Summary of the invention
First technical purpose of the present invention, is to provide a kind of new JAK inhibitor compound; Second technical purpose of the present invention, is to provide JAK inhibitor compound of the present invention in preparation treatment and the application in the medicine of JAK inhibitor relative disease.
In order to realize technical purpose of the present invention, technical scheme of the present invention is as follows:
A compound as shown in chemical structural formula I,
Comprise its tautomer, mesomeride, racemic modification, enantiomer, diastereomer or its form of mixtures or pharmacy acceptable salt, wherein:
A, B, C, D are independently selected from CR6, CR7, CR8, CR9and N;
X is selected from N and CR10;
R1, R2and R3independently selected from hydrogen, halogen, cyano group, nitro, amino, hydroxyl, amido, sulfoamido, ester group, C1-C8alkyl, C3-C8cycloalkyl, C6-C10aryl, C5-C10heteroaryl, C3-C8heterocyclylalkyl, C1-C6alkyl oxy, C1-C6alkylamino, C1-C6alkyl C3-C8cycloalkyl, C1-C6alkyl C6-C10aryl, C1-C6alkyl C6-C10heteroaryl, C1-C6alkyl C3-C8heterocyclylalkyl;
Y is selected from amino, amido, ester group, sulfoamido, C1-C8alkyl, C3-C8cycloalkyl, C6-C10aryl, C5-C10heteroaryl, C3-C8heterocyclylalkyl, C1-C6alkyl oxy, C1-C6alkylamino, C1-C6alkyl C3-C8cycloalkyl, C1-C6alkyl C6-C10aryl, C1-C6alkyl C6-C10heteroaryl, C1-C6alkyl C3-C8heterocyclylalkyl.Wherein Y can by 0-3 C1-C6alkyl, hydroxyl, alkoxyl group, halogen, nitro, amino, amido, sulfoamido, cyano group, ester group, C1-C8alkyl cyano group, C6-C10aryl, C6-C10heteroaryl, C3-C8cycloalkyl, C3-C8heterocyclylalkyl, C6-C14bicyclic cycloalkyl, C8-C14bicyclic heterocycloaliphatic, C6-C14volution cycloalkyl or C8-C14spiral shell heteroalicyclyl replaces;
N=0 or 1;
R4, R5independently selected from hydrogen, C1-C8alkyl, C2-C4thiazolinyl, C2-C4alkynyl, C3-C8cycloalkyl, C6-C10aryl, C5-C10heteroaryl, C3-C8heterocyclylalkyl, OR11, SR11, NR11,-C (=O) R11r12,-C (=O) NR11r12,-S (O)2r11r12,-NR11c (=O) R12r13,-NR11s (O)2r12r13,-OC (=O) R11r12;
R11, R12and R13independently selected from hydrogen, halogen, nitro, amino, hydroxyl, amido, sulfoamido, ester group, C1-C8alkyl, C3-C8cycloalkyl, C6-C10aryl, C5-C10heteroaryl, C3-C8heterocyclylalkyl, C1-C6alkyl oxy, C1-C6alkylamino, C1-C6alkyl C3-C8cycloalkyl, C1-C6alkyl C6-C10aryl, C1-C6alkyl C6-C10heteroaryl, C1-C6alkyl C3-C8heterocyclylalkyl;
R6, R7, R8, R9and R10be selected from hydrogen, cyano group, halogen, nitro, amino, hydroxyl, C1-C8alkyl, C3-C8cycloalkyl, C6-C10aryl, C5-C10heteroaryl, C3-C8heterocyclylalkyl, C1-C6alkyl oxy, C1-C6alkylamino, C1-C6alkyl C3-C8cycloalkyl, C1-C6alkyl C6-C10aryl, C1-C6alkyl C6-C10heteroaryl, C1-C6alkyl C3-C8heterocyclylalkyl.
Further described compound or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer or its form of mixtures or pharmacy acceptable salt,be selected from:
。
R6, R7, R8, R9and R10be selected from hydrogen, cyano group, halogen, nitro, amino, hydroxyl, C1-C8alkyl, C3-C8cycloalkyl, C6-C10aryl, C5-C10heteroaryl, C3-C8heterocyclylalkyl, C1-C6alkyl oxy, C1-C6alkylamino, C1-C6alkyl C3-C8cycloalkyl, C1-C6alkyl C6-C10aryl, C1-C6alkyl C6-C10heteroaryl, C1-C6alkyl C3-C8heterocyclylalkyl.
Further described compound or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer or its form of mixtures or pharmacy acceptable salt, R6, R7, R8, R9and R10be selected from hydrogen, cyano group, halogen, C1-C8alkyl, C3-C8cycloalkyl, C3-C8heterocyclylalkyl, C6-C10aryl, C5-C10heteroaryl, C1-C6alkyl oxy, C1-C6alkylamino.
Further described compound or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer or its form of mixtures or pharmacy acceptable salt, R1, R2and R3independently selected from hydrogen, halogen, cyano group, C1-C8alkyl, C3-C8cycloalkyl, C6-C10aryl, C5-C10heteroaryl, C3-C8heterocyclylalkyl, C1-C6alkyl oxy, C1-C6alkylamino.
Further described compound or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer or its form of mixtures or pharmacy acceptable salt, Y is selected from C1-C8alkyl, C3-C8cycloalkyl, C6-C10aryl, C5-C10heteroaryl, C3-C8heterocyclylalkyl.Wherein Y can by 0-3 C1-C6alkyl, hydroxyl, alkoxyl group, halogen, nitro, amino, amido, sulfoamido, cyano group, ester group, C1-C8alkyl cyano group, C6-C10aryl, C6-C10heteroaryl, C3-C8cycloalkyl, C3-C8heterocyclylalkyl, C6-C14bicyclic cycloalkyl, C8-C14bicyclic heterocycloaliphatic, C6-C14volution cycloalkyl or C8-C14spiral shell heteroalicyclyl replaces;
N=0 or 1;
R4, R5independently selected from hydrogen, C1-C8alkyl, C3-C8cycloalkyl, C6-C10aryl, C5-C10heteroaryl, C3-C8heterocyclylalkyl ,-C (=O) NR11r12,-S (O)2r11r12,-NR11c (=O) R12r13,-NR11s (O)2r12r13;
R11, R12and R13independently selected from hydrogen, halogen, nitro, amino, hydroxyl, amido, sulfoamido, ester group, C1-C8alkyl, C3-C8cycloalkyl, C6-C10aryl, C5-C10heteroaryl, C3-C8heterocyclylalkyl, C1-C6alkyl oxy, C1-C6alkylamino, C1-C6alkyl C3-C8cycloalkyl, C1-C6alkyl C6-C10aryl, C1-C6alkyl C6-C10heteroaryl, C1-C6alkyl C3-C8heterocyclylalkyl.
Further described compound or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer or its form of mixtures or pharmacy acceptable salt are selected from:
The invention still further relates to a kind of medicinal compositions, it comprises formula (I) compound or its pharmacy acceptable salt and the acceptable vehicle of medicine or thinner for the treatment of significant quantity.
The invention still further relates to the application of the compound shown in chemical structural formula I in the medicine of preparation treatment jak kinase relative disease.
Further compound or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer or its form of mixtures or the application of pharmacy acceptable salt in the medicine for the preparation for the treatment of inflammatory and/or autoimmune disorder as shown in the formula (I).Further described inflammatory conditions is rheumatoid arthritis.
detailed description of the invention
Unless stated to the contrary, following use term in the specification and in the claims has following implication.
" alkyl " refers to saturated aliphatic hydrocarbon group.Comprise the straight or branched group of 1 to 20 carbon atom.Median size alkyl preferably containing 1 to 6 carbon atom, such as methyl, ethyl, propyl group, 2-propyl group, normal-butyl, isobutyl-, the tertiary butyl, amyl group etc.Low alkyl group more preferably containing 1 to 4 carbon atom, such as methyl, ethyl, propyl group, 2-propyl group, normal-butyl, isobutyl-or the tertiary butyl etc.Alkyl can be replacement or unsubstituted, and when substituted, preferred group is: halogen, C2-C6thiazolinyl, C6-C10aryl, C5-C10heteroaryl, halo C1-C6alkyl, 4 to 8 yuan of heteroalicyclyl, hydroxyl, C1-C6alkoxyl group, C6-C10aryloxy.
" cycloalkyl " refers to 3 to 8 yuan of full carbon monocycles, complete 5 yuan/6 yuan, carbon or 6 yuan/6 yuan thick and rings or many rings are thick and ring (" thick and " ring means that each ring in system and other ring in system share a pair carbon atom adjoined) group, wherein one or more rings have the electronic system connected completely, and the example (being not limited to) of cycloalkyl is cyclopropane, tetramethylene, pentamethylene, cyclopentenes, hexanaphthene, diamantane, cyclohexadiene, suberane and cycloheptatriene.Cycloalkyl is commutable and is what replace.When substituted, substituting group is preferably one or more is selected from following group separately, comprise: hydrogen, hydroxyl, sulfydryl, oxo, low alkyl group, lower alkoxy, low-grade cycloalkyl, rudimentary heteroalicyclyl, elementary halogenated alkoxy, alkylthio, halogen, low-grade halogenated alkyl, Lower hydroxy alkyl, low-grade cycloalkyl alkylidene group, rudimentary heteroalicyclyl alkylene, aryl, heteroaryl, alkoxy carbonyl, amino, alkylamino, alkyl sulphonyl, aryl sulfonyl, alkyl amino sulfonyl, n-aryl sulfonyl, alkyl sulfonyl-amino, arlysulfonylamino, alkyl amino-carbonyl, aromatic yl aminocarbonyl, alkyl-carbonyl-amino, aryl-amino-carbonyl.
" aryl " represents full carbon monocycle or the fused polycycle group of 6 to 14 carbon atoms, has the π-electron system of total conjugated." aryl " comprising:
Hexa-atomic carbon aromatic nucleus, e.g., benzene;
Dicyclo, wherein has at least a ring to be carbon aromatic nucleus, e.g., and naphthalene, indenes and 1,2,3,4-tetrahydroquinoline; And three rings, wherein have at least a ring to be carbon aromatic nucleus, e.g., fluorenes.
Such as, aryl comprises containing hexa-atomic carbon aromatic nucleus and a hexa-member heterocycle, and this heterocycle comprises one or more heteroatoms being selected from nitrogen, oxygen and sulphur, and condition is that tie point is on carbon aromatic nucleus.But aryl does not comprise, also not overlapping with the heterocyclic aryl defined respectively below by any mode.Therefore, in this definition, if one or more carbon aromatic nucleus and an assorted aromatic nucleus ring, consequent loop systems is heteroaryl, instead of aryl.The limiting examples of aryl has phenyl, naphthyl.Aryl can be replacement or unsubstituted.When substituted, preferred group is: hydrogen, hydroxyl, nitro, cyano group, oxo, low alkyl group, lower alkoxy, low-grade cycloalkyl, rudimentary heteroalicyclyl, elementary halogenated alkoxy, alkylthio, halogen, low-grade halogenated alkyl, Lower hydroxy alkyl, low-grade cycloalkyl alkylidene group, rudimentary heteroalicyclyl alkylene, aryl, heteroaryl, alkoxy carbonyl, amino, alkylamino, alkyl sulphonyl, aryl sulfonyl, alkyl amino sulfonyl, n-aryl sulfonyl, alkyl sulfonyl-amino, arlysulfonylamino, alkyl amino-carbonyl, aromatic yl aminocarbonyl, alkyl-carbonyl-amino, aryl-amino-carbonyl.
" heteroaryl " represents monocycle or the fused ring group of 5 to 14 annular atomses, and be selected from the ring hetero atom of N, O or S containing one, two, three or four, all the other annular atomses are C, has the π-electron system of total conjugated in addition.Heteroaryl refers to:
The mononuclear aromatics of 5-8 unit, containing one or more heteroatoms being selected from N, O and S, as 1-4 heteroatoms, in some embodiments, 1-3 heteroatoms, on ring, other atoms are carbon atoms;
The double ring arene of 8-12 unit, containing one or more heteroatoms being selected from N, O and S, as 1-4 heteroatoms, in some embodiments, 1-3 heteroatoms, on ring, other atoms are carbon atoms; A ring is wherein had at least to be aromatic nucleus; And
The thrcylic aromatic hydrocarbon of 11-14 unit, containing one or more heteroatoms being selected from N, O and S, as 1-4 heteroatoms, in some embodiments, 1-3 heteroatoms, on ring, other atoms are carbon atoms; A ring is wherein had at least to be aromatic nucleus.
Such as, heteroaryl comprises the assorted aromatic nucleus of a 5-6 unit and the cycloalkyl of a 5-6 unit.For such dicyclo and the heteroaryl got up, wherein only have a ring to contain one or more heteroatoms, connection site is on assorted aromatic nucleus.
When the sulphur atom on heteroaryl and Sauerstoffatom sum are more than 1, these heteroatomss can not be adjacent one by one.In some embodiments, sulphur atom and the Sauerstoffatom sum in heteroaryl is no more than 2.In some embodiments, sulphur atom and the Sauerstoffatom sum in heteroaryl is no more than 1.
The example of heteroaryl, include but not limited to, pyrroles, furans, thiophene, imidazoles, oxazole, thiazole, pyrazoles, triazole, pyrimidine, pyridine, pyridone, miaow pyridine, pyrazine, pyridazine, indoles, azaindole, benzoglyoxaline, benzotriazole, indoline, indolone, quinoline, isoquinoline 99.9, quinazoline, thienopyridine, Thienopyrimidine etc.The preferred embodiment of this type of group is pyrryl, pyrazolyl, imidazolyl, triazol radical, furyl, oxazolyl, thienyl, thiazolyl, benzimidazolyl-, benzotriazole.One or all hydrogen atom in heteroaryl can be replaced by following groups: hydrogen, hydroxyl, nitro, cyano group, oxo, low alkyl group, lower alkoxy, low-grade cycloalkyl, rudimentary heteroalicyclyl, elementary halogenated alkoxy, alkylthio, halogen, low-grade halogenated alkyl, Lower hydroxy alkyl, low-grade cycloalkyl alkylidene group, rudimentary heteroalicyclyl alkylene, aryl, heteroaryl, alkoxy carbonyl, amino, alkylamino, alkyl sulphonyl, aryl sulfonyl, alkyl amino sulfonyl, n-aryl sulfonyl, alkyl sulfonyl-amino, arlysulfonylamino, alkyl amino-carbonyl, aromatic yl aminocarbonyl, alkyl-carbonyl-amino, aryl-amino-carbonyl.
" Heterocyclylalkyl " represents monocycle or thick and cyclic group, has 5 to 9 annular atomses in ring, and wherein one or two annular atoms is selected from N, O or S (O)pthe heteroatoms of (wherein p is the integer of 0 to 2), all the other annular atomses are C.These rings can have one or more double bond, but these rings do not have the π-electron system of total conjugated.The limiting examples of unsubstituted heteroalicyclyl has pyrrolidyl, piperidino-(1-position only), Piperazino, morpholino base, thiomorpholine for base, homopiperazino etc.Heteroalicyclyl can be replacement or unsubstituted.When substituted, substituting group is preferably one or more, more be preferably one, two or three, and then be more preferably one or two, described substituting group is selected from: hydrogen, hydroxyl, sulfydryl, oxo, low alkyl group, lower alkoxy, low-grade cycloalkyl, rudimentary heteroalicyclyl, elementary halogenated alkoxy, alkylthio, halogen, low-grade halogenated alkyl, Lower hydroxy alkyl, low-grade cycloalkyl alkylidene group, rudimentary heteroalicyclyl alkylene, aryl, heteroaryl, alkoxy carbonyl, amino, alkylamino, alkyl sulphonyl, aryl sulfonyl, alkyl amino sulfonyl, n-aryl sulfonyl, alkyl sulfonyl-amino, arlysulfonylamino, alkyl amino-carbonyl, aromatic yl aminocarbonyl, alkyl-carbonyl-amino, aryl-amino-carbonyl.Unless otherwise noted.The example of heteroalicyclyl includes but not limited to, morpholinyl, piperazinyl, piperidyl, azetidinyl, pyrrolidyl, six hydrogen azepine bases, oxetanyl, tetrahydrofuran base, tetrahydro-thienyl, oxazolidinyl, thiazolidyl, isoxazole alkyl, THP trtrahydropyranyl, sulfo-Lin Ji, quinuclidinyl and imidazolinyl, each group as previously mentioned, example can also be dicyclo, such as, such as, 3, 8-diaza-dicyclo [3.2.1] octane, 2, 5-diazabicyclo [2.2.2] octane or octahydro-pyrazine also [2, 1-c] [1, 4] oxazines.Its heteroalicyclyl (and derivative) comprises its ionic species.
" alkoxyl group " represents the unsubstituted alkyl of-O-() and the unsubstituted cycloalkyl of-O().Representational example includes but not limited to methoxyl group, oxyethyl group, propoxy-, butoxy, ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc.
" hydroxyl " represents-OH group.
" halogen " represents fluorine, chlorine, bromine or iodine, is preferably fluorine or chlorine.
" haloalkyl " represents alkyl, preferably low alkyl group as defined above, and it is replaced by one or more identical or different halogen atom, such as-CH2cl ,-CF3,-CCl3,-CH2cF3,-CH2cCl3deng.
" cyano group " represents-CN group.
" amino " expression-NH2group.
The meaning of so-called " optionally " refers to that the event of subsequent descriptions or situation may also may can not occur, and this description comprises things or situation may also may can not occur, and this description comprises things or situation occurs and two kinds of situations do not occur.
In some embodiments, " replaced " of referring in the atom of specifying or group by one or more group, two, three or four hydrogen atoms are designated the identical or different group selected in the group of scope respectively and replace.
" pharmacy acceptable salt " represents the reservation biological effectiveness of parent compound and those salt of character.This kind of salt comprises:
(1) with sour salify, react by the free alkali of parent compound and mineral acid or organic acid and obtain, mineral acid comprises hydrochloric acid, Hydrogen bromide, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid and perchloric acid etc., organic acid comprises acetic acid, propionic acid, vinylformic acid, oxalic acid, or (L) oxysuccinic acid (D), fumaric acid, toxilic acid, hydroxy-benzoic acid, gamma-hydroxybutyric acid, methoxybenzoic acid, phthalic acid, methylsulfonic acid, ethyl sulfonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, tosic acid, Whitfield's ointment, tartrate, citric acid, lactic acid, amygdalic acid, succsinic acid or propanedioic acid etc.
(2) acid proton be present in parent compound replaced by metal ion or with organic bases ligand compound the salt that generates, metal ion is alkalimetal ion, alkaline-earth metal ions or aluminum ion such as, and organic bases is as thanomin, diethanolamine, trolamine, Trometamol, N-METHYL-ALPHA-L-GLUCOSAMINE etc.
" pharmaceutical composition " refers to such as, by one or more or its pharmacy acceptable salt, solvate, hydrate or the prodrug in the compound in the present invention and other chemical composition, pharmaceutically acceptable carrier, mixing.The object of pharmaceutical composition promotes that administration is to the process of animal.
" pharmaceutical carrier " refers to and does not cause obvious pungency to organism and do not disturb the non-active ingredient in the biological activity of given compound and the pharmaceutical composition of character, such as but not limited to: calcium carbonate, calcium phosphate, various sugar (such as lactose, N.F,USP MANNITOL etc.), starch, cyclodextrin, Magnesium Stearate, Mierocrystalline cellulose, magnesiumcarbonate, acrylate copolymer or methacrylate polymer, gel, water, polyoxyethylene glycol, propylene glycol, ethylene glycol, Viscotrol C or hydrogenated castor oil or many ethoxy aluminium Viscotrol C, sesame oil, Semen Maydis oil, peanut wet goods.
In aforesaid pharmaceutical composition, except comprising pharmaceutically acceptable carrier, assistant agent conventional in medicine (agent) can also be included in, such as: antibacterial agent, anti-mycotic agent, biocide, preservative, toning agent, solubilizing agent, thickening material, tensio-active agent, complexing agent, protein, amino acid, fat, carbohydrate, VITAMIN, mineral substance, trace element, sweeting agent, pigment, essence or their combination etc.