KR100793688B1 - 6-alkoxy-pyrido-pyrimidine as P-38 mitogen active protein kinase inhibitor - Google Patents

Abstract

The present invention provides a compound of formula (I), a pharmaceutical composition comprising the same, and a method of using the same:

Formula I

Where

R ¹ is alkyl, cycloalkyl, cycloalkylalkyl or —CH ₂ -alkenyl;

X ¹ is O, NR ⁴ , where R ⁴ is hydrogen or alkyl, S or C═O;

Z is N or CH;

R ² and R ³ are as defined herein.

Description

6-Alkoxy-pyrido-pyrimidine as P-38 mitogen active protein kinase inhibitor {6-ALKOXY-PYRIDO-PYRIMIDINES AS P-38 MAP KINASE INHIBITORS}             

The present invention relates to pyridopyrimidines and derivatives thereof. Specifically, the present invention provides 2,6-disubstituted 7-oxo-pyrido [2,3-d] pyrimidines, pharmaceutical formulations comprising the same and methods of using the same.

Mitogen activating protein kinases (MAPs) are a class of proline-derived serine / threonine kinases that activate their substrate by double phosphorylation. Kinases are activated by a variety of signals, including nutrition and osmotic pressure, UV light, growth factors, endotoxins and inflammatory cytokines. One group of MAP kinases is the p38 kinase group, which includes a variety of isoforms (eg, p38α, p38β, p38γ, and p38δ). p38 kinases are responsible for phosphorylating and activating transcription factors as well as other kinases and are activated by physical and chemical forces, proinflammatory cytokines and bacterial lipopolysaccharides.

More importantly, the products of p38 phosphorylation have been found to mediate the production of inflammatory cytokines and cyclooxygenase-2, including TNF and IL-1. Each of these cytokines is associated with many disease states and symptoms. For example, TNF-α is a cytokine produced primarily by activated monocytes and macrophages. Its excessive or unregulated production is related by playing a causal role in the pathogenesis of rheumatoid arthritis. Recently, it has been reported that inhibition of TNF production is widely applied in the treatment of inflammation, inflammatory bowel disease, multiple sclerosis and asthma.

TNF is also a viral infection such as HIV, influenza virus, and herpes simplex virus type-1 (HSV-1), herpes simplex virus type-2 (HSV-2), cytomegalovirus (CMV), varicella zoster Herpes viral infection, pseudorabies, including virus (VZV), Epstein Barr virus, human herpes virus-6 (HHV-6), human herpes virus-7 (HHV-7), human herpes virus-8 (HHV-8) And rhinitis.

Similarly, interleukin-1 (IL-1) is produced by activated monocytes and macrophages and plays a role in many pathogenic responses, including rheumatoid arthritis, fever and reduced bone resorption.

In addition, the incidence of p38 is associated with stroke, Alzheimer's disease, osteoarthritis, lung injury, infection shock, angiogenesis, dermatitis, psoriasis and atopic dermatitis (J. Exp. Opin. Ther. Patents, (2000) , Vol. 10 (1)].

Inhibition of these cytokines by p38 kinase inhibition has the advantage of controlling, reducing and alleviating many of these disease states.

Certain 6-aryl-pyrido [2,3-d] pyrimidin-7-ones, 7-imines and -7-thiones are disclosed in WO 96/34867 as inhibitors of protein tyrosine kinase mediated cell proliferation. It is. In addition, other 6-aryl-pyrido [2,3-d] pyrimidines and naphthyridine are disclosed in WO 96/15128 as inhibitors of tyrosine kinases. 6-alkyl-pyrido [2,3-d] pyrimidin-7-ones are disclosed in WO 98/33798 as cyclin dependent kinases. Certain 4-amino-pyridopyrimidines are disclosed in European Patent No. 0 278 686 as inhibitors of dihydrofolate reductase. Compounds that are p38 kinase inhibitors are disclosed in the following patents and patent applications: US Pat. Nos. 6,316,464, 6,451,804, 6,506,749, 6,518,276 B2; And US Patent Application Nos. 09 / 693,364 (International Patent Publication No. 01/29042) and 10 / 073,845 (International Patent Publication No. 02/64594).

One embodiment (i) of the present invention provides a compound represented by the following formula (I), and a pharmaceutically acceptable salt, hydrate or prodrug thereof:

Where

Z is N or CH;

X ¹ is O, NR ⁴ , where R ⁴ is hydrogen or alkyl, S or C═O;

R ¹ is alkyl, cycloalkyl, cycloalkylalkyl or —CH ₂ -alkenyl;

R ² is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, haloalkyl, heteroalkyl, cyanoalkyl, alkylene-C (O) —R ²¹ where R ²¹ is hydrogen, alkyl, hydr Oxy, alkoxy, amino, monoalkylamino or dialkylamino), amino, monoalkylamino, dialkylamino, acyl or NR ²² -YR ²³ , wherein Y is -C (O), -C (O) O ^{-, -C (O) NR 24} , S (O) 2 or S (O) ₂ NR ²⁵ a; R ^22, R ²⁴ and R ²⁵ are independently hydrogen or alkyl; R ²³ is hydrogen, alkyl, cycloalkyl , Cycloalkylalkyl, heteroalkyl or optionally substituted phenyl;

R ³ is alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heteroalkylsubstituted cycloalkyl, heterosubstituted cycloalkyl, heteroalkyl, cyanoalkyl, heterocyclyl , Heterocyclylalkyl or -heterocycloamino-SO ₂ -R ¹² , wherein R ¹² is haloalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl.

More specifically, the present invention provides the following compounds:

(ii) R ¹ is -CH ₂ - instead of the compound of the alkenyl and alkenylene of (i) R ³ is H to add, or a pharmaceutically acceptable salt, hydrate, or prodrug;

(iii) a compound of (i) or (ii) wherein Z is N, X ¹ is O, R ¹ is alkyl, R ² is H or alkyl, and R ³ is heteroalkyl or heterocyclyl;

(iv) Saturated non-aromatic cyclic radicals of 6 ring atoms wherein heteroalkyl is alkoxyalkyl, heterocyclyl is not one ring atom but C or O or N and optionally N is substituted by alkyl-SO ₂ -or alkoxycarbonyl Compounds of phosphorus (iii);

(v) a compound of (i) or (ii) wherein X ¹ is -O-;

(vi) a compound wherein (i), (ii) or (v) wherein R ¹ is alkyl or cycloalkyl;

(vii) (i), (ii), (v) wherein R ³ is cycloalkyl, cycloalkylalkyl, heteroalkylsubstituted cycloalkyl, heterosubstituted cycloalkyl, heteroalkyl, heterocyclyl or heterocyclylalkyl a compound of (vi);

(viii) A compound of (i), (ii), (v), (vi) or (vii) wherein R ³ is cycloalkyl, heteroalkylsubstituted cycloalkyl, heterosubstituted cycloalkyl, heteroalkyl or heterocyclyl ;

(ix) a compound of (i), (ii), (v), (vi), (vii) or (viii), wherein R ³ is optionally substituted heterocyclyl;

(x) a compound of (i), (ii), (v), (vi), (vii), (viii) or (ix), wherein R ³ is hydroxyalkyl or alkoxyalkyl;

(xi) of (i), (ii), (v), (vi), (vii), (viii), (ix) or (x), wherein R ² is hydrogen, alkyl, aryl, cycloalkyl or heteroalkyl compound;

(xii) a compound of (i), (ii), (v), (vi), (vii), (viii), (ix), (x) or (xi), wherein R ² is alkyl or hydroxyalkyl;

(xiii) a compound of (i) or (ii) having the formula (I '') or a pharmaceutically acceptable salt thereof:

Formula I ''

[Wherein,

R ¹ is alkyl;

R ² is selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl and heteroalkyl;

R ³ is heteroalkyl or heterocyclyl];

(xiv) R ³ is (1-hydroxy-2-methyl) -prop-2-yl, 1-hydroxy-pentane-2-yl, (S) -2-hydroxy-1,2-di Methyl-propyl, (R) -2-hydroxy-1,2-dimethyl-propyl, (S) -2-hydroxy-1-methyl-ethyl, 1-hydroxymethyl-cyclopentane-1-yl , 2-hydroxy-2-methyl-propyl, 3-methoxy-1- (2-methoxy-ethyl) propyl, tetrahydro-2H-pyran-4-yl, 1- (methylsulfonyl) piperi (Xiii) selected from the group consisting of din-4-yl, 1-carboxyethyl-piperidin-4-yl, 1,1-dioxidotetrahydro-2H-thiopyran-4-yl and morpholinyl Compound of;

(xv) R ¹ is ethyl, R ² is methyl, R ³ is (1-hydroxy-2-methyl) -prop-2-yl, 1-hydroxy-pentin-2-yl, (S ) -2-hydroxy-1,2-dimethyl-propyl, (R) -2-hydroxy-1,2-dimethyl-propyl, (S) -2-hydroxy-1-methyl-ethyl, 1 -Hydroxymethyl-cyclopentane-1-yl, 2-hydroxy-2-methyl-propyl, 3-methoxy-1- (2-methoxy-ethyl) propyl, tetrahydro-2H-pyran-4 -Yl, 1- (methylsulfonyl) piperidin-4-yl, 1-carboxyethyl-piperidin-4-yl, 1,1-dioxidotetrahydro-2H-thiopyran-4-yl And (xiv) selected from the group consisting of morpholinyl;

(xvi) A compound of (xiii) having the formula II:

[Wherein,

X is -O-, -C (= 0)-, -N (R ^12a )-or -CH (R ^12b )-;

R ^12a is selected from the group consisting of hydrogen, C _1-4 alkyl, —C (═O) R ¹⁵ , —C (O) ₂ R ¹⁵ and —S (O) ₂ (C _1-4 alkyl);

R ^12b is selected from the group consisting of hydrogen, C _1-4 alkyl, -OR ¹⁵ , -C (= 0) R ¹⁵ , -C (O) ₂ R ¹⁵ and -S (O) ₂ (C _1-4 alkyl) Selected;

R ¹⁴ is C _1-4 alkyl, oxo (═O), —OR ¹⁵ , —C (═O) R ¹⁵ , —C (O) ₂ R ¹⁵ and —S (O) ₂ (C _1-4 alkyl) It is selected from the group consisting of;

Each R ¹⁵ is independently selected from hydrogen and C _1-4 alkyl;

q is 0 or 1;

r is 0, 1 or 2; or

(xvii) A compound of (xvi) wherein X is -N (R ^12a )-and R ^12a is -S (O) ₂ (C _1-4 alkyl).

Another aspect of the invention provides a pharmaceutical formulation comprising a compound of formula (I) and a pharmaceutically acceptable carrier, diluent or excipient therewith.

Compounds of formula (I) and the salts disclosed above are inhibitors of protein kinases and exhibit effective in vivo activity against p38. They are also selective for p38 for cyclin dependent kinases and tyrosine kinases. Therefore, the compounds of the present invention can be used for the treatment of diseases mediated by proinflammatory cytokines such as TNF and IL-1. Accordingly, another aspect of the present invention provides a method of treating a P38 mediated disease or condition by administering a therapeutically effective amount of a compound of Formula (I) to a patient in need of treatment for a P38 mediated disease or condition.

Unless stated otherwise, the following terms used in this specification and claims have the meanings given below:

H ¹ or these are exemplified in detail herein.

The term "acyl" refers to the radical -C (O) R, wherein R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl, of which alkyl, cycloalkyl, cycloalkylalkyl and phenylalkyl are described herein. As defined in the above). Representative examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl, and the like, or those specifically exemplified herein.

"Acylamino" is a radical -NR'C (O) R wherein R 'is hydrogen or alkyl, R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl, of which alkyl, cycloalkyl , Cycloalkylalkyl and phenylalkyl are as defined herein). Representative examples include, but are not limited to, formylamino, acetylamino, cyclohexylcarbonylamino, cyclohexylmethylcarbonylamino, benzoylamino, benzylcarbonylamino, or the like specifically exemplified herein.

"Alkenyl" means a monovalent linear hydrocarbon radical of 2 to 6 carbon atoms or a monovalent branched hydrocarbon radical of 3 to 6 carbon atoms containing one or more double bonds, such as ethenyl, propenyl, or the like herein There are those specifically illustrated.

Thus, when referring to the group -CH ₂ -R, wherein R is an alkenyl radical as defined herein, it is preferred that (-CH ₂ -CH = CH ₂ ), (-CH ₂ -CH = CH-CH ₃ ), or the like or those specifically exemplified herein.

"Alkoxy" means a radical -OR where R is alkyl as defined herein, such as methoxy, ethoxy, propoxy, butoxy, or the like, as specifically exemplified herein.

"Alkyl" means a monovalent linear saturated hydrocarbon radical of 1 to 8 carbon atoms or a monovalent branched saturated hydrocarbon radical of 3 to 8 carbon atoms, examples of which include methyl, ethyl, propyl, 2-propyl, n-butyl, Isobutyl, t-butyl, pentyl and the like or those specifically exemplified herein. Preferably the alkyl group is linear alkyl of 1 to 6 carbon atoms or branched alkyl of 3 to 6 carbon atoms, more preferably linear alkyl of 1 to 4 carbon atoms or branched alkyl of 3 or 4 carbon atoms.

"Alkylene" means a divalent linear saturated hydrocarbon radical of 1 to 6 carbon atoms or a divalent branched saturated hydrocarbon radical of 3 to 6 carbon atoms, examples being methylene, ethylene, 2,2-dimethylethylene, propylene , 2-methylpropylene, butylene, pentylene and the like or those specifically exemplified herein.

"Alkylthio" means a radical -SR where R is alkyl as defined above, examples of which are methylthio, ethylthio, propylthio, butylthio, etc. or those specifically exemplified herein. .

"Aryl" means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical, which may be optionally substituted with one or more substituents, preferably one, two or three substituents, which substituents are preferably alkyl, hydroxy, alkoxy , Haloalkyl, haloalkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, -SO ₂ NR'R ", where R 'and R" are independently hydrogen or alkyl, YC (O) -R, , Y is absent or an alkylene group, R is hydrogen, alkyl, haloalkyl, haloalkoxy, hydroxy, alkoxy, amino, monoalkylamino or dialkylamino), heteroalkyl, heteroalkyloxy, heteroalkylamino, Halo, nitro, cyano, amino, monoalkylamino, dialkylamino, alkylsulfonylamino, heteroalkylsulfonylamino, sulfonamido, methylenedioxy, ethylenedioxy, heterocyclyl and / or heterocyclylalkyl It is selected from the group consisting. More specifically the term aryl is phenyl, chlorophenyl, methoxyphenyl, 2-fluorophenyl, 2,4-difluorophenyl, 1-naphthyl, 2-naphthyl and derivatives thereof or as specifically exemplified herein But not limited to these.

"Aryloxy" means a radical -OR where R is aryl as defined herein, examples of which are phenoxy or those specifically exemplified herein.

“Aryloxycarbonyl” means a radical R—C (═O) —, where R is aryloxy, examples of which are phenoxycarbonyl or those specifically exemplified herein.

"Cycloalkyl" means a monovalent cyclic saturated hydrocarbon radical having 3 to 7 ring carbon atoms, examples of which include cyclopropyl, cyclobutyl, cyclohexyl, 4-methyl-cyclohexyl, etc. or those specifically exemplified herein. .

"Cycloalkylalkyl" means a radical -R ^a R ^b where R ^a and R ^b are each an alkylene group and a cycloalkyl group as defined herein, examples of which include cyclohexylmethyl or the like There are those specifically illustrated.

“Substituted cycloalkyl” is cyano or YC (O) —R, wherein Y is absent or an alkylene group, R is hydrogen, alkyl, haloalkyl, hydroxy, alkoxy, amino, monoalkylamino, dialkyl A cycloalkyl radical having 1, 2 or 3 (preferably 1) of ring hydrogen as defined herein, independently substituted with amino or optionally substituted phenyl, examples of which are specifically Some are illustrated. "Dialkylamino" means the radical -NRR 'wherein R and R' independently represent an alkyl, hydroxyalkyl, cycloalkyl or cycloalkylalkyl group as defined herein. Representative examples include dimethylamino, methylethylamino, di (1-methylethyl) amino, (methyl) (hydroxymethyl) amino, (cyclohexyl) (methyl) amino, (cyclohexyl) (ethyl) amino, (cyclo Hexyl) (propyl) amino, (cyclohexylmethyl) (methyl) amino, (cyclohexylmethyl) (ethyl) amino, and the like, or the like and specifically illustrated herein, but are not limited thereto.

"Halo" means fluoro, chloro, bromo or iodo, preferably fluoro or chloro.

"Haloalkyl" refers to alkyl substituted with one or more identical or different halo atoms, examples of which include -CH ₂ Cl, -CF ₃ , -CH ₂ CF ₃ , -CH ₂ CCl _3, etc. or specifically herein Some are illustrated.

"Heteroalkyl" means that one, two or three hydrogen atoms are selected from -OR ^a , -N (O) _m R ^b R ^c where m is 0 or 1 and -S (O) _n R ^d where n Means an alkyl radical as defined herein substituted with a substituent independently selected from the group consisting of 0 to 2, wherein the heteroalkyl radical is linked via a carbon atom of the heteroalkyl radical. Wherein R ^a is hydrogen, acyl, alkoxycarbonyl, alkyl, cycloalkyl or cycloalkylalkyl; R ^b and R ^c are independently hydrogen, acyl, alkoxycarbonyl, alkyl, cycloalkyl, cycloalkylalkyl, alkylsulfonyl, aminosulfonyl, mono- or di-alkylaminosulfonyl, aminoalkyl, mono- or di -Alkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkylsulfonyl or alkoxyalkylsulfonyl, provided that when m is 1 R ^b and R ^c are both independently alkyl, cycloalkyl and cycloalkylalkyl Is selected from; when n is 0 R ^d is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl or optionally substituted phenyl; when n is 1 or 2 R ^d is alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl , Amino, acylamino, monoalkylamino or dialkylamino. Preferably heteroalkyl is alkyl as defined herein substituted with -OR ^a where R ^a is alkyl. Representative examples include 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2,3-dihydroxypropyl, 1-hydroxymethylethyl, 3-hydroxybutyl, 2 3-dihydroxybutyl, 2-hydroxy-1-methylpropyl, 2-aminoethyl, 3-aminopropyl, 2-methylsulfonylethyl, aminosulfonylmethyl, aminosulfonylethyl, aminosulfonylpropyl, Methylaminosulfonylmethyl, methylaminosulfonylethyl, methylaminosulfonylpropyl, and the like or those specifically exemplified herein, but are not limited thereto.

"Heteroalkylcarbonyl" means the group R _a -C (= 0), where R _a is a heteroalkyl group. Representative examples include acetyloxymethylcarbonyl, aminomethylcarbonyl, 4-acetyloxy-2,2-dimethyl-butane-2-oil, 2-amino-4-methyl-pentane-2-oil, and the like. Are specifically illustrated in the following.

"Heteroalkyloxy" means the group R _a -O-, wherein R _a is a heteroalkyl group. Representative examples include Me-C (═O) —O—CH ₂ —O, and the like or specifically exemplified herein.

"Heteroalkyloxycarbonyl" means the group R _a -C (= 0), where R _a is a heteroalkyloxy group. Representative examples include 1-acetyloxy-methoxycarbonyl (Me-C (═O) —O—CH ₂ —OC (═O) —), or the like, or those specifically exemplified herein.

"Heteroaryl" refers to a monovalent monocyclic or bicyclic radical of 5 to 12 ring atoms having one or more aromatic rings and containing one, two or three ring heteroatoms selected from N, O and S and the remaining ring atoms being carbon Wherein the heteroaryl radical is linked on the aromatic ring. Heteroaryl rings may be optionally substituted independently with one or more, preferably one or two substituents, which substituents are selected from alkyl, haloalkyl, heteroalkyl, hydroxy, alkoxy, halo, nitro and cyano . More specifically, examples of heteroaryl include pyridyl, furanyl, thienyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, isoxazolyl, pyrroylyl, pyrazolyl, pyrimidinyl, benzofura Nyl, tetrahydrobenzofuranyl, isobenzofuranyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, indolyl, isoindolyl, benzoxazolyl, quinolyl, tetrahydroquinolinyl, isoquinolyl , Benzimidazolyl, benzisoxazolyl or benzothienyl, imidazo [1,2-a] pyridinyl, imidazo [2,1-b] thiazolyl and derivatives thereof or specifically illustrated herein There are, but are not limited to.

"Heteroaralkyl" means a radical -R ^a R ^b where R ^a and R ^b are each an alkylene group and a heteroaryl group as defined herein, examples of which are pyridin-3-ylmethyl , Imidazolylethyl, pyridinylethyl, 3- (benzofurin-2-yl) propyl, and the like or those specifically exemplified herein.

"Heteroalkylsubstituted cycloalkyl" means a cycloalkyl radical as defined herein in which one, two or three hydrogen atoms in a cycloalkyl radical are substituted with a heteroalkyl group, wherein the heteroalkyl radical is via a carbon-carbon bond To a cycloalkyl radical. Representative examples include, but are not limited to, 1-hydroxymethylcyclopentyl, 2-hydroxymethylcyclohexyl, and the like, or those specifically exemplified herein.

"Heterosubstituted cycloalkyl" means that one, two or three hydrogen atoms in a cycloalkyl radical are hydroxy, alkoxy, amino, acylamino, monoalkylamino, dialkylamino, oxo (C = O), imino, hydroxides Mino (= NOH), NR'SO ₂ R ^d (where R 'is hydrogen or alkyl, R ^d is alkyl, cycloalkyl, hydroxyalkyl, amino, monoalkylamino or dialkylamino), -XYC ( O) R where X is O or NR ', Y is alkylene or absent, R is hydrogen, alkyl, haloalkyl, alkoxy, amino, monoalkylamino, dialkylamino or optionally substituted phenyl, R 'is hydrogen or alkyl, and -S (O) _n R (where n is an integer from 0 to 2, where n is 0, R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted Phenyl or thienyl, and when n is 1 or 2, R is alkyl, cycloalkyl, cycloal Alkyl, optionally, means a cycloalkyl radical as defined herein substituted by substituted phenyl, thienyl, amino, acylamino, monoalkyl amino or dialkyl amino) substituents independently selected from the group consisting of. Representative examples include 2-, 3- or 4-hydroxychlorohexyl, 2-, 3- or 4-aminocyclohexyl, 2-, 3- or 4-methanesulfonamido-cyclohexyl, and the like. Are 4-hydroxycyclohexyl, 3,5-dihydroxy-cyclohexyl, 2-aminocyclohexyl or 4-methanesulfonamido-cyclohexyl, or those specifically illustrated herein, but are not limited thereto. .

"Heterosubstituted cycloalkylalkyl" means a radical -R ^a R ^b where R ^a is a heterosubstituted cycloalkyl radical and R ^b is an alkylene radical, examples of which are specifically illustrated herein. There are things that happen.

"Heterocycloamino" means a monovalent saturated cyclic group having 4 to 8 ring atoms wherein one ring atom is N and the remaining ring atoms are carbon. Representative examples include piperidine and pyrrolidine or those specifically exemplified herein.

"Heterocyclyl" is a heteroatom wherein one or two, preferably one ring atom is selected from N, O and S (O) _n , where n is an integer from 0 to 2, preferably a non-O And a saturated or unsaturated non-aromatic cyclic radical having 3 to 8, preferably 6, ring carbon atoms, wherein one or two carbon atoms may be optionally substituted with a carbonyl group. Heterocyclyl rings may be optionally substituted independently with one, two or three, preferably one substituent, such substituents being alkyl, haloalkyl, heteroalkyl, halo, nitro, cyano, cyano Alkyl, hydroxy, alkoxy, amino, monoalkylamino, dialkylamino, aralkyl,-(X) _n -C (O) R, wherein X is O or NR ', n is 0 or 1, and R Is hydrogen, alkyl, haloalkyl, hydroxy (if n is 0), alkoxy, amino, monoalkylamino, dialkylamino or optionally substituted phenyl and R 'is hydrogen or alkyl), alkylene-C (O) R ^a , where R ^a is alkyl, OR or NR'R ", R is hydrogen, alkyl or haloalkyl and R 'and R" are independently hydrogen or alkyl) or -S (O) _n R where n is an integer from 0 to 2, where n is 0, R is hydrogen, alkyl, cycloalkyl or cycloalkylalkyl, and n is 1 or 2 And R is independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, amino, acylamino, monoalkylamino, dialkylamino or heteroalkyl, preferably alkylsuloxy or alkoxy carbonyl). More specifically heterocyclyl is tetrahydropyranyl, piperidino, N-methylpiperidin-3-yl, 2-oxo-piperidinyl, pyrerazino, N-methylpyrrolidin-3-yl, 3-pyrrolidino, morpholino, thiomorpholino, thiomorpholino-1-oxide, thiomorpholino-1,1-dioxide, 4- (1,1-dioxo-tetrahydro-2H- Thiopyranyl), pyrrolinyl, imidazolinyl, N-methanesulfonyl-piperidin-4-yl and derivatives thereof or those specifically exemplified herein.

"Heterocyclylalkyl" means a radical -R ^a R ^b where R ^a and R ^b are each an alkylene group and a heterocyclyl group as defined above, for example tetrahydropyrane-2- Monomethyl, 2- or 3-piperidinylmethyl, 3- (4-methyl-piperazin-1) propyl, and the like, or those specifically exemplified herein.

"Hydroxyalkyl" means an alkyl radical as defined herein wherein one or more, preferably one, two or three hydroxy groups are substituted so that the same carbon atom does not have one or more hydroxy groups. Representative examples include hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1- (hydroxymethyl) -2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl, 1,5-di Hydroxy-pent-3-yl and 2- (hydroxymethyl) -3-hydroxypropyl, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl and 1- (hydroxymethyl) -2 Hydroxyethyl, but are not limited to these. Thus, the term "hydroxyalkyl" is used herein to define a subgroup of heteroalkyl groups or those specifically exemplified herein.

"Leaving group" means a group having a meaning commonly associated with leaving group in synthetic organic chemistry, i.e., an atom or group which may be substituted with a nucleophile, examples of which are halo (such as chloro, bromo, iodo), alkanesulf Phenyloxy, arerensulfonyloxy, alkylcarbonyloxy (eg, acetoxy), arylcarbonyloxy, mesyloxy, tosyloxy, trifluoromethane sulfonyloxy, aryloxy (eg, 2, 4-dinitrophenoxy), methoxy and N, O-dimethylhydroxyamino and the like, or those specifically exemplified herein.

"Monoalkylamino" means the radical -NHR, wherein R is an alkyl, hydroxyalkyl, cycloalkyl or cycloalkylalkyl group as defined above, examples of which include methylamino, (1-methylethyl) amino, Hydroxymethylamino, cyclohexylamino, cyclohexylmethylamino, cyclohexylethylamino and the like, or those specifically exemplified herein.

"Optionally substituted phenyl" is independently one or more selected from alkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, heteroalkyl, halo, nitro, cyano, amino, methylenedioxy, ethylenedioxy and acyl Means a phenyl ring optionally substituted with one or two substituents, examples of which are specifically illustrated herein.

"Pharmaceutically acceptable excipient" means an excipient that is useful for preparing a pharmaceutical composition that is generally safe, nontoxic, and which is not biologically or otherwise undesirable, and includes excipients that are acceptable for veterinary and human pharmaceutical use. . "Pharmaceutically acceptable excipient" as used herein and in the claims includes one or more such excipients.

The term "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and has the required pharmacological activity of the parent compound. These salts are:

(1) inorganic acids (eg, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.); Or organic acids (e.g. acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4- Hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2 Naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [2.2.2] -oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, t Acid addition salts formed with butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or

(2) salts formed by substitution by metal ions such as alkali metal ions, alkaline earth ions, or aluminum ions when acidic protons are present in the parent compound; Or coordination compounds with organic bases such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like.

"Prodrug" refers to any compound that, when administered to a mammalian subject, releases the active parent drug according to formula (I). Prodrugs of a compound of formula (I) are prepared to modify one or more functional group (s) present in a compound of formula (I) to separate in vivo to release the parent compound. Prodrugs include compounds of formula (I) in which the hydroxy, amino, sulfidyl, carboxy, or carbonyl groups in the compounds of formula (I) are bonded to any group that can separate in vivo to generate free hydroxyl, amino, or sulfidyl groups, respectively. Include. Examples of prodrugs include esters of hydroxy functional groups of compounds of formula I (eg, acetate, dialkylaminoacetate, formate, phosphate, sulfate and benzoate derivatives) or carbamate (eg, N, N- Dimethylaminocarbonyl), an ester group of the carboxyl functional group of the compound of formula I (e.g. ethyl ester, morpholinoethanol ester), an N-acyl derivative of the amino functional group of the compound of formula I (e.g., N -Acetyl) N-mannich bases, sif bases and enaminones, and oximes, acetals, ketals and enol esters of cannon and aldehyde functional groups of the compounds of formula (I), and the like (Bundegard, H. Design of Prodrugs "p1-92, Elesevier, New York-Oxford (1985)].

"Protective group" refers to a group of atoms linked to a reactive group of a molecular mask to reduce or inhibit reactivity. Examples of protecting groups include TW Green and PG Futs, Protective Groups in Organic Chemistry , (Wiley, 2 ^nd ed. 1991) and Harrison and Harrison et al., Compendium of Synthetic Organic Methods , Vols. 1-8 (John Wiley and Sons, 1971-1996). Representative amino protecting groups include formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (CBZ), t-butoxycarbonyl (Boc), trimethyl silyl (TMS), 2-trimethylsilyl-ethanesulfonyl (SES), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (FMOC), nitro-veratriloxycarbonyl (NVOC), and the like. Representative hydroxy protecting groups include compounds in which the hydroxy groups are acylated or alkylated, such as benzyl and trityl ethers, alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers and allyl ethers.

"Healing" or "treatment" of a disease,

(1) preventing disease, ie, experiencing or not experiencing the symptoms of the disease without progressing the clinical symptoms of the disease in mammals exposed to or susceptible to the disease;

(2) inhibiting the disease, i.e. stopping or slowing the progression of the disease or its clinical symptoms; or

(3) alleviation of the disease, ie, improving the disease or its clinical symptoms.

A "therapeutically effective amount" means an amount of a compound that is sufficient to treat a disease when administered to a mammal for the treatment of the disease. A "therapeutically effective amount" will depend on the compound, the disease and its severity, the age and weight of the mammal to be treated, and the like.

One embodiment of the present invention provides a compound of formula I:

Formula I

Where

R ¹ , R ² , Z and X ¹ are as defined above.

Preferably Z is N.

Preferably X ¹ is O, S or C═O, more preferably O.

Preferably R ¹ is alkyl. More preferably R ¹ is ethyl.

Preferably R ² is alkyl, aryl, cycloalkyl or heteroalkyl, more preferably methyl or hydroxyalkyl.

Preferably R ³ is cycloalkyl, cycloalkylalkyl, heteroalkylsubstituted cycloalkyl, heterosubstituted cycloalkyl, heteroalkyl, heterocyclyl or heterocyclylalkyl. More preferably R ³ is cycloalkyl, heteroalkylsubstituted cycloalkyl, heterosubstituted cycloalkyl, heteroalkyl or heterocyclyl. Particularly preferred examples of heteroalkyl R ³ groups when R ³ is heteroalkyl are hydroxyalkyl and / or alkoxyalkyl, for example (1-hydroxy-2-methyl) -prop-2-yl, 1- Hydroxy-pentane-2-yl, (S) -2-hydroxy-1,2-dimethyl-propyl, (R) -2-hydroxy-1,2-dimethyl-propyl, (S)- 2-hydroxy-1-methyl-ethyl, 1-hydroxymethyl-cyclopentane-1-yl, 2-hydroxy-2-methyl-propyl and 3-methoxy-1- (2-methoxy-ethyl ) A profile. Particularly preferred examples of heteroalkyl R ³ are tetrahydro-2H-pyrazin-4-yl, 1- (methylsulfonyl) piperidin-4-yl, 1-carboxyethyl-piperidin-4-yl, 1 , 1-dioxidotetrahydro-2H-thiopyridin-4-yl and morpholinyl. According to another embodiment of the invention, preferred compounds of formula I are those wherein R ³ is 4-hydroxycyclohexyl, tetrahydro-2H-pyran-4-yl, 1- (methylsulfonyl) piperidine -4-yl, cyclopentyl, (S) -2-hydroxy-1,2-dimethyl-propyl, 2,2-dimethoxyethyl, 3-hydroxypyridin-2-yl, (S)-( 1-hydroxymethyl-2-methyl) propyl, 4- (2-N, N-diethylamino) ethoxy) phenyl, benzyl, phenyl, butyl, dodecyl, 2-hydroxypropyl, 3-methylbutyl, 2-methylpropyl, (2-methylpropyl, (2-hydroxy-1,1-dimethyl) ethyl, 2,3-dihydroxypropyl, 3-hydroxypropyl, hexyl, pyridin-2-yl, 2 Morpholinoethyl, 2- (piperidin-1-yl) ethyl, cyclohexylmethyl, 1- (hydroxymethyl) butyl, 4-fluorophenyl, cyclopropylmethyl, 2-methoxyethyl, 3- (N, N-dimethylamino) propyl, isopropyl, methyl, 3-furylmethyl, 1-oxyotetetrahy Dro-2H-thiopyrazin-4-yl, 1,1-dioxidotetrahydro-2H-thiopyrazin-4-yl, 1-phenylpropyl, phenethyl, 4- (2-hydroxyethyl) phenyl , 3- (4-methylpiperazin-1-yl) propyl, 4-hydroxybutyl, 3-morpholinopropyl, 3- (2-pyrrolidinone-1-yl) propyl, 2-acetamidoethyl , 2- (pyridin-2-yl) ethyl, pentyl, 2- (N, N-dimethylamino) ethyl, 2- (pyrrolidin-1yl) ethyl, 3- (pyrrolidin-1-yl) Propyl, ethyl, 5-methylpyridin-2-yl, propyl, methyl, cyclopropyl, (1-hydroxymethyl-3-methylthio) propyl, (1-hydroxymethyl) cyclopentyl, 1,1-dimethyl Propyl, 3-ethoxy-3-oxo-propyl, 3-methoxypropyl, cyclobutyl, 1- (oxo-ethoxymethyl) piperidin-4-yl, 4-methoxycyclohexyl, 3,5- Dihydroxy-cyclohexyl, 2-cyclohexylethyl, (2-methylthiazol-5-yl) methyl, imidazo [2,1-b] thiazol-6-ylmethyl, 4-phenylbutyl, 2- To (4-aminophenyl) Yl, pyridin-3-yl, tetrahydro-2H-thiopyridin-4-yl and (1-hydroxymethyl) butyl.

Another group of preferred compounds are those compounds having the formula

Formula I ''

Where

R ¹ is alkyl, more preferably ethyl;

R ² is selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl and heteroalkyl (more preferably is methyl or hydroxyalkyl);

R ³ is heteroalkyl or heterocyclyl.

As defined directly above, R ¹ and R ² are selected from the groups defined above and R ³ is (1-hydroxy-2-methyl) -prop-2-yl, 1-hydroxy-pentane -2-yl, (S) -2-hydroxy-1,2-dimethyl-propyl, (R) -2-hydroxy-1,2-dimethyl-propyl, (S) -2-hydroxy- 1-methyl-ethyl, 1-hydroxymethyl-cyclopentane-1-yl, 2-hydroxy-2-methyl-propyl, 3-methoxy-1- (2-methoxy-ethyl) propyl, tetrahydro -2H-pyrazin-4-yl, 1- (methylsulfonyl) piperidin-4-yl, 1-carboxyethyl-piperidin-4-yl, 1,1-dioxidotetrahydro-2H- Even more preferred are compounds of formula (I '') selected from the group consisting of thiopyreninyl-yl and morpholinyl. Even more preferred compounds are those wherein R ¹ is ethyl, R ² is methyl, R ³ is (1-hydroxy-2-methyl) -prop-2-yl, 1-hydroxy-pentin-2-yl, (S) -2-hydroxy-1,2-dimethyl-propyl, (R) -2-hydroxy-1,2-dimethyl-propyl, (S) -2-hydroxy-1-methyl-ethyl , 1-hydroxymethyl-cyclopentane-1-yl, 2-hydroxy-2-methyl-propyl, 3-methoxy-1- (2-methoxy-ethyl) propyl, tetrahydro-2H-pyrane 4-yl, 1- (methylsulfonyl) piperidin-4-yl, 1-carboxyethyl-piperidin-4-yl, 1,1-dioxidotetrahydro-2H-thiopyrane-4 -Yl and morpholinyl.

Yet another group of preferred compounds are those compounds having Formula II:

Formula II

Where

X is -O-, -C (= 0)-, -N (R ^12a )-or -CH (R ^12b )-;

R ^12a is selected from the group consisting of hydrogen, C _1-4 alkyl, —C (═O) R ¹⁵ , —C (O) ₂ R ¹⁵ and —S (O) ₂ (C _1-4 alkyl);

R ^12b is selected from the group consisting of hydrogen, C _1-4 alkyl, -OR ¹⁵ , -C (= 0) R ¹⁵ , -C (O) ₂ R ¹⁵ and -S (O) ₂ (C _1-4 alkyl) Selected;

R ¹⁴ is C _1-4 alkyl, oxo (═O), —OR ¹⁵ , —C (═O) R ¹⁵ , —C (O) ₂ R ¹⁵ and —S (O) ₂ (C _1-4 alkyl) It is selected from the group consisting of;

Each R ¹⁵ is independently selected from hydrogen and C _1-4 alkyl;

q is 0 or 1;

r is 0, 1 or 2.

Among these preferred compounds, compounds in which X is -N (R ^12a )-and R ^12a is -S (O) ₂ (C _1-4 alkyl) are more preferred.

The compounds of the present invention may exist in solvated forms, including unsolvated and hydrated forms. In general, solvated forms, including hydrated forms, correspond to unsolvated forms and are included within the scope of the present invention. In addition to the compounds disclosed above, the compounds of the present invention include all tautomeric forms. In addition, the present invention includes all pharmaceutically acceptable salts of these compounds, along with their prodrug forms, and includes all stereoisomers that are pure chiral or racemic mixtures or other mixtures.

Compounds of formula (I) may further form pharmaceutically acceptable acid addition salts. All such forms are within the scope of the present invention.

Pharmaceutically acceptable acid addition salts of compounds of formula (I) include organic acids such as aliphatic mono- and salts derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, and the like. Salts derived from di-carboxylic acids, phenyl substituted alkanoic acids, hydroxy alkanoic acids, alkenidaioic acids, aromatic acids, aliphatic and aromatic sulfonic acids and the like. Thus, such salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorine, bromide, iodides, acetates , Propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suverate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzo Ates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrate, lactates, methates, tartrates, methanesulfonates and the like. Amino acid salts such as alginate and the like and gluconate, galacturonate are also foreseen (see, eg, Berge SM, et al., "Pharmaceutical Salts", J. of Pharmaceutical Science , 1977, 66, 1 -19].

The acid addition salts of the basic compounds can be prepared by contacting the free base form with the required acid in an amount sufficient to prepare the salt in a conventional manner. The free base form can be reproduced by contacting the salt form with a base and isolating the free base in conventional manner. The free base forms differ somewhat from the forms of their respective salts in terms of being soluble in certain physical properties, such as polar solvents, but otherwise the salts correspond to their respective free bases for the purposes of the present invention.

 While the present forms of the present invention constitute preferred embodiments herein, many other things are possible. This application is not intended to mention all possible equivalent forms or results of the invention. It is to be understood that the terminology used herein is for the purpose of disclosure only and is not intended to be limiting, as various changes may be made without departing from the scope of the present invention.

The following abbreviations are used in the preparation methods and examples herein for ease of reference:

EtOH = ethanol

MeOH = Methanol

DCE = dichloroethane

DCM = dichloromethane

EtOAc = ethyl acetate

THF = Tetrahydropurine

The compounds of the present invention can be prepared by a variety of methods. In one embodiment of the invention, methods for preparing compounds of Compound I 'wherein Z is N are shown in Schemes 1 and 4 below. The method for preparing the compound of formula I, wherein R ² is an amino group, is shown in Scheme 2 below. The process for preparing compounds of formula I '' wherein Z is CH is shown in Schemes 3 and 3a.

Although the schemes often indicate precise structural formulas, it is recognized that the methods of the present invention, where appropriate consideration is given to the protection and deprotection of reactive functional groups by methods standard in the field of organic chemistry, apply broadly to analogous compounds of the compounds of formula (I). Should be. For example, hydroxy groups are sometimes required to be converted into ethers or esters during chemical reactions at other sites in the molecule to prevent unwanted side reactions. The hydroxy protecting group is then removed to provide a free hydroxy group. Similarly, amino groups and carboxylic acid groups can be derivatized to protect them against unwanted side reactions. Typical protecting groups, and methods for attaching them, and cutting the literature [TW Green and PGM Wuts, Protective Groups in Organic Synthesis, 3 ^rd edition, John Wiley & Sons, New York, 1999)] incorporated in its entirety by reference above, and Harrison and Harrison et al., Compendium of Synthetic Organic Methods , Vols. 1-8 (John Wiley and Sons, 1971-1996).

Treatment of primary amines (R ² -NH ₂ ) of compounds of formula (Ia) provides compounds of formula (Ib). Such reactions are usually carried out in solvents which are inert under the reaction conditions, preferably halogenated aliphatic hydrocarbons, in particular DCM, optionally halogenated aromatic hydrocarbons, or branched or cyclic ethers such as THF, formamide or lower alkanols. Suitably, the reaction is carried out at about -20 to about 120 ° C.

Reduction of the compound of formula Ib provides the alcohol of formula Ic. Such reactions are typically catalyzed or cyclic ethers, in particular THF, in a manner known to those skilled in the art (eg, inert solvents under reducing conditions, preferably from about −20 to about 70 ° C., preferably from about 0 to about room temperature). In) using lithium aluminum hydride.

Oxidation of an alcohol of formula (Ic) provides a carboxaldehyde of formula (Id). This oxidation has many other methods that may be used (see, eg, ADVANCED ORGANIC CHEMISTRY, 4 ^TH ED., March, John Wiley & Sons, New York (1992)), but is typically performed using manganese dioxide. do. Depending on the oxidant used, this reaction is usually carried out in a solvent which is inert under certain oxidizing conditions, preferably halogenated aliphatic hydrocarbons, in particular DCM or optionally halogenated aromatic hydrocarbons. Suitably, the oxidation is carried out at about 0 to about 60 ° C.

In the presence of a base, the reaction of the carboxaldehyde of formula Id with the ester, R ¹ -X ¹ CH ₂ -CO ₂ R ', wherein R' is an alkyl group and R ¹ and X ¹ are as defined above, Provided are compounds of Ie. Carbonates such as potassium carbonate, lithium carbonate and sodium carbonate; Bicarbonates such as potassium bicarbonate, lithium bicarbonate and sodium bicarbonate; Potassium t-butoxide, sodium hexamethyldisilazein, potassium hexamethyldisilazein, lithium hexamethyldisilazein, LDA, sodium hydride or amines such as secondary and tertiary amines; And resin-bonded amines, such as any relatively nonnucleophilic base, including 1,3,4,6,7,8-hexahydro-2H pyrimido [1,2-a] pyrimidine. Typically, the reaction is about 25 to about 150 in a relatively polar but inert solvent, preferably an amide such as dimethyl formamide, N-substituted pyrrolidinone, especially 1-methyl-2-pyrrolidinone under reaction conditions. It is carried out at ℃.

Oxidation of a compound of formula (Ie) with an oxidizing agent, such as peracid, such as 3-chloroperbenzoic acid (ie MCPBA) or Oxone®, provides sulfones that can be converted into various target compounds. . Typically the oxidation of the compound of formula (Ie) is carried out in a solvent which is inert under oxidizing conditions. For example, when MCPBA is used as the oxidizing agent, the solvent is preferably a halogenated aliphatic hydrocarbon, in particular chloroform. If oxone® is used as the oxidizing agent, the solvent is preferably MeOH, aqueous ethanol or aqueous THF. The reaction temperature depends on the solvent used. For organic solvents the reaction temperature is generally about -20 to about 50 ° C, preferably about 0 ° C to about room temperature. When water is used as the solvent, the reaction temperature is generally about 0 to 50 ° C, preferably about 0 ° C to about room temperature. Alternatively, the oxidation can be carried out under catalytic conditions using rhenium / peroxide based reagents (“Oxidaation of Sulfoxides by Hydrogen Peroxide, Catalyzed by Methyltrioxorhenium (VII)”, Lahti, David W .: Espenson, James H, Inorg. Chem . (2000) 39 (10) pp. 2164-2167]; "Rhenium oxo complexes in catalytic oxidations, Catal. Today (2000) 54 (4), pp317-363); and [" A Simple and Efficient Method for the Preparation of Pyridine N-Oxides ", Coperet, Christophe; Adolfsson, Hans; Khuong, Tinh-Alfrede V .; Yudin, Andrei K .; Sharpless, K. Barry, J. Org. Chem. (1998) 63 (5), pp 1740-1741).

The reaction of a compound of formula If with an amine R ³ -NH ₂ provides a compound of formula I '. This reaction can be carried out in the presence or absence of a solvent. Typically, the reaction is carried out at about 0 to about 200 ° C, more preferably at about room temperature to about 150 ° C. Optionally, in some cases using rather sulfone (If), sulfide (Ie) or the corresponding sulfoxide can be reacted directly with amine (R ³ -NH ₂ ) to provide a compound of formula (I ′).

Thus, the present invention treats a compound of Formula Ie or If, or the corresponding sulfoxide, with amines (R ³ -NH ₂ ) and the resulting compound is R ² -L, wherein R ² is alkyl and L is leaving Group) to provide a process for preparing a compound of formula (I):

Compounds of formula (I) wherein R ² is amino, monoalkylamino, dialkylamino or NR ²² -YR ²³ are represented by the corresponding 2-alkylthio-8-amino- as shown in Scheme 2. [2,3-d] -pyridopyrimidin-7 (8H) -one (IV, Z = N) or 7-alkylthio-1-amino-1,6-naphthyridin-2-one (IV, Z = CH) from A-diphenylphosphinylhydroxyamine (Colvin, EW; Kirby, GW; Wilson, AC Tetrahedron Lett . (1982), 23, 3835) and See Klottzer, W .; Stadlwieser, J .; Raneburger, J. Org. Synth. (1986), 64, p96-103 for such examples. The resulting amines can then be substituted in a variety of different ways. Mono- or di-alkylation is possible via staged reductive alkylation (using substituted aldehydes). Optionally, the amine may be acylated with an acyl halide, haloformate or halocarbonate. The amines may also be sulfonylated with sulfonyl halides. Finally, the substitution of sulfide (or the corresponding sulfoxide or sulfone) with amine R ³ NH ₂ , as already disclosed for compound (Ie) in Scheme 1, is a compound of formula (I) wherein Z is CH and R ² is NA Compound of I).

Ethyl 2,4-dichloropyridine-5-carboxylate is treated with amine R ³ NH ₂ to give ester (3 g). This reaction is usually carried out in a solvent which is inert under the reaction conditions, preferably acetonitrile, optionally a halogenated aromatic hydrocarbon or a branched or cyclic ether such as THF, formamide or lower alkanol. Suitably, the reaction is carried out at about -20 to about 120 ° C.

Reduction of the compound of formula 3g provides an alcohol. Such reduction is typically carried out in a manner known to the person skilled in the art (e.g., in a solvent which is inert under reducing conditions, preferably from about -20 to about 70 ° C, preferably from about 0 to about room temperature, in a modified or cyclic ether, in particular (In THF) using lithium aluminum hydride.

Oxidation of the alcohol provides the carboxaldehyde of formula 3h. This oxidation has many other methods that may be used (see, eg, ADVANCED ORGANIC CHEMISTRY, 4 ^TH ED., March, John Wiley & Sons, New York (1992)), but is typically performed using manganese dioxide. do. Depending on the oxidizing agent used, this reaction is usually carried out in a solvent which is inert under certain oxidizing conditions, preferably halogenated aliphatic hydrocarbons, in particular DCM or optionally halogenated aromatic hydrocarbons. Suitably, the oxidation is carried out at about 0 to about 60 ° C.

In the presence of a base, the reaction of the carboxaldehyde of formula 3h with the ester, R ¹ -X ¹ CH ₂ -CO ₂ R ', wherein R' is an alkyl group and R ¹ and X ¹ are as defined above, It provides a compound of 3i. Carbonates such as potassium carbonate, lithium carbonate and sodium carbonate; Bicarbonates such as potassium bicarbonate, lithium bicarbonate and sodium bicarbonate; Potassium t-butoxide, sodium hexamethyldisilazein, potassium hexamethyldisilazein, lithium hexamethyldisilazein, LDA, sodium hydride or amines such as secondary and tertiary amines; And resin-bonded amines such as any relatively nonnucleophilic base, including 1,3,4,6,7,8-hexahydro-2H pyrimido [1,2-a] pyridinedine. Typically, the reaction is about 25 to about in a relatively polar but inert solvent, preferably an amide such as dimethyl formamide, N-substituted pyrrolidinone, especially 1-methyl-2-pyrrolidinone under reaction conditions. It is carried out at 150 ° C.

Substitution of the chlorides as previously disclosed for Formula Ie with amines (R ³ -NH ₂ ) (preferably near 150 to 160 ° C.) is a compound of Formula I '' (compound of Formula I wherein Z is CH) Provides:

4-amino-3,6-dibromopyridine (Den Hertog et al., Rec. Trav. Chim. Pays-Bas, 64 , 85-100 (1945)) treated with sodium methyl thiorate to 4-amino Obtain 3-bromo-6-methylthio-pyridine (see step a, Windschief, P; Voegtle, F .; Synthesis , 87092 (1994)). Catalyzed methylthiopyridine in the presence of a base. Coupling with vinyl ester (3a) in a Heck reaction under to give a compound of formula 3b (Dong, Y .; Busacca, CAJ Org. Chem., 62, 6464-65 (1997)). Ring closure under basic conditions affords 1,6-naphthyridone of formula 3c.Alkyl halide (or any other acylating agent R ³ -X, wherein x is a leaving group) of the compound of formula 3e. acylation of the formula to give the 1-alkylated pyrrolidone naphthyridin of 3d. 3d of amine oxide and polysulfone, as already described in scheme 1 for formula Ie (R ³ -NH ₂₎ values Provides a compound of formula I '' (compounds of Formula I where Z is CH). An optional route is shown in Reaction Scheme 3a.

The compound of formula 4d may be reacted with ethyl ethoxyacetate with the addition of potassium t-butoxide in a suitable solvent such as toluene to give the compound of formula 4h. Compound (4h) can be converted to the corresponding sulfonyl compound (4i) upon reaction with an oxidizing agent or peracid such as chloroperbenzoic acid in a solvent such as DCM. Compound (4i) may be converted to the compound of formula (I '') upon reaction with the required amine (R ³ -NH ₂ ) in a solvent such as DCE.

Those skilled in the art will appreciate that certain modifications are anticipated in the above schemes and are within the scope of the present invention. For example, certain steps will include the use of protecting groups for functional groups that are incompatible with certain reaction conditions.

These processes are also an object of the present invention.

Pharmaceutically acceptable salts of the basic compounds of formula (I) with compounds of formula (I) and acids can be used in the form of medicaments, for example pharmaceutical preparations. Pharmaceutical formulations are enteric, for example tablets, coated tablets, dragees. It may be administered orally in the form of hard and soft capsules, solutions, emulsions or suspensions, or by nasal, for example nasal spray, or in the form of rectal, eg suppositories. However, they may also be administered parenterally, for example in the form of injection solutions.

The compounds of formula I and their pharmaceutically acceptable salts as described above can be processed with pharmaceutically inert organic or inorganic carriers for the preparation of pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, as carriers for tablets, coated tablets, dragees and hard gelatin capsules. Suitable carriers for soft gelatin capsules include, for example, vegetable oils, waxes, fats, semisolid and fluid polyols; Depending on the nature of the active ingredient without the carrier, it is usually required in the case of soft gelatin capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semisolid or fluid polyols and the like.

The pharmaceutical formulation may contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for controlling osmotic pressure, buffers, blockers and antioxidants. They may also contain other therapeutically useful substances in addition to the compounds of formula (I) and their pharmaceutically acceptable salts as defined above.

A medicament containing a compatible pharmaceutical carrier material together with a pharmaceutically acceptable salt of a compound of formula (I) or a basic compound of formula (I) with an acid may contain one or more of these compounds or salts and, if desired, one or more other treatments in herbal dosage forms. It is an object of the present invention as a method of producing said medicament comprising a pharmaceutical carrier which is compatible with a substance which is usefully useful.

As mentioned above, the compounds of formula (I) and their pharmaceutically acceptable salts as defined above may be used according to the invention as therapeutically active substances, in particular as anti-inflammatory agents or to prevent transplant rejection following transplant surgery. . The dosage may vary within wide limits and may, of course, meet the individual requirements in each particular case. Generally, when administered to adults, a typical daily dosage is about 0.1 to about 100 mg / kg, preferably about 0.5 to about 5 mg / kg. The daily dose may be administered as a single dose or in divided doses, and may, if further prescribed, exceed the upper limit of dose as mentioned above.

Finally, drugs, in particular inflammatory, immune, cancerous, bronchial lung disease, dermatological, treatment or prevention of cardiovascular disease, treatment of asthma, central nervous system disease or diabetic complications, or prevention of transplant rejection after transplant surgery The use of the compounds of formula (I) and their pharmaceutically acceptable salts as defined above in the preparation of a medicament for is also an object of the present invention.

Compounds of Formula (I) include, but are not limited to, any disease or disease state of human or other mammals that is exacerbated or caused by excessive or unregulated TNF or p38 kinase production by humans or other mammals. It is useful for treatment. Accordingly, the present invention provides methods for treating cytokine mediated diseases comprising administering an effective cytokine-interfering amount of a compound of Formula (I), or a pharmaceutically acceptable salt or tautomer thereof.

Compounds of formula (I) are useful for use as antipyretic agents for the treatment of inflammation and for the treatment of fever in a subject, but not limited to these. Compounds of the present invention include but are not limited to arthritis (eg rheumatoid arthritis, spondyloarthritis (eg ankylosing spondylitis), gouty arthritis, psoriatic arthritis, osteoarthritis, systemic lupus erythematosus, juvenile arthritis and other arthritis symptoms) Is not useful). Such compounds are useful for the treatment of pulmonary disease or pulmonary inflammation, such as adult respiratory disease syndrome, pulmonary sarcoidosis, asthma, silicon pulmonary disease and chronic lung inflammatory disease. Such compounds may also be used for viral and bacterial infections, such as sepsis, infection shock, Gram-negative sepsis, malaria, meningitis, secondary apocalypse to infection or cancer, secondary apocalypse to AIDS, AIDS , ARC (AIDS-related complications), pneumonia and herpes virus. This compound is also useful for bone resorption diseases such as osteoporosis, endotoxin shock, toxic shock syndrome, reperfusion injury, autoimmune diseases, eg transplantation versus host response and allograft rejection, cardiovascular diseases such as atherosclerosis, thrombosis, congestion It is useful for the treatment of heart failure and heart reperfusion injury, kidney reperfusion injury, liver disease and nephritis, and myalgia due to infection.

The compound is also useful for the treatment of Alzheimer's disease, influenza, multiple sclerosis, cancer, diabetes, systemic lupus erythematosus (SLE), skin related symptoms such as psoriasis, eczema, burns, dermatitis, keloid formation and scar tissue formation. In addition, the compounds of the present invention are also effective in the treatment of gastrointestinal symptoms such as inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis. This compound is useful for the treatment of acute injuries to eye diseases such as retinitis, retinopathy, uveitis, eye glare and eye tissue. This compound is also useful for angiogenesis such as tumors; transition; Ophthalmic symptoms such as corneal transplant rejection, ocular neovascularization, retinal neovascularization such as neovascularization after injury or infection, diabetic retinopathy, posterior capsular fibrosis and neovascular glaucoma; Ulcer diseases such as gastric ulcer; Pathological but nonmalignant conditions such as hemangiomas such as infantile hemangiomas, angiofibromas of the nasopharynx and avascular necrosis of the skeleton; Diabetic nephropathy and cardiomyopathy; And the treatment of female reproductive system diseases such as endometriosis. This compound can also be used to prevent the production of cyclooxygenase-2.

Preferably, the compounds of the present invention may be used for rheumatoid arthritis, spondyloarthropathies, psoriatic arthritis, Crohn's disease, irritable bowel syndrome, inflammatory bowel disease, psoriasis, adult respiratory disease syndrome, asthma or chronic obstructive pulmonary disease or Alzheimer's disease or neoplastic disease. It is useful for treatment.

In addition to being useful for the treatment of humans, these compounds are also useful for veterinary treatment of fellow animals, exotic animals and farm animals such as mammals, rodents and the like. More preferred animals include horses, dogs, and cats.

Compounds of the invention may be co-therapeutic, partially or completely, in place of other conventional anti-inflammatory agents such as steroids, cyclooxygenase-2 inhibitors, NSAIDs, DMARDS, immunosuppressants, 5-lipoxygenase inhibitors, LTB _It can also be used with ₄ antagonists and LTA ₄ hydrolase inhibitors.

The term "TNF mediated disease" as used herein includes, but is not limited to, another monokine (eg, IL-1, IL-6 or IL-8) in which TNF will play a role or be released as a TNF self-regulatory. Reference is made to any and all diseases and disease states that play a role by TNF. Thus, for example, a disease state in which IL-1 is a major component and whose production or action is exacerbated or secreted in response to TNF is considered a disease mediated by TNF.

As used herein, the term “p38 mediated disease” includes but is not limited to another monokine (eg, IL-1, IL-6 or IL-8) in which p38 will play a role as p38 self-regulation or be released. Reference is made to any and all diseases and disease states that play a role by p38. Thus, for example, a disease state in which IL-1 is a major component and whose production or action is exacerbated or secreted in response to p38 is considered a disease mediated by p38.

TNF-β has a close structural homology with TNF-α (also known as cachectin), which induces similar biological responses and binds to the same cellular receptor, respectively, and all TNF-α and TNF-β Synthesis is inhibited by the compounds of the present invention and is referred to collectively as "TNF", unless stated otherwise herein.

Unless otherwise noted, all temperatures, including melting point, are degrees Celsius (° C.).

Preparation Example 1 4-methylamino-2-methylthiopyrimidine-5-carboxaldehyde

Step A: Preparation of ethyl 4-methylamino-2-methylthiopyrimidine-5-carboxylate

To a solution of ethyl 4-chloro-2-methylthiopyrimidine-5-carboxylate (Aldrich, 20 g, 86 mmol) in 250 ml DCM at 0 ° C. was added a solution of methylamine in EtOH (33%, 35 ml, 281 mmol). Slowly added. After stirring for 30 minutes, water (150 ml) was added and the phases were separated. The organic phase was dried (MgSO ₄ ) and filtered. The filtrate was evaporated under reduced pressure to afford 19 g of ethyl-4-methylamino-2-methylthiopyrimidine-5-carboxylate as a white solid.

Step B: Preparation of 4-methylamino-2-methylthiopyrimidine-5-methanol

Stir lithium aluminum hydride (8.2 g, 215 mmol) in dry THF (300 ml) at 5 ° C. and ethyl 4-methylamino-2-methylthio-pyrimidine-5-carboxylate (46 g, 215 mmol) in dry THF (450 ml) Treated dropwise with a solution. The reaction mixture was stirred for 15 minutes, then water (18 ml) was added dropwise carefully. After the reaction was stirred for 30 minutes, an aqueous sodium hydroxide solution (15%, 8.5 ml) was added dropwise followed by water (25.5 ml) dropwise. The resulting suspension was stirred at rt for 17 h and then filtered. The filter residue was washed with THF (2 ×, 100 ml) and the combined filtrates and washes were evaporated under reduced pressure. The residue was suspended in EtOAc / hexane (1/2, 200 ml) and the solids were filtered and dried to give 32.7 g of 4-methylamino-2-methylthiopyrimidine-5-methanol as a yellow solid.

Step C: Preparation of 4-methylamino-2-methylthiopyrimidine-5-carboxaldehyde

4-methylamino-2-methylthiopyrimidine-5-methanol (20 g, 108 mmol) and 1 L DCM were combined with stirring and treated with manganese dioxide (87 g, 1 mol). The resulting suspension was stirred for 24 hours and then filtered through celite. The filter residue was washed with DCM (100 ml) and the combined filtrates and washes were evaporated under reduced pressure to give 15.8 g of 4-methylamino-2-methylthiopyrimidine-5-carboxaldehyde as a white solid.                 

Preparation Example 2 4- (cyclopropylamino) -2- (methylthio) pyrimidine-5-carboxaldehyde

As described in Preparation Example 1 (Steps A to C), ethyl 4-chloro-2-methylthiopyrimidine-5-carboxylate (Aldrich Chemical Co.) and cyclopropyl amine (Aldrich Chemical) 4- (cyclopropylamino) -2- (methylthio) pyrimidine-5-carboxaldehyde was prepared using, as a starting material).

Preparation Example 3: 4-[(4-fluorophenyl) amino] -2- (methylthio) pyrimidine-5-carboxaldehyde

As disclosed in Preparation Example 1 (Steps A to C), ethyl 4-chloro-2-methylthiopyrimidine-5-carboxylate (Aldrich Chemical Company) and 4-fluoroaniline (Aldrich Chemical Company) 4-[(4-fluorophenyl) amino] -2- (methylthio) pyrimidine-5-carboxaldehyde was prepared as starting material.

Preparation Example 4 4- (Ethylamino) -2- (methylthio) pyrimidine-5-carboxaldehyde

Step A: Preparation of ethyl 4-ethylamino-2-methylthiopyrimidine-5-carboxylate

To a solution of 25 g (107 mmol) of ethyl 4-chloro-2-methylthio-5-pyrimidinecarboxylate in 250 ml of THF was added 47 ml (337 mmol) of triethylamine and 43 ml of 70% ethylamine solution (668 mmol). . The mixture was stirred at rt for 4 h and evaporated to dryness. The material obtained was dissolved in a mixture of EtOAc / water, washed twice with 10% NaHCO ₃ solution, then dried (MgSO ₄ ) and evaporated to dryness to afford the title compound as a solid: yield 24.1 g.

Step B: Preparation of 4-ethylamino-2-methylthiopyrimidine-5-methanol

A solution of ethyl 4-ethylamino-2-methylthio-pyrimidinecarboxylate (24.1 g, 100 mmol) in 250 ml of THF was cooled in an 0 ° C. ice bath. To the obtained solution was added lithium aluminum hydride (4.3 g, 113 mmol) in small amounts over 1 hour. After 1 hour of addition, water (4.3 ml) was added slowly, then NaOH solution (4.3 ml, 15%) was added and 13 ml of water was further added and the resulting mixture was stirred for 1 hour. The resulting suspension was filtered and the filter residue was washed twice with 100 ml of THF. The resulting solution was evaporated under reduced pressure. The residue was stirred with 150 ml Et ₂ O, then filtered and dried: yield 19.1 g.

Step C: Preparation of 4-ethylamino-2-methylthiopyrimidine-5-carboxaldehyde

To a solution of 4-ethylamino-2-methylthiopyrimidine-5-methanol (19.1 g, 96 mmol) in 1000 ml DCM was added 87 g manganese dioxide. The resulting suspension was stirred for 20 hours and filtered through celite. The residue was washed twice with 100 ml of DCM and the combined filtrates and washes were evaporated under reduced pressure to give the title compound as a solid: yield 12.8 g.

Preparation Example 5 4-Amino-2-methylthiopyrimidine-5-carbaldehyde

Step A: Preparation of 3,3-diethoxy-2-formylpropionitrile potassium salt (P-5A)

THF (2.2 L, 2.2) in a stirred solution of 3,3-diethoxypropane-nitrile (283.80 g, 1.98 mol) and methyl formate (148.80 g, 2.48 mol) in anhydrous THF (1.1 L) at 10 ° C. 1.0 M potassium t-butoxide in mol) was added. The temperature was kept at 10-15 ° C. for 45 minutes to be added. After addition, the resulting slurry was stirred at ambient temperature for 2 hours. Hexane (400 ml) was added and stirring continued for an additional 20 minutes. The slurry was filtered and the cake washed with 1/1 hexanes / THF and dried overnight in a 60 ° C. vacuum oven to afford the title compound P-5A as a pale tan powder in a yield of 302.g (73.0%). ¹ H-HMR (CD ₃ OD) results were consistent with the required structure.

Step B: Preparation of 4-amino-2-sulfanylpyrimidine-5-carbaldehyde (P-5B)

A slurry of thiourea (92.8 g, 1.22 mol) in EtOH (90 ml) was heated to reflux and stirred vigorously. To the slurry obtained while maintaining the reflux state 3,3-diethoxy-2-formylpropionitrile potassium salt (P-5A) in 25% sodium methoxide / MeOH (85.5 ml, 0.37 mol) and EtOH (285 ml) A suspension of (222.20 g, 1.06 mol) was added in 5 drops over 10 minutes (optionally, the resulting slurry could be heated to 50 ° C. to obtain a homogeneous solution during the addition). An additional portion of EtOH (150 ml) was added to facilitate stirring. The thick slurry turned bright yellow after addition and remained at reflux for an additional hour. The mixture was then cooled and evaporated to near dryness on a rotary evaporator. The residue was dissolved in water (940 ml). 30% acetic acid (280 ml) was added to precipitate the crude product from solution and isolated via filtration using an intermediate glass stock sintered glass filtration fuel. The cake was washed with water (800 ml). Filtered by grinding in hot water (1 L) for 30 minutes, then cooled and filtered, then dried overnight in a 60 ° C. vacuum oven (subsequent formulation proved to require this grinding) of 118.9 g (72.3%) The title compound was obtained as a light yellow solid. HPLC showed a purity of 98.6%. ¹ H-HMR (DMSO-d ₆ ) results were consistent with the required structure (P-5B).

Step C: Preparation of 4-amino-2-methylthiopyrimidine-5-carbaldehyde

A solution of 4-amino-2-sulfanyl-pyrimidine-5-carbaldehyde (P-5B) (100.00 g, 644.4 mmol) and 325 mesh potassium carbonate (178.10 g, 1.29 mol) in acetone (1.5 L) was prepared. Iodomethane (128.10 g, 902.2 mmol) was added dropwise over 20 minutes with gentle cooling. The mixture was stirred at ambient temperature over the weekend. TLC showed residual product (P-5B) from step B, followed by further dropwise addition of iodomethane (8 ml) and stirring continued overnight. TLC again showed that some product (P-5B) remained from step B, then an additional amount of iodomethane (8 ml) was added and stirring continued for an additional 24 hours. HPLC identified 95.9% of S-alkylated product and 3.7% of compound (P-5B). The reaction mixture was stripped until nearly dry in a rotary evaporator. Water (1 L) was added to the residue and the product was collected by filtration and washed with water (200 ml). The product was dried overnight in a 60 ° C. vacuum oven. 103.37 g (94.8%) of the title compound were obtained. HPLC showed 95.8% of the title compound of the present preparation and 4.2% of the compound (P-5B).

Preparation Example 6 4-Amino-2-n-butylthiopyrimidine-5-carbaldehyde

Substituting iodobutane (Aldrich Chemical Company) for iodomethane (Aldrich Chemical Company) in Step C, 4-amino-2- (n as described for Preparation Example 5 (Steps A-C) -Butylthio) pyrimidine-5-carbaldehyde was prepared.

Example 1 6-ethoxy-2 [3-methoxy-1 (2-methoxy-ethyl) -propylamino] -8,8a-dihydro-4aH-pyrido [2,3-d] pyrimidine -7 temperature

Step A: 2-Butylsulfanyl-6-ethoxy-8,8a-dihydro-4aH-pyrido [2,3-d] pyrimidin-7one

Processed by 4-amino-2-butylsulfanyl-4,5-dihydro-pyrimidine-5-carbaldehyde (3 g, 14.2 mmol, scaleup) in 80 ml of toluene at 0-5 ° C. under nitrogen. ) And ethyl ethoxyacetate (2.34 g, 2.4 ml, 17.75 mmol) were stirred. Potassium t-butoxide (1.75 g, 15.6 mmol) was added gradually. The mixture was stirred at ambient temperature and then at 65 ° C. for 48 hours. An additional 20 ml of toluene and 2.4 ml of ethyl ethoxyacetate were added and the reaction was kept at 65 ° C. over the weekend. The reaction mixture was concentrated in vacuo and triturated with EtOAc to remove residual starting aldehyde. The residual solid was further triturated with chloroform to remove additional impurities. 3.66 g 2-butylsulfanyl-6-ethoxy-8,8a-dihydro-4aH-pyrido [2,3-d] pyrimidine- with a purity> 80% as determined by MS / HPLC 7-one (1A) was obtained and NMR data collected.

Step B: 2- (Butane-1-sulfonyl) -6-ethoxy-8H-pyrido [2,3-d] pyrimidin-7-one

A solution of Compound (1A) (3 g, 10.7 mmol) suspended in 40 ml of DCM was cooled to 0-5 ° C. in an ice bath and metachloroperbenzoic acid (5.5 g, 32.3 mmol) was added gradually. The resulting mixture was stirred at ambient temperature overnight and then concentrated in vacuo. The residue was triturated with EtOAc and subjected to column chromatography using CH ₂ Cl ₂ : MeOH: acetone (96: 2: 2) as eluent to 1 g of 2- (butane-1-sulfonyl) -6-. Toxoxy-8H-pyrido [2,3-d] pyrimidin-7-one (3B) was obtained.

Step C: 6-ethoxy-2 [3-methoxy-1 (2-methoxy-ethyl) -propylamino] -8,8a-dihydro-4aH-pyrido [2,3-d] pyrimidine- 7-on

A solution of compound 3B (50 mg, 0.16 mmol) and 3-methoxy-1- (2-methoxy-ethyl) -propylamine (140 mg, 0.96 mmol) in 1 ml DCE was heated to 85 ° C. for 72 hours. Was carried out directly chromatography to a final solvent mixture of a number of the reaction mixture Pelco (Supelco, brand) 2g / 12ml on a silica column in gradient solvent of _{CH 2 Cl 2 CH 2 Cl 2} : MeOH: acetone (396: 3) . 24 additional 6 mg of 6-ethoxy-2 [3-methoxy-1 (2-methoxy-ethyl) -propylamino] with 86% purity as determined by MS / HPLC by two additional chromatography runs -8,8a-dihydro-4aH-pyrido [2,3-d] pyrimidin-7-one was obtained: M ⁺ +337.

Example 2: 6-methoxy-8-methyl-2- (tetrahydro-pyran-4-ylamino) -8H-pyrido [2,3-d] pyrimidin-7one

Step A

4-methylamino-2-methylthio-5-pyrimidinecarboxaldehyde (2 g, 10.9 mmol), methyl methoxyacetate (1.6 ml, 16.4 mmol), potassium carbonate (2.26 g, 16.4 mmol) and NMP at 120 ° C. (40 ml) was stirred for 66 hours. The reaction mixture was cooled to rt, poured into water (300 ml) and extracted with EtOAc (3 × 100 ml). The organic layer was washed with water and brine, then dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography using 20-50% acetone / hexane as eluent to afford 502 mg of compound 2A.                 

Step B

Compound (2A) (450 mg, 1.90 mmol), 72% mCPBA (1.36 g, 5.69 mmol) and methylene chloride (100 ml) were stirred at room temperature for 3 hours. Aqueous sodium bisulfite solution (10%, 100 ml) was added to the reaction mixture, stirred at room temperature for 1 hour and then extracted with EtOAc (200 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution, water and brine, then dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography using 0-3% MeOH / DCM as eluent to afford 235 mg of compound 2B.

Step C: Example 2

Compound (2B) (50 mg, 0.186 mmol), 4-aminotetrahydropyrain (38 g, 0.371 mmol) and NMP (1 ml) were stirred at 80 ° C. for 66 hours. The reaction mixture was cooled to room temperature and purified by flash chromatography using 1-5% MeOH / DCM as eluent to afford 47 mg of compound 4a. The free base was dissolved in MeOH, treated with 1 equivalent 1N HCl / Et ₂ O and concentrated in vacuo to afford the title compound of Example 2 as a hydrochloride salt (44 mg).

Example 3: 6-ethoxy-8-methyl-2- (tetrahydro-pyran-4-ylamino) -8H-pyrido [2,3-d] pyrimidin-7-one

Step A

4-methylamino-2-methylthio-5-pyrimidinecarboxaldehyde (3 g, 16.4 mmol), ethyl ethoxyacetate (3.3 ml, 24.6 mmol), potassium carbonate (3.4 g, 24.6 mmol) and NMP at 120 ° C. (50 ml) was stirred for 18 hours. The reaction mixture was lowered to 80 [deg.] C. for 66 hours and the temperature was again raised to 120 [deg.] C. after the second addition of ethyl ethoxyacetate and potassium carbonate. The reaction mixture was poured into water (300 ml) and stirred at rt for 1 h. The precipitate was collected by filtration, washed with water and hexanes and dried in vacuo to yield 2.14 g of compound 3A.

Step B

Compound (3A) (2 g, 7.96 mmol), 72% mCPBA (5.7 g, 23.9 mmol) and methylene chloride (100 ml) were stirred at room temperature for 1 hour. Aqueous sodium bisulfite solution (10%, 100 ml) was added to the reaction mixture, stirred at room temperature for 15 minutes and then extracted with EtOAc (200 ml). The organic layer was washed with saturated aqueous solution of sodium bicarbonate, water and brine, dried over magnesium sulfate and concentrated in vacuo to yield 1.45 g of compound 3B.

Step C: Example 3

Compound (3B) (100 mg, 0.353 mmol), ethyl 4-amino-1-piperidinecarboxylate (0.12 ml, 0.706 mmol) and NMP (3 ml) were stirred at 120 ° C. for 18 hours. The reaction mixture was cooled to room temperature and separated between water and EtOAc. The organic layer was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was dissolved in MeOH and DCM, treated with 1N HCl / Et ₂ O (0.35 ml) and concentrated in vacuo. The resulting solid was washed with ether ether and concentrated in vacuo to give the hydrochloride salt of Example 3 (56 mg).

Example 4: 6-ethoxy-8-methyl-2- (piperidin-4-ylamino) -8H-pyrido [2,3-d] pyrimidin-7one

Step A: Preparation of 6- (2,6-difluorophenoxy) -8-methyl-2- (methylthio) pyrido [2,3-d] pyrimidin-7 (8H) -one

4-Methylamino-2-methylthiopyrimidine-5-carboxaldehyde (Preparation Example 1) (4.8 g, 26.2 mmol) in 50 ml of 1-methyl-2-pyrrolidinone and methyl 2,6-difluoro Potassium carbonate (6.0 g, 43.5 mmol) was added to a mixture of phenoxyacetate (prepared in Preparation Example 4 using 2,6-difluorophenol, 5.9 g, 32 mmol). The reaction mixture was heated to 120 ° C. and after 12 h additional phenoxyacetate (2 ×, 2.0 g, 10.8 mmol) and potassium carbonate (2.0 g, 15 mmol) were added. After stirring at 120 ° C. for 6 hours, the reaction was cooled to room temperature and water (70 ml) was added. The solution was stirred for 30 minutes and filtered. The resulting solid was washed with water (2 ×), EtOAc and ether. The solid was then dried to give 7.0 g of the title compound sulfide (mass spectrum M + 1 = 336, melting point 247-250.7 ° C).

Step B: Preparation of 6- (2,6-difluorophenoxy) -8-methyl-2- (methylsulfonyl pyrido [2,3-d] pyrimidin-7 (8H) -one

Compound 4A (7.0 g, 20.8 mmol) was dissolved in 50 ml of methylene chloride and 3-cloperbenzoic acid (77%, 11.5 g, 51.5 mmol) was added. The mixture was stirred at rt for 16 h and filtered, then washed with aqueous sodium sulfite solution (2x, 75ml) followed by saturated sodium bicarbonate solution (3x, 75ml). The organic solution was then dried (salt, Na ₂ SO ₄ ) and evaporated. The resulting solid was stirred with ether for 1 hour and filtered to give the title compound sulfone (4B) (mass spectrum M + 1 = 368, melting point 215.2-216.4 DEG C) in a yield of 5.5 g.

Step C: Ethyl 4-{[6- (2,6-difluorophenoxy) -8-methyl-7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine-2- Production of Amino} piperidine-1-carboxylate

A mixture of compound 4B (1.0 g, 2.7 mmol) and ethyl 4-amino-1-piperidinecarboxylate (0.93 ml, 5.4 mmol) in 5 ml of 1-methyl-2-pyrrolidinone at 100 ° C. was added for 1 hour. After stirring, it was cooled to room temperature. The reaction slurry was added to 20 ml of distilled water and the yellow precipitate was collected by vacuum filtration, and then dried in vacuo to yield 1.28 g of compound (4C). About 80 mg of the obtained product was dissolved in MeOH (1-2 ml) and then treated with hydrochloric acid in ether (1M). After evaporation of the organics, ether (1-2 ml) was added to give a solid. The solid obtained was isolated via filtration and dried and 66 mg of compound (4C) was obtained as a hydrochloride salt (melting point 197-204 ° C.).

Step D: 6-Ethoxy-8-methyl-2-{[1-methanesulfonyl) piperidin-4-yl] amino} pyrido [2,3-d] pyrimidin-7 (8H) one ( Example 4

Ethyl 4-{[6- (2,6-difluorophenoxy) -8-methyl-7-oxo-7,8-dihydropyrido [2,3-d obtained in Step C in 20 ml of EtOH. ] Pyrimidin-2-yl] amino} piperidine-1-carboxylate (1.2 g, 2.52 mmol) and potassium hydroxide (2.83 g, 50.4 mmol) were refluxed for 48 hours, then reaction solvent Was evaporated under reduced pressure. The residue was redissolved in 100 ml water and cooled in an ice bath and then oxidized by the dropwise addition of concentrated HCl. The acidic aqueous solution was then extracted with DCM (twice). The aqueous solution was cooled in an ice bath and realkalized with sodium hydroxide. The alkaline solution was extracted with DCM (twice). The organic extracts from the alkaline aqueous solution were combined, dried over magnesium sulfate, concentrated and dried in vacuo to give 92 mg of crude product.

Optionally, the free base of Example 3 (prepared as disclosed above, 358 mg, 0.954 mmol), a mixture of potassium hydroxide (1.07 g, 19.1 mmol) and EtOH (10 ml) was refluxed for 5 days to give Example 4 Was prepared. The reaction mixture was concentrated in vacuo. The residue was dissolved in water, acidified with 2N HCl and extracted with DCM. The aqueous layer was alkalized with saturated aqueous sodium bicarbonate solution and reextracted with DCM (2 × 100 ml). The combined organic extracts from the alkaline solution were dried over magnesium sulfate and concentrated in vacuo to afford 24 mg of the compound of Example 4. A portion (3 mg) of the compound of Example 4 was dissolved in MeOH, treated with 1 equivalent 1N HCl / Et ₂ O and concentrated in vacuo to give the hydrochloride salt of Example 4 (4 mg).

Example 5: 6-ethoxy-8-methyl-2-{(1-methanesulfonyl) piperidin-4-yl] amino} pyrido [2,3-d] pyrimidine-7 (8H)- On

The crude piperidine product (0.92 g, 0.237 mmol) obtained from Example 4 was dissolved in 5 ml of DCM with sodium carbonate (0.050 g, 0.475 mmol) and methanesulfonyl chloride (0.022 ml, 0.285 mmol) and at room temperature Stir for 17 hours. Additional drops of methane sulfonyl chloride (0.040 ml) and sodium carbonate (50 mg) were added and the reaction stirred at room temperature for 24 hours. The last drops of methane sulfonyl chloride (0.080 ml) and sodium carbonate (150 mg) were added and the reaction stirred at room temperature for 48 hours. All starting materials were removed and the organic layer was washed with water, dried over magnesium sulfate and concentrated in vacuo to an oil. The reaction mixture was purified by column chromatography (SiO ₂ , CH ₂ Cl ₂ /MeOH-0.5/99.5 to 3/97 gradient). The column fractions were combined and concentrated under reduced pressure to give the desired product (25 mg). The product was dissolved in EtOc (1-2 ml) and then treated with hydrochloric acid (1M, 1 equiv) in ether. Washing with ether isolated the solid, filtered and dried in vacuo and 19 mg of the compound of Example 5 was obtained as a hydrochloride salt (melting point 219.56 to 221.2 ° C.).

A mixture of Example 4 compound (21 mg, 0.069 mmol), sodium carbonate (15 mg, 0.138 mmol), methanesulfonyl chloride (0.06 ml) and DCM (10 ml) was stirred at room temperature for 18 hours. The reaction mixture was poured into water (100 ml) and extracted with DCM (2 × 100 ml). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo. The anhydrous residue was dissolved in MeOH, treated with 1N HCl / Et ₂ O and concentrated in vacuo. The resulting solid was washed with Et ₂ O, dried in vacuo and the Example 5 compound was obtained as a hydrochloride salt (15 mg).

Example 6

This example illustrates a p38 (MAP) kinase in vitro assay useful for evaluating the compounds of the present invention.

See Ahn et al., J. Biol. Chem ., 266: 4220-4227 (1991), measuring the conversion of γ-phosphate from γ- ³³ P-ATP to myelin basic protein (MBP) by p-38 kinase using a slightly modified method. In vitro p38 MAP kinase inhibitory activity of the compounds of the present invention was measured.

Phosphorylated forms of recombinant p38 MAP kinase were co-expressed with SEK-1 and MEKK in E. coli (see Khokhlatchev, et al., J. Biol. Chem . 272: 11057-11062 (1997)), using nickel columns Purification was carried out by affinity chromatography.

Phosphorylated p38 MAP kinase in kinase buffer (20 mM 3- (N-morpholino) propanesulfonic acid, pH 7.2, 25 mM β-glycerol phosphate, 5 mM ethylene glycol-bis (beta-aminoethyl ether) -N, N, N ', N'-tetraacetic acid, 1 mM sodium ortho-vanadate, 1 mM dithiothreitol, 40 mM magnesium chloride). Test compounds dissolved in DMSO or single DMSO (control) were added and the samples incubated at 30 ° C. for 10 minutes. Kinase reactions were initiated by addition of a substrate mixture containing MBP and γ- ³³ p-ATP. After incubation for another 20 minutes at 30 ° C., the reaction was terminated by addition of 0.75% phosphoric acid. Subsequently, phosphorylated MBP was isolated from residual γ- ³³ P-ATP using a phosphocellulose membrane (Millipore, Bedford, Mass.) And scintillation counter (Packard, Meriden, Connecticut, USA). Material).

IC ₅₀ values were defined as the concentration of test compound corresponding to half-maximum reduction at 450 nm absorbance.

Example 7

This example illustrates an in vitro assay to assess the inhibition of production of LPS induced TNF-α in THP1 cells.

The ability of the compounds of the present invention to inhibit TNF-α release was measured using a method slightly modified from the method disclosed in Blifeld, et al., Transplantation, 51: 498-503 (1991).                 

(a) Induction of TNF biosynthesis

THP-1 cell culture medium [15% fetal calf serum, 0.02mM 2- mercaptoethanol RPMI containing (co-Ziv-El BRL (Gibco-BRL), Maryland, USA clear up Tuscan bug material)] 2.5x10 ⁶ to Suspensions at a concentration of cells / ml were then plated into 96 well plates (0.2 ml droplets per well). Test compounds were dissolved in DMSO and then diluted with culture medium to bring the final DMSO concentration to 5%. 25 μl of test solution droplets or medium with single DMSO (control) was added to each well. Cells were incubated at 37 ° C. for 30 minutes. LPS (Sigma, St. Louis, MO) was added to each well at a final concentration of 0.5 μg / ml and cells were incubated for an additional 2 hours. At the end of the culture, the culture supernatants were collected and the amount of TNF-α present was measured using the ELISA assay described below.

(b) ELISA analysis

Reimund, J.M., et al., GUT. Vol. 39 (5), 684-689 (1996) of human TNF-α present in a specific trapping ELISA assay using two anti-TNF-α antibodies (2TNF-H12 and 2TNF-H34). The amount was measured.

Polystyrene 96 well plates were coated with antibody 2TNF-H12 (10 μg / ml) in 50 μl PBS per well and incubated overnight in a 4 ° C. humid chamber. Plates were washed with PBS and blocked with 5% fat free dry milk in PBS for 1 hour at room temperature followed by 0.1% BSA (bovine serum albumin) in PBS.

TNF standards were prepared from human recombinant TNF-α stock solutions (R & D system, Minneapolis, Minnesota, USA). In the analysis, the concentration of the standard solution was started at 10 ng / ml, followed by 6 half log serial dilution.

25 μl of the culture supernatant drop or TNF standard solution or control medium (control) was mixed with 20 μl of biotinylated monoclonal antibody 2TNF-H34 drop (2 μg / ml in PBS containing 0.1% BSA). Next, each well was added. Samples were incubated for 2 hours at room temperature with gentle stirring and then washed three times with 0.1% BSA in PBS. A 50 μl peroxidase-streptavidin (Zymed, San Francisco, CA, USA) solution containing 0.416 μg / ml of peroxidase-streptavidin and 0.1% BSA was added to each well. Was added. Samples were incubated for an additional hour at room temperature and then washed four times with 0.1% BSA in PBS. 50 μl of O-phenylenediamine solution (1 μg / ml O-phenylene-diamine and 0.03% hydrogen peroxide in 0.2 M citrate buffer, pH 4.5) was added to each well and the sample was allowed to stand at room temperature for 30 minutes. Cultured in the dark. The optical densities of the samples and the controls were recorded at 450 nm and 650 nm, respectively. The amount of TNF-α was measured from a graph of optical density at 450 nm against the concentration used.

IC ₅₀ values were defined as the concentration of test compound corresponding to half-maximum reduction at 450 nm absorbance.

Example 8

This example illustrates an in vivo assay to assess the inhibition of production of LPS induced TNF-α in mice (or mice).                 

The ability of compounds of the invention to inhibit TNF-α release in vivo is described by Zanetti, et al., J. Immunol. , 148: 1890 (1992) and Sekut, et al., J. Lab. Clin. Med ., 124: 813 (1994)], using a slightly modified method.

Female BALB / c mice (Charles River, Hollister, CA, USA) weighing 18-21 g were acclimated for a week. A test compound suspended or dissolved in an aqueous vehicle containing 0.9% sodium chloride, 0.5% sodium carboxymethylcellulose, 0.4% polysorbate 80, 0.9% benzyl alcohol (CMC vehicle) in a group of 8 mice each Single vehicle (control) was orally administered. After 30 minutes, mice were intraperitoneally injected with 20 μg of LPS (Sigma, St. Louis, MO). After 1.5 hours, mice were sacrificed by CO ₂ inhalation and blood was collected by cardidocentesis. Blood was separated by centrifugation at 15,600 × g for 5 minutes, the serum was transferred to a clean container and for TNF-α by ELISA assay (Biosource International, Camarillo, CA, USA) according to the protocol of the guidelines. Frozen at −20 ° C. until analysis.

Claims (23)

A compound of formula (I), or a pharmaceutically acceptable salt thereof: Formula I

Where Z is N or CH; X ¹ is O, NR ⁴ , where R ⁴ is hydrogen or alkyl, S or C═O; R ¹ is alkyl, cycloalkyl, cycloalkylalkyl or —CH ₂ -alkenyl; R ² is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, haloalkyl, heteroalkyl, cyanoalkyl, alkylene-C (O) —R ²¹ where R ²¹ is hydrogen, alkyl, hydr Oxy, alkoxy, amino, monoalkylamino or dialkylamino), amino, monoalkylamino, dialkylamino, acyl or NR ²² -YR ²³ , wherein Y is -C (O), -C (O) O -, -C (O) NR ²⁴ , S (O) ₂ or S (O) ₂ NR ²⁵ ; R ²² , R ²⁴ and R ²⁵ are independently hydrogen or alkyl; R ²³ is hydrogen, alkyl, cycloalkyl , Cycloalkylalkyl, heteroalkyl or optionally substituted phenyl), wherein R ² is not cyclopentyl; R ³ is alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heteroalkylsubstituted cycloalkyl, heterosubstituted cycloalkyl, heteroalkyl, cyanoalkyl, heterocyclyl , Heterocyclylalkyl or -heterocycloamino-SO ₂ -R ¹² , wherein R ¹² is haloalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl, wherein "alkyl" is C _1-8 Alkyl; "Cycloalkyl" refers to C _3-7 cycloalkyl; "Alkylene" refers to C _1-6 alkylene; "Alkoxy" means C _1-8 alkoxy; “Acyl” refers to a radical —C (O) R wherein R is hydrogen, C _1-8 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl C _1-8 alkyl, phenyl or phenyl C _1-8 Alkyl); "Heteroalkyl" is a C _1- wherein 1, 2 or 3 hydrogen atoms are independently substituted with a substituent selected from the group consisting of -OR ^a , -N (O) _m R ^b R ^c and -S (O) _n R ^d ₈ alkyl, where m is 0 or 1; n is an integer from 0 to 2; R ^a is hydrogen, acyl, C _1-8 alkoxycarbonyl, C _1-8 alkyl, C _3-7 cyclo Alkyl or C _3-7 cycloalkyl C _1-8 alkyl; R ^b and R ^c are independently hydrogen, acyl, C _1-8 alkoxycarbonyl, C _1-8 alkyl, C _3-7 cycloalkyl, C _{3 -7} cycloalkyl C _1-8 alkyl, C _1-8 alkylsulfonyl, aminosulfonyl, mono- or di -C _1-8 alkylamino-sulfonyl, amino C _1-8 alkyl, mono- or di -C _{1 -8} alkyl amino C _1-8 alkyl, hydroxy C _1-8 alkyl, C _1-8 alkoxy C _1-8 alkyl, hydroxy C _1-8 alkylsulfonyl or C _1-8 alkoxy C _1-8 alkylsulphate Phenyl; provided that when m is 1 R ^b and R ^c are both independently C _1-8 alkyl, C _3-7 cycloalkyl And C _3-7 cycloalkyl C _1-8 alkyl; when n is 0, R ^d is hydrogen, C _1-8 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl C _1-8 alkyl Or substituted or unsubstituted phenyl and when n is 1 or 2 R ^d is C _1-8 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl C _1-8 alkyl, substituted or unsubstituted phenyl , Amino, acylamino, mono C _1-8 alkylamino or di C _1-8 alkylamino; "Heteroaryl" means pyridyl, furanyl, thienyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, isoxazolyl, pyrroyl, pyrazolyl, pyrimidinyl, benzofuranyl, tetrahydro Benzofuranyl, isobenzofuranyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, indolyl, isoindolyl, benzoxazolyl, quinolyl, tetrahydroquinolinyl, isoquinolyl, benzimida Zolyl, benzisoxazolyl or benzothienyl, imidazo [1,2-a] -pyridinyl, imidazo [2,1-b] thiazolyl; "Heterosubstituted cycloalkyl" means that one, two or three hydrogen atoms are hydroxy, C _1-8 alkoxy, amino, acylamino, mono C _1-8 alkylamino, di C _1-8 alkylamino, oxo (C = O), imino, hydroxideimino (= NOH), NR'SO ₂ R ^d , where R 'is hydrogen or C _1-8 alkyl, R ^d is C _1-8 alkyl, C _3-7 cycloalkyl , Hydroxy C _1-8 alkyl, amino, mono C _1-8 alkylamino or di C _1-8 alkylamino), -XYC (O) R, wherein X is O or NR 'and Y is C _{1 -6} alkylene or absent, R is hydrogen, C _1-8 alkyl, halo C _1-8 alkyl, C _1-8 alkoxy, amino, mono C _1-8 alkylamino, di C _1-8 alkylamino or substituted Or unsubstituted phenyl, R 'is hydrogen or C _1-8 alkyl), or -S (O) _n R (where n is an integer from 0 to 2, where n is 0, R is hydrogen, C _1-8 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl C _1-8 alkyl, substituted or unsubstituted Is phenyl or thienyl, and when n is 1 or 2, R is C _1-8 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl C _1-8 alkyl, substituted or unsubstituted phenyl, thienyl C _3-7 cycloalkyl independently substituted with a substituent selected from the group consisting of: amino, acylamino, mono C _1-8 alkylamino or di C _1-8 alkylamino; “Aryl” or “ar” refers to C _1-8 alkyl, hydroxy, C _1-8 alkoxy, halo C _1-8 alkyl, halo C _1-8 alkoxy, C _1-8 alkylthio, C _1-8 alkylsulphi Nyl, C _1-8 alkylsulfonyl, —SO ₂ NR′R ″, wherein R ′ and R ″ are independently hydrogen or C _1-8 alkyl, YC (O) —R, wherein Y is absent Or a C _1-6 alkylene group, R is hydrogen, C _1-8 alkyl, halo C _1-8 alkyl, halo C _1-8 alkoxy, hydroxy, C _1-8 alkoxy, amino, mono C _1-8 Alkylamino or di C _1-8 alkylamino), heteroalkyl, heteroalkyloxy, heteroalkylamino, halo, nitro, cyano, amino, mono C _1-8 alkylamino, di C _1-8 alkylamino, C _1-8 alkylsulfonyl, amino, heteroaryl-alkyl-sulfonylamino, sulfonamido, methylenedioxy, ethylene-dioxane City, heterocyclyl, and heterocyclyl C _1-8 1, 2 or 3 substituents selected from the group consisting of alkyl Independently substituted or substituted by Means that the phenyl or naphthyl, and; "Heterocyclyl" is a ring of 3 to 8 ring members wherein one or two ring atoms are heteroatoms selected from N, O or S (O) _n , where n is an integer from 0 to 2 and the remaining ring atoms are carbon. Saturated or unsaturated non-aromatic cyclic radicals, wherein one or two carbon atoms may be substituted with a carbonyl group. The method of claim 1, R ¹ is alkenylene instead of —CH ₂ -alkenyl and R ³ is additionally H, or a pharmaceutically acceptable salt thereof. The method of claim 1, Z is N, X ¹ is O, R ¹ is alkyl, R ² is H or alkyl, and R ³ is heteroalkyl or heterocyclyl, wherein “alkyl”, “heteroalkyl” and “hetero Cyclyl "is as defined in claim 1). Claim 4 was abandoned when the registration fee was paid. The method of claim 3, wherein Heteroalkyl is alkoxyalkyl, heterocyclyl is a saturated non-aromatic cyclic radical of 6 ring atoms in which one ring atom is not C and is O or N and optionally N is substituted with alkyl-SO ₂ -or alkoxycarbonyl ( Wherein "alkyl" and "alkoxy" are as defined in claim 1). The method of claim 1, X ¹ is —O—. The method of claim 1, Compounds wherein R ¹ is alkyl or cycloalkyl, wherein “alkyl” and “cycloalkyl” are as defined in claim 1. The method of claim 1, R ³ is cycloalkyl, cycloalkylalkyl, heteroalkylsubstituted cycloalkyl, heterosubstituted cycloalkyl, heteroalkyl, heterocyclyl or heterocyclylalkyl, wherein “alkyl”, “cycloalkyl”, “hetero Alkyl "," heterosubstituted cycloalkyl "and" heterocyclyl "are as defined in claim 1). Claim 8 was abandoned when the registration fee was paid. The method of claim 1, R ³ is cycloalkyl, heteroalkylsubstituted cycloalkyl, heterosubstituted cycloalkyl, heteroalkyl or heterocyclyl, wherein “cycloalkyl”, “heteroalkyl”, “heterosubstituted cycloalkyl” and “hetero Cyclyl "is as defined in claim 1). Claim 9 was abandoned upon payment of a set-up fee. The method of claim 1, R ³ is alkyl, haloalkyl, heteroalkyl, halo, nitro, cyano, cyanoalkyl, hydroxy, alkoxy, amino, monoalkylamino, dialkylamino, aralkyl,-(X) _n -C (O) R where X is O or NR ', n is 0 or 1, and R is hydrogen, alkyl, haloalkyl, hydroxy (if n is 0), alkoxy, amino, monoalkylamino, dialkylamino or Substituted or unsubstituted phenyl, R 'is hydrogen or alkyl, alkylene-C (O) R ^a , wherein R ^a is alkyl, OR or NR'R ", and R is hydrogen, alkyl or haloalkyl R 'and R "are independently hydrogen or alkyl), or -S (O) _n R (where n is an integer from 0 to 2, when n is 0, R is hydrogen, alkyl, cycloalkyl or When cycloalkylalkyl and n is 1 or 2, R is alkyl, cycloalkyl, cycloalkylalkyl, amino, acylamino, monoalkylamino, dialkylamino or heteroalkyl , Heterosulfyl, unsubstituted or substituted independently with one, two or three substituents selected from the group consisting of alkyl sulfoxy or alkoxy carbonyl, wherein "alkyl", "cycloalkyl", "alkylene" , “Alkoxy”, “acyl”, “heteroalkyl”, “aryl” or “ar”, and “heterocyclyl” are as defined in claim 1). Claim 10 was abandoned upon payment of a setup registration fee. The method of claim 1, R ³ is hydroxyalkyl or alkoxyalkyl, wherein “alkyl” and “alkoxy” are as defined in claim 1. The method of claim 1, R ² is hydrogen, alkyl, aryl, cycloalkyl or heteroalkyl, wherein “alkyl”, “cycloalkyl”, “heteroalkyl” and “aryl” are as defined in claim 1. Claim 12 was abandoned upon payment of a registration fee. The method of claim 1, R ² is alkyl or hydroxyalkyl, wherein “alkyl” is as defined in claim 1. The method of claim 1, A compound having the formula (I '') or a pharmaceutically acceptable salt thereof: Formula I ''

Where R ¹ is alkyl; R ² is selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl and heteroalkyl; R ³ is heteroalkyl or heterocyclyl, wherein "alkyl", "cycloalkyl", "heteroalkyl", "aryl" and "heterocyclyl" are as defined in claim 1. Claim 14 was abandoned when the registration fee was paid. The method of claim 13, R ³ is (1-hydroxy-2-methyl) -prop-2-yl, 1-hydroxy-pentane-2-yl, (S) -2-hydroxy-1,2-dimethyl-propyl , (R) -2-hydroxy-1,2-dimethyl-propyl, (S) -2-hydroxy-1-methyl-ethyl, 1-hydroxymethyl-cyclopentane-1-yl, 2- Hydroxy-2-methyl-propyl, 3-methoxy-1- (2-methoxy-ethyl) propyl, tetrahydro-2H-pyran-4-yl, 1- (methylsulfonyl) piperidine-4 A compound selected from the group consisting of -yl, 1-carboxyethyl-piperidin-4-yl, 1,1-dioxidotetrahydro-2H-thiopyrene-4-yl and morpholinyl. Claim 15 was abandoned upon payment of a registration fee. The method of claim 14, R ¹ is ethyl; R ² is methyl; R ³ is (1-hydroxy-2-methyl) -prop-2-yl, 1-hydroxy-pentane-2-yl, (S) -2-hydroxy-1,2-dimethyl-propyl , (R) -2-hydroxy-1,2-dimethyl-propyl, (S) -2-hydroxy-1-methyl-ethyl, 1-hydroxymethyl-cyclopentane-1-yl, 2- Hydroxy-2-methyl-propyl, 3-methoxy-1- (2-methoxy-ethyl) propyl, tetrahydro-2H-pyran-4-yl, 1- (methylsulfonyl) piperidine-4 A compound selected from the group consisting of -yl, 1-carboxyethyl-piperidin-4-yl, 1,1-dioxidotetrahydro-2H-thiopyrene-4-yl and morpholinyl. Claim 16 was abandoned upon payment of a setup registration fee. The method of claim 13, Compounds having Formula II: Formula II

Where X is -O-, -C (= 0)-, -N (R ^12a )-or -CH (R ^12b )-; R ^12a is selected from the group consisting of hydrogen, C _1-4 alkyl, —C (═O) R ¹⁵ , —C (O) ₂ R ¹⁵ and —S (O) ₂ (C _1-4 alkyl); R ^12b is selected from the group consisting of hydrogen, C _1-4 alkyl, -OR ¹⁵ , -C (= 0) R ¹⁵ , -C (O) ₂ R ¹⁵ and -S (O) ₂ (C _1-4 alkyl) Selected; R ¹⁴ is C _1-4 alkyl, oxo (═O), —OR ¹⁵ , —C (═O) R ¹⁵ , —C (O) ₂ R ¹⁵ and —S (O) ₂ (C _1-4 alkyl) It is selected from the group consisting of; Each R ¹⁵ is independently selected from hydrogen and C _1-4 alkyl; q is 0 or 1; r is 0, 1 or 2. Claim 17 was abandoned upon payment of a registration fee. The method of claim 16, A compound wherein X is -N (R ^12a )-and R ^12a is -S (O) ₂ (C _1-4 alkyl), or a pharmaceutically acceptable salt thereof. delete The compound of formula (Ie) or a corresponding sulfoxide thereof is treated with R ³ -NH ₂ , wherein R ³ is as defined in claim 1, and the resulting product is R ² -L where R ² is Alkyl, L is a leaving group), to prepare a compound of formula (I) according to any one of claims 1 to 17.

Where R ¹ , X ¹ and R ² are as defined in claim 1; R is alkyl, where "alkyl" is as defined in claim 1. 18. An exotherm comprising a compound according to any one of claims 1 to 17 and a pharmaceutically acceptable excipient; arthritis; Adult respiratory disease syndrome, pulmonary sarcoidosis, asthma, silicosis and chronic pulmonary inflammatory disease or lung inflammation; Viral or bacterial infections; osteoporosis; Toxic shock, toxic shock syndrome; Reperfusion injury; Autoimmune diseases; Atherosclerosis, thrombosis, congestive heart failure and heart reperfusion injury; Kidney reperfusion injury; Nephritis; Muscle pain due to infection; Alzheimer's disease; influenza; Multiple sclerosis; cancer; diabetes; Systemic lupus erythematosus (SLE); Psoriasis, eczema, burns, dermatitis, keloid formation and scar tissue formation; Inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis; Acute injuries to retinitis, retinopathy, uveitis, eye glare and eye tissue; Angiogenesis; transition; Corneal graft rejection, ocular neovascularization, retinal neovascularization, diabetic retinopathy, posterior capsular fibrosis and neovascular glaucoma; Ulcer disease; Hemangioma; Diabetic nephropathy, cardiomyopathy; And endometriosis p38 mediated disease treatment pharmaceutical composition selected from the group consisting of. delete Claim 22 was abandoned upon payment of a registration fee. The method of claim 20, A pharmaceutical composition wherein the p38 mediated disease is rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, Crohn's disease, irritable bowel syndrome, inflammatory bowel disease, psoriasis, adult respiratory disease syndrome, asthma or chronic obstructive pulmonary disease. Claim 23 was abandoned upon payment of a set-up fee. The method of claim 20, A pharmaceutical composition wherein the p38 mediated disease is Alzheimer's disease.