add trifluoroacetic acid (4.7 eq.), and the mixture is heated to room temperature to obtain a solution. After 18 hours, more urea-hydrogen peroxide (2.eq. .) and trifluoroacetic acid (2 eq.), and stirring is continued for another 2 hours. The mixture is quenched with saturated aqueous (ee) sodium metabisulfite, diluted with methylene chloride, and the organic phase is washed with IM aqueous CARRIER, then with saturated salt solution and water, dried and evaporated. Crude the product is chromatographed on silica gel, eluting with 40956 toluene in acetone to give the title compound as a solid IC o) substance. b"

TN nMR (SOSIS) 5 0.66 (m, 2H), 0.85 (m, 2H), 2.97 (m, 1H), 3.52 (s, ЗН), 7.48 (m, 1H) , 7.58-7.65 (m, 3H), 7.72-7.78 (m, 2H), 8.15 (d, 1H), 8.54 (s, 1H), 8.68 ( .s, 1H), 8.81 (d, 1H), 9.01 (s, 1H), 9.71 (ush, MH). uh-

Example 76

M-Cyclopropyl-1-15-bromo-3-(6-(1-hydroxy-1-methylethyl)-1-oxidopyridin-3-ylIfenyl)-1,4-dihydro|/1,8|naphthyridine-4- on-3-carboxamide « i ZHE Z Z 3 s shi schi Yash 4. " SCHI i -. g How

Hey - 50; sa CHE echny

WITH

IR e) c,

According to the method of stage 2 of example ZO, but replacing

M-cyclopropyl-1-(5-bromo-3-(6-(1-hydroxy-1-methylethyl)pyridin-3-yl|Ifenyl)-1,4-dihydro|!1,8|Inaphthyridin-4-one -3-carboxamide from Example 47 with 5-bromo-2-(1-hydroxy-1-methylethyl)pyridine, the title compound is obtained as a solid. where TN nNMR (SOCI5) 5 0.71 (m, 2H ), 0.90 (m, 2H), 1.75 (s, 6H), 3.02 (m, 1), 7.48-7.60 (m, 5H), 7.73 (s, 1H) , 7.88 (s, 1H), 8.52 (s, 1H), 8.72 (m, 1H), 8.84 (dd, 1H), 9.04 (s, 1H), 9.7 Mus ., MN). because Example 77

M-Cyclopropyl-1-13-I6-(1,2-dihydroxy-1-methylethyl)-1-oxidopyridin-3-ylphenyl)-1,4-dihydro|1,8)Inaphthyridin-4-one-3-carboxamide b5

Knn neck!

Stage 1: 5-bromo-2-(1-methylvinyl)pyridine M-Oxide

A mixture of M-oxide 5-bromo-2-(1-hydroxy-1-methyl ethyl)pyridine from stage 2 of example 30 (1.29g) and 2595 of aqueous sulfuric acid is heated at a temperature of 1302 for 2 days. After cooling, the mixture is made slightly basic by the addition of 10M aqueous sodium hydroxide, and partitioned between ethyl acetate and water. The crude product of evaporation of the organic phase is used as such in stage 2.

Stage 2: M-Oxide 5-bromo-2-(1,2-dihydroxy-1-methylethyl)pyridine

The crude product from stage 1 is dissolved in a 3:1 mixture of acetone and water (1bml) and M-oxide of 4-methylmorpholine (1g) and potassium osmate dihydrate (9Omg) are added. The resulting mixture is stirred at room temperature for three days, then an excess of solid sodium bisulfite is added and the mixture is evaporated. The residue is diluted with methylene chloride and filtered. The filtrate was evaporated and the residue was chromatographed on silica gel eluting (8) with ethyl acetate to give the title compound as a white solid.

Stage C: M-Cyclopropyl-1-13-I6-(1,2-dihydroxy-1-methyl ethyl)-1-oxidopyridin-3-ylIfenyl)-1,4-dihydro|1,8|Inaphthyridin-4-one -3-carboxamide so so According to the method of stage 2 of example 32, but replacing the M-oxide of 5-bromo-2-(1,2-dihydroxy-1-methylethyl)pyridine from stage 2 with 3-bromo-5-methylsulfonylpyridine, the indicated in title compound in the form of a solid substance. -- "YAN NMR (SOSIz) 5 0.66 (m, 2H), 0.85 (m, 2H), 1.61 (s, ZN), 2.78 (m, IN, OH), 2.97 (m, 1H), 3.90 (m, 1Hn), 3.97 (m, 1H), 7.48 (m, 71H), 7.53 (m, 2H), 7.60 (m, 2H ), 7.69-7.72 (m, 2H), 7.92 (s, 1H, OH), 8.49 (s, 1H), 8.68 (m, 1H), 8.80 (dd, 1H), 9.02 (c, 1H), 9.73 (ush., MH). b

Inhibitor PDE-4, example V rchso I Shchi tih shi s;" -I se) 1 -l 70 M-Cyclopropyl-1-(3-(1-oxidopyridin-3-yl)ethynyl|Ifenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide so (a combination of them)

Stage 1:

F) name) 60 b5

TO nyu yam "o shle SHE Nikiovyan ether chna " zyhe zt: ; vyrtirino fey gen petiyaenu shiy piy tlia po

Not Z Tel lan. sha di usch. bis s :i i iii i satani I trick PI ekz Al va p : R, i vi : y : CYA 25 uki y mol (o, v: chok ten OZLVZH OK Ovod 025 M) shi so 30 i shk i. - (KA) n solutions t -e4 po.

A 100-liter round-bottom flask is equipped with a dephlegmator and a device for the passage of nitrogen, and is loaded with NSI salt of bromopyridine-M-oxide, followed by the addition of 12.5 liters of ХОМас, and cooled in an ice bath. Pure tert-amylamine is added through a dropper for 1 hour. It is noted that the addition of -v s amine causes a slight exothermic reaction: the temperature rises from 592C to 10927. A phosphine solution is added to obtain a light yellow homogeneous solution. Then add P-allylpalladium dimer in the form

G.Y -. . . and suspensions in 1.5 liters of OMas. The reaction is stirred at a temperature of 102 for 30 minutes. The acetylene compound is weighed in a bottle and 9.9 kg of ХОМас is added. This acetylene solution is added to the reaction flask. The bottle is washed with 22 kg of OMas, and it is added to the reaction mixture. Add the amount of OMas necessary to obtain -I total volume of bbl. The resulting milky-yellow solution is heated to a temperature of 602C, during which it becomes a homogeneous brown solution, until the complete completion of the reaction, which is determined by the absorption of ee, an acetylene compound. The reaction mixture is cooled to a temperature of 09C before adding 9O0l of water to precipitate the product from the solution. The suspension is filtered to collect the product. To remove palladium, this precipitate is washed with 87.5 l of n-butanol on a filter apparatus, and then dried in a vacuum oven at a temperature of 5090 in a stream of nitrogen overnight to obtain a white solid, 2.68 kg, 8395 yield. and 42) H NMR (SOSIZ 400MHz) 8: 1.35 (t, 9-7.1Hz, ZN), 4.34 (q., U-7.1GHz, 2H), 7.28 (dd, U- 8.0, 6.8Hz, 1H), 7.34 (dtT, 9-8.0, 1.2Hz, 7H), 7.38 (dd, U-8.0, 4.4Hz, 7H), 7 .49 (ddd, U-8.0, 2.4, 1.2Hz, 7H), 7.58 (t,

U-7.9Hz, 1H), 7.64 (t, 9U-1.8Hz, 1H), 7.67 (dt, 9U-7.6, 1.2Hz, 1H), 8.12 (dt, 9U -6.5, 1.1Hz, 1H), 8.27 (s, 1H), 8.59 (dd, U-4.4, 1.9Hz, 1H), 8.64 (s, 1H), 8 .74 (dd, U-8.0, 1.9Hz, 1H).

NMR ZS (SOSIz 400MHz) 5: 14.3, 61.1, 84.7, 92.4, 112.8, 121.4, 122.7, 123.0, 123.2, 125.8, 128, 3,

F) yuyu 128.5, 129.8, 130.7, 132.5, 136.8, 139.1, 141.0, 149.0, 149.9, 152.5, 164.6, 174.5 .

The following palladium recovery method is also used:

Ether product /411.14 O.718 kg 7.85 1.0

Bagso 0-60 -- O.3BOKg | --- BO mass.

Methanol solvent) 82l - 5O vol. b After precipitation with water, the wet filtered sediment is dried in a stream of nitrogen. A 100-liter round-bottomed flask is equipped with a dephlegmator, a stirrer, and a device for passing nitrogen, then the ether product and 72 liters of methanol are loaded. The mixture is heated to a temperature of 6b02C until the solids dissolve. The mixture is cooled to a temperature of 552C and Yuagso 0-60 is added in the form of a suspension in one liter of methanol. The mixture is heated to a temperature of 602 for four hours. The solution is filtered through a warm Rise filter to remove

DVagso. The ZoiYika Riose layer is washed with another 4 liters of methanol. The combined filtrates are concentrated to 25 l, at this moment an abundant white precipitate begins to form. This suspension can be used directly at the stage of amide production.

Stage 2: is in the same Higher Education Institution.

M. i i k v dz Zitdnnkef zpli i YOU: o background, water Ж 00o--- 00 yiv,

Butyuofoophyt 5 pit B bbzhnaschu s; | | in

Zhetinot razlinnik: il takt Moi, - ti shiy and -ee nn from ekeojnynu rezzkni z ov, sh eKMy left lizhe butalboefnu that skocershiene « yu loavovodeyuti as with; so and bsz to be fasschitu; A 100-liter round-bottom flask is equipped with a dephlegmator and a device for passing nitrogen, and the penultimate ether and methanol are loaded into it, followed by the addition of cyclopropylamine. As indicated above, a catalyst or a Lewis acid may be added. The reaction mixture is heated to 60°C until the ether is completely absorbed. The end of the reaction is determined when the ether content becomes less than 295 by HPLC. After completion, the reaction mixture is cooled to 40°C and concentrated to about half the volume.

Sh- Add isopropyl acetate, simultaneously driving off the rest of methanol and amine. After the completion of the replacement of CO solvents with isopropyl acetate, the final volume is 20 l. A sample of the suspension is taken and filtered. The sediment is washed with 2 liters of isopropyl acetate and then dried in a vacuum oven at a temperature of 502C in a stream of nitrogen overnight. The second 72-liter round-bottomed flask is equipped with a dephlegmator and a device for the passage of nitrogen, and 20 liters of the solid product of compound IX and 24 liters of 1595 aqueous acetonitrile are loaded into it. The suspension is heated to a temperature of 602C. All solids dissolve. The solution is filtered through a 1-micron filter while simultaneously heated in a second 72 L round-bottom flask, then cooled to 2296.

The suspension is filtered and the solids are dried in a vacuum oven at a temperature of 502C in a stream of nitrogen overnight to obtain 0.86 kg of crystalline compound IX, 6095 yield.

H NMR (SOSIZ 400 MHz) 5: 0.61-0.73 (m, 2H), 0.79-0.92 (m, 2H), 2.95-3.01 (m, 1), 7, 28 (dd, 9-80, (F. 6.8Hz, 71), 7.40 (d, U-8.0Hz, 71H), 7.48 (dt, uU-8.0, 4.4Hz, 1 ), 7.49 (ddd, 9U-8.0, 2.0, 1.2Hz, МН), 7.61 (t, ko U-8,О0Хц, 71), 7.64 (m, 9U-2 ... .70 (dd, U-4.6, 1.8Hz, 1H), 8.80 (dd, U-8.0, 1.9Gu, 1H), 9.00 (s, 1H), 9.74 ( us.d, U-3.6Hz, 1H). in NMR ZS (SOSIz 400MHz) 85: 6.5, 22.4, 84.6, 92.5, 113.5, 121.4, 122.0, 122.9, 123.2, 125.7, 1284, 128.6, 129.8, 130.7, 132.6, 136.4, 139.0, 140.4, 141.1, 148.0, 149.7, 153.0, 165.1, 1771.

An alternative method illustrating the preparation of amide using magnesium chloride b5 r s h i r s w i d a y N a s h y s h e More | I y y E: and zhydny fi shi "kg veni che

Pikooratslynya: Bey - Zav, sch you tjazh Chveb.

From - ach chyny i I sik: y ad SCHE zn ob soshe av i" GE, same as I: this is also with Cykreg noy V kyu for ab yy - z a dyny tu in kry oy

Description of the process Ge"! A 72-liter round-bottomed flask is equipped with a dephlegmator and a device for the passage of nitrogen, and the penultimate ether and acetonitrile are charged into it 325, followed by the addition of magnesium chloride and, then, cyclopropylamine. The reaction mixture is heated to a temperature of 602C until the ether is consumed.

The end of the reaction is determined when the ether content becomes less than 0.595 according to HPLC. After completion, the reaction mixture is cooled to a temperature of 402C and concentrated to approximately half the volume. Add acetonitrile while driving off the rest of the cyclopropylamine. After replacing the solvents with acetonitrile, the final volume is 8 liters. Add water and heat the suspension to a temperature of 602C. All solid substances dissolve. The solution is filtered through a 1-micron pass filter, while simultaneously heating in the second. on but : . . and: in a 22-liter round-bottomed flask, then cooled to a temperature of 222C. The suspension is filtered, and the solids are dried in a vacuum oven at a temperature of 502C in a stream of nitrogen overnight to obtain 0.82 kg of 191, 8095 yield. -I Stage 3: recrystallization of their compound

F g Compound IX 422.45 O.8bkg 2.0 1.0

Ethanol solvent 20 l -- A, See - 50 A 72-liter round-bottom flask is equipped with a dephlegmator and a device for the passage of nitrogen, and compound IX and ethanol are loaded into it. The suspension is heated to a temperature of 502 with stirring until recrystallization is complete. Recrystallization is considered complete if there are more than 9596 forms of A according to solid-state NMR or powder X-ray diffraction. The mixture is cooled to 222C, then filtered 29 to collect the solid, which is dried in a vacuum oven at 502C under a stream of nitrogen overnight

GF) with obtaining 0.74 kg of the desired form. The solids are sieved through 12 mesh to obtain 0.719 kg of fluffy t solids.

PDE-4 inhibitor, example 2 60 b5

Her

M-cyclopropyl-1-(3-(pyridin-3-yl)lethynyl|phenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide (compounds

IXa)

Compound IXa is obtained according to the method of example 1, replacing 33-bromopyridine with 3-bromothridine-M-oxide.

Other changes or modifications that are obvious to those skilled in the art are not beyond the scope of this invention. This invention is limited only by the claims.

Claims (1)

The formula of the invention p 1. The method of obtaining a compound of formula IX or IXa: (5) | | | | N "- sow. y iv) M nn (22) | m. cm - x more m - them | and them g" of their IXa Z. which differs in that it includes -I stage C: interaction in the solvent A of the compounds of the formula Ma, (Ma Te o o "a) claim 1 i! where BC is selected from C-C-C alkyl and solvent A is selected from dimethylaminoacetamide, dimethylformamide, acetonitrile, DMSO, methylacetamide, simple ethers or their mixtures; with a compound of formula MII or formula Ma b5 g Vg and ZK mith MI Ma in the presence of palladium of a catalyst and a phosphine ligand, and an amine base to obtain a compound of the formula MI or the formula MPa. with cyclopropylamine in solvent B selected from C.-C/-alkanol, trifluoroethanol or their mixture, or acetonitrile. (is) 35 2. The method according to claim 1, which is characterized by the fact that the phosphine ligand is selected from P(C.-Cv-alkyl)z. what- C. The method according to claim 1, which differs in that the palladium catalyst is selected from the group: P(tre;-butyl)z-Pa-P(tre-butyl)z and (P("tre;-butyl)zRap". 4. The method according to claim 1, which differs in that the molar ratio of the compound of the formula Ma and the compound of the formula MII or Ma is chosen from approximately 1:1.5 to 1.5:1. " 5. The method according to claim 1, which differs in that the ratio of molar equivalents of the amine base per mol of the compound of the formula MI! or Miia choose from 2:1 to 3.5:1. 6. The method according to claim 1, which is characterized by the fact that the molar ratio of the palladium catalyst and the compound "c" of the formula Ma is chosen from 0.05:1 to 0.101. 7. The method according to claim 1, which differs in that stage C is carried out at a temperature from 40 to 70 2b. 8. The method according to claim 1, which differs in that stage O is carried out in the presence of a catalyst. -And 9. The method according to claim 8, which differs in that the catalyst is selected from butyl phosphite (VyO)zP and magnesium chloride. ise) 10. The method according to claim 1, which is characterized by the fact that the molar ratio of cyclopropylamine and compounds of the formula c MI or MPa is chosen as at least 1:1. 11. The method according to claim 1, which differs in that stage O is carried out at a temperature from 40 to 60 2С. - 12. The method according to claim 1, which differs in that stage C and stage Y are carried out in the same reactor without purification of c or separation of the product of stage C before the transition to stage Y. 13. The method according to claim 1, which is characterized in that it additionally includes mixing a compound of formula IX or IXa with a conversion solvent for recrystallization of a compound of formula IX or IXa, and the conversion solvent is selected from dry ethanol, methanol, M-methylpyrrolidinone, trifluoroethanol, methyl- tert-butyl ether or their mixtures. Ф) 14. The method according to any of the preceding clauses, which is characterized by the fact that the compounds of the formula IX or IXa are recrystallized in such an amount of solvent that is sufficient to suspend the compounds of the formula IX or IXa. 15. The method according to claim 14, which differs in that the specified solvent is selected from dimethylformamide, n-dimethylacetamide, M-methylpyrrolidinone and C.-C.-alkanol. 16. The method according to claim 15, which is characterized by the fact that the specified solvent contains water in an amount less than 5 95. Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2007, M 9, 25.06.2007. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine.