TWI282334B - A61p 17/00 200601 a i vhtw a61p 29/00 200601 a i vhtw a61p 35/00 200601 a i vhtw a61p 37/00 200601 a i vhtw - Google Patents

Abstract

The present invention relates to inhibitors of p38, a mammalian protein kinase involved cell proliferation, cell death and response to extracellular stimuli. The invention also relates to methods for producing these inhibitors. The invention also provides pharmaceutical compositions comprising the inhibitors of the invention and methods of utilizing those compositions in the treatment and prevention of various disorders.

Description

1282334

V. INSTRUCTION DESCRIPTION OF THE INVENTION (1) Field of the Invention The present invention relates to a p38 inhibitor, a mammalian protein activating enzyme involved in cell proliferation, cell death, and reactive extracellular stimulation. The invention is also directed to methods of making these inhibitors. The invention also provides pharmaceutical compositions comprising the inhibitors of the invention and methods of using the compositions to treat and prevent different abnormalities. ^ Background of the Invention Protein-activated enzymes are involved in different cellular responses to extracellular messages. Recently, a family of protein-activated enzymes (MAPKs) activated by the silk fission factor has been discovered. A member of this family is a Ser/Thr activator that activates its shellfish by phosphorylation [B. Stein et al., Ann. Rep. Med. Chem. 31, pp. 289-98 (1996)]. MAPKs are themselves activated by a variety of messages including reagents such as growth factors, cytokines, UV radiation and bursting pressure. A particularly interesting MAPK is p38. P38, also known as cytokine-inhibiting anti-inflammatory drug-binding protein (CSBP) and RK, is a lipopolysaccharide receptor (LPS) 'CD14 metastatic infection isolated from mice and per-B cells induced by LPS. P38 has been isolated and sequenced, and its cDNA coding in humans and mice is known. Activation of p38 can be observed in cells stimulated by pressure (e.g., lipopolysaccharide, LPS), UV, amygdalin treatment or osmotic shock and treatment with cytokines such as IL-1 and TNF. Inhibition of p3 8 activase results in a blockade in the production of IL-1 and TNF. IL-1 and TNF stimulate the production of other pro-inflammatory cells such as IL-6 and IL-8, and are associated with acute and chronic inflammatory diseases and postmenopausal osteoporosis [RB Kimble et al., Endocrinol.. 136, Pp. 3054-61 (1995)] ° -4- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) (please read the notes on the back side and then fill out this page) ------- Line j Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1282334 A7 ---______B7 _ V. Invention description (2) Based on this discovery, Xianxin p38 and other MApKs are in the inflammatory stimulus (such as white blood cells) Aggregation, giant cell/mononuclear leukocyte activation cells = absorption, fever, acute phase response, and neutropenia have a role. In addition, MApKs, such as p38, are associated with cancer, thrombocytosis, platelet aggregation, immunodeficiency, autoimmune disease, cell death, allergy, osteoporosis, and neurodegenerative abnormalities. Inhibition of P38 is linked to the management of pain management by inhibition of peroxidase synthetase _ 2 bursts in prostaglandins. Other related diseases, the disease of -6, il_8 or TNF overproduction is an announcement in ~〇 96/21654. Others have begun experimenting with drugs that specifically inhibit MApKs. For example, PC Din Publication W0 95/3 145 1 describes pyrazole compounds which inhibit MAPKs and in particular p38. However, the efficacy of these inhibitors in vivo is still being explored. Accordingly, there is still a great need to develop other P38-specific inhibitors that have potential and are suitable for treating different P38 activation conditions. . SUMMARY OF THE INVENTION The present invention addresses this problem by providing compounds that demonstrate a strong and specific inhibition of ρ38. ' These compounds have a general structural formula: .---------------- order--------- line ^ (please read the back of the >i intentions again Fill in this page}

1282334

°2 111, or a pharmaceutically acceptable salt thereof. (Please read the notes on the back and fill out this page.) For structural I and 11: HET疋 is a 5-7 member! To 4 isomers of N, s or deuterium atoms, this heteropoly is substituted with 1 to 3 c rC: 4 branched or linear alkyl groups. HET is replaced by _, cyano, N(Ir)2, 〇R, c〇2R, c〇n (r% and S02N(R2)Jsl as needed. X is 0 or η is 1 to 3 For the structural formula III: each of Q! & Q2 is an aromatic cyclic or heterocyclic ring system selected from 5-6 members, or n members include an aromatic ring. A bicyclic system of a cyclic substance, an aromatic heterocyclic ring type or a combination of an aromatic cyclic ring type and an aromatic heterocyclic ring type. Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative The ring comprising the composition Q i is optionally substituted with 1 to 4 substituents, each of which is individually selected from J: halogen; optionally substituted with Nr, 2, 〇R, c〇2R, or CONR' CVCq alkyl of 2; optionally substituted with a, TC(0)R', 0P03H2, NR'2, OR', C〇2r, or CONR'j〇-(CrC4)_alkyl; NR'2; OCF3 ; CF3 ; N02 ; C02R' ; CONR,; SR,; S(02)N(R')2 ; SCF3 ; CN ; N(R')C(0)R4 ; N(R,)C(0)0R4 ; N(R')C(0)C(0)R4 ; N(R,)S(02)R4 ; N(R,)R4 ; N(R4)2 ; OR4 ; -6- This paper size applies to China National standard Quasi-CNS A4 size (210 x 297. mm) 1282334 A7 B7 V. INSTRUCTION DESCRIPTION (4 0C(0)R4 ; OP(〇)3h2 or N=CN(R,)2. The ring that makes up Q2 j is substituted and optionally substituted with a halogen, a linear or branched chain of a Cl-c4 group, a hydroxyl group, a methoxy group, a trifluoromethyl group, a trifluoromethoxy group, a cyano group or an amine group. J is a CrC4 linear chain. Or a branched alkyl derivative substituted with 1 to 3 substituents selected from A, -TC(0)R3_〇p〇3h2. A is selected from the group: R4

Ο

•T R4 R· NH2

T or the Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed T is 0 or NH. G is NH2 or 0H. Z is CH or N. For structural formulae I, II and III: R' is selected from hydrogen, (C"C3)-alkyl, (c2-c3)-alkenyl or alkynyl, phenyl or substituted with 1 to 3 substituents a phenyl group (each selected from the group consisting of _, methoxy, ammonia, nitro, amine, hydroxy, methyl or ethyl); or a heterocyclic ring system of 5 to 6 members, optionally 1 to 3 substituents each selected from the group consisting of γ, methoxy, cyanide, nitro, amine, hydroxy, methyl or ethyl. Ri is selected from hydrogen, (C "C3)-fe , 0H or a radical. R3 is an aromatic cyclic or heterocyclic ring system selected from 5-6 members. R4 is (C"C4)-alkyl, optionally substituted by n(R,)2. 0R,, -7- This paper scale applies to China National Standard (CNS) A4 specification (210 297 297 mm) ---*-----------------^---- ----— (Please read the note on the back? Please fill out this page again) A7 1282334 V. Invention description (5) 0: 〇211,, (:〇>1(尺,)2 or 3〇2&gt ;1(&2)2; a 5-6 membered aromatic cyclic or heterocyclic ring system, optionally with one (crC4) branched or linear alkyl group, N(R,) 2, OR ', co2r', con(r')2 or so2n(r2)2 is substituted; or one (-alkyl is desired as a 5-6 member aromatic ring, or a heterocyclic ring system as needed Substituted by a (CrC4) branched or linear alkyl group, N(R')2, OR', co2r*, CON(R')2 or S02N(R2)2K. R2 is selected from hydrogen, (CVC3) -alkyl or (cvco-alkenyl; each optionally with -N(R,)2, -OR*, SR*, -C(0)-N(R*)2, -S(02)-N (R,) 2, -C(0)-OR/ or R3 is substituted. One W is selected from Η; N(R2)S02-N(R2)2; N(R2)S02-N(R2)(R3) ; N(R2)C(0)-0R2 ; N(R2)C(0)-N(R2)2 ; N(R2)C(0)-N(R2)(R3); N(R2)C( 0)-R2; N(R2)2; C(0)-R2; CH(OH)-R2; C(0). N(R2)2; C(0)-0R2; or (CrC4) straight or The branched fluorenyl group is substituted with A, T-(CO)Rf, N(R')2, OR', c〇2R', CON(R')2, R3 or S〇2N(R2)2 or one as needed. The cyclic or heterocyclic ring system of 5-6 members is replaced by N(R')2, OR', C02R', CONCRJASC^NCR2) as needed. In another embodiment, the present invention provides a A pharmaceutical composition of the inventive p38 inhibitor. These compositions are useful for treating or preventing diverse heterogeneities (eg, cancer, inflammatory diseases, autoimmune disorders, destructive bone metaplasia, proliferative disorders, infectious diseases, viral diseases, and neurodegenerative disorders) method. These compositions are also useful in methods for preventing cell death and hyperproliferation, and are therefore useful for treating or preventing hyperemia/ischemic stroke, heart disease, and hypoxia. These compositions are also suitable for use in the prevention of thrombin-induced blood sap. Each of the above methods is a paper size standard (CNS) A4 specification for the paper scale of the present invention (21Q χ i i ----- (please read the phonetic note on the back side and then fill out this page). -------- Line _ Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperative Printed 1282334 A7 B7 Description of the Invention (Partially. The detailed description is such that the invention described herein can be described in (4). In this description , using the following terms. - ' This terminology ''Different (four), or "heterocyclic," refers to a stable 5-7 member of the early ring-shaped saturated or unsaturated heterocyclic ring, and if The shape may be benzene-fused as needed. Each __Lianyishan 7 is composed of one or more deuterium atoms and one to four heteroatoms selected from the group consisting of nitrogen and sulfur. As used herein, this Zheng language, nitrogen and sulfur heteroatoms, includes any oxidized form of nitrogen and stone and any tetravalent form of basic nitrogen. An anthracene ring group can be attached to cause a stable structure Examples of such a group of carbon or ^ atom 2 in any ring include imidazolyl, imidazolinyl Tetrahydroimidazolyl, hydroquinone, isohydroindenyl, fluorenyl, oxazolyl, oxazoline, hydroxamic, argon, pyridyl, pyrrolyl, pyrrolinyl, pyrrolidinyl , pyrazolyl, pyridinyl, quinolinyl fluorenyl, hexahydropyridyl, piperidyl, piperazolinyl, hexahydropyrryl, pyrimidinyl, pyridinium, morpholinyl, pyrazoline Base, furanyl, porphinyl, triazolyl, oxazolyl, sulfonyl, tetrazolyl, tetrahydrocarbazolyl, benzofuranyl, pyromorphinyl sulfone, carbazolyl, benzoxazole Keto, ketohexahydropyridyl, ketopyrrolyl, fluorenyl sulphate, sulphide sulphate, iso-4-propenyl, iso-p-propenyl, fluorenyl, tetrahydro- ethane , tetrahydrofuranyl, P-septyl, P-diazo, di-u-methyl, dioxinyl, oxazinyl, phenyldiphenyl, dithiol, thiophenyl, tetrahydrothiobenzene Base, cyclodecylalkyl, dioxanyl, didecylalkyl, tetrahydroethylenedihydrofurancarbyl, tetrahydropyranohydrofurancarbyl, double negative^-9- 'paper The scale applies to the Chinese National Standard (CNS) A4 specification 210 X 297 public) (Please read the notes on the back and fill out this page) Order---------Line | Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing • Bu 1282334 A7 Description (7), tetrahydrofuranylmercaptomethyl and tetrahydro, (iv): pharmaceutically acceptable salts" means a compound according to the invention derived from a salt of an acid or a base of a mining machine or organic Use in the form of a class. Examples of acid salts to be included are as follows: ^ Cow " Lower Acetate, Adipate, Brown Bath, Aspartate, Benzoate, Laugh, ^ 本飧铋Salt, bis-sulphate butyrate, citrate, camphor _ dark, culture with fine bismuth salt, camphor sulfonate, cyclopentyl propionate, bis-glucoside, dodecyl sulfate, rp, TI ant, Ethane sulfonate, fumarate, glucoheptanoate, glycerol phosphate, hemisulfate, heptanoate, hexose sulphate, hydrochlorohydrazine, hydrobromic acid, hydroiodine: acid, 2-hydroxyethyl sulfonate Acid salt, lactate, butyrate, methanesulfonate, naphthalenesulfonate, nicotinic acid salt, straw salt, bismuth citrate, pectate, peracid Salt, phenylpropionate, scented from paternal salt, dimercaptoacetate, propionate, succinate, tartrate, thiocyanate, toluene sulfonate and eleven sulfonium salt. Bamboo is derived from suitable salt tests including metal (e · g · nano), organic soil (e.g. magnesium), ammonium and NW4+ (where w is CrC4 alkyl). A physiologically acceptable salt of a hydrogen atom or an amine group includes a salt or an organic carboxylic acid (such as acetic acid, lactic acid, tartaric acid, malic acid, isosulfuric acid, lactobionic acid, and succinic acid); an organic sulfonic acid (such as methanesulfonate) Acid, ethanesulfonic acid, benzenesulfonic acid, P-toluenesulfonic acid) and inorganic acids (such as gas, sulfuric acid, phosphoric acid and aminesulfonic acid). Physiologically acceptable salts of a compound having a hydroxyl group include a combination of an anion of the compound with a suitable cation such as Na+, NH4+, NW4+ (wherein W is a CrC4 alkyl group). The pharmaceutically acceptable salts include organic carboxylic acids (such as ascorbic acid, acetic acid, citric acid, lactic acid, tartaric acid, malic acid, malic acid, isosulfuric acid. The paper scale applies to the Chinese National Standard (CNS) A4 specification (210 x 297 public) PCT — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — Consumer Cooperative Printing \ 1 1 1282334

5. Description of the invention (8 salts of lactobionic acid, P-amine benzoic acid and No. (4)); organic acid (such as sulfonic acid: alkanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid) and inorganic acid (heart palpitations) , sulfuric acid, phosphoric acid, amine sulfonic acid and pyrophosphoric acid). "For treatment, the salts of the compounds according to the invention will be pharmaceutically acceptable. However, it will also be found that the use of non-pharmaceutically acceptable acids and bases, for example, in the case of a pharmaceutically acceptable compound When produced or purified. 4 Preferred salts include the formation of self-acids, sulfuric acid, acetic acid, claric acid, citrate and ascorbate. 1 The term "chemically practicable" refers to a bond of atoms. Thus, each of the original chemical bonds is satisfied. For example, one oxygen atom has two bonds and one carbon atom has four bonds, which is chemically practicable. The term "tautomerism" refers to one of them. A phenomenon in which a proton of one atom of a molecule is transferred to another atom. See Jerry March,

Mechanisms and Fourth Edition, J〇hn Wiley & sons, pp. 69-74 (1992). This PP "mutual isomer refers to the compound produced by proton transfer. For example, when the compound of Ri in a formula is 〇H, the compound may exist as a tautomer as shown below:

CI

This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 public)

Fives,

Printed by the Intellectual Property Office of the Ministry of Economic Affairs, Staff Consumer Cooperatives A282334 A7 B7 Description of the Invention (9) The present invention provides a p38 inhibitor having a general structural formula

II, and

, q2 111, or a pharmaceutically acceptable hoof thereof. For compounds of formula I and oxime: ^ ^HET is a 5-7 member heterocyclic ring with an N, s or 〇 atom, which is 1 to 3 c "C4 branched or straight chain Substituted by a burn group. HET is optionally substituted by halogen, cyano, N(R,)2, 〇R, c〇2R, c〇N(R,)2 and so2n(r2)2. 0 or NR*. η is 1 to 3. With respect to the compound of formula III: each of Q1 and Q2 is an aromatic cyclic or heterocyclic ring system each selected from 516 members, or 8 _ 成员 Members contain an aromatic cyclic ring 'aromatic heterocyclic ring or an aromatic ring ring _ -12- This paper scale applies to China National Standard (CNS) A4 Specifications (21〇X 297 mm)

Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative 1282334 A7 B7 V. INSTRUCTIONS (10) A double-ring system of a combination of a substance and an aromatic heterocyclic ring. The 5 garments constituting Q 1 are optionally substituted by 1 to 4 substituents, each of which is individually selected from J; halogen; optionally substituted with Nr, 2, 0R, c〇2r, or CONRf2 Substituting 0-((^-(^4)-alkyl; NR'2 for a, TC(〇)R,, 〇P03H2, NR'2, OR', C02R' or CONR'2 as needed ; 0CF3 ; CF3 ; N02 ; C02R,; CONR 丨; SR,; S(02)N(R')2 ; SCF3 ; CN ; N(R')C(0)R4 ; N(R')C(0 ) 0R4 ; N(Rf)C(0)C(0)R4 ; N(R')S(02)R4 ; NiR*)^ ; N(R4)2 ; OR4 ; 0C(0)R4 ; 0P(0 3H24N=CN(R,:r2. The ring constituting Q2 is substituted with J, and if necessary, a halogen, C!-C4 linear or branched alkyl group, hydroxyl group, methoxy group, trifluoromethyl group, three Substituted by fluoromethoxy, cyano or amine. J is a C"C4 linear or branched alkyl derivative with 1 to 3 selected from A, -TC(0)R' or -OP〇3H2 Substituted by a substituent. A is selected from this group: R4 〇

T is 0 or NH. G is NH2 or 0H. Z is CH or N. -13- This paper size applies to China National Standard (CNS) A4 specification (210x2^7·publicity); ------- order--------- line (please read the back note first) 1⁄2 write this page) 1282334 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7 V. Description of invention (for structural formulas I, II and III: R' is selected from hydrogen, ((VCD-alkyl, ( (VC3)-alkenyl or alkynyl, phenyl or substituted with 1 to 3 substituents (each selected from halogen, methoxy, cyanide, nitro, amine, hydroxy, methyl or ethyl) Phenyl; or a 5 _ 6 member of the ring-shaped ring system, if desired, from 1 to 3, each selected from the group consisting of dentate, decyloxy, cyanide, nitro, amine, hydroxy, decyl or Substituted by a substituent of the group I is selected from hydrogen, (CVC3)-alkyl, 0H, or an alkyl group. R3 is an aromatic ring-like or heterocyclic ring system selected from 5-6 members. (CVCd-alkyl is optionally substituted with n(r,)2, 〇R, c〇2R, CON(R')2 or S〇2N(R2)2; a 5-6 member aromatic ring a ring-shaped or heterocyclic ring system, optionally with a branched or linear alkyl group, N(R')2, OR', C02R' , (:0Ν(β;)2 or S02N(R2)2 is substituted; or one (CrC4)-alkyl is required to have a 5-6 member aromatic ring, or a heterocyclic ring system as needed A (CrC4) branched or linear alkyl group, N(R')2, OR1, C02Rf, C0N(R')^S02N(R2)2 is substituted. R2 is selected from hydrogen, ((VC}alkyl) Or (cvq)-alkenyl; each optionally with -N(R,)2, -OR', SR', -C(0)-N(R,)2, -S(02)-N(Rf 2, -C(〇)-0R' or R3 is substituted. W is selected from H; N(R2)S02-N(R2)2; N(R2)S02-N(R2)(R3); N(R2 )C(0)-0R2 ; N(R2)C(0)-N(R2)2 ; N(R2)C(0)-N(R2)(R3); N(R2)C(0)-R2 ; N(R2)2 ; C(0).R2 ; CH(0H)-R2 ^ C(0)- N(R2)2 ; C(0)-0R2 ; or (CVC4) straight or branched alkyl Replace with A, T-(C〇)R, N(R,)2, 〇R, c〇2R, C0N(R')2, R3 or -14-^ Standard (CNS) A4 specification (210 X 297 mm)

Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 1282334 A/ B7 V. Invention Description (12) S02N(R2)2 or a 5-6 member aromatic ring or heterocyclic ring system as needed N(R) , ) 2, OR', C02R, CON(R,)2 or S02N(R2)2 is substituted. According to a preferred embodiment, (^ is selected from a phenyl or pyridyl group having 1 to 3 substituents, wherein at least one of the substituents is in the ortho position and the substituent is each selected from the group consisting of chlorine and fluorine. , bromine, -CH3, u〇CH3, ·0Η, -CF3, -OCF3, -0(CH2)2CH3, NH2, 3,4-decylenedioxy, -N(CH3)2, -NH-S( 〇) 2-phenyl, -NH-C(0)0-CH2-4-pyridine, -NH-C(0)CH2-morpholine, -NH-C(0)CH2-N(CH3)2 -NFI-C(0)CH2-hexahydropyridine, -NH-C(0)CH2-^:rolidine, -NH-C(0)C(0)-morpholine, -NH-C(0) C(0)-hexahydropyridine, -NH-C(0)C(0)-pyrrolidine, -0-C(0)CH2-N(CH3)2- or -0-(CH2)2-N ( CH3)2 〇 even more preferred is that at least two of the substituents listed above are phenyl or pyridyl at the ortho position. Some specific examples of preferred Qi are:

-15- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page)

---------Book --------- Line I 1282334 A7 B7 V. Description of invention (13)

OCH3 0CH3 Please read the back of the note first.

OCH3

0CH3

Order

Printed by the Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative H3<

H3« f H3 c 6

This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1282334 A7 _B7 V. Invention description (14 ) OCH3

This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1282334 A7 B7 V. Description of invention (15)

CI 〇一

(Please read the notes on the back and fill out this page)

Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumption Cooperative, Printed Clothes

Most preferably, Q! is selected from the group consisting of 2-fluoro-6-perfluoromethylphenyl, 2,6-bisfluorophenyl, 2,6-dichlorophenyl, 2-ox-4-hydroxyphenyl, 2-Chloro-4-aminephenyl, 2,6-bis-cyclo-4-aminophenyl, 2,6-bis-o-3-aminophenyl, 2,6-bismethyl-4--18- The paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) --------^定--------- 1282334

Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Printing 5, Invention Description (π) I Fengji, 2·Methane-3,5-Dual Gas-4-ρ Ratio, 2-Chloro-4,5-Asia Methyldioxyphenyl or 2-chloro-4-(N-2-morphine-acetamidoamino)phenyl. According to a preferred embodiment, Q2 is a phenyl or pyridyl group, wherein the phenyl or pyridyl group contains a substituent J and hydrazine to 3 other substituents, wherein each of these other substituents is independently selected from chlorine , fluorine, bromine, methyl, ethyl, isopropyl, -OCH3, -OH, -NH2, -CF3, -〇CF3, -SCH3, -〇ch3, c(o)〇H, -c(o) Och3, -CH2NH2, -N(CH3)2, _CHr pyrrolidine and -CH2OH(R) For those skilled in the art, the compounds of the invention are apparently present as tautomers. These tautomers may be temporary or separable into a stable product. These tautomers are intended to be encompassed within the scope of the invention. These compounds are also p38 inhibitors and are included in the scope of the invention. For those skilled in the art, when the z of the compound of formula m is CH, it is apparent that a polarizing compound is formed. In this example, both enantiomers are encompassed within the scope of the invention. According to a preferred embodiment, R^H, ^丨, and het is an imidazole, triazole, pyrazole, oxazole, pyridine substituted with 1 to 3 Ci-C4 branched or linear alkyl groups. Or a pyrimidine ring. According to a better embodiment, R is Η, n has]τττ^^ σ . 疋, η疋1, and HET is one

The Ci-C3 group replaces the miso or p-precipitate ring. According to the particularly good embodiment of Chemical Formula I,

1282334 A7 B7 V. Description of invention (17)

N

Compound 1 2, Compound 1 3, and Please read the back of the compound 1 1

Item write this page

I I I I I Compound 14. According to the specialization of Chemical Formula III, the Ministry of Economic Affairs’ Intellectual Property Bureau’s staff consumption cooperative prints clothes.

and

^rc

Compound 1 6 -20-

Deaf, Compound 1 7 This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1282334

V. INSTRUCTION DESCRIPTION OF THE INVENTION (18) According to another embodiment, the present invention provides a method of making the above identified P38 inhibitor of chemistries and II. A method for making a compound hydrazine is shown in Example 1. The activity of the P38 inhibitor of the present invention can be tested in vitro, in vivo or in a cell line. In vitro assays include tests that determine inhibition of protein activase activity or inhibition of activated P38 ATPase activity. Interactive in-vitro test = ability of the inhibitor to bond to P38 and measure: the radiolabel is applied to the inhibitor bond, then the inhibitor/p38 complex is separated and the amount of radiolabeling of the bond is determined Or a competitive assay in which a new inhibitor is incubated with p3 8 that is bound to a known radioligand. The cell culture assay for the inhibitory effect of the compounds of the invention can be used to determine the amount of TNF, H, 匕^ or 制造^ produced in whole blood or cell fraction, and the cells treated with the inhibitor and the cells treated with the negative control Comparison. An in vivo test suitable for determining the inhibitory activity of the p38 inhibitor of the present invention is inhibition of foot edema after adjuvant arthritis caused by Mycobacterium tuberculosis in mice. It is described in j. C. Boehm et al., J. Med. Chem. « 39, ρ ρ 3929-37 (1996), the disclosure of which is incorporated herein by reference. This disclosure is incorporated herein by reference. The ρ38 inhibitor of the present invention can also be described by 关节炎·Μ· Badger et al., J, Pharmacol. Experimental Therapeutics. 279, pp. 1453-61 (1996) for arthritis, bone resorption, endotoxic shock and immunity. Animal model experiments, the disclosure of which is incorporated herein by reference. • The p38 inhibitor or a pharmaceutically acceptable salt thereof can be formulated into a pharmaceutical composition for administration to an animal or human. These pharmaceutical compositions (including an effective serving size - 21 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm (please read the phonetic on the back? Please fill out this page) ----- ---Order---------Line. Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1282334 A7 B7 V. Invention Description (19) P38 inhibitor for treatment or prevention ~ P38-regulation And a medically acceptable carrier is another embodiment of the present invention. This item 黉p3 8 - regulation situation " soil ^ p j. , , 吏 used herein means any disease or other known The role of p38 in the role of ^ ^ TNF, m Ge IL-W system ^ f ^ condition. 14 contains the situation caused by 1L · 1, W. These conditions include, but are not limited to, inflammatory disease, ^ Tian Rain, autoimmune diseases, destructive bones, abnormal hyperplasia, salty stains, ^, ~, schizophrenia, neurodegenerative diseases, allergies, hyperemia / ischemic shock, dysfunction / U dirty, blood vessels Sexual abnormalities, organ hypoxia, blood stagnation, cardiac hypertrophy, coagulation ^ ^ ϋ ^ fresh-induced platelet aggregation and About the case of peroxidase synthetase-2 in serotonin. Inflammatory diseases that can be treated or prevented include pancreatitis, chronic pancreatitis, asthma, heart sore group, and allergies and adult respiratory distress syndrome. Autoimmune diseases that can be (4) or prevented include, but are not limited to, renal glomerulonephritis, rheumatoid arthritis, whole body, ^ ^ . Royal lupus erythematosus, cutaneous sclerosis, spastic thyroiditis, convex line Human ocular thyroid disease, autoimmune gastritis, sugar = blood anemia, autoimmune neutropenia, =:; atopic dermatitis, chronic active hepatitis, severe myopathy / benign colon Inflammation, localized recanal dog, cognac or graft vs host disease. Destructive orthopedics that can be treated or prevented U hang U 'but not limited to osteoporosis, osteoarthritis and multiple myeloma-related Bone abnormalities. Proliferative disease abnormalities that can be treated or prevented include, but are not limited to, acute myeloid leukemia, chronic myelogenous leukemia, metastatic melanoma, 22- This paper scale applies to Chinese national standard (CN) S) A4 size (210 X 297 mm 1282334 A7 V. Invention description (2〇) Kaposi's tumor and multiple hair tumors. Vascular abnormalities that can be treated or prevented include tumors, ocular neovascularization, infants Infantile hemangioma. Infectious diseases that can be treated or prevented include septic, septic shock and Shigella. Viral diseases that can be treated or prevented include hepatitis infections (including hepatitis A, hepatitis B and hepatitis B). CMV retinitis. < Heart, wood, neurodegenerative diseases that can be treated or prevented by the compounds of the invention include, but are not limited to, neurodegenerative diseases caused by Alzheimer's disease, Parkinson's disease, and brain injury . / ’’P38-regulations" also include hyperemia/ischemic shock, heart disease, blood, organ hypoxia, vascular hyperplasia, and small plate aggregation. ~Dirty hypertrophy and thrombin-induced blood:: Two p38 inhibitors in the present invention can also inhibit pre-inflammation of protein _ 发 蛋白 ,, such as prostaglandin peroxidase synthetase 2 (pGH: refers to cyclooxygenase-2 (C0X_2) performance. Because &, other, state two " brother: is edema, pain, fever and pain, such as neuromuscular pain; 蹋, cancer-induced pain, toothache and joint pain. = The disease treated or prevented by the p38 inhibitor of the present invention can also be conveniently referred to as the cytokine corresponding to the disease], coffee, il_6, several seven and two: 1: ΓΤ: t disease or love? Rheumatoid arthritis, bone man stroke, endogenous nephroemia and/or toxic shock syndrome, endotoxin but not limited to, solid swelling but not limited to, but not limited to, acute order 23- paper scale tWii?B7s)A4 specification curry 297 public) I282334

Description of the invention (21, inflammatory bowel disease, tuberculosis, atherosclerosis, muscle atrophy, ^ disease, dry arthritis, Reiter's syndrome, gout, traumatic Guan Langyan, wind wire joints, acute slip Membrane inflammation, diabetes, pancreatic cell disease, and inflammatory response caused by Alzheimer's disease. TNF-regulated diseases or conditions include rheumatoid arthritis, rheumatoid spondylitis, #arthritis, gout Arthritis and other joint conditions: septicemia, septic shock, endotoxic shock, Gram-negative septicaemia, toxic shock syndrome, adult respiratory distress syndrome, cerebral dysentery, chronic pulmonary inflammatory disease, sedative (4) Tumor, bone resorption, congestion, injury, graft vs host response, allograft rejection, fever and infection caused by myasthenia gravis, cachexia secondary to infection, aids, or malignancy, tumor formation,疤 tissue formation, local ileitis, ulcerative colitis or fever. TNF-regulated diseases also include viral infections such as HIV, CMV, colds and cancer rash; and beast disease viruses Infections, such as lentiviral subfamily infections, include, #not limited to horse-infected anemia virus, sheep arthritis virus, sheep demyelinating leukoencephalitis virus or sheep lung adenoma virus; or retrovirus infection (including Cat immunodeficiency virus, bovine immunodeficiency virus or dog immunodeficiency virus.) IL-8 dying diseases or conditions include diseases characterized by large invasive leukocyte infiltration, such as dryness, inflammatory bowel disease, asthma, Cardiac and renal congestive injuries, adult respiratory distress syndrome, thrombosis, and renal glomeruli. In addition, the compounds of the present invention are used topically to treat or prevent conditions caused or exacerbated by chemotherapy or TNF. Such conditions include inflamed joints, -24- The paper size is over the 圑 圑 圑 UN UN (UNb) A4 specifications (210 X 297 public love) C Please read the phonetic transcription on the back? Please fill out this page) -------- --------- Line Age Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1282334

V. DESCRIPTION OF THE INVENTION (22) Eczema, dryness, inflammatory eye conditions such as sunburned inflammatory skin and other inflammatory conditions associated with inflammation, other than the compounds of the present invention Medically acceptable. The pharmaceutically acceptable salts of the compounds of the present invention which are recognized by the oral therapy or the prevention of the above include those derived from medically acceptable inorganic and organic acids and bases. Examples of suitable acid salts include: salt: salt, adipate, alginate, aspartate, benzoic acid, salt, disulfate, acid salt, citrate, camphoric acid^樟 铋 sulfonate, cyclopentyl propionate, digluconate, dodecyl sulfate, ethane sulfonate, formaldehyde salt, butyl---" Liding 埽 铋 salt, glucose octanoic acid Ministry of Economics Property Bureau employee consumption cooperative printing solitary, glycerol phosphate, glycolate, hemisulfate, heptanoate, hexanoate, hydrogen acid, hydrobromic acid, hydroiodic acid, 2-hydroxysulfonate, lactic acid Salt, cis enedionate, malonate, methane sulfonate, 2-naphthalene sulfonate, saponin, nitrate, oxalate, palmitate, pectate, over Sulfate, 3-phenylpropionate, phosphate, picrate, trimethylacetate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, sulfonate Citrate and eleventh salt. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, can be used in the manufacture of a salt suitable for use as an intermediate product to obtain a compound of the invention and a pharmaceutically acceptable, parent-added salt thereof. Derived from suitable basic salts include alkali metals (e g • sodium and clock) 'scientific soil metals (e.g. magnesium), ammonium too N-(CrC4 alkyl) 4+ salts. The invention also encompasses an organic nitrogen-containing tetra-based structure of any of the compounds disclosed herein. Water-based or oil-soluble or dispersible products can be obtained by this four-based method. - This paper scale applies to the Chinese National Standard (CNtS) a4 specification (210 X 297 mm 1282334 A7 _____B7__ V. Inventions (23) (Read first Precautions on the back side of this page) Pharmaceutically acceptable carriers for pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (eg humans) Serum albumin), buffer substances (such as phosphate, glycerol, sorbic acid, potassium sorbate, partial glycerin mixture of saturated vegetable fatty acids), water, salt or electrolytes (such as protamine sulfate, double steel nitrogen salt, Potassium hydrogen phosphate, sodium chloride, zinc salt, tannin, magnesium tridecanoate, polyvinylpyrrolidine), cellulose-based material, polyethylene glycol glycerol, sodium carboxymethyl cellulose, polyacrylate, wax Quality, polyethylene _ polyoxypropylene - block polymer, polyethylene glycerin and lanolin. The composition of the present invention can be administered orally, intravenously, spray inhalation, salivary, rectal, nasal, annoying of Transvaginal or via _ implanted storage, etc. The "venous" used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intraspinal, Intrahepatic, intralesional, intracranial, etc. injection or incorporation techniques. Preferably, the composition is administered orally, intraperitoneally, and intravenously. The Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, prints the sterilizable injection of the composition of the present invention. The form is a suspension in the form of water or oil. 1. These suspensions are prepared according to the techniques known in the art using suitable dispersion or (iv) agents. The bacteriostatic injectable preparation can also be a non-toxic vein. An injectable solution or suspension of an acceptable diluent or solvent (eg, a solution of 3 butyl alcohol). Among these acceptable morphing agents and solvents, water- 疋 格 格 格 格Isotonic sodium solution. In addition, sterile water, Anding Temple emulsification or - medium. For this purpose, any brand of stabilizer oil includes synthetic -26 paper size 顾 _ home standard (CNSM4 specification (210 X 29 ^?!" 1282334 A7 B7 V. Inventive Note (24) Mono- or di-glycerides. Fatty acids, such as oleic acid and its glycerol derivatives, are suitable for the manufacture of injectables, as are natural pharmaceutical-acceptable fats (such as eucalyptus oil or Castor oil), especially in the form of their polyoxyethylation. This oil liquid or suspension may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar, commonly used in medicine. Dispersing agents formulated in acceptable dosage forms (including emulsifiers and suspending agents). Other commonly used one-sided agents, such as Tween, Span, and other emulsifiers commonly used in pharmaceutically acceptable solid, liquid or other dosage forms. Reagents or bioavailability modifiers can also be used to achieve the printed print. The pharmaceutical composition of the present invention can be orally administered at any orally acceptable dosage (including, but not limited to, 'capsules, tablets, aqueous suspensions or solutions^. In the case of tablets for oral use, f-coated lactose And corn starch. Lubricants, such as magnesium stearate, are also blood-supplemented with gum (4), "Applicable (4) release agents include ^ and = Yu Yu Dian powder. When aqueous suspension is required to be orally emulsified and suspended The agent may be added, if necessary, the sexual coloring agent may also be added. Right, some sweeteners, flavors or alternatively, the pharmaceutical composition of the present invention may be a suppository. These may be mixed with the reagent and a suitable one. It is made by intestines (in the form of a solid at a temperature, and a liquid at the temperature of the rectum, so it is prepared by dissolving and releasing the drug). This material is 直=straight fine polyacetyl glycerin. T ^, beeswax and the invented pharmaceutical composition can also be locally applied to the target inclusion area or to the local organs that are not allowed to be treated, including the paper size standard (CNSM4 f Please read the phonetic transcription on the back first. Matters then fill out this page}

--------Book --------- Line I Economics and Intelligence Bureau of Bureau of Labor and Expenditure Cooperation Cooperative Printing 27- 1282334

5. Description of the invention (25) or pain in the lower intestinal tract. Suitable topical formulations are readily made for each of the & fields or organs. Bottom: The topical application of the tract can be achieved with a colonic agent formulation. Topical _ percutaneous (four) drugs can also be used in the second round: application of 'pharmaceutical compositions can be formulated into a combination of ointments containing ::= on the active ingredient of the species or carriers. The present invention: The carrier of paeoniflorin includes, but is not limited to, mineral oil liquid, dicalcium, propylene carbonate, polyoxypropylene, polyoxypropylene, and water. The alternative 'pharmaceutical compositions can be formulated to be dissolved in one or more pharmaceutically acceptable carriers or creams. Suitable carriers include, but are not limited to: n, sorbitan monostearate, polysorbate 60, decantil, _alcohol, 2 octyldodecanol, benzyl alcohol and water. The pharmaceutical composition can be formulated into an isotonic suspension of fine particles of sputum sputum, or, preferably, an isotonic and sterilized saline solution. The solution can be stored in the presence or absence of ammonium. Alternatively, ..., "卞, several formulated into a kind of ointment such as soft paraffin: Shao application, pharmaceutical composition can also be a nasal spray or a physiological saline solution, using benzene heart::: :: Γ 吸收 absorption enhancer to enhance bioavailable #, fluorocarbon: two melting or dispersing agent. Eight he traditionally -28- U82334 A7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing five, invention description (26) : The combination of the carrier materials to produce a single-dose form of p38 inhibition: 1 depending on the particular mode of treatment and the specific mode of administration. Preferably, the composition of the W composition should be formulated as an inhibitor at a dose of 001_100 mg/ It is recommended to know the specific dosage and the reading method of any particular patient, including the activity, age and weight of the specific compound used. , health status, gender, diet, time of administration, rate of discharge, composition of the drug, and judgment of the treating physician and the severity of the particular disease being treated. The amount of inhibitor is also considered . Depending on the particular compound according to the other of eight, the present invention provides methods of treating or preventing a p38- regulated square case 4, it contains "an L-described pharmaceutical composition to the drug only Man - a step of suffering from the disease. The "patient" used herein refers to an animal, preferably a person. Preferably, the method is used for treating or preventing a disease selected from the group consisting of an inflammatory disease, an autoimmune disease, a bone-breaking bone abnormality, a hyperplastic abnormality, an infectious disease, a disease, a degenerative disease, an allergy, a hyperemia/ischemic shock. , heart disease, blood abnormalities, organ hypoxia, vascular hyperplasia, cardiac hypertrophy, thrombocytosis caused by platelet aggregation. According to another embodiment, the inhibitor of the invention is used to treat or prevent a disease or condition modulated by 1-1, IL-6, IL-8 or TNF-. The description of the situation is as above. Depending on the particular condition of the heart to be treated or prevented, an additional drug that is normally administered with 'oral therapy or preventing this condition can also be used together with the inhibitor of the present invention. For example, 'chemotherapeutic agents or other anti-proliferative agents can be combined with the p38 of the present invention (please read the notes on the back and fill out this page) -------- order-----

I n HI | __- 29 - This paper size applies to Chinese National Standard (CNS) A4 specification (21〇X 297 public love; 1282334 A7 B7 5. Invention description (27) Formulation combined to treat proliferative diseases. The portion of the multiple dose therapy is administered separately from the composition containing the p38 inhibitor. Alternatively, the agents may be part of a single dosage form, mixed with the 3 8 inhibitor in a single composition. The following examples are set forth to provide a more complete understanding of the invention as described herein. These examples are intended to be illustrative only, and are not intended to limit the invention in any way. Preparation no2

H2S〇4/HOAc/H2〇 CuBr/HBr(aq) 40% C, "T" C 丨 NaN02 60°C NH2

100 ° C

Cl

Ci Br 90%

O cr

K2CO3/DMF 50°C O/N

2 H2S04(conc)/HOAc/H20 Reflux 125bC 5 h Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

EtOH/SnCI2/HCI(conc)

I I ϋ I I-0, I ϋ» I i I ϋ I (please read the notes on the back first ^^ write this page) % Writer

N=N 1) 2 eq t-BuOK/THF· 60oC. 30 min

-30- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1282334 A7 ---------B7 Five 'Inventions (28) 0

F 90% 11 Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, Printing and Disposal Compound 1 is dissolved in a solution of concentrated sulfuric acid and glacial acetic acid (1:4) in a ratio of 1 · 20 . Aqueous NaN02 was added dropwise to the solution over two hours. The reaction mixture was stirred at 60 ° C for one hour. This solution was transferred to an aliquot of CuBr and a three aliquot of HBr (the concentration of HBr was 48%) in 100 Torr. The reaction mixture was stirred at 1 ° C for one hour. This reaction mixture was poured into ice. Compound 2 was filtered by precipitation and further purified by chromatography. The yield of Compound 2 was 99%. An aliquot of Compound 2 and an aliquot of methyl cyanoacetate are dissolved in dimethylmethionine (DMF). A second aliquot of 20: 〇3· at 5 (TC was added to this DMF solution. The reaction mixture was stirred at 50 ° C overnight. The reaction mixture was poured into L HC 1 / crushed ice bath. Compound 3 was precipitated by filtration and used directly. In the next step -31 · ^ paper scale application of the Central Standards (CNS) A4 specification (210 X 297 public) A7 1282334 V, invention description (29), the yield of compound 3 is 90%. a solution of 5 % concentrated sulfuric acid, 47.5% acetic acid and 47.5% water. The reaction mixture was stirred at 125 ° C for five hours. The reaction mixture was poured into a large amount of crushed ice. Compound 4 was filtered by filtration and used directly without further purification. Next step. The yield of compound 4 was 90%. Compound 4 was suspended in ethanol. Concentrated HCl containing 4.5 aliquots of SnCl2 was added at 75 ° C. The reaction mixture was refluxed at 75 ° C for 3 〇 minutes. Thin layer chromatography (TLC) indicated that the reaction was completed. The reaction solution was cooled to room temperature. The precipitate was filtered, dissolved in ethyl acetate, and then rinsed with saturated K.sub.2 C.sub.3 and NaCl. Obtained pure compound 5 with a yield of 90%. Compound 5 was mixed with an aliquot of 3,6-dichloropyridinium P in 6 (rc dissolved in tetrahydrofuran (THF). A two aliquot of t-butyl light potassium was added. The reaction mixture was stirred at 60 ° C. One hour. Saturated NaC1 and ethyl acetate were added to the reaction mixture. The pH of the aqueous phase was adjusted to 7 with HCl and extracted with ethyl acetate. The organic phase was washed twice with saturated NaCl and dried with MgSO 4 . The falling agent was removed. Compound 6 was purified by chromatography and the yield was 6 %. A solution of 2,4-difluorothiobenzene was added to 〇_5χ: this suspension was 欣-5°. C is stirred until no more bubbles are released and the reaction mixture becomes a clear solution. This solution is then warmed to 6 (rc. Compound 6 is at 6 Torr. (: This solution is added. This reaction is refluxed to TLC to indicate the depletion of compound 6 Saturated NaCl and ethyl acetate were added to the reaction mixture. The organic phase was washed twice with saturated (d) and dried over MgSO4. 〇〇/0. (Please read the notes on the back and fill out this page) --------Book --------- Line | Ministry of Economic Affairs Intellectual Property Bureau employees Printed cooperatives

1282334 A7 B7 V. Description of the Invention (3〇) A toluene solution of Compound 7 and aldehyde 8 were refluxed for 24 hours. The resulting imine is purified by chromatography, dissolved in anhydrous decyl alcohol and reduced to the amine 9 with NaBH4 and in the presence of a catalytic amount of acetic acid. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was removed under a hollow, and the crude amine was stirred in a concentrated sulfuric acid solution at 30 ° C. Indole 10 precipitated from a NaCl/crushed ice bath, filtered and used directly in the ring closure step. Indoleamine 1 is dissolved in THF. Excess DMF-DMA was added to this solution. The reaction solution was stirred at 70 ° C for one to two hours. The product 1 1 was purified by crystallizing from ethyl acetate. Example "2 p38 Protein Activase Enzymes in Insect Cells Two conjugative variants of human p38 protein activase, CSBP1 and CSBP2, have been identified. The coding region of the CSBP2 cDNA was amplified using a special oligonucleic acid primer using a HeLa cell library (layered gene) as a chessboard. The polymerase chain reaction product was cloned into the pET-15b vector (Novagen). The baculovirus transfer vector pVL-(His) 6-p38 was constructed by sub-selecting a Xbal-BamHI fragment of pET15b-(His) 6-p38 into the complementary position of plastid pVL 1392 (Pharmingen). The plastid pVL-(His) 6-p38 indicates the synthesis of a recombinant protein that is fused by a group of 23-residues fused to the N-terminus of p38 (MGSSHHHHHHSSGLVPRGSHMLE, where LVPRGS represents a thrombin break The position consists of, for example, the DNA sequence and the N-terminal sequence of the expressed protein. A single culture layer of S. serrata (Sf9) insect cells (ATCC) was kept at 27 ° C in a T-flask of TNM-FH medium (Gibco BRL) containing 10% fetal calf serum. Sf9 cells are applied to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) % in the logarithmic stage at the logarithmic stage (please read the notes on the back and fill out this page) --- -------- £9 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1282334 A7 B7 V. Description of Invention (31) Pharmingon's linear virus DNA and the use of lipoprotein ( The transfer vector pVL_(His) 6-p38 of Up〇fectin) co-transfers infection. This individual recombinant baculovirus was purified by plate method using 1% low resolution medium. Example 3 Expression and Purification of Recombinant P38 Protein Activase Enzymes of T. sylvestris (Tn-3 68) High·5TM Cells (Invitrogen) were grown at 27 ° C, ExceM〇5 protein-free medium (JRH Bioscience) suspension Shake the flask. The cells were subjected to a multi-infection of 5 with a density of 1·5 X 106 fine-cell/ml as described above for the recombinant baculovirus infection. The expression level of recombinant p38 was followed by immunoblot identification using a rabbit anti-p38 antibody (Santa Cruz Biotechnology). Cell quality was harvested when the expression level of p38 was maximal at 72 hours after infection. Frozen cell paste from expressed (His) 6-calibrated p38 cells in five times the amount of buffer solution A (50 mM NaH2P04 pH 8.0, 200 mM NaCl, 2 mM thiol alcohol, 1% glycerol and 〇2 mM PMSF) thawed. After the cells were mechanically disrupted by a microfluidizer, the lysate was centrifuged at 30,000 x g for 3 minutes. The supernatant was incubated with Talon (Clontech) metal affinity resin in batches of 4 ml per 2 - 4 mg of expected P38 for 3 - 5 hours. The resin was precipitated by centrifugation at 500 X g for 5 minutes and gently rinsed with buffer solution A in batches. The resin was treated in suspension and poured into a column (approximately 2·6 & 5.〇 centimeters) and rinsed with buffer solution Α + 5 mM imidazole. This (His)6_p38 is flushed out with buffer solution A + 100 mM imidazole and subsequently applied to 2 liters of buffer solution B (50 mM HEPES, pH 7.5, 25 mM /?- Gan-34- this paper scale applies to Chinese national standards (CNS) A4 specification (210 297 297 mm) (Please read the note on the back and fill out this page) Printed by the Intellectual Property Office of the Ministry of Economic Affairs

Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1282334 A7 B7 V. Description of the Invention (32) Oil sulphate '5 % glycerol' 2 mM DTT) was dialyzed overnight at 4 °C. This His6 calibration was removed by adding 1.5 units of thrombin per mg of p38 (Calbiochem) and incubating at 20 PC for 2-3 hours. This thrombin was stopped by the addition of 0.2 mM PMSF, and this complete sample was then placed on a 2 ml benzamidine agarose (American International Chemical) column. The fractionated stream was directly placed on a 2.6 X 5.0 cm Q-Joint Sugar Gel (Pharmacia) column equilibrated with buffer solution B + 0.2 mM PMSF. P38 was eluted with a 20-fold column volume containing a linear gradient to 0.6 M NaCl in buffer solution B. The released protein spikes were pooled and dialyzed overnight at 4 °C with buffer solution C (50 mM HEPES, pH 7.5, 5% glycerol, 50 mM NaCl, 2 mM DTT, 0.2 mM PMSF). The dialyzed protein was concentrated to 3 - 4 ml in a Centriprep and placed in a 2·6 X 100 cm Sephacryl S-100HR (Pharmacia) column. This protein was released at a flow rate of 35 ml/hr. This major spike was pooled, adjusted to 20 mM DTT, concentrated to 10-80 mg/ml and chilled to -70 °C in aliquots or used immediately. Example 4 Activation of p38 p38 was activated by binding 0.5 mg/ml P38 with 0.005 mg/ml DD-double-variant MKK6 in buffer solution B + 10 mM MgC12, 2 mM ATP, 0.2 mM Na2V04 for 30 minutes at 20 °C. The activation mixture was then placed on a 1.0 x 10 cm MonoQ column (Pharmacia) and released in a 20 column volume containing a linear gradient to a buffer solution B of 1. 〇 μ NaCl. Activated p38 is released after ADP and ATP. This activated p38 spike-35- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm), --------- - -----------^ — — — — — — — I— (Please read the notes on the back and fill out this page) A7 1282334 B7_ V. INSTRUCTIONS (33) Collected and dialyzed against buffer solution B + 0.2 mM Na2V〇4 to remove NaCl . The dialyzed protein was adjusted to 1 · 1M potassium phosphate by adding a 4.0 Μ stock solution, and the device was first equilibrated with buffer D (10% glycerol, 20 mM glycerol phosphate, 2.0 mM DTT) + 1.1M K2HP〇4 On a 1.00 x 10 cm HIC (Rainin Hydropore) column. The protein was released in a 20-fold column with a linear gradient to buffer solution D + 50 mM Κ2ΗΡ04. This double phosphorylated p38 was released as a main spike and pooled with a buffer solution B + 0.2 mM Na2V04. This activated p38 was stored at -70 °C. Example "5 p3 8 inhibitory reagent A. EGF receptor peptide phosphorylation inhibition This assay is in 10 mM MgCl2, 25 mM /?-glycerophosphate, 10% glycerol and 100 mM HEPES buffer solution (pH 7.6) Appears to proceed. For the purpose of a typical IC5G decision, a stock solution containing all of the above ingredients and activating ρ38 (5 ηΜ) was prepared. This raw material solution was equally divided into glass bottles. A fixed amount of DMS0 or inhibitor-containing DMSO (DMS0 at a final concentration of 5% of the reaction) was added to each vial, mixed and incubated for 15 minutes at room temperature. The EGF acceptor is a phosphorylation receptor in the protein activation enzyme reaction of KRELVEPLTPSGEAPNQALLR, ρ38- 匕4匕, added to each glass bottle to a final concentration of 200 μΜ. This protein activates the enzyme reaction with ΑΤΡ (100 "Μ) and the glass bottle is cultured at 30 °C. After 30 minutes, the reaction was stopped with an equal amount of 10% trifluoroacetic acid (TFA). This _acidified peptide was quantified by HPLC analysis. The acidification of the citrate is separated from the unphosphorized peptide by a reverse phase column (Deltapak, 5 " m, -36- This paper scale applies the Chinese National Standard (CNS) A4 specification (210 297 297 mm) (Please read the notes on the back and fill out this page) --------Book --------- Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1282334 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employees Consumer Cooperatives Printed V. Inventions (34)

Cl8 100D, part number 01 1795) was achieved with a binary gradient of water and acetonitrile (each containing 0.1% TFA). The ic5G (concentration at which the inhibitor produces 50% inhibition) is determined by the remaining % activity indicated by the concentration of the inhibitor. B · Inhibition of ATPase activity The specific test was carried out in the presence of 10 mM MgCl2, 25 mM /?-glycerophosphate, 1% glycerol and 100 mM HEPES buffer solution (pH 7.6). For a typical Ki decision, the Km of ATPase activity of ATP in the activated p38 reaction was determined in the absence of inhibitor and the presence of two concentrations of inhibitor.丨 is the rate data that is determined as a function of inhibitor and ATP concentration. A raw material solution containing all of the above components and activated P38 (60 nM) was prepared. This raw material solution was equally divided into glass bottles. A fixed amount of DMSO or inhibitor-containing DMSO (DMSO at a final concentration of 2.5%) was added to each vial, mixed and incubated for 15 minutes at room temperature. The reaction was initiated by the addition of different concentrations of ATP and then cultured at 3 ° C. After 30 minutes, the reaction was stopped with 5 〇 EDTA (0.1 Μ, final concentration), pH 8.0. The product of this p38 ATPase activity, ADP, was quantified by HPLC analysis. ADP is separated from ATP by a reverse phase column (Supelcosil, LC-18, 3 "m 'part number 5-8985) using a binary solvent gradient of the following composition: Solvent A - contains 8 mM tetrabutyl Ammonium hydrogen sulfate (Sigma Chemical Co., Cat. No. T-7158) 0.1 Μ phosphate buffer solution, solvent Β - solvent hydrazine containing 30% methanol.

c. In LPS-stimulated PBMCs IL-1 'TNF, IL-6 and IL-8 M inhibitors were serially diluted in DMSO from 20 mM stock solution. Make at least 6 -37- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the phonetic note on the back side and then fill out this page) -ϋ n ϋ ϋ — H ϋ ·ϋ δ,· ϋ tmt ί ί «ϋ A7 1282334 B7__ V. Description of invention (35) series dilution. The 4 X inhibitor medium was then prepared by adding 4 ^ 1 to 1 well of RPMI 1640 medium / 1% fetal calf serum diluted with one inhibitor. The 4x inhibitor raw material contains 80 "M, 32// Μ, 12.8, 5.12 aM, 2·048/^Μ, 0.819//M, 0·328" Μ, 0.131//M, 0.052//M, 0· 021 "Μ, an inhibitor of equal concentration. The 4 χ inhibitor material was preheated to 37 ° C until use. Fresh human blood clotting cells were isolated from a Vacutainer CPT from Becton & Dickinson (containing 4 ml of blood and enough Mg2+/Ca2+-free DPBS to fill the tube) by centrifugation at 1500 χ g for 15 minutes. Other cells. Peripheral blood mononuclear cells (PBMCs) located on top of the Vacutainer ladder were removed and washed twice with RPMI 1640 medium/10% fetal blood. PBMCs were collected by centrifugation at 500 χ g for 1 minute. The total number of cells was determined by a Neubauer* cell compartment, and the cells were adjusted to a concentration of 4.8 χ 106 cells/ml in cell culture medium (RPMI1640 containing 1% fetal calf serum). Alternatively, whole blood containing an anticoagulant is used directly in this test. 100/1 of the cell suspension or whole blood was placed in each well of a 96-well cell culture dish. Then, 50 d of the 4 χ inhibitor raw material was added to the cells. Finally, a 50"1 lipopolysaccharide (LPS) working stock solution (16 ng/love in cell culture medium) was added to produce a final concentration of 4 ng/ml LPS in this assay. 50 〆 1 of cell culture medium was added to adjust the total amount of vector control to 200 a 1 . This PBMC cell or whole blood was then cultured overnight (ms hour) at 37 ° C in a humidified environment containing 5% C〇2. The next day, the cells were mixed for 3 - 5 minutes with a vibrator before centrifugation at 500 χ g. The cell culture supernatant was harvested and analyzed by Elisa according to the manufacturer's instructions. IL-lb (R & D Systems, Quantikine kits, #DBL50), TNF- -38- This paper scale applies to the Chinese National Standard (CNSM4 specification (210) χ 29Γ )) (Please read the notes on the back and fill out this page) --------Book --------- Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1282334 Ministry of Economics The property bureau employee consumption cooperative printed B7 V. Invention description (36) Han (BioSource, #KHC3012), IL-6 (Endogen, #EH2-IL6) and IL_8 (Endogen, #EH2-IL8) degree. Use this ELISA The data is generated to generate a dose-response curve, IC50, which is obtained therefrom. The p38 inhibitor of the present invention will inhibit phosphorylation of EGF receptor peptides and LPS-stimulated PBMCs or IL-1, TNF and IL in whole blood. -6 and IL-8 production D. Inhibition of IL-6 and IL-8 production in IL-1-stimulated PBMCs This assay was performed on PBMCs as described above except for a 50^1 IL-lb The raw material solution (2 ng/ml in fine 1 pack medium) was substituted for the lipopolysaccharide (LPS) working raw material solution and added to the test. The supernatant of the cell culture was harvested and the extent of IL-6 (Endogen, #EH2-IL6) and IL-8 (Endogen, #EH2-IL8) was analyzed by ELISA according to the manufacturer's instructions. This ELISA data was used to generate the dose - The reaction curve, IC50値, is obtained from this. E. In LPS-burst prostaglandin peroxidase synthase-2 (PGHS-2, or COX-2) in PBMCs, it inhibits human peripheral blood mononuclear cells ( PBMCs) were centrifuged from fresh human blood clotting cells in a Vacutainer CPT (Becton & Dickinson). 15 X 106 cells/ml were inoculated into a 6-well tissue culture m (containing supplemental 10% fetal calf) Serum, 50 U/ml penicillin, 50 μg/ml streptomycin, and 2 mM L-glutamine in RPMI 1640 medium). The final concentration of an inhibitor of the invention added to DMSO was 0.2, 2.0 and 20. Then, LPS was added at a final concentration of 4 ng/ml to express the eucalyptin. The final culture was 10 ml/well. _-39- This paper scale is applicable to the Chinese National Standard (CNS) A4 specification (21〇X 297). Public love) --------11--------- (Please read the notes on the back and fill in this Page) 1282334 A7 B7 V. Description of Invention (37) (Please read the notes on the back and fill out this page) Printed by the Intellectual Property Office of the Ministry of Economic Affairs

After overnight incubation at 37 ° C, 5% CO 2 , the cells were harvested by scraping and subsequent centrifugation, then the supernatant was removed and the cells were washed twice with ice-cold DPBS (Dulbecco's Phosphate Buffered Saline, BioWhittaker). These cells were placed on ice in 50 "1 lysis buffer containing 1 microliter of benzoylase (DNAse from Merck) (20 mM Tris-HCl, pH 7.2, 150 mM NaCl, 1% Triton-X- 100,1% deoxycholic acid, 0.1% SDS, 1 mM EDTA, 2% anti-protease peptide (Sigma), 10 μg/ml pepsin, 10 μg/3⁄4 liter anti-plasmin peptide, 2' mM PMSF, 1 mM benzamidine, 1 mM DTT) dissolved in 10 minutes. The protein concentration of each sample was determined by the BCA test (Pierce) and the bovine serum albumin was used as a standard. Then, the protein concentration of each sample was adjusted to 1 mg/ml with cold solubilization buffer. An equal amount of 2 X SDS PAGE device buffer was added to the 100" 1 dissolved product and the sample was boiled for 5 minutes. Protein (30 μg/diameter) was size-divided on a 4-20% SDS PAGE gradient gel (Novex) and subsequently electrophoresed in Towbin transfer buffer (25 mM Tris, 192) containing 20 °/〇 methanol. mM glycerol) 100 mA was transferred to the nitrocellulose membrane for 2 hours. The membrane was pretreated with blocking buffer (5% fat-free dry milk powder in DPBS supplemented with 〇·ι% Tween-20) for 1 hour at room temperature and washed three times with DPBS/〇1% Tween-20. This membrane was cultured overnight at 4 C in a 1:25 〇 dilution of blocking buffer in a single anti-COX-2 antibody (Transduction Laboratory). After washing three times with DPBS/Ol% Tween-20, the membrane was cultured at room temperature in a 1:1000 dilution of goat serum of Wasabi peroxidase-conjugated mouse Ig (Amersham) in blocking buffer. hour. The membrane was then washed three times with DPBS/0.1% Tween-20 using an eCl detection system (SupersignalTM -40 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1282334 A7 _B7_ V. DESCRIPTION OF THE INVENTION (38) CL-HRP Substrate System, Pierce) The degree of expression of C0X-2 is determined by 湏ij. While we have provided some of the embodiments of the invention above, it will be apparent that our basic construction can be modified to provide other embodiments of the method of the invention. (Please read the notes on the back and fill out this page.) Ministry of Economic Affairs, Intellectual Property Office, Staff and Consumer Cooperatives Printed 4 Paper Sizes Applicable to China National Standard (CNS) A4 Specification (210 X 297 mm) 1282334 Application Date Case Number ^) 〇\〇^ —- Category

The above columns are filled in by the Department)~| 丨UH Inventions ±New Patent Specification Chinese SI Name English Name Name Nationality New compounds for the treatment of p38 and pharmaceutical compositions containing their novel compounds

Novel compounds and pharmaceutical COMPOSITIONS CONTAINING THE SAME FOR TREATMENT OF p38 MEDIATED CONDITIONS 1. 可西可塞里奥2. Gaybemi FRANCESCO SALITURO GUY BEMIS 3. Getas vista ghotas evindar Inventor's residence, residence? Name f Nationality 1.2. United States 3. Canada 1. Nursing State No. 25, Baker Road, M. Buffalo, Ningsa, Malaysia 2. 256 Apelon Street, Arlington, Massachusetts, USA 3. Tarot Head, Ottawa, Canada City 6〇9 大^3rd Charles Street

US VERTEX PHARMACEUTICALS INCORPORATED US Binding Applicant No. 130, Waverley Street, Cambridge, MA, USA S Table i

Andrew S. Marcus ANDREW S. MARKS This paper size applies to the towel s s fresh (CNS) A4 specifications (χ 297 gong sauce)

Claims (1)

More than 1282 Chinese application for the next month) ?5? ^rn, Α8 Β8 C8 D8 \i. A compound of the formula: Or a tautomer thereof or a pharmaceutically acceptable salt thereof, wherein: Q! and the oxime are each independently selected from the group consisting of a 5- to 6-membered aromatic carbocyclic ring system, a pyridyl group, or an aromatic carbocyclic ring containing 8 - a double ring system of a 10 membered ring; wherein the ring view constituting Q! needs to be substituted with 1 to 4 substituents, each substituent being independently selected from the group consisting of halogen, CrC4 alkyl, CKCrC^)-alkyl, NH2. OH, OCF3, CF3, 3,4-methylenedioxy, -N(CH3)2, -NH-S(0)2_phenyl, -NH-C(0)0-CH2-4-pyridine, - NH-C(0)CH2-morpholine, -NH-C(0)CH2-N(CH3)2, -NH-C(〇)CH2-hexahydropyrazine, -NH-C(0)CH2- Pyrrolidine, -NH-C(0)C(0)-morpholine, -NH-C(0)C(0)-hexahydroindole, -NH-c(o)c(〇)j ratio Pyridine, -0_C(0)CH2-N(CH3)2 or -0"CH2)2-n(ch3)2; and wherein the ring constituting Q2 is substituted with J and optionally halogen, c"c4 straight or branched The alkyl, methoxy, trifluoromethyl or trifluoromethoxy group of the chain is substituted; J is a (: "(: 4 linear or branched alkyl derivative, 1-3 selected from A, -TC(0)m-〇P〇3Hj^j Substituted; This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 29) 7 mm) 1282334 A8 B8 C8 D8, the scope of patent application A is selected from this group: 〇 R4 • T, \/\ • Ding ‘ G W R1 〇〇R4 or T is 〇 or NH; G is NH2 or 0H; Z is CH or N; R' is selected from hydrogen, (CVC3)-alkyl, (c2-c3)-alkenyl or alkynyl; R3 is An aromatic ring or heterocyclic ring system selected from the group consisting of 5-6 membered rings; R4 is deuterium or optionally substituted with N(R')2, ORf, C02R', con(r,)2 or S〇2N(R2)2 (CrCd-alkyl; R2 is selected from hydrogen, (crc3)-alkyl or (c2-c3)-fluorenyl; and w is selected from Η, n(r2)c(o)-or2, n( R2)c(〇)-n(r2)2, N(R2)C(0)-N(R2)(R3), N(R2)C(0)-R2, N(R2)2, C(0 )-R2, CH(〇H)-R2, C(0)-N(R2)2, C(0)-〇R2 or (CVC4) linear or branched alkyl group as required A, T-(CO R, N(R,)2, OR', C02R', CON(Rf)2, R3 or S〇2N(R2)2 are substituted. 2. The compound of claim i, wherein Ql is selected From a phenyl or pyridyl group containing from i to 3 substituents, and the substituents are independently selected from the group consisting of chlorine, fluorine, bromine, _CH3, -〇CH3, -〇H, -CF3, _0CF3, _0(CH2)2CH3, -2- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 x 297 mm) 4 3 32 82 8 8 8 8 AB c D VI. Patent application scope NH2, 3, 4_A Dioxo, -N(CH3)2, -NH-S(〇)2-phenyl, -NH-C(〇)0-CH2-4-pyridine, -NH-C(〇)CH2-morpholine , -NH-C(〇)CH2-N(CH3)2, -NH-C(0)CH2-hexahydropyridine, -NH-C(0)CH2-pyrrolidine, -NH-C(0)C( 〇)-morphine, -NH-C(0)C(〇)-hexahydropyridine'-NH-C(〇)C(〇)-pyrrolidine, -〇-C(0)CH2-N(CH3 2-' or -0-(CH2)2-N(CH3)2, wherein at least one of the substituents is in the ortho position. 3. The compound of claim 2, wherein Q i contains at least two Substituents, both in the adjacent position. 4 · The compound of claim 2, where h is selected from: -3- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm) ) 4 3 3 2 8 2 8 8 8 8 AB c D Patent application scope F OCH3A^〇ch3 CF, H3CO T 〇CH3 /λ Ch3 Cl h3^ b" Cr 丫, 〇ch3 h3 NH 2 H2N 0CH3 h3c Och3 H3 .nh2 OCH3 H3C^f^-〇CH Cl OCH, Cl H3 Q , Sr^ocHs Cl OH This paper scale applies to China National Standard (CNS) A4 specification (210 x 297 mm) 1282334 8 8 8 8 ABCD Patent application scope nh2 H31 OH 〇Y〇 CH3 h3c 丫 \ch3 H3i 〇CH3 OH NH2 ch3 H3ct -V- ^ch3 h3cc5 ~ch3 OCH3 OCH3 u NH OH OCH3 ^^^och3 cr 丫 ci,ci OH . i fly Cl Cl Cl H3C, N is OCH, ij Cl Cl Och3 Cl , CI N...〇CH: Nh2 hn 〇 Cl 人丨 〇 . r nh HN,vN,^ * HN^ Cl , CI - Cl HN This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) Μ 32 82 8 8 8 8 ABCD Patent application scope n , NH Ο r 〇 HN HN-Cl Cl N. \ HN Cl HN HN N. Cl _ Cl Cl 〇 r^NH HN 〇, CI cr , or a compound according to claim 4, wherein Qi is selected from the group consisting of 2-fluoro-6-trifluoromethylphenyl, 2,6-difluorophenyl, 2,6-dichlorobenzene Base, 2-chloro-4-hydroxyphenyl, 2-chloro-4-aminephenyl, 2,6-dichloro-4-aminephenyl, 2,6-dichloro-3-aminephenyl, 2, 6-Dimethyl-4-hydroxyphenyl, 2-methoxy-3,5-di 6- This paper scale applies to Chinese National Standard (CNS) Α4 specification (210 X 297 mm) 8 8 8 8 AB c D 1282334, the patentable range of chloro-4-pyridyl, 2-chloro-4,5-methylenedioxyphenyl or 2-chloro-4-(N-2 -moffene-ethanoyl)benzene base. 6. The compound of claim 1, wherein (^2 is selected from a phenyl group or a pyridyl group, the phenyl group or the pyridyl group containing a substituent J and 0 to 3 other substituents, wherein the other substituent Is independently selected from the group consisting of chlorine, fluorine, bromine, methyl, ethyl, isopropyl, -OCH3, -OH, -NH2, -CF3 or -OCF3. 7. The compound of claim 1 wherein The compound is Compound 1 5. 8 · A compound as claimed in claim 1 wherein the compound is The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X 297 mm) 1282334 A8 B8 C8 D8 VI. Patent application scope 9 · If the compound of claim 1 is the compound, the compound is Compound 1 7. 10. The compound of claim 1, wherein the compound is \ ii: A pharmaceutical composition for treating or preventing a P 3 8 -regulated disease, which is packaged as a compound of claim 1 and a pharmaceutically acceptable carrier. 12·- Treating or preventing inflammatory diseases, autoimmune diseases, destructive bone abnormalities, proliferative abnormalities, infectious diseases, neurodegenerative diseases, allergies, congestion/ischemic shock, heart disease, vasospasm Abnormalities in abnormalities, organ hypoxia, vascular hyperplasia, cardiac hypertrophy, thrombin aggregation, and pharmaceutical compositions related to prostaglandin peroxidase synthesis of marinade-2, which comprise an effective amount of inhibiting p3 8 -8 - This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1282334 Compound of the first item of Lifanyuan. 13. The pharmaceutical composition of claim 12, wherein the pharmaceutical composition is for treating or preventing an inflammation selected from the group consisting of acute pancreatitis, chronic pancreatitis, asthma, allergy or adult respiratory distress syndrome. Sexual disease. 14. The pharmaceutical composition of claim 12, wherein the pharmaceutical composition is for treating or preventing a condition selected from the group consisting of renal glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, cutaneous sclerosis, chronic thyroid gland Inflammation, ocular thyroid disease, autoimmune gastritis, diabetes, autoimmune bleeding anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis Autoimmune disease of inflammatory bowel disease, ulcerative colitis, colitis, dryness or graft vs host disease. 15. The pharmaceutical composition of claim i, wherein the pharmaceutical composition is for treating or preventing a destructive bone abnormality selected from the group consisting of osteoporosis, osteoarthritis and multiple myeloma-related bone abnormalities . 16. The pharmaceutical composition according to claim 2, wherein the pharmaceutical composition is for treating or preventing a patient selected from the group consisting of acute myeloid leukemia, osseous osteoneukemia, metastatic melanoma, Kaposi Proliferative diseases of the tumor and multiple myeloma. 17. The pharmaceutical composition according to claim 12, wherein the pharmaceutical composition is for treating or preventing an infectious disease selected from the group consisting of sepsis, septic shock and Shigella. -9- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1282334, patent application scope 18. If the patent application scope item 12 is obtained, the fflm, /, medical head composition Which of the pharmaceutical groups has eliminated 1CMV? Treatment or prevention - a viral disease selected from the group consisting of acute hepatitis infection, HIV sensory or CMV retinitis. I9·If the scope of patent application is item 12, the composition of the human, the, and the head, wherein the medical group disease, cerebral hemorrhage or trauma induces Heilongjiang, Parkinson's disease. The neurodegenerative disease of the neurodegenerative disease is as follows. For example, in the patent application, item 12, person, and medical order composition, wherein the second group of the medical group is treated with heart-suffering ischemia/congestion towel wind or myocardial ischemia, Kidney set. "Dirty disease, erythetic hypoxia or thrombin-induced platelet aggregation 2 = pharmaceutical composition of claim 12, wherein the medical group & system is used for treatment or prevention - selected from edema, fever, analgesia or And pain and the like related to prostaglandin peroxidase synthase-2. 22. The pharmaceutical composition according to the scope of the patent application, wherein the pain is selected from the group consisting of neuromuscular pain, headache, pain caused by cancer, toothache Or a joint pain. A pharmaceutical composition according to claim 12, wherein the pharmaceutical composition is used for treating or preventing a vascular abnormality selected from the group consisting of solid tumors, new blood stasis hyperplasia, and infantile hemangiomas. -10- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm)